The Digestive System

Commissioning Editor: Timothy Horne

Development Editor: Lulu Stader
Project Manager: Janaki Srinivasan Kumar
Designer/Design Direction: Charles Gray
 Systems of the Body

The Digestive System

basic science and clinical conditions

second edition

Margaret E. Smith   PhD DSc Dion G. Morton   MD DSc

Professor of Experimental Neurology Professor of Surgery
School of Clinical and Experimental Medicine Academic Department of Surgery
College of Medical and Dental Sciences University Hospital Birmingham
University of Birmingham Birmingham, UK
Birmingham, UK

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2010
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Preface

Many medical schools in the UK and other countries are illustrate a number of different aspects of each area of
using systems-based courses. In addition, many are tak- the digestive system, and not all of them are common
ing a problem-based learning approach to the systems. diseases. Indeed, some of them are uncommon, or even
This textbook provides the basic science needed by the rare. However, common, relevant diseases are described
medical students following such courses, and places it in (mostly in boxes), where relevant, in the text. This aspect
a clinical context. The first edition of The Digestive System has been expanded in this second edition. The last chap-
is a basic text that has been used on many university ter draws together information on the common diseases
courses over the past 8 years, including those taught by of the digestive system. It has been found that this case-
the authors at the University of Birmingham. During that based approach stimulates the student to learn more
time, it has been highly commended by the Royal Society about the system and its diseases and helps to motivate
of Medicine and the Society of Authors, and has been them to study basic science.
translated into Portuguese and Chinese. The book has a further purpose; to demonstrate the
Over the past few years, the approach taken in this importance of integration of knowledge of the diges-
textbook to emphasize the importance of a knowledge tive system with that of the other systems of the body.
of basic science for the understanding of medicine was In medicine, no physiological system can be successfully
found to stimulate the students to think, rather than studied in isolation from the others. Various systems and
just learn didactically. It has helped to motivate them at many organs can be involved in a disease state, either as
a very early stage in their courses. In the second edition the primary foci of the lesion or the result of secondary
of The Digestive System, much of the material has been complications. Furthermore, the treatment of disease by
updated. drug therapy or surgical intervention can have untoward
The subject matter of each chapter is illustrated by the side-effects that affect systems other than manifesting
problems encountered in carefully selected clinical situa- the primary defect. With these considerations in mind,
tions. Additional case studies have been included in this many of the cases and problems given in The Digestive
second edition. The clinical cases chosen are those that System address relevant aspects of other physiological
demonstrate the relevance of many aspects of basic sci- systems. The approach taken by this book will therefore
ence to the understanding of each specific clinical prob- ensure not only a better understanding of the function-
lem and by inference, to the understanding of medicine ing of body as a whole but also the causes and treatment
as a whole. The clinical problems chosen are ones that of disease.
Acknowledgements

We are grateful for the help given by various people in of the Department of Biological Sciences at the University
the preparation of both editions of this book. Mr John of Aston made useful comments on the Absorptive and
Hamburger of Birmingham University Dental School Post-absorptive States chapter. Professor Barry Hirst of the
read The Mouth chapter, and he and Dr Linda Shaw Department of Physiological Sciences at the University of
made some useful general suggestions. Mr Hamburger Newcastle upon Tyne suggested some important revisions
and Dr John Rippin kindly provided the photographs for concerning ion transport in Chapters 2 and 3 of this second
The Mouth chapter. The late Professor Roger Coleman edition. Dr Chris Tselepis of the School of Cancer Studies
and Dr Rosemary Waring of the School of Bioscience at in the University of Birmingham made useful suggestions
Birmingham University provided some useful information for revision of the section on iron absorption in Chapter 8.
for The Liver chapter. Dr Peter Guest, consultant radiologist The encouragement of Dexter Smith and the drawing skills
at the University Hospital, Birmingham provided many of of Dr Imogen Smith (for two of the figures) were much
the X-rays and clinical photographs. Professor Cliff Bailey appreciated.
Overview of the
digestive system 1
Chapter objectives
After studying this chapter you should be able to:

1. Understand the key mechanisms of secretion, absorption and

motility in the gastrointestinal system.

2. Understand the coordinated and integrated functioning of the

digestive system.

3. Understand how function of the digestive system depends on other

systems, such as the cardiovascular system.
1
OVERVIEW OF THE DIGESTIVE SYSTEM

Introduction: overall function of the Case

digestive system 1.1 Non-occlusive ischaemic disease of
the gut: 1
The cells of the body require adequate amounts of raw
materials for their energy requiring and synthetic pro- An elderly patient, who was being treated with digitalis for
cesses. The raw materials are obtained from the external congestive heart failure, suddenly developed severe, con-
environment through the ingestion of food. The overall stant, abdominal pain. The consultant physician examined
function of the digestive system is to transfer the nutri- him and found that he was in circulatory shock, with a low
ents in food from the external environment to the internal arterial blood pressure, a thready pulse and a sinus tachycar-
environment, where they can be distributed to the cells of dia (rapid heart rate). His abdomen was exquisitely tender to
the body via the circulation. In this chapter, the general palpitation, with diffuse peritonism (tenderness). The physi-
principles and basic mechanisms involved in the func- cian suspected from the clinical findings that the patient
tioning of the digestive system will be discussed in the was suffering from non-occlusive ischaemic disease of the
context of the system as a whole. The importance of the gut. In this condition, the decreased cardiac output results in
integration of the digestive system with the other body decreased intestinal perfusion and this, together with other
systems is well illustrated by the problems encountered mechanisms, results in the flow of blood to the gastrointes-
in non-occlusive ischaemic disease of the gut: a condition tinal tissues being cut off. This disease is often fatal.
in which the defect originates in the vascular system, but Upon consideration of the details of this case, we can ask
serious consequences result from abnormal absorption in the following questions:
the small intestine (see Case 1.1: 1 and Case 1.1: 2).
l What are the main causes of the sudden development of
this condition in patients with cardiac failure?
Components of the digestive system l What are the physiological consequences of reduced

flow of blood for the functioning of the small intestine?

Figure 1.1 illustrates the component organs of the gas- l What is the origin of the patient’s pain?
trointestinal tract, and the associated organs that are l How are the normal homeostatic mechanisms which
essential for the functioning of the digestive system. The
control the flow of blood to the gastrointestinal tract
gastrointestinal tract consists of the mouth, oesophagus,
perturbed in this condition?
stomach, small intestine and large intestine. The food is l How can this patient be treated?
taken into the mouth and moved into the pharynx by the
activity of skeletal muscle, then along the rest of the tract
by the activity of smooth muscle. The food material is
brought to an appropriate semi-fluid consistency, and the
nutrients in it are dissolved and degraded by secretions
that enter the tract at different locations. These processes Physiological processes of the digestive
are aided by the contractions of the muscles that serve to system
mix the secretions with the food.
The associated organs situated outside the gastrointes- The physiological processes that are important for the
tinal tract that are essential for the digestive process are functioning of the digestive system are:
exocrine glands that secrete important digestive juices. l Digestion
These are as follows: l Absorption
The three pairs of salivary glands which produce saliva
l l Motility
which has a range of functions, but most importantly it l Secretion (and excretion).
provides lubrication of the upper gastrointestinal tract
to allow the food to be moved along
Digestion
l The exocrine pancreas which secretes pancreatic
juice which contains most of the important digestive Digestion is the process whereby large molecules are
enzymes required to degrade the food into molecules broken down to smaller ones. Food is ingested as large
which can be absorbed pieces of matter, containing high molecular weight sub-
stances such as protein and starch that are unable to cross
l The exocrine liver which produces bile, a secretion
the cell membranes of the gut epithelium. Before these
which is important for fat digestion and absorption.
complex molecules can be utilized they are degraded to
The bile is also a medium for the excretion of waste
smaller molecules, such as glucose and amino acids.
metabolites and drugs.
Saliva is released into the mouth. Pancreatic juice and
bile enter the duodenum in the upper small intestine
Absorption
(Fig. 1.1). The release of these juices is stimulated when a The mixture of ingested material and secretions in the gas-
meal is present in the gastrointestinal tract. trointestinal tract contains water, minerals and vitamins

 SYSTEMS OF THE BODY

 1

OVERVIEW OF THE DIGESTIVE SYSTEM

Case
1.1 Non-occlusive ischaemic disease of the gut: 2

Defect, diagnosis and treatment

Decreased cardiac output results in decreased intestinal per- profound toxaemia and impairment of the normal body
fusion with blood. As the velocity of flow decreases, the vis- defences, resulting in septic shock. Loss of fluid, electrolytes
cosity of the blood increases and the blood tends to stagnate and blood from the gut will also occur. (This effect mirrors loss
in the small vessels. Then microthrombi develop and dissemi- in the skin in burns). The loss of the external barrier allows pen-
nate in the blood vessels of the mesenteric circulation. There etration of bacteria into the body as well as fluid loss from it.
is also a generalized vasoconstriction of the blood vessels The abdominal pain is due to the inflammatory response to
that diverts the arterial flow to essential organs. This causes ischaemia that accompanies the necrosis. The abdominal ten-
small vessels to collapse. The consequent increase in resist- derness (peritonism) is due to transmural ischaemia of the intes-
ance to flow in the splanchnic circulation, together with the tinal wall, which in turn results in secondary inflammation of
decreased cardiac output and reduced arterial blood pressure the parietal peritoneum. Differentiation of this condition from
results in severely reduced blood flow to the intestines, which occlusive arterial disease is difficult. Selective angiography, a
eventually become ischaemic. technique involving the introduction of a radio-opaque sub-
Reduced blood flow to the gastrointestinal tract results in stance into the blood, followed by X-radiography, may show
lack of oxygen and reduced energy substrate supply to the narrowed and irregular branches of the superior mesenteric
tissues (hypoxia). The result is widespread necrosis of the gas- artery, and impaired filling of intramural vessels. In contrast,
trointestinal mucosa which is most sensitive to hypoxia. This occlusive disease (such as an embolus) would more often be
quickly leads to disruption of its functions. The necrosis starts associated with loss of blood flow to major branches of the
at the tips of the villi that become hypoxic first. It seems prob- mesenteric arteries.
able also that disruption of the brush border of the enterocytes Management of this condition requires measures to main-
exposes the underlying tissue to the effects of the digestive tain the cardiac output, blood pressure, and tissue oxygena-
proteolytic enzymes in the lumen. The intestines become per- tion, treatment of infection, and replacement of fluid and
meable to toxic substances from the contents of the gut lumen, electrolytes lost from the gastrointestinal tract. Surgery for
such as bacteria and bacterial toxins, and toxic substances from heart failure is not safe in the presence of gut infarction. If
the necrotic cells. These substances enter the portal circulation. peritonitis is present, abdominal surgery is required to remove
In summary, the barrier function of the gut is lost. There is a the necrotic intestinal tissue.

as well as complex nutrients. The products of digestion of the stomach and intestines, or outside it (salivary
and other small molecules and ions and water are trans- glands, pancreas, liver, see above). Secretion is under the
ported across the epithelial cell membranes, mainly in control of nerves and hormones.
the small intestine. This is the process of absorption. The Some substances are excreted, by the liver, into the
transported molecules enter the blood or lymph for circu- gastrointestinal tract as components of bile. The gut
lation to the tissues. This process is central to the diges- lumen is continuous with the external environment and
tive system, and the other physiological processes of the its contents are therefore technically outside the body.
gastrointestinal tract subserve it. The faeces eliminated by the intestinal tract are com-
posed mainly of bacteria that have proliferated in the
Motility tract, and undigested material such as cellulose, a com-
ponent of plant cell membranes that cannot be absorbed.
The gastrointestinal tract is a tube of variable diameter, Undigested residues are largely material which was never
approximately 15 feet long in living human adults. It actually inside the body, and is therefore not excreted but
extends through the body from the mouth to the anus. eliminated from the body. However, a small portion of
The food must be moved along it to reach the appropri- the faecal material consists of excreted substances such as
ate sites for mixing, digestion and absorption. Two lay- the pigments (breakdown products of haemoglobin) that
ers of smooth muscle line the gastrointestinal tract, and impart the characteristic colour to the faeces.
contractions of this muscle mix the contents of the lumen
and move them through the tract. The process of motility
is under the control of nerves and hormones.
Quantities of material processed by the
gastrointestinal tract
Secretion
Exocrine glands secrete enzymes, ions, water, mucins During the course of the day, an adult usually consumes
and other substances into the digestive tract. The glands about 800 g of food and upto 2 litres of water. However, the
are situated within the gastrointestinal tract, in the walls ingested material is a small part of the material that enters

THE digestive SYSTEM 

1
1200mL water
OVERVIEW OF THE DIGESTIVE SYSTEM

800g food

Oral cavity
Parotid 1500mL saliva
Sublingual salivary gland
salivary gland
Pharynx
Submandibular
salivary gland Stomach 2000mL
gastric juice

Oesophagus
Small
intestine
Liver Liver
500mL
8500mL
Stomach
Pancreas
1500mL

Pancreas
1500mL
500mL intestinal
350mL secretions
Large
Large intestine
intestine

Small intestine

Rectum
100mL water
50g solids
Anus
Fig. 1.2  Volumes of material handled by the gastrointestinal tract. The
Fig. 1.1  The digestive system and associated exocrine glands. food and fluid ingested, may amount to 2 L per day. In addition to the
material ingested, large volumes of secretions enter the tract. Most of
the nutrients and water are normally absorbed in the small intestine
the gastrointestinal tract because secretion into the tract but a small proportion is absorbed in the colon.
may amount to 7–8 L of fluid, the exact amount depend-
ing on the frequency and composition of the meals eaten.
Figure 1.2 indicates the approximate volumes of fluid it causes obesity. Food ingestion is determined by the sen-
entering or leaving the gastrointestinal tract during the sation of hunger. Hunger induces an individual to search
average day, and the locations where the processes occur. for an adequate supply of food. A desire for specific foods
Thus 9–10 L of fluid may enter the tract per day. Most is known as appetite. Satiety is the opposite of hunger. It
of this has been processed when the chyme reaches the is a sensation that usually results from the ingestion of a
large intestine and only 5–10% of it is left to pass on into meal in a normal individual. The control of hunger can be
the colon. Most of this is absorbed in the colon and only considered in relation to two categories of sensation:
approximately 150 g is eliminated from the body as faeces.
The latter contain about 30–40% solids that are undigested 1. Sensations from the stomach known as hunger
residues and a few excreted substances (see above). contractions or hunger pangs, i.e. ‘alimentary’
regulation concerned with the immediate effects of
feeding, on the gastrointestinal tract
Regulation of ingestion 2. Subjective sensations associated with low levels of
nutrients in the blood, i.e. ‘nutritional’ regulation,
Intake of food should be adequate to meet the metabolic concerned with the maintenance of normal stores of
needs of the individual, but it should not be so much that fat and glycogen in the body.

 SYSTEMS OF THE BODY

 1
The regulation of food intake is coordinated by neurones Stimulation

OVERVIEW OF THE DIGESTIVE SYSTEM

Psychological External stimuli
in two areas of the brain, known as the feeding (or hun- or inhibition Stimulation
factors (sight, smell)
ger) centre and the satiety centre. Figure 1.3 indicates
some of the factors involved in the regulation of food
intake, and the areas of the brain upon which they act. TEMPERATURE
The feeding centre is located in the lateral hypothalamus.
Inhibition or Inhibition or
Stimulation of neurones in this area causes an animal to stimulation stimulation Stimulation
Cortex
eat voraciously (hyperphagia). On the other hand, lesions
of this area can cause a lack of desire for food and pro-
gressive inanition (loss of weight). In summary, this area
excites the emotional drive to search for food. It controls HYPOTHALAMUS HYPOTHALAMUS
Inhibition
the amount of food eaten and also excites the various
FEEDING CENTRE SATIETY CENTRE
centres in the brainstem that control chewing, salivation
and swallowing.
The satiety centre is situated in the ventromedial Stimulation Stimulation
nuclei of the hypothalamus. Stimulation of neurones
G.I.T. SENSATION
in this area results in complete satiety, and the animal FEEDING distension, STOMACH
refuses to eat (aphagia), whereas lesions in this area can chemicals contractions
cause voracious eating and obesity. The satiety centre
operates primarily by inhibiting the feeding centre.
The control of appetite appears to be via higher cen- Inhibition
tres than the hypothalamus, including areas in the amyg- INCREASES IN
BLOOD NUTRIENTS
dala, where sensations of smell have an important role in glucose, amino acids
this control, and cortical areas of the limbic system. These fat metabolites
areas are closely coupled to the feeding and satiety cen-
tres in the hypothalamus. Fig. 1.3  Schematic representation of the role of some factors involved
in the regulation of food intake.
Alimentary regulation of feeding
The regulation of feeding by sensation from the alimen- short-lived, lasting only 30 min or so. The functional sig-
tary tract is short-term regulation. The feeling of hunger nificance of this is probably that the individual is stimu-
when the stomach is empty is due to stimulation of nerve lated to eat only when the gastrointestinal tract can cope
fibres in the vagus nerve that causes the stomach to con- efficiently with food, so that digestion, absorption and
tract. These contractions are known as hunger contrac- metabolism can work at an appropriate pace.
tions, or hunger ‘pains’. They are triggered by low blood
sugar, which stimulates the vagus nerve fibres. However,
feelings of hunger or satiety at different times of the day Nutritional regulation of feeding
depend to a large extent on habit. Individuals who are in The regulation of feeding via nutrient levels in the blood
the habit of eating three meals a day at regular times, but serves to help maintain body energy stores. An individual
miss a meal on an occasion are likely to feel hungry, even who has been fasting for some time tends to eat more when
if adequate nutritional stores are present in the tissues. presented with food, than one who has been eating regular
The mechanisms responsible for this are not understood. meals. Conversely if an animal is force-fed for some time,
Other factors are also important in the alimentary it eats very little when the force-feeding ceases but food is
control of hunger, such as distension of the stomach or made available. The activity of the feeding centre is there-
duodenum. This causes inhibition of the feeding centre fore geared to the nutritional status of the body. The factors
and reduces the desire for food. It depends mainly on that reflect this and control the feeding and satiety centres
the activation of mechanoreceptors in these areas of the are the levels of glucose, amino acids and fat metabolites
tract, which results in signals being transmitted in sen- available to them. Glucose is very important in this respect.
sory fibres in the vagus nerves. The chemical composi- When blood glucose levels fall, an animal increases its feed-
tion of the food in the duodenum is also important. Thus ing. This returns its blood glucose concentration to normal.
fat in the duodenum stimulates satiety via release of the Furthermore, an increase in blood glucose concentration
hormone cholecystokinin (CCK) into the blood, from the increases the electrical activity in neurones in the satiety
walls of the duodenum (see Ch. 5). centre. Neurones in the satiety centre, but not other areas
Functional activity of the oral cavity, such as taste, of the hypothalamus, concentrate glucose, and this may
salivation, chewing and swallowing is also important be related to its role in the control of hunger. The control
in monitoring the amount of food that passes through of feeding by blood glucose levels is known as the ‘gluco-
the mouth. Thus, the degree of hunger is reduced after static’ theory of hunger. To a lesser extent, an increase in the
a certain amount of food has passed through the mouth. concentration of amino acids in the blood can also reduce
However, the inhibition of hunger by this mechanism is feeding, and a decrease enhances feeding.

THE digestive SYSTEM 

1
The extent of feeding in an animal depends on the to eat less than normal. These effects involve interaction
OVERVIEW OF THE DIGESTIVE SYSTEM

amount of adipose tissue in the body, indicating a role between centres in the hypothalamus that regulate tem-
for fat metabolites in the control of feeding behaviour. If perature and the centres that regulate food intake.
adipose tissue mass is low, feeding is increased. It seems
likely that lipid metabolites exert a negative feedback con-
trol of feeding. This is known as the ‘lipostatic’ theory of Thirst
hunger. The nature of the metabolites responsible for this
effect is unknown. However, the average concentration of The sensation of thirst occurs when there is an increase
unesterified fatty acid in the blood is approximately pro- in plasma osmolality, a decrease in blood volume, or
portional to the quantity of adipose tissue fat in the body. a decrease in arterial blood pressure. However, thirst
Thus, free fatty acids or their metabolites probably also can be satisfied by drinking water before sufficient is
regulate long-term feeding habits, and so enable the indi- absorbed to correct these changes. Receptors located in
vidual’s nutritional stores to remain constant. the mouth, pharynx and upper oesophagus are involved
Obesity can be due to an abnormality of the feeding in this rapid response. However, the relief of thirst by
mechanism, resulting from either psychogenic factors or this mechanism is short-lived. Complete satisfaction of
from an abnormality of the hypothalamic feeding centres. thirst occurs only when the plasma osmolality, blood
These can be genetic or environmental factors; overeating volume, and arterial blood pressure are returned to nor-
in childhood is probably one environmental determinant mal. Body fluid hyperosmolality is the most potent of
of obesity. Excessive feeding results in increased energy these stimuli. An increase of only 2% can cause thirst.
input over energy output. However, this may occur only Water intake is regulated by neurones in the hypothala-
during the phase when obesity is developing. Once the mus in the ‘thirst centre’. Some of these cells are osmore-
fat has been deposited the obesity will be maintained ceptors that are stimulated by an increase in osmolality.
by normal food intake. It can only be reduced if energy The neural pathways involved in the response are not
input is lower than energy output. This can be achieved clear, but they may be the same pathways that regulate
only by reducing food intake, or by increasing energy the release of antidiuretic hormone (ADH, vasopressin),
output via exercise. which controls water reabsorption in the kidney tubules.
Various drugs have been used in the treatment of obes- ADH is released from the posterior pituitary in response
ity. These include amphetamines that increase activity to changes in osmolality, blood volume and arterial
levels and inhibit the feeding centre in the hypothalamus. blood pressure (see the companion volume The Endocrine
More recently developed drugs include endocannabi- System). Thirst and vasopressin work in concert to main-
noids that are involved in metabolic homeostasis. These tain the water balance of the body. This axis is disrupted
also act by (among other mechanisms) modulation of in the hyperglycaemia associated with diabetes melli-
central nervous system pathways, to suppress hunger tus. The raised serum glucose concentration increases
via the feeding centre. A promising new drug, orlistat the osmolality thereby stimulating thirst. In addition the
(tetrahydrolipstatin), acts by inhibiting pancreatic lipase, increase in plasma glucose (which results in excretion of
the enzyme that breaks down neutral fat (triacylglycerol) glucose in the urine, causes an osmotic diuresis (exces-
in the small intestine (see Ch. 8). Undegraded triacyl- sive production of urine). For this reason patients with
glycerol is not absorbed in the digestive tract. Although new onset diabetes often present with polydipsia and
this drug provides an effective treatment for obesity, the polyuria (see Ch. 9). The resulting hypovolaemia (low
absorption of fat-soluble vitamins may also be reduced blood volume) exacerbates the situation by stimulating
and the diet should be supplemented with these vitamins thirst even more.
to increase the amount absorbed.
Modern treatment of obesity can include surgery to
restrict the ability of the stomach to distend, hence pro-
viding the sensation of satiety (through suppression Distribution of blood to the
of the feeding centre in the hypothalamus), or even, in digestive organs
severe cases, wiring of the jaw to restrict food intake.
Inanition is the opposite of obesity. It can be caused The proper functioning of the digestive system depends
by food deprivation, hypothalamic abnormalities, psy- on the gastrointestinal tract and associated organs receiv-
chogenic abnormalities or a catabolic state such as that ing an adequate supply of oxygen and nutrients to meet
present in advanced cancer. Anorexia nervosa is an their metabolic needs. These substances are carried to the
abnormal state, believed to be of psychogenic origin, in tissues by the blood circulation. The blood vessels that
which the desire for food is lost. supply the digestive organs located in the abdomen (and
Body temperature is also important in the regulation the spleen) comprise the splanchnic circulation. Over
of feeding. Exposure of an animal to cold causes it to 25% of the output from the left ventricle of the heart can
eat more than usual. This has physiological significance flow through the splanchnic circulation. It is the largest of
because increased food intake increases the metabolic rate, the regional circulations arising from the aorta. A major
and therefore heat production. It also increases fat deposi- function of the splanchnic circulation is to provide fuel
tion for insulation. Exposure to heat in an animal causes it to enable the processes of secretion, motility, digestion,

 SYSTEMS OF THE BODY

 1
absorption, and excretion, to take place. It also functions

OVERVIEW OF THE DIGESTIVE SYSTEM

Liver Heart
as a storage site for a large volume of blood that can be
mobilized when the need arises. Thus, during exercise,
Aorta
for example, the blood is diverted away from the diges-
tive organs to the skeletal and heart musculature. Hepatic Brain
The distribution of the blood in the splanchnic circu- artery
lation to the various abdominal organs is indicated in
Upper
Figures 1.4 and 1.5. Three major arteries in the splanch- limbs
nic circulation, the coeliac artery, the inferior mesenteric Portal Stomach
artery and the superior mesenteric artery, supply the vein
abdominal organs. The coeliac artery supplies the liver, Coeliac artery
stomach, spleen and pancreas. Approximately 20% of Spleen
the liver’s blood supply arises from the hepatic branch
of the coeliac artery. The rest is supplied by blood in the
Pancreas
portal vein (see Ch. 6), which is returning from the stom-
ach, spleen, pancreas, and small and large intestines that
Superior
are supplied by other branches of the coeliac artery and Small mesenteric
branches of the superior and inferior mesenteric arteries. intestine artery
The blood vessels of the splanchnic circulation are there-
fore arranged both in series and parallel (Fig. 1.4), and Large Inferior
most of its blood flows through the liver, either directly, intestine mesenteric
or after passing through other abdominal organs. It artery
leaves the liver via the hepatic veins to drain back to
the inferior vena cava. The branches of the major arter- Lower limbs
ies give rise to smaller branches that penetrate the organs
Fig. 1.4  Arrangement of the blood supply to the abdominal organs.
of the gastrointestinal tract and their muscular coats.
The coeliac artery directly provides only approximately 20% of the
These smaller branches divide to give rise to an exten- blood supply of the liver. This provides it with oxygenated arterial
sive network of small arteries in the submucosa. These blood. The rest of the output of the coeliac artery supplies the
in turn give rise to the mucosal arterioles that carry the stomach and spleen with oxygenated blood. The superior mesenteric
blood to the capillaries. This arrangement of blood ves- artery supplies the pancreas and small intestines and provides part
sels leads to considerable overlap in the distribution of of the oxygenated blood supply of the large intestine. The inferior
blood by adjacent arteries, and helps to prevent loss of mesenteric artery also supplies the large intestine with oxygenated
blood flow to a specific region if a major arterial branch blood. The venous blood arising from the abdominal organs contains
is occluded by a thrombus or embolus. It is not uncom- the absorbed nutrients that have been absorbed from the intestines.
mon to find the inferior mesenteric artery to be occluded This constitutes the portal blood that transports the nutrients in the
portal vein to the liver.
in elderly patients, but this rarely gives rise to symptoms
because the blood supply is sustained from the superior
mesenteric bowel.
Transport of an unionized substance across a mem-
The problems seen in a more serious condition where
brane can be described by the Fick equation:
generalized ischaemia of the gut is present are described
in described in Case 1.1: 3 and Case 1.1: 4. ds
 P(Ci  Co )A
dt
(ds/dt, rate of transport, P, permeability constant, Ci con-
Membrane transport
centration inside, Co concentration outside, A, surface area).
It is worth noting that the huge surface area of the small
The processes of absorption and secretion both depend intestine makes this organ ideal for the processes of absorp-
on the transport of molecules or ions across the plasma tion and secretion. In addition the high blood flow through
membrane of the cell. The mechanisms involved in these the splanchnic circulation ensures (Ci  Co) is maximized.
two processes share many common characteristics. The problems experienced when there is a reduced surface
Net transport of a substance by passive diffusion is area for absorption are described in Case 1.1: 3.
down its concentration or electrical gradient and it is
proportional to the surface area of the membrane across
which it is taking place. However, molecules are usu- Potential difference
ally moving across a cell membrane in both directions.
Absorption involves net transport from the intestinal In the case of a charged ion the transport is proportional
lumen to the blood or lymph. Secretion involves trans- to the sum of the concentration gradient and the potential
port into the lumen of a glandular duct or the lumen of difference across the membrane. The potential difference
the gastrointestinal tract. across the membranes of secretory cells and absorptive

THE digestive SYSTEM 

1
cells (enterocytes) varies from region to region in the where Ei  Eo is the electrical potential difference across
OVERVIEW OF THE DIGESTIVE SYSTEM

digestive system (see Ch. 7). An ion that diffuses pas- the membrane, z is the number of charges on the ion, F is
sively across a membrane will distribute itself on the two the Faraday number, R is the gas constant, T is the abso-
sides of the membrane until electrochemical equilibrium lute temperature, [X]o and [X]i are the concentrations
is reached. At this point the forces caused by the electri- of the ion (in this case a cation) on the two sides of the
cal potential gradient and the concentration difference membrane.
are equal and opposite, and there are no net forces on the
ion, and no net movement occurs. The electrical potential Mechanisms of transport
difference across a membrane can be calculated from the
Nernst equation: Some substances are transported solely by passive diffu-
sion. Others are transported slowly by passive diffusion
RT [X]o and more rapidly by special mechanisms. The special mech-
Ei  Eo  ln
zF [X]i anisms include active transport and facilitated diffusion.

A
AORT
Aorta
Brain
Legs GIT S
IMA SMA CA

PV

Liver B

Heart

C
Vena cava
VER
LI

IMA – Inferior mesenteric artery P

SMA – Superior mesenteric artery
CA – Coeliac artery
PV – Portal vein
A GIT – Gastrointestinal tract

Fig. 1.5  (A) The splanchnic blood flow. The blood supply is dependent
on three arteries, and drains via the portal system to the liver, before
returning to the systemic circulation. The blood flow is demonstrated
in the accompanying arteriograms (B and C). The contrast material
has been injected through a catheter (C) into the superior mesenteric
artery (S), and flows through the capillary beds in the wall of the
small bowel, before collecting in the portal vein (P) and draining
into the liver. C

 SYSTEMS OF THE BODY

 1
Active transport gradient or, in the case of an ion, against an electrical

OVERVIEW OF THE DIGESTIVE SYSTEM

gradient. In the small intestine the serosal surface of the
Table 1.1 shows the criteria used to distinguish active
membrane is positive with respect to the luminal surface.
and passive transport processes. A source of energy is
Thus net absorption of cations into the blood must be
required for active transport to take place. Passive trans-
accomplished by means of active transport. Active trans-
port requires no measurable amount of energy. If an
port of an ion may involve exchange for another ion of
active transport mechanism exists for the absorption of
the same charge, or it may be accompanied by transport
a substance it can be transported against a concentration
of an ion of the opposite charge. These arrangements
preserve the electrical status of the cell. Furthermore,
in secretory tissues the rate of transport for an actively
Case transported fluid (for example saliva, bile) can be con-
1.1 Non-occlusive ischaemic disease of stant until a pressure above the systolic arterial pressure
the gut: 3 of the blood serving the secreting tissue is reached.
Passive diffusion is transport down a concentration
gradient and the rate of transport is proportional to the
Effects on membrane transport
concentration difference of the substance across the mem-
Under hypoxic conditions, cellular metabolism becomes
brane, over a wide range of concentration differences.
anaerobic. Adenosine, a metabolite of ATP is degraded to
However, for active transport the rate is only proportional
hypoxanthine. The enzyme hypoxanthine oxidase then
to the concentration gradient at low concentration differ-
catalyses the conversion of hypoxanthine to superox-
ences. This is because at high concentrations the process
ide and hydroxyl free radicals, which are cytotoxic. These
becomes saturated and a transport maximum (Tm) is
compounds oxidize cell membrane lipids, and this in turn
reached (Fig. 1.6). Active transport of a substance is much
causes irreversible changes in the permeability of cell mem-
faster than passive transport of that substance.
branes and disruption of active transport systems in the
A 10°C rise in temperature can result in a 3–5-fold
cell plasma membranes. As a consequence, the cells can no
increase in the rate of an active transport process. Finally,
longer maintain their normal intracellular composition and
an active transport process is unidirectional. Thus glu-
they die. Because of its high metabolic activity the mucosa
cose, for example, is actively transported from the lumen
has the highest requirement for oxygen of all layers of the
of the small intestine into the blood but it is not actively
gastrointestinal tract, and consequently it is the most sensi-
transported in the opposite direction.
tive to anoxia. Necrosis of the absorptive cells reduces the
surface area for absorption and disrupts the specialized
transport mechanisms for the absorption of nutrients. In
Facilitated diffusion
addition, because the normal barrier to diffusion has been
removed as the mucosal cells die, toxic metabolites and Transport via facilitated diffusion does not occur against
other substances diffuse into the blood. Under normal con- a concentration gradient. However, for a given sub-
ditions mucosal cell loss would result in rapid cell prolifera- stance, it is a more rapid than passive diffusion. Like
tion and replacement. As this process requires oxygen, it active transport, it is proportional to the concentration
will not take place unless the blood supply is restored. Thus, difference across the membrane only at low favourable
aggressive treatment of the heart failure is central to the concentration gradients. At high concentration differ-
survival of these patients. ences the mechanism becomes saturated, usually because
it depends on the binding of the substance to a carrier

Table 1.1  Comparison between active and passive transport

Criterion Passive Active

1. Effect of opposing concentration No net transport against a gradient Transport against a gradient
or electrical gradient
2. Variation with concentration Transport proportional to concentration Transport proportional only at low concentrations,
difference difference over a wide range saturation at high concentrations
3. Energy supply Not required Required, glucose, O2, ATP, etc.
4. Inhibitors Not inhibited by metabolic or competitive Inhibited by metabolic inhibitors (F, DNP, etc.)
inhibitors
5. Temperature change No appreciable effect Sensitive to temperature change (Q10 is high)
6. Direction Bidirectional Unidirectional

DNP, dinitrophenol; Q10, effect of a 10°C increase in temperature.

THE digestive SYSTEM 

1
inner circular coat (Fig. 1.7A). In most regions of the gas-
OVERVIEW OF THE DIGESTIVE SYSTEM

Tm trointestinal tract, the muscular coat is composed entirely

Active
of smooth muscle. However, skeletal muscle is present in
the pharynx and the upper third of the oesophagus, and
the external anal sphincter.
The smooth muscle of the gastrointestinal tract is of
two types, phasic and tonic. Phasic muscle contracts
and relaxes in a matter of seconds (i.e. phasically). This
ds/dt

type of smooth muscle is present in the main body of the

oesophagus, the gastric antrum and the small intestine.
Tonic muscle contracts in a slow and sustained manner
(i.e. tonically). The duration of tonic muscle contractions
can be minutes or hours. This type of smooth muscle is
Passive present in the lower oesophageal sphincter, the ileocaecal
sphincter and the internal anal sphincter. The differences
between phasic and tonic muscle reflect the different
functions they perform. Thus, phasic contraction of the
Concentration difference antrum muscle empties food rapidly into the intestines,
whereas the tonic contractions of the muscle of the ileo-
Fig. 1.6  The effect of concentration gradient on active and passive
transport processes. Tm, transport maximum, ds/dt, rate of transport.
caecal sphincter keep the junction between the ileum
and the colon closed for long periods of time and enables
the entry of chyme into the colon to be carefully con-
protein in the membrane. Facilitated diffusion can be trolled. Whether the muscle is phasic or tonic depends on
inhibited competitively, by substances that bind to the properties intrinsic to the muscle cells. Neurotransmitters
same site as the natural substrate. and hormones alter the amplitude of phasic contractions,
and the tone of tonic muscle. These differences relate to
the electrical properties of the cells but the basic mecha-
Pinocytosis
nisms underlying the contractile activity are similar in all
Some large macromolecules or particles may be absorbed smooth muscle cells.
in the small intestine via pinocytosis (endocytosis). This The smooth muscle is composed of small spindle-
process involves the molecule becoming surrounded by shaped cells. Unlike those in skeletal muscle, these cells
the cell membrane and engulfed into the cell. It resembles are not arranged in orderly sarcomeres. There are no stri-
phagocytosis but pinocytotic vesicles are small (usually ations, although thick and thin myofilaments are present.
100–200 nM in diameter) while phagocytosed particles Actin and tropomyosin are the contractile proteins that
are larger (e.g. bacteria). The macromolecules usually constitute the thin filaments and myosin is the contractile
attach to specific receptors that are concentrated in small, protein of the thick filaments. Troponin is present only in
coated pits in the membrane. The cytoplasmic surface of negligible amounts, if at all. There are many more actin
the pit is coated with a dense material containing contrac- than myosin filaments. The ratio of thin to thick fila-
tile filaments. After the protein molecule has attached to ments is between 12:1 and 18:1. This can be contrasted
its receptors, the entire pit invaginates into the cell and its with skeletal muscle, where the ratio is 2:1. The thin fila-
borders close over the attached macromolecules together ments are anchored either to the plasma membrane or
with a small amount of fluid. The invaginated portion to structures known as dense bodies that are attached
of the membrane breaks away from the rest of the mem- to a network of another type of filament of intermedi-
brane. Thus, the endocytosed particle is surrounded ate thickness between the thick and thin filaments. These
by the plasma membrane of the cell and engulfed. It is intermediate filaments form an internal skeleton on
then a membrane-bound particle within the cytoplasm which the contractile filaments are anchored. Figure 1.7B
of the cell. The process is active, requiring energy in the shows the organization of the structures in smooth mus-
form of ATP within the cell, and Ca2 ions in the extra- cle. The dense bodies correspond to the Z lines in skeletal
cellular fluid. Inside the cell Ca2 may activate the con- muscle. Contractions of smooth muscle occur by a sliding
tractile microfilaments to pinch the vesicles off the cell filament mechanism similar to that in skeletal and cardiac
membrane. muscle, with cross-bridge formation occurring between
the overlapping thick and thin filaments. The muscle
cells are organized as sheets that behave as effector units
Motility because the individual cells are functionally coupled
to one another. Opposing membranes of the cells are
Smooth muscle in the gastrointestinal tract fused to form gap junctions or nexuses. These are low-
resistance junctions that allow the spread of excitation
The muscle of the gastrointestinal tract is arranged from one cell to another. Contractions of the bundles of
mainly in two layers, an outer longitudinal coat, and an cells are therefore synchronous.

10 SYSTEMS OF THE BODY

 1

OVERVIEW OF THE DIGESTIVE SYSTEM

Ca2+ INFLUX Inactive myosin
Gland outside tract
light-chain kinase
(e.g. pancreas)

Longitudinal muscle layer Ca2+

+
Circular muscle layer Epithelium Calmodulin-Ca2+ Calmodulin
Submucosa binding protein
complex
Active myosin
Lamina propria light-chain-kinase
ATP ADP

Lumen Phosphorylation

Myosin Myosin-P Actin

(low Ca2+)
Muscularis mucosa Myosin ATP
Pi light-chain H2O
Brunner’s gland
in submucosa phosphatase ADP + Pi

Myenteric
Connective tissue plexus CONTRACTION
layer (serosa)
Submucosal
plexus Fig. 1.8  Role of Ca2 in the contraction of smooth muscle.
A

Dense body Nexus Intermediate filament

Ca2 channels (VDCCs). When the cell membrane is depo-
(of internal skeleton)
larized to threshold an action potential is generated and the
VDCCs open. Ca2 enters down its concentration gradient
causing the cell to contract. The resulting influx of Ca2
initiates the contractile response of the (non-pacemaker)
cells. The intracellular events that trigger muscle contrac-
tion are outlined in Figure 1.8. Inside the cell, the Ca2
binds to calmodulin, a Ca2 binding protein. This complex
activates a kinase enzyme on the light chain of the myosin
molecules in the thick filaments. The activated myosin
light chain kinase catalyses the phosphorylation of myosin,
utilizing ATP that is dephosphorylated to form ADP. The
Thin filament
phosphorylated myosin can then interact with actin, to
Dense body split ATP, causing the movement of the cross bridges. The
Cell membrane Thick filament
myofilaments slide past each other and the muscle con-
B tracts. The myosin is inactivated by dephosphorylation
and the ADP formed is converted back to ATP. The proc-
Fig. 1.7  (A) Layers of the gastrointestinal tract showing the ess of contraction requires energy, so an ischaemic bowel
locations of glands, the smooth muscle coats, and the enteric nerve can quickly become atonic, and passively dilate, resulting
plexi. (B) Structural features of visceral smooth muscle.
in abdominal distension (Fig. 1.9).

Initiation of smooth muscle contraction Control of smooth muscle

Contraction of smooth muscle cells is triggered by Ca2 Action potentials are triggered in only a few cells by nerv-
influx. Neurotransmitters, hormones and other factors ous and hormonal influences. These are known as pace-
can promote Ca2 influx. In resting muscle, the intra- maker cells. The action potentials set up in these cells are
cellular Ca2 concentration is low (approximately 107 M) transmitted throughout the muscle sheet. The pacemaker
and there is no interaction between actin and myosin. The cells are most numerous in the longitudinal muscle layer.
extracellular Ca2 concentration is approximately 2 mM. In these cells, the resting membrane potential (RMP) is
In phasic muscle cells Ca2 enters via voltage-determined continuously oscillating. This activity is known as the

THE digestive SYSTEM 11

1
basal electrical rhythm. The control of tension develop-
OVERVIEW OF THE DIGESTIVE SYSTEM

ment in smooth muscle is exerted via changing the offset

of this basal electrical rhythm (Fig. 1.10). If the amplitude
of the depolarization phase of the oscillation reaches the
threshold level, an action potential is triggered. The action
potential is conducted via nexuses from cell to cell, caus-
ing Ca2 influx, and contraction of the smooth muscle
cells. With increased frequency of action potentials there
is summation of the contractile response and the mus-
cle contracts with increased force. The force generated is
related to the intracellular Ca2 concentration.
Action potentials occur spontaneously in pacemaker
cells as the amplitude of the oscillations occasionally
reaches the threshold potential in the absence of exter-
nal stimulation. The muscle is therefore under a certain
amount of tension even in the resting state. This property
of spontaneous contraction is known as tone.
Increased Ca2 influx leads to increased force of con-
traction. Conversely, because there is normally always a
degree of tone present, a reduction in Ca2 influx leads to
a decrease in the force of contraction, i.e. relative relaxa-
tion. Control is exerted largely by shifts in the mean
RMP (Fig. 1.10). If the membrane potential is shifted
closer to threshold (depolarization), more oscillations
reach threshold and more action potentials are gener-
ated and the force of contraction will be increased. If the
A B membrane potential is shifted further from the threshold
Fig. 1.9  A plain X-ray of large bowel ischaemia, showing dilated large (hyperpolarization) fewer of the oscillations reach the
bowel (A), with gas in the oedematous bowel wall, underneath the threshold, the frequency of action potentials decreases,
ischaemic mucosa (B). and the force of contraction decreases.

Electrical
threshold
Contraction
threshold Membrane
potential

Muscle
tension

Fig. 1.10  Control of pacemaker cells in gastrointestinal smooth muscle. The generation of action potentials by the cell and their frequency
depend on the amplitude of the oscillations in the membrane potential. (A) Oscillating membrane potential. The solid line represents a recording
from a cell that is not under the influence of hormones or transmitters. Stimulation shifts the resting membrane potential towards the threshold
for electrical excitation (depolarization), resulting in the generation of action potentials (dotted line). When the membrane potential exceeds the
threshold level muscle tension is developed. Inhibition shifts the resting membrane potential further away from the threshold (hyperpolarization,
dashed line). (B) Development of muscle tension. An increased frequency of action potentials causes the development of increased muscle
tension via summation of the contractile response. The contraction threshold of the membrane potential may be slightly lower than the action
potential threshold (see A). Solid line, tension developed in the absence of external stimulation. Dotted line, tension developed in response to
stimulation.

12 SYSTEMS OF THE BODY

 1

OVERVIEW OF THE DIGESTIVE SYSTEM

Table 1.2  Some biologically active peptides of the digestive
system, their cellular sites of origin in the gastrointestinal tract,
and their sites of action

Peptide Main site of Site of action

Tension

origin

Gastrin APUD cells Secretory cells of

(stomach antrum) stomach, pancreas
Smooth muscle of
gallbladder, small
intestine
GRP Intrinsic neurones Secretory and smooth
Stretch (stomach) muscle cells of
stomach
Fig. 1.11  Effect of stretch on tension development in smooth muscle.
Somatostatin APUD cells Secretory cells of
Tension is proportional to stretch at low or moderate levels of stretch,
(stomach) stomach
but excessive stretch results in reduced tension.
Secretin APUD cells Secretory cells of
(duodenum) stomach, pancreas,
liver, small intestine
Smooth muscle contracts in response to stretch. This is
known as the myogenic reflex. It is an intrinsic property Cholecystokinin APUD cells Secretory cells of
of smooth muscle and does not occur in skeletal muscle. (duodenum) stomach, pancreas
Figure 1.11 shows the relationship between the degree Smooth muscle of
of stretch and the force of contraction in visceral smooth gallbladder, blood
muscle. Stretching the membrane opens Ca2 channels in vessels
it and Ca2 flows into the cell. However, whereas moder- Motilin APUD cells Smooth muscle of
ate stretch results in depolarization of the membrane and (duodenum, small intestine
muscle contraction, excessive stretch inhibits the force of jejunum)
contraction. GIP APUD cells Secretory cells of
The membrane potential of the pacemaker cells can (duodenum, stomach
be controlled by neurotransmitters and hormones. These jejunum)
act on receptors to cause either depolarization or hyper- Enteroglucagon APUD cells (ileum Secretory cells of
polarization of the cells. The nerve axons that enter and colon) stomach
smooth muscle release neurotransmitters from swellings, Smooth muscle cells
known as varicosities, along their length. No discrete of stomach, intestines
neuromuscular junctions exist between the muscle cells VIP Intrinsic neurones Secretory cells of
and the nerve release sites. Indeed the varicosities are (throughout the salivary glands, small
usually some distance from the muscle cells. GIT) intestines, pancreas
Smooth muscle of
stomach and large
Control of secretion and motility intestine, sphincters,
blood vessels
The control of secretion and motility in the gastrointes-
tinal tract is by neural, hormonal and paracrine mecha- GRP, gastrin releasing peptide; GIP, gastric inhibitory peptide; VIP,
nisms. The neural control is via both extrinsic nerves of vasoactive intestinal peptide. APUD cells are the endocrine cells
the autonomic nervous system and nerves in the intrinsic of the gastrointestinal tract.
enteric nerve plexi of the gastrointestinal tract. In many
instances the mediators of neural or hormonal control
are peptides. In some cases a given peptide acts as both controls motility, secretion and blood flow. However,
a neurotransmitter and a hormone. Table 1.2 shows some signals from the central nervous system, travelling in
of the neuropeptides involved in control of the gastroin- both sympathetic and parasympathetic nerves can alter
testinal tract. the activity of the nerves in the intrinsic plexi.

Neural control Enteric nervous system

The gastrointestinal tract is innervated by both auto-
nomic nerves and by nerves in the enteric plexi in the The enteric nervous system may be regarded as a third
walls of the tract (Fig. 1.7A). The enteric nervous system division of the autonomic nervous system, after the

THE digestive SYSTEM 13

1
sympathetic and parasympathetic divisions. However, in information from the gut epithelium and from stretch
OVERVIEW OF THE DIGESTIVE SYSTEM

contrast to the sympathetic and parasympathetic nerves, receptors in the wall of the tract. Smaller plexi reside
the enteric nerves can perform many functions inde- within the smooth muscle layers and within the mucosa.
pendently of the central nervous system. The importance Within each plexus the neuronal cell bodies are
of this becomes apparent following surgical resection of arranged in ganglia. Intrinsic nerves of the enteric nerv-
segments of the bowel, which may result in disruption of ous system connect the plexi together, synapsing on to
the autonomic nerve supply, particularly the parasym- the ganglion cells. They also innervate smooth muscle,
pathetic vagal nerves (see later, Fig. 1.13). Activity in the secretory glands and blood vessels of the tract. In addi-
intrinsic enteric nerves ensures that effective peristalsis tion many of them synapse with postganglionic sympa-
and food propulsion along the intestine is maintained thetic and parasympathetic nerves, or sensory nerves.
after such operations. These arrangements are shown schematically in Figure
1.12. The enteric nervous system is therefore composed of
four categories of nerves, extrinsic fibres, intrinsic motor
Anatomy of the enteric nervous system fibres, intrinsic interneurones, and sensory neurones. If
the extrinsic nerves are sectioned there is little impair-
The enteric nervous system consists of two major plexi, ment of gastrointestinal function, except in the mouth,
together with lesser plexi, in the wall of the gastrointesti- oesophagus and anal regions, where control by extrinsic
nal tract. Figure 1.12 shows the anatomical arrangement nerves is more important than in the rest of the gastroin-
of the enteric nervous system in the tract. The major plexi testinal tract. Such extrinsic control is clearly required in
are the myenteric plexus (Auerbach’s plexus), which is these regions for the ingestion of food and the expulsion
situated between the layers of longitudinal and circular of faeces.
smooth muscle, and the submucous plexus (Meissner’s Both excitatory and inhibitory nerves innervate the
plexus), which lies in the mucosa. The myenteric plexus smooth muscle, blood vessels and glands of the gas-
is involved mainly in the control of gastrointestinal motil- trointestinal tract. In addition there are both excitatory
ity. This is exemplified in Hirschsprung’s disease where and inhibitory interneurones in the plexi. Furthermore,
ganglion cells are missing from a region of the myenteric enteric neurones (as well as gastrointestinal smooth
plexus (see Ch. 10), resulting in severe constipation, muscle cells) exhibit spontaneous rhythmic activity (see
which in the neonate can be life threatening. The submu- below).
cous plexus is more important in the control of secretion In general, stimulation of the myenteric plexus increases
and blood flow. It is also important in receiving sensory the motor activity of the gut, by increasing tonic contrac-
tions (tone), the intensity and rate of rhythmic contractions
of the smooth muscle, and the velocity of waves of con-
traction (peristalsis) along the tract. However, some fibres
in the myenteric plexus are inhibitory. Many different
excitatory and inhibitory neurotransmitters are involved.
Capillary

Parasympathetic nerve
Intrinsic motoneurones
Longitudinal muscle
Intrinsic motor nerves are predominantly excitatory.
Some of the excitatory neurones are cholinergic and their
Myenteric plexus effects can be blocked by atropine, indicating that the
receptors involved are muscarinic. However, other excita-
tory neurones release other transmitters such as substance
Interneurone P. Stimulation of excitatory motor nerves can cause con-
Circular muscle traction of both circular and longitudinal smooth muscle,
Submucosal plexus relaxation of sphincter muscle, or glandular secretion.
Stimulation of inhibitory motor fibres in the enteric nerv-
Gland of Brunner ous system causes smooth muscle relaxation. The inhibi-
tory transmitters involved may be ATP or vasoactive
Submucosa intestinal peptide (VIP).

Mucosa
Intrinsic interneurones
Intrinsic interneurones can also be excitatory or inhibi-
Mucosal gland tory. The transmitter released by excitatory neurones is
(crypt of Lieberkühn)
Lumen of small intestine probably acetylcholine that acts on nicotinic receptors on
postsynaptic neurones. The transmitters released by the
Fig. 1.12  The arrangement of neurones in the enteric nerve plexi. inhibitory interneurones are largely unknown.

14 SYSTEMS OF THE BODY

 1
Sensory neurones nerves is to stimulate secretion and motility in the gas-

OVERVIEW OF THE DIGESTIVE SYSTEM

trointestinal tract. The transmitter released by the pre-
Many afferent sensory neurones are present in the gas-
ganglionic parasympathetic nerves is acetylcholine and it
trointestinal tract. Some of these have their cell bod-
acts on nicotinic receptors on interneurones in the enteric
ies in the enteric nervous system. They are stimulated
nerve plexi.
by distension or irritation of the gut wall that activates
mechanoreceptors and by substances in the food, which
activate chemoreceptors. They form part of reflex path- Sympathetic nerves
ways, which may or may not be influenced by control via
extrinsic nerves. Some of these sensory fibres also termi- The preganglionic sympathetic nerves that supply the
nate on interneurones that in turn can activate excitatory gastrointestinal tract arise from segments T8–L2 in the
or inhibitory motor neurones. thoracic spinal cord (Fig. 1.13). This is why pain from
Some afferent sensory fibres that have their cell bodies the gastrointestinal tract is referred to these somatic der-
in the enteric nerve plexi, terminate in the sympathetic matomes (areas of the skin innervated by neurones which
ganglia. Other sensory fibres from the gastrointestinal enter the spinal cord at the same level). The intestine is a
tract have their cell bodies in the dorsal root ganglia of the midline embryological structure, so this ‘autonomic’ pain
spinal cord or in the cranial nerve ganglia. These nerve is referred to the midline. Thus, for example, appendicitis
fibres travel in the same nerve trunks as the autonomic initially produces pain felt around the umbilicus (i.e. via
nerves. They transmit information to the medulla, which segment T10 nerves). The fibres pass through the sympa-
in turn transmits efferent signals back to the gastrointes- thetic chains and synapse with postganglionic neurones
tinal tract to influence its functions. Specific reflexes are in the coeliac ganglion and various mesenteric ganglia.
described in the appropriate chapters in this book. The postganglionic fibres travel together with blood ves-
sels to innervate all regions of the tract. They terminate
mainly on neurones in the enteric nerve plexi, although
Control by autonomic nerves a few terminate directly on smooth muscle cells or secre-
tory cells. In general, activity in the sympathetic nerves
At any one time, activity in autonomic nerves can alter inhibits activity in the gastrointestinal tract, having oppo-
the activity of the entire gastrointestinal tract, or of a site effects to stimulation of the parasympathetic nerves.
discrete part of it, via its influences on the enteric nerv- Stimulation of postganglionic sympathetic nerve fibres
ous system. In addition, autonomic nerves may synapse can inhibit the release of acetylcholine from excitatory
directly on smooth muscle and secretory cells to influ- motoneurones, to cause relaxation of the smooth muscle
ence their activity directly, although they synapse prin- indirectly. They can also cause constriction of sphincter
cipally with enteric interneurones to influence function
indirectly.

Parasympathetic nerves

Preganglionic nerves from both the cranial and sacral divi-

sions of the parasympathetic nervous system supply the
gastrointestinal tract. The cranial parasympathetic pregan-
glionic nerve fibres travel in the vagus nerve, except for a
few which innervate the mouth and pharyngeal regions.
CG
The vagal fibres innervate the oesophagus, stomach, pan-
creas, liver, small intestine and the ascending and trans-
verse colon (Fig. 1.13). The preganglionic nerves of the
sacral division of the parasympathetic nervous system,
which innervate the tract, originate in the second, third and SMG
fourth segments of the sacral spinal cord and travel in the
pelvic nerves to the distal part of the large intestine. The
IMG
parasympathetic innervation of the tract is more extensive
in the upper (orad) region and the distal (rectal and anal)
regions than elsewhere. The preganglionic parasympa- Fig. 1.13  The autonomic innervation of the gastrointestinal tract. LHS,
dotted lines indicate the preganglionic parasympathetic innervation
thetic nerve fibres form excitatory synapses with postgan-
by the vagus nerve (cranial nerve 10) from the brainstem, and nerves
glionic neurones in both the myenteric and submucosal of the sacral outflow of the spinal cord. RHS, the dotted lines indicate
plexi. These are mainly excitatory interneurones of the the postganglionic sympathetic innervation arising from the cervical
enteric nerve plexi. Stimulation of the parasympathetic ganglion (CG), the superior mesenteric ganglion (SMG) and the
nerves can have a diffuse, far-reaching effect to activate inferior mesenteric ganglion (IMG). The preganglionic sympathetic
the entire enteric nervous system via these interneurones. nerves arise in the thoracic and upper lumbar regions of the spinal
In general, the effects of activity in the ­ parasympathetic cord, and pass through the paravertebral chains to ganglia.

THE digestive SYSTEM 15

1
muscle, or inhibit glandular secretion, and importantly, base of the cell. The open APUD cell is the most com-
OVERVIEW OF THE DIGESTIVE SYSTEM

cause vasoconstriction of arterioles of the gastrointesti- mon type of endocrine cell in the gastrointestinal tract. It
nal tract, redirecting blood flow away from the splanch- is found in areas extending from the pyloric antrum to
nic bed. Most effects of activation of sympathetic nerves the rectum. These cells sense chemical substances in the
are exerted indirectly via their connections in the enteric food. Thus they behave as chemoreceptors or ‘taste’ cells.
nervous system. Movement of food through the gastroin- In addition they may respond to mechanical stimulation.
testinal tract can be completely blocked by strong activa- The closed APUD cells are numerous in the oxyntic
tion of the sympathetic nervous system. The transmitter area of the stomach mucosa. They sometimes have hori-
released by postganglionic nerve fibres is noradrenaline. zontal processes. They usually make synaptic contacts
with intrinsic nerve cells as well as with other APUD
cells. Cells of both types release hormones into the inter-
stitial spaces from where they are transported by diffu-
Endocrine control
sion or vesicular transport (cytopempsis) into the blood
capillaries.
The gastrointestinal tract is the largest endocrine organ
Upon stimulation both the open and the closed types
in the body, but the hormone-secreting cells are diffusely
of APUD cells release hormones. The hormones circulate
distributed in the mucosa, scattered among numerous
in the blood to act at sites that may be distant from the
other types of cell, in contrast to other endocrine organs
location where they are secreted. Gastrin, for example, is
such as the pituitary, thyroid and adrenals, where the
a hormone secreted by the stomach antrum, but it acts on
cells are organized ‘en masse’. The endocrine cells of the
the liver and pancreas as well as the stomach. However,
gastrointestinal tract are APUD cells. This acronym stands
the hormones are secreted first into the interstitial spaces
for amine precursor uptake and decarboxylation, after the
where they can regulate cells that are in close proxim-
classical function of the cells, which may relate to their
ity to the hormone release sites. They can therefore have
role in hormone synthesis. The APUD cells in different
local and distant influences. The local influences are
regions of the tract secrete different hormones. Table 1.2
known as paracrine control.
indicates some of the peptides secreted, and the locations
in the gastrointestinal tract where they are secreted.
The APUD cells that contain peptide hormones can
be stained with silver. They contain dense core vesicles Control of blood flow
in which the peptide hormones are packaged. These cells
are of two types: ‘open’ and ‘closed’ (Fig. 1.14).
The blood flow to the digestive organs is relatively low
The open cells in the gastrointestinal mucosa extend
in the fasting state but it increases several-fold when a
to the lumen of the tract and their luminal surface is
meal is present in the tract and the tissues are actively
covered with microvilli. In some cases only a thin neck
secreting digestive juices, or absorbing nutrients. Blood
of cytoplasm exists between the luminal margin and the
flow to the gut is controlled by many factors including
basilar side of the cell. The secretory vesicles are at the
haemodynamic factors such as cardiac output, systemic
arterial pressure, blood viscosity and blood volume,
which regulate the flow to all tissues in the body. Other
Stimulus (food substance)
factors include increased activity in sympathetic nerves
that causes vasoconstriction and reduced blood flow, via
release of noradrenaline that activates -adrenergic recep-
Intrinsic Extrinsic Intrinsic Extrinsic tors. However this effect is short-lived for several reasons,
neurone neurone neurone neurone one of these being changes in local factors. Thus there is
Process Process a reduction in oxygen tension (hypoxia), when the blood
flow is reduced, and this induces vasodilatation. In addi-
tion sympathetic nerve stimulation relaxes gut smooth
Vesicles Vesicles muscle which results in reduced mechanical resistance to
blood flow to the gastrointestinal tract. Other substances
which constrict the splanchnic blood vessels are circulat-
Blood Blood ing adrenaline, angiotensin II and vasopressin.
Stimulation of the parasympathetic nerves to the gas-
Fig. 1.14  Schematic representation of open and closed APUD cells. trointestinal tract causes an increase in blood flow by
(A) open cell, (B) closed cell. The peptide hormones are stored in
various indirect mechanisms. These are a result of the
secretory vesicles, and released by exocytosis into the blood. They
may also be secreted from extensions, or processes. They can also
increased secretory activity of the tissues induced by
act in a paracrine manner on other cells, including other APUD cells, parasympathetic nerve stimulation. Secretion requires
in the mucosa. Open cells can be stimulated by substances within an increased metabolism of the actively secreting tissues,
the lumen of the gastrointestinal tract. Both open and closed cells which results in an increased production of metabolites
can be stimulated by peptides released from other APUD cells, or by such as K, amines and polypeptides, and CO2, and
transmitters released from intrinsic or extrinsic nerves. reduced O2 tension, all of which may cause localized

16 SYSTEMS OF THE BODY

 1
vasodilatation, with a consequent increase in blood flow.

OVERVIEW OF THE DIGESTIVE SYSTEM

Case
The transmitter released from these parasympathetic
1.1 Non-occlusive ischaemic disease of
nerves may be VIP. the gut: 4
Stimulation of tissues to secrete can also result in the
release of proteolytic enzymes, known as kallikreins,
which activate precursors of the vasodilator bradykinin, Involvement of control mechanisms
in the intercellular spaces, to form the active vasodilator Arterial hypotension causes generalized activation of the sym-
(see Ch. 2). These local responses are feedback mecha- pathetic nervous system through baroreceptor and chemore-
nisms whereby the consumption of energy metabolites ceptor mechanisms. This results in the release of noradrenaline
results in a greater supply of metabolites via increased from sympathetic nerves, which causes generalized vasocon-
blood flow. Other substances that dilate the blood vessels striction of the small blood vessels in the gastrointestinal circu-
of the gastrointestinal tract are the hormones gastrin and lation. Reflex responses involving the brain and kidneys result
cholecystokinin (CCK) that are released into the blood in the release of vasopressin and angiotensin II, respectively,
when food is present in the stomach and duodenum, both of which also cause vasoconstriction. The vasoconstriction
respectively. These have a more localized effect, with gas- of the small vessels exacerbates the effect on the mesenteric
trin increasing the blood flow to the stomach and CCK blood circulation of reduced perfusion pressure, increased
increasing blood flow to the pancreas and intestines. blood viscosity, and microthrombi formation, and resistance
During a meal, the different organs of the diges- to blood flow through the gut increases. Eventually the criti-
tive system are activated in sequence to secrete, absorb cal closing pressure of the small blood vessels is reached and
or contract, and their demand for energy substrates they collapse, and the flow of blood through the intestines
and oxygen increases accordingly. These requirements effectively ceases. The patient was being treated with digitalis,
are met by an increased blood supply to the individual a cardiac glycoside, for his heart condition. Such drugs may
component organs as they require them. Neural activity exacerbate the ischaemia as they are known to cause vasocon-
in efferent nerves from the higher centres in the brain, striction in the mesenteric circulation. Patients with hypoten-
autonomic nerves, and enteric nerves, and hormones sion can be treated with -adrenergic vasoconstrictor drugs to
and local metabolites all interact to mediate the increased elevate the arterial blood pressure. However, in patients with
regional blood flow (hyperaemia) as each region requires non-occlusive disease of the gut, this would also compound
it. During a meal there is also a generalized increase in the problem of reduced perfusion of the gut, by their effect
blood flow due to an increased cardiac output. Thus on the sympathetic receptors in the gastrointestinal tract.
when food enters the stomach, the release of gastrin and
local metabolites in the stomach stimulates its blood flow.
When the food enters the small intestine, the release of
CCK and local metabolites results in increased blood
flow to the small intestine.
The splanchnic circulation can be compromised in a
2. The gastric phase is due to the presence of food in the
number of pathological conditions that may arise in other
stomach.
organs of the body, such as haemorrhage and congestive
3. The intestinal phase is when the food is present in the
heart failure, or by diseases of the digestive organs. Such
small intestines.
diseases include nonocclusive ischaemic disease of the
intestines, or cirrhosis of the liver. The effects of general- The sequential effects of food or chyme in these various
ized abnormal activation of the sympathetic nervous sys- locations enables synchronization and coordination of
tem due to hypotension in congestive heart failure, on the activity of smooth muscle, secretory tissues and the vas-
blood vessels of the gastrointestinal tract, are described cular system of the different regions and organs.
in Case 1.1: 4. Food in the mouth stimulates pressure receptors and
chemo- (taste) receptors and this results in increased
blood flow to the salivary glands and secretion of saliva
Control of gastrointestinal functions during that starts the digestion of starch. It also initiates the
a meal secretions of the stomach, pancreas and liver to prepare
the gastrointestinal tract to perform its digestive and
absorptive functions. At this time the motility of the stom-
In general, the presence of food in the gastrointestinal
ach is transiently inhibited.
tract stimulates smooth muscle in the main body of the
Food in the stomach causes increased blood flow to the
tract and the gall bladder, relaxes the smooth muscle of
stomach and secretion of gastric juice, and stimulates the
the sphincters, and stimulates secretion and blood flow
smooth muscle of the stomach. This enables the stomach
in salivary glands, pancreas and liver. The control can be
to churn the food present within it and start the digestion
considered in three phases, depending on the location of
of the food. However, food in the stomach also stimulates
the food:
the secretion of pancreatic juice, bile and intestinal juices
1. The cephalic phase is due to the approach of food and in preparation for the chyme when it arrives in the small
the presence of food in the mouth. intestine where most digestion and absorption occurs.

THE digestive SYSTEM 17

1
In addition, it stimulates motility in the ileum and colon. intestine also stimulates secretion of intestinal juice, pan-
OVERVIEW OF THE DIGESTIVE SYSTEM

This moves the chyme present in those regions into the creatic juice and alkaline bile and the blood flow to the
next region to make way for the arrival of more chyme. intestines, pancreas and liver. It also stimulates contrac-
Chyme in the duodenum exerts the major control over tion of the gall bladder and relaxation of the sphincter of
gastrointestinal function. It inhibits gastric secretion and Oddi to allow the pancreatic juice and bile to enter the
motility that transiently prevents further emptying of the duodenum. These digestive juices can then perform the
stomach, allowing the processing of the food material digestion of the complex nutrients, enabling absorption
already present in the small intestine. Food in the small to take place in the small intestine.

18 SYSTEMS OF THE BODY

 2
The mouth, salivary
glands and
oesophagus

Chapter objectives
After studying this chapter you should be able to:

1. Describe the structures of the mouth and oesophagus.

2. Understand the mechanisms of taste, mastication, salivary secretion

and swallowing.
2
and mucous glands that result in impaired secretion (see
The mouth, salivary glands and oesophagus

Introduction
Boxes 1 and 2). A second problem, involving denervation
of structures following oral surgery is used to highlight
The functions of the mouth and oesophagus include: the importance of nerves in control of functions in the
mouth (see Boxes 3 and 5).
l Mastication
l Taste
l Swallowing
l Lubrication The mouth
l Digestion
l Speech Anatomical features of the mouth
l Signalling of thirst
l Protection of the body from harmful ingested The oral cavity (mouth) is closed by the apposition of
substances. the lips. The lips and the cheeks are composed mainly of
skeletal muscle embedded in elastic fibro-connective tis-
The performance of all of these functions depends on the sue. Figure 2.4 shows the anatomical features of the oral
presence of saliva. In this chapter, the functional impor- cavity and the structures within it, including the tongue
tance of saliva is illustrated by the problems encountered and the teeth. It also shows associated structures, such as
in individuals with xerostomia (dry mouth), a condition the olfactory mucosa, which are important for the func-
characterized by pathological changes in the salivary tioning of the digestive system.

Case
2.1 Xerostomia: 1

A 60-year-old woman visited her general practitioner and

complained of a persistent dry mouth, difficulties in chew-
ing and swallowing, and sore gritty, eyes. She also said that
her food seemed tasteless. The doctor examined the patient’s
mouth. Her gums and teeth appeared inflamed and infected,
and her tongue appeared lobulated. The patient was sent for
investigation of salivary function.
The most frequent cause of dry mouth (xerostomia) is hypo-
function of the salivary glands (which is often accompanied
by hypofunction of the lacrimal glands). Figure 2.1 shows the
appearance of the tongue in a patient with xerostomia.
The following questions will be addressed:

l What are the major causes of dry mouth? Which oral

conditions are associated with xerostomia? Which systemic
conditions are associated with xerostomia?
l How can salivary function be assessed?

l Why is saliva important for oral and dental health?

l Which functions of the mouth would be impaired in

xerostomia?
l Why is saliva important for the functioning of the

oesophagus?
l Which drugs or other treatments can be used to alleviate

xerostomia and what side-effects might be expected from

these treatments?

Fig. 2.1  The tongue of a patient with xerostomia, showing a

characteristic grooved appearance. (Courtesy of Mr J. Hamburger,
Dental School, University of Birmingham.)

20 SYSTEMS OF THE BODY

 2

The mouth, salivary glands and oesophagus

Case
2.1 Xerostomia: 2

Causes and diagnosis

Causes over the opening of Stensen’s duct. This creates a vacuum and
Xerostomia is a fairly common condition. Its prevalence is saliva can be collected. Saliva can also be collected with a pre-
approximately 2% of the general population. It affects more weighed sponge. Swallowing difficulty can also be assessed, i.e.
women than men. The incidence increases with age. It is asso- whether water has to be taken with dry food for swallowing to
ciated with conditions that are commoner in middle and old be accomplished (e.g. the ‘cream cracker’ test). All of these tests
age, possibly partly because of the higher incidence of peo- have to be interpreted with care, but on the basis of such tests
ple on medication in these age groups. The symptoms are dry patients are initially categorized into ‘responders’ who have
eyes and dry mouth. The major causes are: functional salivary gland tissue and ‘non-responders’ who do
not. Scintigraphy (scintiscanning) is a technique involving intra-
l Medication, especially tricyclic antidepressants and venous administration of a radioisotope, usually ­ technetium
sympathomimetic drugs pertechnetate, a gamma emitter with a short half-life. This is
l Head and neck irradiation
taken up into the salivary acinar cells. Uptake with time can be
l Autoimmune inflammatory diseases such as Sjögren’s

syndrome, which targets exocrine glands in general.

Sjögren’s syndrome
In some patients with Sjögren’s syndrome the ducts of the sub-
mandibular glands are obstructed and the glands become swol-
len (Fig. 2.2). In such patients the submandibular glands in the
neck are clearly located. Characteristically in Sjögren’s syndrome,
there is atrophy of acinar tissue. It should be noted however,
that there is normally an average loss of approximately 40% of
acinar tissue between the ages of 40 and 65 years. Ductal hyper-
plasia and focal periductal infiltrates of lymphocytes (largely
helper T cells) are also seen in Sjögren’s syndrome.
Figure 2.3 shows a histological section of a minor salivary
gland in a patient with Sjögren’s syndrome, in which focal aggre-
gates of lymphocytes can be clearly seen. In non-autoimmune
inflammatory disease, the infiltration with lymphocytes is more
Fig. 2.2  Swollen submandibular glands (arrowed) in a patient
diffuse. Atrophy of the mucous glands in the buccal mucosa may with Sjögren’s syndrome. The inflammatory process can cause the
also be present. Primary Sjögren’s syndrome is characterized by ducts to become blocked with mucoid saliva. The ducts may also be
dry mouth and eyes, but a secondary form exists in which these narrowed (stenosis). As a consequence, the glands swell. (Courtesy
symptoms are accompanied by connective tissue disease, usually of Mr J. Hamburger, Dental School, University of Birmingham.)
rheumatoid arthritis or lupus erythematosus, primary biliary cir-
rhosis, polymyositis, and a number of other conditions. In some
patients with HIV disease the condition resembles Sjögren’s syn-
drome. Diabetes mellitus and diabetes insipidus can also cause
symptoms of xerostomia as these conditions are accompanied by
dehydration resulting from copious urine flow.

Symptomatic xerostomia
The ‘perception’ of oral dryness, in the absence of actual
oral dryness, termed ‘symptomatic xerostomia’, can be the
result of sensory or cognitive disorder. In addition, altered
perception of oral sensation (oral dysaesthesia) is a feature
of anxiety, although acute anxiety can actually cause clinical
symptoms and signs of xerostomia.

Diagnosis
A simple test for xerostomia that can be carried out in the Fig. 2.3  Histological section of a minor salivary gland of the lip in
surgery involves swabbing the tongue with 5% citric acid, a patient with Sjögren’s syndrome. Focal infiltrates of lymphocytes
and measuring the volume of saliva that can be spat out into are indicated by the arrows. (Courtesy of Mr J. Hamburger, Dental
a graduated tube. Alternatively, a Curby cup can be placed School, University of Birmingham.)

THE digestive SYSTEM 21

2
The mouth, salivary glands and oesophagus

Case
2.1 Xerostomia: 2 (continued)

measured using a Geiger counter. Responders by definition have Non-responders have no functional epithelium and therefore
functioning Na/K/Cl co-transporters that can carry Cl ions cannot handle pertechnetate correctly. In Sjögren’s syndrome,
or technetium pertechnetate across the acinar cell ­ membrane. there is a slow uptake of the isotope, a low peak value and a
Water moves passively across the membrane as a consequence. prolonged excretory phase.

Trigeminal ganglion
Chorda
tympani

Otic ganglion
Olfactory bulb
Anterior division
Olfactory mucosa Cribriform plate
Lingual nerve
Nasopharynx
Palate Sublingual Auriculo-
Parotid salivary temporal
Tongue salivary gland gland nerve
Teeth
Maxillary
Sublingual artery
salivary gland Epiglottis
Submandibular Inferior dental nerve
salivary gland
Pharynx

Glottis Upper
oesophageal
Trachea
sphincter Fig. 2.5  The mandibular division of the trigeminal nerve. The lingual
nerve innervates the anterior two-thirds of the tongue and the
Oesophagus sublingual and submandibular salivary glands. The inferior dental
nerve innervates the tooth pulp, periodontal ligaments and gums. The
Fig. 2.4  Structures in the mouth, and associated structures. anterior division innervates the muscles of mastication (not shown). The
auriculotemporal nerve innervates structures of the ear (not shown).

Innervation
fibres innervate the submandibular and sublingual sali-
The innervation of many structures of the mouth is via
vary glands. Nerve damage is not uncommon following
the four branches of the mandibular division of the
dental procedures, and this is described for a patient who
trigeminal nerve (Fig. 2.5). These are:
had undergone a wisdom tooth extraction (see Box 3).
1. The anterior division, which innervates the lateral
pterygoid, temporal, and masseter muscles which are
involved in mastication (see below) Anatomy and histology of the tongue
2. The auriculotemporal nerve, which innervates
The tongue has a freely moveable portion known as the
structures of the ear
body, and a basal or root portion that is attached to the
3. The inferior dental nerve, which innervates the lower floor of the oral cavity, and forms part of the anterior
lip and the tooth pulp, periodontal ligaments and gums wall of the pharynx. It is divided into anterior and poste-
rior regions by the sulcus terminalis, a V-shaped groove
4. The lingual nerve, which innervates the anterior two-
with the apex of the V directed posteriorly. It is com-
thirds of the tongue, the floor of the mouth, and the
posed largely of skeletal muscle fibres and glands, and
gum on the lingual side of the lower teeth.
is covered by a mucous membrane. Some of the muscle
The lingual nerve is joined by the chorda tympani that fibres are intrinsic, and are confined to the tongue. These
run through the lateral pterygoid muscle. The chorda are arranged vertically, transversely and longitudinally.
tympani carries sensory taste fibres from the lingual nerve There are also extrinsic fibres, which originate outside
to the facial nerve, and secretomotor (parasympathetic) the tongue, mainly on the mandible and hyoid bone, and
fibres from the facial nerve to the lingual nerve. These pass into the tongue (Fig. 2.7A). The glands are located

22 SYSTEMS OF THE BODY

 2
Tongue

The mouth, salivary glands and oesophagus

Case
2.2 Denervation following wisdom
tooth extraction: 1
Styloglossus
Genioglossus
An 18-year-old man was admitted to hospital to have an
Stylohyoideus
impacted wisdom tooth extracted. The operation involved
reflection of a flap of tissue to allow extraction of the
tooth. In this patient the inferior dental nerve ran unusually
close to the apical part of the tooth root and the nerve was
accidentally damaged. (Figure 2.6 shows an X-­radiograph Geniohyoideus Hypoglossus
from a subject in whom the dental nerve is abnormally
A
close to the root of a wisdom tooth). Unfortunately, in the
patient the lingual nerve was also damaged during the sur- Tongue surface Taste pore
gical procedure because it also ran unusually close to the
tooth. As a result, after the anaesthetic had worn off, the
side of the patient’s tongue and the lower lip on the oper- Microvilli
(taste hairs)
ated side of his mouth were numb.
Perusal of this case history may provoke the following
Sustentacular
questions:
(supporting) cells

l Would the damage to the inferior dental nerve and

Neuroepithelial
the lingual nerve affect the patient’s ability to chew, (sensory) cells
swallow, or his speech?
l Would the nerve damage affect the patient’s sense of Nerve endings
taste?
l Would the patient have defective salivary secretion and

defective sense of taste?

Basal (stem) cells
l Would loss of pain sensation be a problem for this

patient? Why was the patient’s lower lip numb?

Sensory nerve axons

Myelin sheath

Fig. 2.7  (A) Locations of the extrinsic muscles of the tongue. (B)
Structure of a taste bud.

On the upper surface of the tongue are numerous

small protuberances, or papillae, which give the tongue
its roughened appearance. Different types of papillae
Fig. 2.6  An X-ray in a patient in which the inferior dental nerve are present and these have different distributions on the
(arrow) runs close to a wisdom tooth. In this individual, the root tongue; fungiform and foliate papillae are present on
of the tooth has become grooved as it developed around the the anterior and lateral surface and circumvallate papil-
abnormally close nerve. lae are on the base of the tongue. Papillae contain numer-
ous nerve endings that sense touch. Most papillae have
associated taste buds (see below). Lymphatic nodules (the
between the muscle fibres. The glands in the base of the lingual tonsil) protrude from the surface of the posterior
tongue are mainly mucous and their ducts open behind one third of the tongue and give it a nodular, irregular
the sulcus terminalis. In the body of the tongue, the appearance. Between the nodules are crypts where the
glands are mainly serous and their ducts open anterior epithelium is infiltrated with numerous lymphocytes. The
to the sulcus. Near the tip, the glands are mixed and their inferior surface of the tongue is smooth and is underlain
ducts open onto the inferior surface of the tongue. by a submucosa.

THE digestive SYSTEM 23

2
Taste Sweet: the front of the tongue
The mouth, salivary glands and oesophagus

l Bitter: the rear of the tongue.

Taste buds There are however, no obvious structural differences in
There are several thousand taste buds on the human taste buds in the different regions. The differences in sen-
tongue. Each circumvallate papilla contains several hun- sitivity are partly due to precise projections of the affer-
dred taste buds. The taste buds contain the gustatory ent nerves to the central nervous system and partly to
(taste) receptor cells. Figure 2.7B shows the structure of the patterns of impulses from a population of chemore-
a taste bud. They are located in the oral (stratified squa- ceptors. The nerves from the taste buds in the anterior of
mous) epithelium, mainly in association with the papillae, the tongue pass in the chorda tympani (a branch of the
but can be situated elsewhere in the oral cavity such as the facial nerve) and those from the taste buds in the pos-
palate and the epiglottis. They lie within the epithelium. terior third travel in the glossopharyngeal nerve. These
They have a pale, barrel-shaped appearance with a depres- nerves project to the tractus solitarius (Fig. 2.8). The sen-
sion, the taste pore, in the surface. This is an aperture that sory nerves from the taste buds in the palate and epiglot-
provides communication with the exterior. It contains tis ascend in the vagus nerve. The possible pathological
three types of cell: supporting (sustentacular) cells, neuro- sequelae following damage to some of the nerves during
epithelial taste cells, and basal cells. The supporting cells oral surgery are discussed in Box 5.
lie at the periphery, and are arranged like the staves of a The dissolved chemicals in the saliva diffuse into the
barrel. The neuroepithelial cells, 10–14 in each taste bud, taste pore from the fluid layer on the tongue. Appropriate
lie more centrally. Two types of neuroepithelial sensory chemicals, such as NaCl, are detected by receptor mol-
cell can be distinguished under the electron microscope; ecules on the taste hairs, and this results in a depolariza-
one type contains clear vesicles within its cytoplasm and tion of the cell membrane (receptor potential) of the taste
the other contains dense core vesicles. The presence of dif- bud cell which causes the release of an excitatory trans-
ferent vesicles is consistent with the presence of different mitter that evokes a generator potential in the sensory
transmitter substances. These are stored in the vesicles nerve endings (see the companion volume The Nervous
prior to being released from the cell. Both the sensory cells System). The mechanism of the response to salt (NaCl)
and the support cells have long apical microvilli, or taste has been well studied (Fig. 2.9).
hairs, which project into the taste pore. The taste hairs lie
in amorphous polysaccharide material that is secreted by
the supporting cells. The basal cell is located peripher- Smell
ally near the basal lamina. These are the stem cells for the
other cell types. There are club-shaped endings of sensory Taste as defined by the layman includes smell (olfaction).
nerves lying between the cells. Chemical (taste) stimuli are Activation of olfactory receptors, in conjunction with
received by the neuroepithelial cells and transmitted via central nervous system processing of their responses,
the release of neurotransmitters from the cells to the nerve enables many different types of odour, or flavours, to
endings. The secretions of the serous glands of the papil- be distinguished. Smell has more primary qualities
lae wash away food material and permit new taste stimuli than taste. These include floral, ethereal, musky, cam-
to be received by the receptors. phor, putrid and pungent submodalities. Blockage of
the nose by the common cold, or olfactory nerve lesions,
Taste sensation renders taste discrimination crude as it then relies only
The solubilization of food constituents by saliva enables
the sense of taste to be experienced. Thus, taste depends
on the detection of chemicals that are dissolved in the Parotid gland Superior and inferior
salivary nuclei
saliva and for this reason, taste is compromised in xero-
stomia (see Box 4). There are four submodalities: salt, Glossopharyngeal
sour (acid), sweet and bitter. Dissolved substances with nerve
these properties stimulate the receptors (the taste buds) Otic ganglion
on the tongue. Acid is the most potent stimulus; in Tongue Nucleus
humans, sucking a lemon can lead to the maximum rate tractus
of secretion, which can be 7–8 mL of saliva per minute. A solitarius
taste bud responds to several or all of these submodali-
Chorda
ties, but each taste bud is most sensitive to one particular tympani
taste. However, all taste buds respond to all four stimuli,
given high enough concentrations of the appropriate Submandibular Submandibular
chemicals. The taste buds that respond primarily to each gland ganglion
Sublingual Lingual
submodality are situated as follows: gland nerve
l Sour: the posterior sides of the tongue Fig. 2.8  Reflex pathway for the secretion of saliva in response to the
l Salt: the anterior sides stimulation of taste bud receptors.

24 SYSTEMS OF THE BODY

 2

The mouth, salivary glands and oesophagus

Case
2.1 Xerostomia: 3

Consequences for the functioning of the mouth

and oesophagus
Lubrication Protection
Saliva is necessary to aid chewing, swallowing and speech Saliva is also important for oral and dental health: it washes
because of the lubricant properties conferred on it by its mucin the mouth, buffers acids in the food, and contains antimicro-
content. Therefore these functions are all compromised in bial substances. Infections of the mouth are rare following
xerostomia. Saliva is necessary for mastication because it coats dental surgery even though it is difficult to maintain aseptic
the food and lubricates it, making it more easily moved about conditions in the mouth. However, infections of the mouth
in the mouth. During swallowing it is more easily moved back and associated structures are common in xerostomia without
into the pharynx where it stimulates the pressure receptors the protective properties of saliva. In addition the constant
that initiate the process, enabling it to pass smoothly into the rinsing of the oesophagus by saliva and its buffering and anti-
oesophagus. Individuals with xerostomia therefore require fluid microbial properties, help to protect the oesophagus from
intake with food to enable chewing and swallowing to take damage by acids, and to prevent infections.
place. The lubricant properties of saliva also assist the passage
of the food bolus down the oesophagus and prevent abrasion
of the walls by hard material in the swallowed food. Dental and oral health
Dental health depends on saliva for many reasons including its
Digestion continuous rinsing of the oral and buccal cavities to wash away
particles in which microorganisms grow, its ability to buffer acids
Lack of salivary -amylase does not result in malabsorption
(saliva is more alkaline at high rates of flow), its specific and
of starch if pancreatic -amylase secretion is adequate, as the
non-specific immune functions due to the presence of immu-
amylases from the two sources have similar catalytic actions
noglobulins, the antimicrobial constituents sialoperoxidase, thio-
in starch digestion, and adequate amounts of -amylase are
cyanate and lysozyme, and the presence of calcium phosphate,
secreted by the pancreas.
which prevents demineralization of the teeth. As a consequence
of the decreased production of saliva various oral diseases are
Solution associated with xerostomia. These are dental caries, gum dis-
Saliva is important for taste as it depends on substances dis- ease, mucosal ulceration and atrophy, infections of the mouth
solved in saliva. It is also important for the solution of sub- (e.g. candida), and ascending infection of the salivary glands.
stances that are absorbed by mouth. In addition, in the absence of saliva, retention of dentures is
more difficult. Patients who have a dry mouth because they are
Moistness being treated with tricyclic antidepressants, ganglion-blocking
Lack of saliva signals thirst. Thirst is therefore a constant sen- drugs, or parasympathomimetic drugs (for hypertension), may
sation in xerostomia. experience difficulty in oral function if they wear dentures.

Case
2.2 Denervation following wisdom tooth extraction: 2

Consequences for the functioning of the mouth

Chewing, swallowing and speech not seriously affected after such nerve damage, because only a
Chewing depends on activation of periodontal receptors that small part of the musculature is likely to be affected.
results in impulses in sensory nerve fibres in the inferior den- Articulation of many sounds depends on fine control of the
tal nerve being transmitted to the chewing centre. However, movements of the muscles of the tongue. These reflexes partly
in practice, chewing is not usually much impaired following depend on tactile information from the tongue, but in practice,
such nerve damage. The tongue, which is innervated by the unilateral damage to these nerves, accompanying wisdom tooth
lingual nerve, moves the food around in the mouth to aid extraction, does not affect speech to any significant extent.
chewing. Therefore if the tongue is partially denervated the
process of mastication could be impaired, but this is not usu- Taste
ally a serious problem. Some nerve fibres in the lingual nerve carry sensory information
The swallowing reflex is initiated when the tongue moves from the taste buds on the tongue (via the chorda tympani).
the food bolus to the back of the mouth where it activates pres- Loss of some taste sensation on one side of the tongue could
sure receptors in the pharynx. However, swallowing is ­ usually occur in the patient but it is not usually a serious problem.

THE digestive SYSTEM 25

2
on the taste buds. The sense of smell, like that of taste, than the lower arc, and this results in the lower teeth being
The mouth, salivary glands and oesophagus

Case
is an important
2.2 Denervation following wisdom tooth extraction: 2 (continued)
stimulant of appetite and digestion. The overlapped by the upper teeth. In the human there are five
olfactory mucosa that detects the odours is located in the primary (milk) teeth in each half jaw (i.e. 20 in total) that

Salivary secretion Loss of pain sensation

The patient is unlikely to suffer from a dry mouth because The numbness experienced by this patient due to the dam-
between meals the mouth is kept moist by saliva from the aged lingual nerve could be a serious problem because the
smaller glands in the oral and buccal mucosa. When food is patient could injure his tongue by biting it without realizing
eaten or at the approach of food over half of the increased it. He may also burn the tongue and other tissues in his mouth
flow comes from the parotid glands. The lingual nerve inner- by drinking liquid that is too hot. The patient’s lower lip was
vates the submandibular and sublingual salivary glands but also numb, because of this structure is innervated by the infe-
not the parotids (Fig. 2.5). The latter are innervated by fibres rior dental nerve. Thus injury could also occur due to acciden-
in the glossopharyngeal nerve. Thus interference with the tal biting or scalding of the lip. Fortunately for this patient,
flow of saliva is not a serious problem after unilateral lingual sensation in the affected areas would probably return over
nerve damage accompanying a wisdom tooth extraction. the subsequent few weeks.

NaCl Taste bud receptor

cell or sensory Axons Basement
nerve ending membrane
mV

Supporting
cells
A
Receptor
Afferent
cells
nerve fibre
mV

Olfactory
B Time mucosa

Fig. 2.9  Electrical potentials in (A) taste bud receptors and

(B) primary afferent nerves from the taste receptors.

upper nasopharynx (Fig. 2.4). The odorant molecules are

borne to the olfactory mucosa via the inspired air, or air
in the oral cavity during feeding. The chemical odours
are detected by receptors in bipolar cells present in the
mucosa (Fig. 2.10). There are about 10 million chemore-
ceptor cells in the human olfactory mucosa. Immobile Fig. 2.10  Structure of the olfactory mucosa.
cilia on the surface of the cells detect odorants dissolved
in the mucous layer that overlies the mucosa. The chemi-
cal odorants depolarize the receptor cell and this triggers erupt between the ages of approximately 6 months and 2
a discharge in the sensory nerve. Coding for a particular years of age. These teeth are shed between 6 and 13 years
smell, like coding for taste, depends on the response of a of age and are gradually replaced by permanent adult
population of receptors. The information is integrated in teeth. The latter number eight in each half jaw (i.e. 32 in
cortical structures. total). The anterior five adult teeth replace the milk teeth.
The sharp incisor teeth are specialized for biting, while
the larger, more flattened molars are specialized for
Teeth grinding. Figure 2.11 shows the basic structure of a tooth.
Each tooth has a basic similar structure with a visible
The teeth are embedded in the bone of the upper and lower crown projecting above the gingiva (gum) and a root that
jaws. They are arranged in two arcs. The upper arc is larger is buried in the alveolus of the maxilla or the mandible.

26 SYSTEMS OF THE BODY

 2
At the junction between the crown and the root is the and horizontal (side to side) movements enable the molars

The mouth, salivary glands and oesophagus

neck. In the centre of each tooth is the pulp cavity that is to crush and break the food into fragments of a size suit-
filled by connective tissue. The latter communicates via able for swallowing. These movements also mix the food
small pores (apical foramina) with the surrounding con- with the saliva. This serves several functions including
nective tissue or periodontal membrane, which holds the taste and digestion (see below). Chewing depends on the
tooth in its socket (alveolus). This arrangement forms a presence of saliva in the mouth. Saliva contains mucins
peg and socket type of joint that permits slight move- that give it its lubricant property (see below). It coats the
ment. The hard tissues of the pulp are: food and makes it slippery and more easily moved about
in the mouth. Consequently, patients with xerostomia
l Dentine: a calcified tissue similar to bone, which
experience difficulty in chewing (see Box 4).
surrounds the pulp cavity and forms the bulk of the tooth
l Enamel: the hardest material which is mainly
The muscles of mastication are capable of exerting
considerable force. The biting forces exerted by the inci-
composed of apatite crystals and covers the dentine of
sors and molars are 110–250 N and 390–900 N, respec-
the crown
l Cementin: which, like dentine, is similar to bone, and
tively. The potential biting force is much greater than the
force needed in ordinary chewing. The occlusal contact
covers the dentine of the root.
area between the molars and between the premolars is
Saliva is important for oral and dental health. The prob- much more decisive than the biting force in determin-
lems encountered by individuals with xerostomia are ing the efficiency of mastication in a person with nor-
described in Box 4. mal dentition. The efficiency of mastication is reduced
in those who wear dentures, and they often tend to eat
Mastication (chewing) foods that are not difficult to chew; the toughness of the
foods chosen seems to be related to the biting force that
The sight, smell and thought of food elicit the secretion of can be exerted on the dentures. The narrow selection of
saliva before food enters the mouth. However, the palat- food, for example the omission of meat in the diet, can
ability of food also depends on orally sensed properties lead to nutritional deficiency.
after food has been taken into the mouth, such as taste, tex-
ture and temperature. Once present in the mouth, the food Control of mastication
is chewed, a process known as mastication. This involves
movements of the jaw and the tongue. It is controlled by The muscles of mastication are the lateral pterygoids that
sensations from touch and pressure receptors located in the are responsible for jaw opening, and the masseters, the
oral mucosa and the periodontium (area around the teeth), temporalis, and the medial pterygoid muscles that are
as well as from stretch and other receptors in the mastica- responsible for jaw closing (Fig. 2.12A). The muscles of
tory muscles, temporomandibular joints and periosteum. closing are more powerful than those involved in opening.
There is a reciprocal arrangement between the opening
Mastication process
The vertical (up and down) movements of the mandibles
result in biting by the incisor teeth. After a piece of food Temporalis
has been taken into the mouth, both vertical movements
Medial pterygoid Lateral pterygoid
(lateral head) (upper head)

Enamel Nerve to
masseter
Clinical Dentine (cut)
Anatomical crown Gingival crevice (sulcus) Lingual nerve
crown Attachment epithelium
Pulp
Epithelium Sphenomandibular
ligament
Odontoblasts
Periodontal membrane
Root Alveolar bone
Cementin (non-cellular)
Cementin (cellular) A Inferior dental nerve
Bone marrow
Fig. 2.12  Mastication and its control. (A) Arrangement of the muscles
of mastication. The lateral pterygoid is responsible for jaw opening,
and the medial pterygoid, the masseters and the temporalis are
Fig. 2.11  Basic structure of a tooth. responsible for jaw closing.

THE digestive SYSTEM 27

2
The mouth, salivary glands and oesophagus

ImV
Brainstem

+ - -
Open Close

Opening + +
Tooth
Muscles Muscles
receptors

Closing
B C

Fig. 2.12 (Cont’d)  (B) The Pattern of electrical activity (EMG) in the muscles of opening and closing. (C) Simplified representation of a pattern
generator that could control the opening and closing of jaws.

and closing muscles. The control is exerted by neural Stimulation of mechanoreceptors associated with the teeth
mechanisms. Two important aspects of the control are: is important. Many sensory receptors are present in the
tooth pulp and the periodontal ligaments. Stimulation of
1. The generation of the movements
these receptors sends impulses in fibres in the lingual nerve
2. The regulation of the bite.
(Fig. 2.5). Activation of the receptors causes information to
be transmitted to the brainstem, to inhibit jaw closing when
Generation of movements the biting force rises, and therefore to regulate the force
A single bite is a voluntary process involving the cerebral applied. This is sometimes described as the jaw-opening
cortex, as are other movements involving skeletal mus- reflex because if a tooth is tapped, for example an upper
cles. However, chewing is not a reflex. It is probably a incisor, the jaw opens. The lingual nerve afferents ascend via
programmed pattern of movements organized in the cen- the trigeminal nerve to the brainstem. When these receptors
tral nervous system. It involves neurones in the nucleus are stimulated, the amplitude of the jaw movement bursting
of the fifth cranial nerve. The ‘chewing centre’ is built responses changes and activity in the masseter jaw closing
into the organization of this group of neurones. Electrical muscles increases. These inputs therefore modify the activ-
stimulation of the cortical masticatory area in an anaes- ity of the pattern generator, and contribute to the control of
thetized animal induces rhythmic jaw movements the chewing force. The texture of food is perceived during
similar to those observed during chewing. When the chewing by excitation of mechanoreceptors in the periodon-
electrical changes in the membranes of the neurones are tal ligaments. Slight displacement of a tooth during chew-
recorded they are seen to exhibit a bursting activity, the ing, causes the periodontal ligaments to be stretched and this
bursts being associated with jaw opening and jaw closing deforms and excites the receptors. Each afferent responds
(Fig. 2.12B). This pattern is involuntary and is present maximally to one particular direction of applied force. The
even if the sensory input is absent. Chewing therefore pressure stimulus threshold for perception of a stimulus
probably depends on a pattern generator (similar to the applied to a tooth is 10 mN and is higher for the molars
pattern generator seen in the respiratory centre, see the than for the incisors or canines. The threshold level depends
companion volume The Respiratory System). Such gen- on the velocity of application of the force. Nevertheless, peo-
erators are rather primitive basic activities. Figure 2.12 ple who have lost their teeth can control masticatory force,
shows the arrangements of the pathways involved in the indicating that tactile sensation in the periodontal ligaments
generation of this chewing activity and its modulation. is not the only input controlling the biting force. In fact mus-
cle spindles in the masticatory muscles, temporomandibular
Regulation of the bite joints and periosteum may also contribute.
As the jaws close, the teeth come into contact with food,
or the opposing set of teeth. Two questions arise: Role of tongue movements in mastication
1. How is the bite terminated? The density of mechanoreceptors is high in the front of
2. How is the force applied regulated? the oral cavity and low in the posterior part. The tip of

28 SYSTEMS OF THE BODY

 2
the tongue has the highest density. Two-point discrimina- some are mixed and contain mucous cells with serous

The mouth, salivary glands and oesophagus

tion on the tip of the tongue can be less than 1 mm. Tactile crescents or demilunes (Fig. 2.13). The saliva secreted by
information from the oral cavity and the tongue is trans- these glands has a weak -amylase activity but contains
mitted to the brain via the trigeminal nerve. The tongue lysozyme that is secreted by the serous demilunes. The
is a sophisticated motor organ that moves rhythmically in sublingual glands contain mainly mucous acini but some
concert with the lower jaw (usually without being bitten) of these have serous demilunes. Very few pure serous
during chewing. The tongue can perform these move- acini are present in the sublingual gland. Consequently,
ments because of the arrangement of its musculature they produce a particularly thick mucous secretion.
(Fig. 2.7). The extrinsic muscles enable it to change its
overall position. These, together with the intrinsic mus-
cles that terminate on the mucosa or on other muscles of
the tongue, enable it to both alter its shape and perform
rapid movements. The nerve endings in the papillae Acinus
transmit the senses of touch, pressure, temperature and
pain. There are also proprioreceptors within the muscles,
and abundant muscle spindles, in the human tongue,
Intercalated duct
and these are also important for the intricate movements
involved in chewing. The tongue mixes saliva with the
crushed food by alternations from one side to the other,
coating it with mucus.

Saliva Striated duct

Saliva is secreted by three major pairs of salivary glands:

1. The parotid glands
2. The submandibular glands (submaxillary glands in
animals)
3. The sublingual glands.
Excretory duct
There are also numerous other, small glands scattered
throughout the oral and buccal mucosa.
The parotids are the largest of the glands. Each parotid
is located below and anterior to the ear, between the
ramus of the mandible and the mastoid process, with an
Main collecting duct
extension onto the face. Its main duct (Stensen’s duct)
passes forward to penetrate the cheek and opens into the A
mouth opposite the second molar tooth.
Demilunes
The submandibular gland lies in the floor of the
mouth beneath the body of the mandible, extending
below its lower border into the side of the neck. It has
a duct (Wharton’s duct) that opens beneath the tip of
the tongue. In some patients with Sjögren’s syndrome
(see Box 2) the ducts of the submandibular glands are
obstructed, and the glands become swollen (Fig. 2.2). In
such patients, the location of the submandibular glands Serous acinus Mucous acinus
in the neck are clearly indicated.
The sublingual gland is actually a collection of glands
that lie near to the duct of the submandibular gland
beneath the mucous membrane of the floor of the mouth.
Each of these sublingual glands has a separate duct that
opens beneath the tongue.
The three pairs of glands differ with respect to the
type of acini present, and they secrete saliva that differs
in composition with respect to the mucus content. The
parotids have acini that contain only serous cells. They
B Intercalated duct Striated duct
produce a watery secretion that has a high content of
-amylase but very little mucus. Most acini of the sub- Fig. 2.13  (A) Regions of a salivary gland. (B) Cell types present in
mandibular glands are serous, but some are mucous, and different regions.

THE digestive SYSTEM 29

2
Composition of saliva
The mouth, salivary glands and oesophagus

Saliva in the mouth is a mixture of secretions from all the

glands present. Human saliva contains less than 1% total
solids. The ions present include Na, K, Ca2, Mg2,
PO43 and HCO3. Saliva is supersaturated with cal-
cium phosphates that help to prevent demineralization
of the teeth. Specific phosphoproteins (proline-rich pro-
teins and statherin) that inhibit the precipitation of cal-
cium phosphate crystals from the supersaturated saliva
onto the teeth, are also present. The alkalinity or acidity
of saliva depends on the rate of flow (see below) but the
pH is usually within the range 6.2 to 8.0. There are proba-
bly around 50 different proteins in saliva, the major ones
being the enzyme -amylase, and mucins, which are
glycoproteins. Those present in smaller amounts include
the enzymes lysozyme and sialoperoxidase (see below),
as well as lactoferrin, histatins and various immunoglob-
ulins, all of which have protective functions in the mouth.
R proteins that bind cobalamins (collectively known as
vitamin B12, see Ch. 8) and keep the cobalamins in an
absorbable form, are also present.

Salivary glands
Fig. 2.14  Histological section of a normal salivary gland, showing
Structure and histology duct cells (solid arrows) and acinar cells (dashed arrows). (Courtesy of
Dr J. Rippin, Dental School, University of Birmingham.)
Figure 2.13A shows the structure of part of a mixed
salivary gland. The glands are branched structures. The
acini where the primary salivary secretion originates Somewhat sparsely distributed myoepithelial cells
are located at the termini of these branches. In many are present around the ducts and the acini of a salivary
respects the structure of a salivary gland resembles that gland. These cells support the glandular elements and
of an exocrine gland of the pancreas. Figure 2.14 shows contract when the glands are stimulated, to assist the
these features in a histological section of a human sali- extrusion of the saliva from the ducts.
vary gland. The cells which surround the acini are either
serous and secrete -amylase but no mucins, or mucous
and secrete the glycoprotein mucins. The acinar cells also Functions of saliva
secrete substances across the basal membrane into the
interstitial spaces. These include the proteolytic enzymes The secretion of saliva in response to food has been stud-
known as kallikreins, which have a role in controlling ied experimentally in animals by surgically making a
the regional blood flow to the glands (see Fig. 2.17). The permanent fistula at the throat, or by inserting a cannula
basal membrane of the serous acinar cell has thin finger- in the appropriate duct under anaesthesia. In humans a
like projections that increase the surface area for secretion variety of methods are used to assess salivary function.
(Fig. 2.13B). The secretions of the acinar cells drain into Some of these are discussed in Box 2.
intercalated ducts (Fig. 2.13A) that are lined with colum-
nar epithelium. These cells probably add constituents
Lubrication
to the secretion as it passes down the ducts. The small,
intercalated ducts from a number of acini merge to form The lubricant property of saliva depends on its content
larger striated ducts that are lined by taller cells. The of mucins. These glycoproteins form a gel that coats
basal membranes of these cells have numerous infold- the food and makes it more easily moved about in the
ings. Between the infoldings are rows of mitochondria mouth. This lubricant property of saliva enables chewing
that impart a striated appearance to the cells, under the and swallowing to be performed.
microscope. These striated ducts drain into larger, excre-
tory ducts, which in turn drain into a large collecting
duct that opens into the mouth. The cells lining the stri-
Digestion
ated ducts and the excretory ducts modify the secretion -Amylase is the major digestive enzyme in saliva. It
as it flows past them. hydrolyses -1,4 glycosidic linkages in starch (see Ch. 8).

30 SYSTEMS OF THE BODY

 2
The efficiency of mastication is important for salivary the mouth resist lysozyme attack by developing protec-

The mouth, salivary glands and oesophagus

amylase to penetrate the food bolus. Despite the short tive cell capsules. Nevertheless, infections in the mouth
exposure of saliva in the mouth, the salivary digestion are rare, even after oral or dental surgery when aseptic
of starch is important because it continues after the food precautions are difficult to maintain, because of the bac-
has reached the stomach. Gastric acid in the stomach teriostatic properties of saliva.
inactivates -amylase but as the bolus of food takes time
to disintegrate in the stomach, salivary digestion can
continue within it for as long as half an hour. When the Control of water intake
acid has completely penetrated the food the enzyme is Thirst is the desire for increased water intake and it is
inactivated. -Amylase works best at a slightly alkaline perceived as a dry mouth. The sensation is signalled by
pH. The starch in potatoes or bread may be digested to receptors in the oropharynx and upper gastrointestinal
the extent of up to 75% by salivary -amylase before the tract but the mechanisms involved in the response of the
enzyme is inactivated by acid in the stomach. receptors are still poorly understood. However, the relief
Small amounts of other enzymes are also present in of thirst sensation via these receptors is short-lived. The
saliva, including lysozyme, sialoperoxidase, lingual desire for increased water intake accompanies an increase
lipase, ribonuclease, deoxyribonuclease and kallikreins. in plasma hypertonicity or a reduction in blood volume
These salivary components are not important for the or pressure (see Ch. 1). The sensation of thirst is initially
digestive process, although lysozyme and sialoperoxi- satisfied by the act of drinking, but this occurs before suf-
dase provide important protective functions (see below). ficient water is absorbed from the gastrointestinal tract
to correct these disturbances. The desire to drink is com-
pletely satisfied only when the plasma osmolarity, volume
Protective functions of saliva and pressure are adjusted to within the normal range.
Saliva has many properties that enable it to promote oral
and dental health: Speech
l The large volume of the fluid produced enables Speech depends on the movements and positioning of
the buccal cavity to be continually rinsed, thereby the tongue, lips and cheeks, during controlled expiration.
removing ingested substances and particles from it. As movements of the tongue are facilitated by the lubri-
l It contains mucins that impart a slippery character to cant effect of saliva, speech can be difficult in xerostomia.
the secretion. It coats the mouth, thereby protecting it Speech is a function that is not directly related to the
against abrasion by sharp pieces of food. digestive process and will not be considered further here.
l The alkaline pH of the saliva produced when a meal
is being eaten buffers acids present in the food. The Absorption in the mouth
copious secretion of saliva prior to vomiting protects Absorption of low molecular weight molecules can
the mouth from gastric acid in the vomit by virtue of occur, to some extent, directly from the oral cavity. This
its mucus content and its pH. Buffering of the acids in route of absorption can be useful for absorption of cer-
food prevents the erosion of tooth enamel. tain drugs, especially when a rapid treatment response
l It is bacteriostatic because it contains an is required. Such drugs are usually placed under the
antimicrobial substance, thiocyanate, and an enzyme, tongue. One example is glyceryl trinitrate that is used
sialoperoxidase which catalyses the reaction of to treat an angina attack. It can also be a useful route
metabolic products of bacteria, such as that of for drugs which are unstable at the pH of the stomach,
hydrogen peroxide with salivary thiocyanate: or which are rapidly metabolized by the liver. Drugs
that are absorbed from the oral cavity enter the systemic
Sialoperoxidase circulation directly and therefore escape the ‘first-pass’
H2O2 + CNS– oxidation products, metabolism that occurs in the liver, unlike substances
Hydrogen thiocyanate e.g. OSCN– that are absorbed into the portal system (see Ch. 6).
peroxide (saliva) hypothiocyanate An example of a drug that is rapidly inactivated in the
(bacterial (toxic to bacteria) liver is isoprenaline that is sometimes used to treat heart
activity) block. This drug can be effective if given sublingually.
Unfortunately, high molecular weight substances are not
well absorbed from the mouth.
The oxidized derivatives produced in this reaction are
highly toxic to bacterial systems. The oxidation products
oxidize SH groups on many enzymes including some Mechanisms of secretion
of those involved in energy metabolism. Saliva also con-
tains the enzyme lysozyme that acts on the cell walls of The basal rate of secretion of saliva is very low during
certain bacteria, including some streptococci, causing sleep; approximately 0.05 mL/min. In the resting, awake
lysis and death. However, most organisms that colonize state it increases to about 0.5 mL/min that is just enough

THE digestive SYSTEM 31

2
to keep the mouth moist. During the course of the day Capillary bed
The mouth, salivary glands and oesophagus

1–2 L of saliva are secreted. Most of it is swallowed. The

proteins in saliva are broken down in the gastrointestinal
tract by digestive enzymes. The amino acids and pep-
tides produced, together with the water and ions, are
re-absorbed across the walls of the intestines.
Efferent
Figure 2.15 is a simplified representation of a sali- arteriole
vary secretory unit (a salivon) that consists of an acinus Venule
and a duct. The blood flows first past the duct and then
past the acinus. The blood supply constitutes a portal
system, because substances reabsorbed from the duct Na+ K+ Acinus
cells into the blood capillaries surrounding the duct are Cl– HCO3– (primary secretion)
transported to the capillaries surrounding the acinus via
an efferent arteriole, prior to being returned to the heart
via the veins. The acinar cells secrete the primary saliva
that passes down the ducts. The primary secretion con-
sists of an ultrafiltrate of plasma to which some compo-
nents synthesized by the acinar cells (such as -amylase
and mucins) have been added. It is therefore almost iso- Duct
tonic with plasma. The rates of secretion of the primary Capillary (secondary
+
juice and the -amylase concentration vary with the type bed Na modification)
of stimulation, but the ionic composition of the primary K+
juice is fairly constant. The main ionic constituents of pri- Cl–
mary saliva are Na, K, Cl and HCO3. HCO3–
Afferent
As the primary juice flows past the duct cells it under- arteriole
goes secondary modification via transport systems in
the membranes of the secretory and striated duct cells.
Certain substances are produced by the duct cells and
secreted into the saliva and others are extracted from
the saliva by the cells. Na and Cl are extracted from Fig. 2.15  Secretion of primary saliva in the acinus of a salivary gland,
the saliva and K is added to it. In fact Na and K are and secondary modification in the duct.
exchanged by an active mechanism in the duct cells.
However, more Na is extracted than K is added by
this mechanism, and the duct epithelium has a very low ions increase with rate of flow until a plateau is reached,
permeability to water. Consequently secondary saliva whilst the concentration of K ions decreases to reach a
becomes more hypotonic as it flows down the ducts and plateau at low flow rates. Na is exchanged for K, but
in the human, saliva is always hypotonic compared to the Na: K exchange ratio is 3:1. It is only at low flow
plasma. The tonicity is higher at high flow rates. rates that the active transport processes for these ions
The HCO3 in saliva is produced from CO2 and water in the ducts makes a measurable difference to their con-
in the duct cells via the reactions: centrations in the saliva. At maximum rates of flow the
tonicity of human saliva is approximately 70% of that of
carbonic anhydrase plasma. The ducts extract more ions than they deliver to
CO2 + H2O H2CO3 H+ the saliva, and the osmotic gradient is therefore in the
+ HCO3– direction of the plasma, but the ducts are relatively imper-
meable to water and so the saliva is always hypotonic to
plasma. Table 2.1 compares the ionic composition of pri-
The duct cells are rich in carbonic anhydrase, an mary saliva produced in the acinus, secondary saliva pro-
enzyme which catalyses the formation of carbonic acid duced at a low flow rate (unstimulated), and secondary
from CO2 and water. HCO3 is secreted across the mem- saliva produced at a high flow rate (stimulated).
branes into the ducts in exchange for Cl (Fig. 2.15). The pH of resting human saliva is only slightly alka-
The composition of saliva changes with rate of line, and its HCO3 concentration is lower than that of
flow because at fast flow rates there is less time for the the primary juice. The reasons are unclear. However,
exchange processes occurring in the ducts to modify the it becomes more alkaline with increasing rate of flow as
composition. Thus at high flow rates the composition the concentration of HCO3 ions increases. At maximum
approaches that of the primary juice. Figure 2.16 shows rates of flow the pH may reach a value of 8.0 and the
the changes in the concentration of some ions in the HCO3 concentration is higher than that of the primary
saliva flowing from the ducts, with the rate of flow, and juice (Table 2.1). At high rates of flow the secretion of
compares them with the concentration of those ions in HCO3 is stimulated. As it is removed from the cell more
the plasma. The concentrations of Na ions and HCO3 is produced by the intracellular mechanism.

32 SYSTEMS OF THE BODY

 2
and sympathetic nerves. The postganglionic sympathetic

The mouth, salivary glands and oesophagus

A B nerve fibres have their cell bodies in the superior cervical
160 Saliva Na+ Plasma ganglion. The preganglionic parasympathetic nerve fibres
(143) travel in branches of the facial (cranial nerve VII) and the
–
glossopharyngeal (cranial nerve XI) nerves. These synapse
Concentration (mmol/L)

120 Cl with postganglionic fibres in or near the glands. There is

(101)
Na+ a parasympathetic innervation of all acini and most usu-
80 HCO3– ally also have a sympathetic innervation. Several nerve
fibres supply each acinus but not every cell is innervated.
– HCO3
– However, the acinar cells are electrically coupled so that
40 Cl
(27) the membrane depolarization brought about by nerve
K+ impulses in the innervated cells is transmitted to the neigh-
K+ (4)
0 bouring cells. Myoepithelial cells in the vicinity of the acini
are innervated by the same nerve fibres. The duct cells and
0 1 2 3 4 the myoepithelial cells and the arterioles of the gland, are
Rate of flow (ml/min) also innervated by both parasympathetic and sympathetic
Fig. 2.16  (A) Changes in concentration of some ions in saliva with nerves.
rate of flow. (B) Concentrations of the same ions in blood plasma. Nerve stimulation increases changes in both the com-
position and the volume of the secretion. Simulation of
either the parasympathetic nerves or the sympathetic
nerves increases the rate of secretion. However, the para-
Table 2.1  Concentrations of some important constituents in sympathetic nerves provide a stronger and longer lasting
primary and secondary saliva stimulus. If the parasympathetic supply is interrupted
the glands atrophy, but interruption of the sympathetic
Ions (mmol/L) Primary Secondary saliva nervous supply causes no major defect in salivary secre-
saliva
tion. The parasympathetic nerves release acetylcholine,
substance P and vasoactive intestinal peptide (VIP),
Unstimulated Stimulated
while the sympathetic nerves release noradrenaline.
The processes which are stimulated by parasympa-
Na 145 2 85
thetic nerve activity include the flow of saliva, the release
K 4 25 18 of -amylase and mucins from the acinar cells, trans-
Cl 100 23 55 port events in the duct cells, the extrusion of the saliva
HCO3 
24 4 40 from the ducts, the blood flow, and the metabolism
-amylase 0.1 1.0 and growth of the acinar and duct cells. Stimulation of
(g/L) the sympathetic nerves is a transient effect causing the
release of saliva rich in -amylase, mucins, HCO3 and
Flow rate 0.5 3.5
(mL/min)
K, and contraction of the myoepithelial cells. It also
causes vasoconstriction that reduces the blood flow to
The ionic composition of the primary juice is similar to that the glands. This effect may be exaggerated when an indi-
of blood plasma. The differences in ionic compositions of the vidual is frightened and may explain why some people
primary and secondary salivas are due to the modifications experience a dry mouth when they are afraid. Circulating
that take place as the saliva flows down the ducts. Thus Na catecholamines reinforce the effect of sympathetic nerve
is extracted and K is added in the ducts. HCO3 secretion is stimulation. Acinar cell membranes have both - and
stimulated at high rates of flow. The fate of Cl is complex; it -adrenergic receptors. Other hormones are not a major
is exchanged for HCO3, and is transported down the electrical
influence in the control of secretion of saliva, although
gradient created by the transport of Na. In stimulated saliva
there is less time for such modifications to take place, as the
both vasopressin and aldosterone can stimulate Na/K
flow rate is faster. The composition of the stimulated secondary exchange in the duct dells.
juice is therefore intermediate between that of the primary juice
and the unstimulated secondary juice. The concentration of
Cellular mechanisms of control
-amylase is higher at high flow rates as its secretion from the
acinar cells is stimulated. The acinar cells of the resting glands contain granules.
These can be stained histologically. They are the locus
of storage of the zymogen precursor of -amylase. If
the gland is stimulated, the number of granules dimin-
Control of secretion ishes as the enzyme is released. The formation of new
enzyme occurs rapidly in the acinar cell after stimulation,
In the human, the secretion of saliva is mainly in response although it is the release, by exocytosis, not the synthesis,
to nerve stimulation. The efferent control is via autonomic that is directly stimulated by the transmitter. It has been
nerves. The glands are innervated by both parasympathetic shown that after stimulation of the rat submandibular

THE digestive SYSTEM 33

2
gland by feeding or by injection of acetylcholine, the con- glands. Two reflexes are involved: a conditioned reflex
The mouth, salivary glands and oesophagus

tent of -amylase increases 10-fold. and an unconditioned reflex.

The second messengers involved in the actions of the The conditioned reflex is due mainly to the sight
neurotransmitters on acinar cells are intracellular cAMP and smell of food, although other sensory inputs such
and Ca2. Activation of either -adrenergic receptors or as sounds can trigger it. The reflex was first studied in
VIP receptors causes an increase in intracellular cAMP, dogs by Pavlov, a Russian physiologist who worked in
while activation of -adrenergic receptors, muscarinic St Petersburg. He usually fed the dogs at a time when the
acetylcholine receptors or substance P receptors results bells of the cathedral chimed. He discovered that they sali-
in increased Ca2 influx into the cell. Substances that vated when the bells chimed even on occasions when they
increase intracellular cAMP tend to produce a secretion
that is richer in -amylase than those that increase intra-
cellular Ca2 concentration, whilst those that increase
intracellular Ca2 concentration tend to produce a greater
increase in the volume of acinar cell secretion. Mucins are
also released by exocytosis as a consequence of influx of Acinar cell Kallikreins
Ca2 into the cell. (proteases) Cell membrane

Blood flow
When the parasympathetic nerves are stimulated there is Kallikreins
a rapid vasodilatation that can result in up to a five-fold Bradykininogen Bradykinin + peptide
increase in blood flow. This is followed by a slower vasodila- (vasodilator)
tory effect. The immediate effect is probably due to a direct
action of the transmitters acetylcholine and VIP released
from parasympathetic nerve fibres that end on the arterioles Bradykininogen Blood
in the glandular tissue. The two transmitters are probably
released from the same nerve terminals. Stimulation of the Fig. 2.17  Mechanism of vasodilation during stimulation of salivary
sympathetic nerves causes vasoconstriction via the release secretion.
of noradrenaline that acts on -adrenergic receptors on the
arteriolar smooth muscle.
The slower vasodilatory effect is an indirect consequence
of stimulation of the parasympathetics. It is due to the for-
Case
mation of vasodilator metabolites, mainly bradykinin,
2.1 Xerostomia: 4
by processes occurring following stimulation of the aci-
nar cells that results in the release of proteolytic enzymes Treatment and side-effects
known as kallikreins, into the interstitial fluid. These The treatment of xerostomia depends on whether the
enzymes catalyse the conversion of a precursor, bradyki- patient can secrete saliva in response to a stimulus, i.e.
ninogen, to bradykinin, the active vasodilator (Fig. 2.17). whether he or she is a ‘responder’ who has functioning
Bradykinin acts on the arteriolar smooth muscle to salivary gland epithelium, or a ‘non-responder’ who does
cause vasodilatation. When the arterioles dilate the pres- not. Artificial salivas can be used in non-responders, but
sure drop across them diminishes and the pressure is these are not wholly satisfactory. Low doses of pilocarpine
transferred to the capillaries. The increased hydrostatic are often used to treat the condition in individuals with
pressure and consequent increased transcapillary pres- residual salivary function. This drug is a partial agonist of
sure result in increased filtration in the gland. The con- muscarinic acetylcholine receptors. It mimics the effect of
sequence is an increased flow of saliva. Furthermore stimulation of the parasympathetic nerves, causing the aci-
saliva can actually be secreted at a pressure higher than nar cells to secrete saliva and kallikreins, which in turn cause
the arterial pressure to the gland, as the triggering of vasodilatation via bradykinin and hence increased secre-
active processes at the luminal surface of the gland by tion. However, systemic parasympathetic side-effects can
the parasympathetic nerves causes secondary water occur, including bradycardia and decreased cardiac output,
transport. Xerostomia can be treated by administration of increased sweating and increased gut motility. If the dry
pilocarpine, a partial cholinergic agonist that mimics the mouth is a consequence of treatment with other medica-
effect of stimulation of the parasympathetics (see Box 6). tion, it is unwise to prescribe pilocarpine to treat the xero-
stomia. In these circumstances the possibility of treatment
of the primary condition with an alternative drug that does
Control of secretion by food
not cause dry mouth should be explored. However, pilo-
Saliva is secreted in response to the approach of food, carpine is often prescribed to treat xerostomia that occurs
and to the presence of food in the mouth. The effect is as a consequence of radiotherapy, although the side-effects
mediated via the parasympathetic nerves. Up to 50% can lead to its use being discontinued.
of the secretion during a meal comes from the parotid

34 SYSTEMS OF THE BODY

 2
were not being fed, presumably in anticipation. Thus the oesophagus contain smooth muscle. The top-third con-

The mouth, salivary glands and oesophagus

conditioned reflex is a learned response because the first tains skeletal muscle. The muscle tissue in an area in the
time the stimulus is presented it does not elicit a secretion. middle of the oesophagus consists of a mixture of skel-
The unconditioned reflex is due to the presence of food etal muscle and smooth muscle fibres, the skeletal muscle
in the mouth. It occurs in response to activation of touch gradually being replaced by smooth muscle in the caudad
or taste receptors. Stimulation by food of taste receptors direction. Both the skeletal muscle fibres and the smooth
on the tongue, or pressure receptors in the mouth, results muscle fibres are under the control of the vagus nerve.
in impulses being set up in the afferent nerves to the The skeletal muscle is innervated directly by somatic
brainstem. Figure 2.8 shows the arrangement of the neu- motor neurones from the nucleus ambigus, whilst the
ral pathways of the secretory reflex that occurs following smooth muscle is innervated indirectly by neurones in the
stimulation of the taste buds. This involves afferent path- vagus nerve that synapse with neurones in the myenteric
ways from the tongue to the superior and inferior sali- plexus. The intrinsic nerves are in effect postganglionic
vary nuclei. The afferent nerve fibres run in the chorda autonomic nerves. Preganglionic parasympathetic neu-
tympani and the glossopharyngeal nerves (see above). rones in the vagus nerve from the dorsal motor nucleus
The efferent preganglionic parasympathetic nerves to the synapse with the cell bodies of these neurones.
salivary glands also run in these nerves. The pregangli- The upper oesophageal sphincter (the hypopharyn-
onic fibres in the glossopharyngeal nerve synapse with geal sphincter or cricopharyngeus muscle) is composed
postganglionic fibres in the otic ganglion and the post- of skeletal muscle. It is a thickening of the circular muscle
ganglionic fibres innervate the parotid glands. The pre- layer. The lower sphincter comprises the last 1–2 cm of
ganglionic fibres in the chorda tympani synapse with the oesophagus. It is not anatomically distinguishable as
postganglionic fibres in the submandibular ganglion and a discrete sphincter but the pressure is normally greater
the postganglionic fibres innervate the submandibular in this region than in the stomach.
and the sublingual glands.
The precise role of the sympathetic nerves in stimulat- Swallowing (deglutition)
ing saliva secretion in different physiological states is still
unclear. The arrangement of the structures associated with swal-
lowing is shown in Figure 2.4. The events involved are
represented in Figure 2.18. The whole process lasts only a
Oesophagus few seconds. It is initiated voluntarily but once initiated
it cannot be stopped voluntarily, i.e. it becomes a classical
Anatomical arrangements of the oesophagus ‘all or none’ reflex. The process can be divided into three
phases: voluntary, pharyngeal, and oesophageal.
The structures associated with the oesophagus are shown
in Figures 2.4, 2.18 and 2.21. The arrangement of the Phases of swallowing
smooth muscle in the wall of the oesophagus is similar
to that of the rest of the gastrointestinal tract in that there Voluntary phase
is an inner circular layer and an outer longitudinal layer In the voluntary phase, the tongue separates the food
(see Ch. 1). However, only the lower two-thirds of the into a bolus and then moves it backwards and upwards

Palate
Pharynx

Food bolus Epiglottis

Tongue

Glottis
Upper
oesophageal
Oesophagus
sphincter
Trachea

A B C D

Fig. 2.18  (A–D) Sequential events involved in swallowing.

THE digestive SYSTEM 35

2
towards the back of the mouth. The lubricating properties Oesophageal phase
The mouth, salivary glands and oesophagus

of saliva are important for swallowing and individuals

The food is moved along the oesophagus by peristal-
suffering from xerostomia have difficulty in swallowing
sis. A peristaltic wave consists of a wave of contraction
(see Box 4).
of the circular muscle, followed by a wave of relaxation.
The wave of contraction passes along the walls of the
Pharyngeal phase oesophagus and moves the food towards the stomach
As the bolus of food moves into the pharynx, it activates (Fig. 2.20). The wave of contraction takes about 9 s to
pressure receptors in the palate and anterior pharynx. travel the length of the oesophagus. The progression of
This results in impulses in the trigeminal and glossopha- the wave is controlled by autonomic nerves and is coor-
ryngeal nerves being transmitted to the swallowing cen- dinated by the swallowing centre in the medulla. Thus
tre in the brainstem. Each impulse serves as a trigger for it is not primarily gravity, but peristalsis that causes the
the swallowing reflex. This causes the elevation of the food to move towards the stomach, although gravity
soft palate that seals the nasal cavity and prevents food assists the process. The importance of peristalsis to the
from entering it. The swallowing centre inhibits respira- process compared to that of gravity is seen by the fact
tion, raises the larynx, and closes the glottis (the opening that food can be swallowed and it will reach the stom-
between the vocal chords). This prevents food from get- ach even in someone who is upside down. It is notewor-
ting into the trachea. As the tongue forces the food further thy that in other parts of the gastrointestinal tract the
back into the pharynx, the bolus tilts the epiglottis back- peristaltic waves are coordinated largely by the internal
wards to cover the closed glottis. It is closure of the glot- nerve plexi and the extrinsic nerves are less important,
tis, however, not the tilting of the epiglottis that is mainly and can be sectioned without gastrointestinal function
responsible for preventing food from entering the trachea. being dramatically affected.
The upper oesophageal sphincter is closed at rest. It As the peristaltic waves begin in the oesophagus, the
opens during swallowing, allowing the bolus of food to muscle of the lower oesophageal sphincter relaxes, opening
pass into the oesophagus. Immediately after the bolus has the sphincter and allowing the food bolus to enter the stom-
passed, it closes again, resealing the junction. The glottis ach. The sphincter muscle then contracts and reseals the
then opens and breathing resumes. The skeletal muscle junction. It remains closed in the absence of peristalsis, pre-
fibres of the upper oesophageal sphincter are so arranged venting reflux of the stomach’s contents. Figure 2.21 shows
that they contract when the sphincter opens and relax the pressure changes in different regions of the oesophagus
when it closes. This pharyngeal phase of swallowing lasts during swallowing.
approximately 1 s. The relationship between the oesopha-
gus and other thoracic structures is shown in Figure 2.19.
Control of swallowing
Swallowing is coordinated by the ‘swallowing centre’
in the medulla oblongata. It involves efferent impulses
from the medulla to 25 different skeletal muscles of the
pharynx, the larynx, and the early oesophagus and the
smooth muscles in the lower oesophagus.

Control of motility in the oesophagus

Swallowed food is propelled along the oesophagus to the
stomach by the coordinated contraction of the muscle in
the body of the oesophagus. This wave of contraction is
due to a sequential activation of the muscles in the phar-
ynx and oesophagus by neural impulses in the segmental
efferent neurones of the vagus nerve that utilize acetyl-
choline as the neurotransmitter (Fig. 2.22).
The smooth muscle of the lower sphincter is innervated
by both extrinsic and intrinsic nerves. Impulses in the
cholinergic nerve fibres in the vagus are partly respon-
sible for the maintained contraction of the muscle, i.e. its
tone, when peristaltic activity is absent in the oesopha-
gus. Stimulation of noradrenergic sympathetic nerves
also causes contraction via activation of -adrenergic
L T O A receptors. However, if the extrinsic nerves are cut there
Fig. 2.19  A cross-section CT scan of the mid-thorax showing the is still some tone indicating that the intrinsic nerves are
anatomical relationship of the lungs (L), aortic arch (A), overlying the also important. An increase in the blood concentration of
trachea (T), and the oesophagus (O). gastrin that is released from the stomach (see Ch. 4) can

36 SYSTEMS OF THE BODY

 2

The mouth, salivary glands and oesophagus

mmHg Swallow
Pharynx 60
30
Upper 0
oesophageal
sphincter
60
Junction 30
of striated 0
and smooth 100
muscle 50
0
100
Body of
oesophagus 0

100

Lower 0
oesophageal
sphincter 60
30
0

0 5 10 15 20 25
Time (seconds)

Fig. 2.21  Sequential pressure changes in different regions of the

oesophagus during swallowing.

Myenteric Swallowing
nerve centre
plexus

Lumen of Striated
oesophagus muscle

Vagus nerve

Smooth
muscle

Circular Longitudinal
muscle muscle
layer layer

Fig. 2.22  Segmental innervation of the skeletal and smooth muscle

of the oesophagus. Somatic motor neurones in the vagus nerve
innervate the skeletal muscle directly. Autonomic nerve fibres in the
Oesophagus Gastro oesophageal vagus innervate the smooth muscle indirectly via the intrinsic nerves
junction in the myenteric plexus. Note: The transition from skeletal muscle to
smooth muscle in a region approximately one-third of the way down
Fig. 2.20  An X-ray of the oesophagus taken after swallowing barium, the oesophagus is gradual.
showing a normal peristaltic wave.

THE digestive SYSTEM 37

2
also increase the tone of the sphincter muscle. This mech-
The mouth, salivary glands and oesophagus

Diffuse oesophageal spasm: a common condition in which

anism may be important in preventing reflux of stom-
prolonged contraction of the lower oesophagus occurs
ach contents into the oesophagus whilst the stomach is
after swallowing (instead of a normal peristaltic wave). The
contracting. If the sphincter is incompetent, the reflux of
aetiology of this condition is not known, but thickening of
stomach contents may damage the mucosa (Box 7).
the smooth muscle of the oesophagus has been observed in
Relaxation of the lower oesophageal sphincter is
many patients.
caused by impulses in inhibitory nerve fibres that
Reflux oesophagitis: gastric contents are refluxed into the
innervate the circular smooth muscle. The transmit-
oesophagus thus causing ‘heartburn’. This may be accompa-
ters involved may be VIP and nitric oxide. A decrease
nied by inflammation of the oesophagus. It is exacerbated
in cholinergic impulses also promotes relaxation of the
by increased intra-abdominal pressure. Simple measures,
sphincter.
such as weight loss and raising the head during sleep can
Motor disease of the oesophagus can be due to dis-
prevent episodes of heartburn, which are often worse dur-
orders of the skeletal muscle or disorders of the smooth
ing the night in susceptible individuals. It is usually treated
muscle. The various conditions are described in Box 7.
by administration of a proton pump inhibitor to inhibit acid
secretion in the stomach (see Ch. 4). In many cases, reflux
is due to dysfunction of the lower oesophageal sphincter.
Box 2.1  Clinical conditions associated with the If the oesophageal sphincter is incompetent passive reflux
of stomach acid into the oesophagus can result in damage
oesophagus
to the unprotected oesophageal mucosa. An incompetent
sphincter can be repaired surgically by wrapping the stom-
Disorders affecting skeletal muscle ach around the lower oesophagus within the abdominal
In primary diseases of skeletal musculature (e.g. myasthe- cavity (known as a stomach wrap). This effectively creates a
nia gravis, myotonic dystrophy), or primary disease of the one-way valve thereby preventing reflux of the gastric con-
nervous system involving the somatic motor nerves (e.g. tents into the oesophagus, but can also prevent the process
amyotrophic lateral sclerosis or poliomyelitis), the striated of vomiting by not allowing opening of the lower oesopha-
muscles affected include: geal sphincter.

• The tongue
• Pharynx
• Upper oesophageal sphincter
• Wall of the upper oesophagus.

Difficulties in swallowing (dysphagia) are experienced and

there is loss of propulsive force of the upper oesophagus.
Following a stroke, lesions in the brainstem can interfere
with the coordination of the movements of the tongue and
pharynx.

Disorders affecting smooth muscle

Cricopharyngeal spasm: characterized by swallowing diffi-
culty, can be due to increased fibrosis of the cricopharyn-
geal muscle.
Achalasia (cardiospasm): a common condition caused by
defective relaxation of the lower sphincter that impedes
the flow of material into the stomach, and an abnormal-
ity of the function of the smooth muscle in the lower
two-thirds of the oesophagus whereby the coordinated
control of peristalsis is lost. These defects are due to defec-
tive innervation of the smooth muscle of the body of the
oesophagus and the lower oesophageal sphincter.
Chaga’s disease: prevalent in Latin America and caused
by infection with the parasite Trypanosoma cruzi that
destroys ganglion cells in the myenteric plexus, can be char-
acterized by similar problems to those seen in achalasia,
although defects in the function of the colon are probably
more common in this condition (see Ch. 10).

38 SYSTEMS OF THE BODY

The stomach: basic
functions 3
Chapter objectives
After studying this chapter you should be able to:

1. Understand the relationship between the structure of the stomach

and its function in the process of digestion.

2. Understand the secretory processes of the stomach mucosa and

how dysfunction may influence digestion, absorption and body
homeostasis in terms of:

a. Acid–base balance

b. Red blood cell formation in the bone marrow.

3. Understand the protective functions of the stomach including those

relating to:

a. Mucosal structure and secretion

b. Acid and pepsin secretion.

4. Understand the importance of stomach smooth muscle function in:

a. The storage of food

b. Mixing the food with the digestive secretions

c. The regulation of the entry of the stomach contents into the small
intestine.

5. Understand the process of vomiting.

3
basic functions of the stomach

Introduction Case
3.1 Gastrectomy: 1
The primary function of the stomach is to store the food
ingested during a meal and to regulate its release into the A 72-year-old man complained to his general practitioner
duodenum. Its other functions are to churn and mix the that he had recently started to feel tired and listless. He also
food with the gastric secretions producing a thick mix- complained of longstanding symptoms of dizziness, sweating
ture known as ‘chyme’. In addition it has a range of exo- and palpitations after meals. Eight years previously, he had
crine, paracrine and endocrine functions. The exocrine undergone a partial (proximal) gastrectomy that involved
secretions, which are released into the stomach lumen are removal of most of the body and fundus of the stomach. At
digestive juices, collectively known as gastric juice. The first, he had felt reasonably well but in the past 2 years he
major paracrine secretion is histamine, a substance that had become forgetful and had neglected to attend for his
stimulates gastric acid secretion. The major endocrine medication – vitamin B12 injections. The doctor told him that
secretion is the hormone gastrin, which acts both locally he should start the medication again, and should also try to
on the stomach smooth muscle and mucosa to stimulate regulate his food intake more carefully by eating smaller, but
gastric motility and acid secretion, and distally on the more frequent meals, as his symptoms were partly due to the
intestines, pancreas and liver. rapid entry of large amounts of material into the small intes-
In this chapter, the secretory and emptying func- tine. The doctor also sent him for a blood test. The patient
tions of the stomach will be considered in the light of a was found to be suffering from megaloblastic anaemia, and
clinical problem concerning the consequences of partial mild metabolic acidosis. His blood vitamin B12 level was low
gastrectomy, a condition in which these functions are and he was found to be mildly iron-deficient.
compromised (Case 3.1: 1). Another clinical problem, the Note: The consequences of partial surgical resection of
consequences of excessive vomiting, is also used to high- the stomach depend on the part being removed. Removal
light the importance of the stomach for homeostasis. The of the upper part of the stomach (body and fundus), as
control of stomach functions is the subject of Chapter 4. in this patient, will remove the majority of the oxyntic
cells, whereas resection of the lower part, the antrum and
pylorus, will remove most of the G cells.
Anatomy and morphology of the stomach It can be inferred from studying the details of this case
that a good quality of life can be maintained after such a
The stomach is a storage sac located between the oesopha- partial gastrectomy if:
gus and the duodenum. Figure 3.1 indicates the major fea-
tures of the stomach. It consists of three regions: the fundus, l The development of pernicious anaemia is prevented
which is the upper region; the main body; and the antrum. l The development of iron-deficiency anaemia is
Folds, known as rugae, are present on the inner surface prevented
l Food intake is carefully regulated.
of the empty stomach. The rugae can be clearly seen in
Figure 3.2 which shows an X-ray of a stomach. The rugae
flatten out as the stomach fills. A rare condition known as We can also infer that the digestive functions of the stom-
Ménétrièr’s disease is characterized by giant gastric folds ach are not essential for life.
due to hypertrophy of the gastric epithelium (Box 3.1).
The wall of the stomach consists of various layers of
tissue (Fig. 3.3). The inner lining is known as the mucosa.
It comprises the lamina propria and the gastric glands tissue from erosion by acid. In addition, the columnar
(or pits). Beneath this lie the submucosa, the muscularis cells secrete mucus and alkaline fluid to further protect
mucosae and the serosa which is covered by the perito- the gastric mucosa from injury. The mechanisms of dam-
neum. The wall structure of the stomach is similar to that age to the mucosal barrier are discussed in Chapter 4.
present throughout the rest of the gastrointestinal tract Numerous gastric pits (approximately 3.5 million in the
(see Ch. 1), except that the stomach has an oblique mus- human) penetrate the surface. These are short ducts into
cle layer in addition to the circular and longitudinal layers which the more deeply lying gastric glands empty their
in the muscularis mucosae. This facilitates distension of secretions. The secretions enter the main compartment of
the stomach and the storage of food. The muscle layers are the stomach via the necks of these ducts.
not evenly distributed over the wall of the stomach. The The stomach is separated from the duodenal bulb by
external circular muscle layer is relatively thin in the fun- the pyloric sphincter. Figure 3.1B shows the main struc-
dus and body, and thick in the antrum, where strong mus- tural features of the pylorus. It is not an anatomically dis-
cular contractions aid the mixing of food. In addition, it is crete sphincter but a development of the circular smooth
highly developed in the pylorus where it becomes a func- muscle layer. A ring of connective tissue separates the
tional sphincter that regulates stomach emptying. pylorus from the duodenum, enabling the contractions of
The lining of the stomach is covered with a protec- the two regions to be independent. However, the myen-
tive layer of columnar epithelial cells. These have well teric nerve plexi of the pylorus and duodenum are con-
developed tight junctions to protect the underlying tinuous (see Ch. 7).

40 SYSTEMS OF THE BODY

 3
Oesophagus

basic functions of the stomach

Secretory mucosa of the stomach
Fundus
Cardiac orifice
The secretory mucosa of the stomach can be considered
Incisura angularis
Pyloric as two separate regions (Fig. 3.1): the upper region com-
orifice Lesser prising the fundus and the body of the stomach, known
Pyloric curvature as the oxyntic glandular area, and the lower antral and
sphincter
pyloric region which secretes the hormone gastrin.
The secretory cells of the oxyntic glandular area pro-
duce most of the exocrine digestive juice known as gas-
tric juice. The major secretory cells present in this area
are oxyntic (or parietal) cells that secrete acid and intrin-
Duodenum
Body sic factor, and chief (or peptic) cells that secrete pepsino-
Antrum Greater gen, the precursor of the proteolytic enzyme pepsin. The
Sulcus curvature stomach also contains enterochromaffin (ECL)-like cells
intermedius Rugae that secrete histamine, and D cells which secrete soma-
A Longitudinal tostatin. The gastrin-secreting cells, G cells, are restricted
Circular
muscle largely to the antral region. The secretions of these cells
Duodenum muscle are involved in the control of many digestive functions
Tarsus including gastric secretion and motility (see Ch. 4).
Rings of
connective
tissue
Antrum Histology

The oxyntic cells and chief cells are located in deeper

Pyloric regions of the pits as are the endocrine cells. Mucus-
canal secreting cells are located in the neck region providing
a protective barrier to the deeper lying secretory cells.
Distal Intermediate The location of endocrine cells in the deeper aspect of the
B sphincter sphincter gastric pits facilitates uptake of their secreted granules by
Fig. 3.1  (A) The main anatomical features of the stomach. The
the underlying capillaries (Fig. 3.4).
diagonal line shows the approximate division of the stomach into Figure 3.5 shows the three major exocrine cell types
the two secretory regions; the oxyntic secretory area consisting of that produce secretions that enter the lumen of the stom-
the fundus and the body, and the pyloric secretory area consisting ach. These cells are all specialized in various ways to per-
of the pyloric antrum. (B) The structural features of the pylorus. form their secretory function. The oxyntic cell has a vast

Oesophagus

Pyloris

Fig. 3.2  An X-ray of the stomach taken after ingestion of barium. The thick mucosal folds (F) are clearly shown.

THE digestive SYSTEM 41

3
Box 3.1  Ménétrièr’s disease
basic functions of the stomach

Canaliculi
Ménétrièr’s disease is a condition characterized by hypertro-
phy of the gastric epithelium that results in the secretion of
abnormally large amounts of mucus, and loss of plasma pro-
teins. This dangerous loss of protein can lead to reduction in Microvilli
the extracellular fluid volume, shock and dehydration. It can
be treated by antisecretory drugs or enteral protein replace-
ment, but these measures are not usually very effective. A
Mitochondria
Basement lamina

Opening of
gastric pit
Zymogen granules
Lamina propria (pepsinogen)
Gastric pits Mucosa

Rough
endoplasmic
Muscularis Submucosa reticulum
mucosae B

Blood vessels Muscularis

mucosae
Oblique
muscle layer Serosa
Mucus granules
Circular
muscle layer
Longitudinal Peritoneum
muscle layer
Connective tissue Golgi complex
Fig. 3.3  Structure of the gastric mucosa.

C
Stomach lumen
Fig. 3.5  Schematic diagrams of the three major types of exocrine
secretory cell in the gastric mucosa (A) oxyntic cell, (B) chief cell, (C)
Epithelial cells mucus (goblet) cell. Note that each cell type has characteristic features
associated with specialization for secretion.

Mucous neck cells microvilli, and these provide a large surface area for
transport of secreted substances (see Ch. 1). When the
cell is actively secreting, the canaliculi enlarge, as they fill
Endocrine Oxyntic cells
with secreted juice. These cells are also rich in mitochon-
cells dria that provide the energy in the form of ATP required
for the secretory process.
Chief cells The chief cell is specialized for the secretion of enzyme
protein. It contains an extensive network of rough
endoplasmic reticulum, the site of protein synthesis.
Numerous dense zymogen granules, the loci of storage
Fig. 3.4  Locations of different cell types in a gastric pit. of the enzyme precursor protein, are located towards the
luminal side of the cell.
The mucous cell also has a fairly extensive network
surface area enabling it to produce large amounts of secre- of endoplasmic reticulum, and a prominent Golgi com-
tion. Invaginations of the luminal cell membrane form plex, a characteristic of cells which are specialized for the
canaliculi (tubular passages) that penetrate deep into secretion of glycoproteins, in this case mucins. This cell
the cell. The canaliculi open on to the cell’s free surface. contains numerous clear vesicles which are the sites of
They are lined with finger-like processes, known as storage of mucins.

42 SYSTEMS OF THE BODY

 3
Absence of HCl secretion (achlorhydria) is seen when

basic functions of the stomach

200
the gastric pits are destroyed. It is usually associated
Cl– with lack of intrinsic factor that results in vitamin B12
H+ deficiency and pernicious anaemia (see below). However,
Concentration (mM)

when loss of HCl secretory capacity occurs, the first

100
clinical manifestation is usually iron-deficiency anae-
mia because lack of acid results in ingested iron being
retained in an unabsorbable form (see Case 3.1: 5).

K+
0 Na+ Cellular mechanisms of secretion
0 1 2 3
Rate of flow (mL/min) Secretions of the oxyntic cell
Fig. 3.6  Variation in the ionic composition of gastric juice with
rate of flow.
Hydrochloric acid
The secretion of H and Cl ions by the stomach are
both active processes. The energy is derived from the
hydrolysis of ATP. The H ions are transported against
Composition of gastric juice an enormous concentration gradient: the concentration
of H ions in the blood is approximately 108 M while
The adult human secretes approximately 2 L of gastric juice the concentration in the stomach lumen can be as high as
per day. When a meal is being eaten, soluble substances in 1.5  101 M.
the food material stimulate the secretion of gastric juice. The mechanism whereby the H ions are generated
The stomach produces two different secretions: an acid within the cell is outlined in Figure 3.7. Carbon dioxide
secretion known as parietal juice which is released from diffuses into the cell from the plasma. Inside the cell it
the oxyntic (parietal) cells, and an alkaline juice released combines with water to form carbonic acid. This reac-
from the mucous cells. Gastric juice is isotonic with plasma tion is catalysed by the enzyme carbonic anhydrase. The
but the concentrations of its various constituents vary with carbonic acid dissociates to give H and HCO3 ions.
the rate of flow: the higher the rate the greater the acidity. The HCO3 ions are transported into the blood, down
During a meal therefore, the chyme becomes more acid; a concentration gradient, in exchange for Cl ions. The
the acidity can reach pH 2.0. Maximum acid secretion can secretion of HCO3 ions into the blood when the stom-
be induced by injection of histamine. Figure 3.6 shows the ach is secreting acid into the lumen results in the plasma
changes in concentration of some of the constituent ions becoming transiently alkaline. This phenomenon is
in an individual in whom secretion was stimulated by known as the ‘alkaline tide’.
injection of histamine. This procedure is used clinically to Hydrogen ion secretion, across the apical surface of
assess the secretory function of the stomach. It is known as the oxyntic cell, into the canaliculus, is accomplished
the Gray and Hollander test after the physicians who first by proton pumps in the membrane of the canaliculus.
developed it in the early twentieth century. More recently, The proton pump, which contains an ATPase, secretes
pentagastrin, a synthetic drug which contains the terminal H ions in exchange for K ions, in a ratio of 1:1. In the
tetrapeptide active site of gastrin, has been used instead unstimulated cell the proton pumps are localized intra-
of histamine, thereby avoiding the side-effects due to the cellularly in tubulovesicles. Upon stimulation of the cell
action of histamine on H1 receptors (e.g. hypertension, to secrete, the vesicles travel to the luminal membrane
dizziness, headache, palpitations). However, intragastric and the vesicle membranes become incorporated into
pH-metry (for 12 or 24 h) has largely superceded the used the plasma membrane, thereby causing a substantial
of gastric secretory tests because this offers more accurate increase in the ‘secretory’ area of the membrane. Drugs
measurement of gastric acidity and is done under more that inhibit the proton pump in the oxyntic cell are used
natural conditions. to treat mucosal disorders such as duodenal ulcers that
The concentration of H ions increases with rate of flow, are potentiated by gastric acid (see Box 3.2 and Ch. 4).
as does that of Cl and K ions, while the concentration of Chloride ions are also secreted against a concentration
Na ions decreases. These changes in composition occur gradient. The concentration of Cl ions in the blood is
because when the stomach is stimulated during a meal it approximately 107 mM whereas in the lumen of the stom-
is only the rate of the acid parietal secretion that increases ach it can reach 170 mM. Chloride is also secreted against
appreciably. The secretion of alkaline fluid is mainly a pas- an electrical gradient, as the apical surface of the resting
sive process and so its rate is relatively unaffected. Thus cell is electronegative (60 to 80 mV) with respect to the
dilution of the chyme by the alkaline juice is therefore less basolateral surface. Na/K coupled pumps are present
at high flow rates and the H and Cl ion concentrations at the basolateral surface. The entry of Cl ions into the
increase. Both acid and alkaline secretions are isotonic cell, down their concentration gradient, at the basolateral
with plasma. surface, occurs in exchange for HCO3 ions (see above

THE digestive SYSTEM 43

3
Box 3.2  Proton pump inhibitors Plasma Stomach lumen
basic functions of the stomach

Drugs that reduce acid secretion in the stomach by inhib- CO2 CO2 + H2O H2O
iting the proton pump are used to treat disorders such as Carbonic K+ K+
duodenal ulcers and reflux oesophagitis that are potenti- anhydrase
ATP
ated by acid (see Chs 3 and 4). Omeprazole, the most com- OH-
H2CO3 H
+
H+
monly used, is a powerful proton pump inhibitor. It is a
weak base which acts by blocking the H/K-ATPase activ- Coupled
HCO3– HCO3- H+ H2O
ity of the proton pump. Omeprazole is inactive at neutral
pH, but it is activated in acid conditions (pH 3.0). Such con- Cl– Cl- Cl–
ditions exist only in the canaliculi of the oxyntic cell. The
action of the drug is therefore restricted to this location in
Fig. 3.7  Hydrochloric acid secretion by the oxyntic cell.
the gastrointestinal tract thereby avoiding the unwanted
side-effects of disruption of Cl ion transport, which could
occur in other organs such as the lungs, pancreas and skin absorbed at a relatively rapid rate (see Ch. 8). Vitamin
(sweating) seen with use of other H transport inhibitors B12 deficiency leads to pernicious anaemia. This condi-
which are active in less acid conditions. The treatment of tion can result from disorders of the stomach mucosa
peptic ulcer disease is discussed in more detail in Chapter 4. that releases intrinsic factor, or from disorders such as
Crohn’s disease that affect the terminal ileum where
vitamin B12 is absorbed (see Ch. 8). The consequence of
and Fig. 3.7). Cl ions are transported across the lumi- vitamin B12 deficiency due to lack of intrinsic factor, after
nal surface via a chloride channel. This channel produces gastrectomy, are discussed in Case 3.1: 3 and the various
net transport of negative charges and operates with- causes of this condition are discussed in Chapter 8.
out the exchange of an anion. Consequently when the
cell is stimulated to secrete, the potential difference falls
(to 30 mV and 50 mV) and the apical surface becomes Role of the stomach in iron absorption
less electronegative. The proton and chloride pumps
on the mucosal surface are coupled in the secreting cell The body’s stores of iron are small and need to be fre-
so that H and Cl ions are secreted in a ratio of 1:1. quently replenished to promote adequate haemoglobin
The coupling mechanism is not yet understood. synthesis and red blood cell function. Iron is absorbed
Acid–base disturbance of the body can follow gastrec- mainly as haem and as the ferrous (Fe2) ion. However,
tomy as the ability to secrete acid is compromised. This Fe2 is oxidized to Fe3 at physiological pH (i.e. pH 7.4).
topic is dealt with in Case 3.1: 2. It can also be a prob- Ferric (Fe3) iron, which is the more abundant dietary
lem in an individual who vomits excessively as may be form of non-haem iron, is absorbed very inefficiently.
the case during chemotherapy. This is because a feedback However, the acid environment in the stomach tends to
mechanism operates whereby if the stomach contents maintain iron in its more soluble and absorbable ferrous
become too acid, secretion is inhibited. If the stomach form. Thus, individuals who take proton pump inhibitors
contents are lost, this feedback mechanism does not oper- such as omeprazole to reduce acid secretion may have a
ate and acid secretion is not regulated in this way. The tendency to develop iron-deficiency anaemia.
consequences of excessive vomiting for the acid–base There is a tendency for Fe2 ions to form insoluble
balance of the body are addressed in Case 3.2: 2 below. complexes with dietary PO43 ions, phytate and oxalate
in the duodenum and jejunum. Fe2 ions are not absorbed
Intrinsic factor when present in these insoluble complexes. However,
if Fe2 is chelated with dietary ascorbate (vitamin C) or
Intrinsic factor is the only substance secreted by the stom- citrate it is kept in an absorbable state. Thus vitamin C
ach that is essential to life. It enables the absorption of or citrate in the diet can protect against iron-deficiency
vitamin B12 (which occurs in the ileum). It is a 55 000 kDa anaemia. Iron-deficiency anaemia following gastrectomy
glycoprotein which complexes with vitamin B12 (cobala- is addressed in Case 3.1: 3.
min). The glycoprotein dimerizes and the dimer binds
two molecules of vitamin B12. The complex is resistant to
digestion. There are four physiologically important forms Secretion of the chief cell
of vitamin B12. These cyanocobalamins bind to protein
in the food, and are released from them by the action of Pepsin, the proteolytic enzyme of the stomach is nor-
acid and pepsin in the stomach. The vitamin is absorbed mally responsible for less than 20% of the protein diges-
inefficiently by passive diffusion in the free, uncom- tion that occurs in the gastrointestinal tract. It is an
plexed state, along the length of the intestine, but a spe- endopeptidase that degrades proteins to peptides. It
cialized absorption mechanism exists in the distal ileum preferentially hydrolyses peptide linkages where one of
whereby vitamin B12 complexed to intrinsic factor can be the amino acids is aromatic. Pepsin, like other protease

44 SYSTEMS OF THE BODY

 3

basic functions of the stomach

Case
3.1 Gastrectomy: 2

Acid–base disturbance
Secretion of acid by the stomach during a meal is accompa-
nied by transport of HCO3 ions into the blood (the alkaline
tide). When the food reaches the duodenum it is mixed with
the alkaline secretions from the pancreas, liver and walls of
the intestines. The cellular mechanisms whereby these alka- Stomach
oxyntic cell
line juices are secreted are in some ways the reverse of those HCO3
–
H2CO3
- +
H
whereby acid is secreted in the stomach (Fig. 3.7). Thus trans-
H2O +
port of HCO3 ions into the glandular ducts of these organs CO2 CO2 + H2O
occurs simultaneously with the transport of an equal number
of H ions into the blood serving these organs. The conse- H2CO3
quent increase in blood H concentration is normally neutral- CO2 + H2O
LUMEN OF
ized by the HCO3 ions of the alkaline tide of the blood from + GASTRO-
BLOOD H H2CO3 HCO3
the stomach. In addition the H ions secreted by the stomach INTESTINAL
Duct cell of
into the lumen are neutralized by the HCO3 ions present pancreas, liver TRACT
in the digestive juices (bile, pancreatic juice and intestinal or intestines

juice) acting in the small intestine (Fig. 3.8). This balance can H2CO3

be upset by gastric resection that restricts acid production. Intestinal cell

Feedback control mechanisms normally regulate the secre- CO2 CO2 CO2 + H2O
tion of H and HCO3 ions to keep the pH values in the gut
lumen within appropriate limits. Many metabolic functions in
the body are extremely sensitive to pH change, and the pH
of body fluids such as plasma, must therefore be maintained
within a very narrow range. Fig. 3.8  Neutralization of acid in the blood and in the
Abnormalities can occur in the acid–base balance of the intestinal lumen.
patient who has undergone partial gastrectomy but the body
usually compensates for these disturbances. After removal of
the stomach, the ‘alkaline’ tide obviously does not occur, but
However, full compensation of the acidosis takes longer and
during a meal H ions are still transported into the blood from
depends on processes in the renal tubules that conserve HCO3
the secreting pancreas, liver and intestines and the blood tends
and secrete acid. In the presence of impaired renal function,
to become acidic. This ‘metabolic’ acidosis can be compensated
the patient’s blood tests would show a low pH, low HCO3 con-
in the short term by the respiratory system that responds with
centration and a low Pco2. In a compensated patient, following
an increase in the rate and depth of breathing. This results in
a meal, acidotic urine would be excreted. A detailed explana-
CO2 being blown off from the blood. The reaction:
tion of the control of acid–base balance can be found in the
H  HCO 3 → H2 CO 3 → CO 2  H2 O companion volumes on the Respiratory and Renal systems.

is consequently driven to the right (the law of mass action) and

the H ion concentration in the blood falls towards ­ normal.

enzymes, is formed from an inactive precursor, pepsino- Pepsinogen is activated in the stomach lumen by
gen, which is stored in granules in the chief cells of the hydrolysis, with the removal of a short peptide:
stomach and released by exocytosis. The synthesis and
exocytosis of the enzyme protein is essentially similar
Pepsinogen pepsin + peptide
to that described for pancreatic enzymes in Chapter 5. H+
(42 500 kDa) (35 000 kDa) (7 500 kDa)
Pepsinogen is also secreted by mucous cells, and cells pepsin
in the glands of Brunner in the duodenum. At least two
immunologically distinct pepsinogens are secreted by H ions are important for pepsin function because:
the stomach, denoted pepsinogens I and II. Pepsinogen I, l Pepsinogen is initially activated by the H ions.
the major pepsin precursor, is secreted by the chief cells
The activated enzyme then acts autocatalytically to
in the oxyntic glandular area, and pepsinogen II by cells
increase the rate of formation of more pepsin.
throughout the stomach as well as in Brunner’s glands.
The role of pepsin in ulcer formation is described in l It provides the appropriate pH for the enzyme to act.
Chapter 4. The optimum pH for pepsin is approximately pH 3.5.

THE digestive SYSTEM 45

3
basic functions of the stomach

Case Case
3.1 Gastrectomy: 3 3.1 Gastrectomy: 4

Anaemia Consequences for digestion

Pernicious anaemia It can be assumed from the fact that gastrectomy is compat-
After gastrectomy, pernicious anaemia eventually develops as ible with life, that the role of the stomach in the digestion
a consequence of vitamin B12 deficiency, due to lack of intrin- of food is not indispensable. If the stomach is removed the
sic factor, unless replacement therapy is instigated. However, lack of pepsin does not pose a problem as far as the overall
vitamin B12 is stored in the liver and pernicious anaemia does digestion of protein is concerned. It is normally responsible
not develop until the stores have become depleted, i.e. prob- for the digestion of only 10–20% of the protein present.
ably after several years. In pernicious anaemia, abnormal In its absence, the proteases secreted by the pancreas,
immature macrocytic (large) red cells are produced by the which act in the small intestine, can normally cope with
bone marrow. The results of the patient’s blood tests would the digestion of all the digestible protein present in the
show a low red cell count and a high mean cell volume of food. Chymotrypsin, an enzyme produced by the pancreas
the cells. The preferred treatment is by intramuscular injec- (see Ch. 5) has a similar substrate specificity to pepsin.
tions of vitamin B12 every 3 months. The different causes of However, pepsin and acid in the stomach have a further
this condition are described in Chapter 8. role in destroying aerobic bacteria that have been ingested
with the food. Thus in a well-fed normal individual, infec-
Iron-deficiency anaemia tions such as cholera, for example, are rare. However, such
After removal of the stomach, iron-deficiency anaemia can infections are more likely to affect individuals who have
develop because the acid in the stomach tends to convert undergone a gastrectomy, or who do not secrete acid
ferric iron (Fe3) in the diet to the ferrous form, the only (achlorhydria). As salivary amylase is normally inactivated
form of non-haem iron that can be absorbed to any appre- by gastric acid in the stomach (see Ch. 2), this enzyme may
ciable extent. Even if only the antrum of the stomach is remain active in the digestive tract for longer after gast-
removed, iron-deficiency can develop because of the removal rectomy, thereby theoretically increasing the rate of break-
of the gastrin-secreting G cells, as gastrin is a major stimulus down of starch.
for acid secretion in the stomach. The body’s iron stores are
more limited than those of vitamin B12, and iron-deficiency
anaemia can manifest itself within a few months of partial
bicarbonate content. This secretion increases when food
gastrectomy, while pernicious anaemia may not occur for 2
is eaten. In addition, the mucus neck cells secrete a clear
years or so. Iron-deficiency is characterized by the presence
mucus in response to food. Mucus is released from the
of small red blood corpuscles (microcytosis), although after
mucous neck cells and surface epithelium by exocytosis.
gastrectomy, this may eventually be obscured by perni-
It can also be released by desquamation of the epithelial
cious anaemia in which the red blood corpuscles are macro-
cells from the surface.
cytic. Iron-deficiency anaemia is discussed in more detail in
Mucin tetramers form a dissolved gel when their con-
Chapter 8.
centration exceeds approximately 50 mg/mL. This gel
forms a layer on the surface of the mucosa. Its stability
depends on charged SO4, COO groups and H bonds,
It denatures ingested protein; denatured protein is a
l and dramatic changes in pH can cause precipitation of the
better substrate for the enzyme than native protein. mucus. The surface epithelial cells secrete non-parietal
alkaline fluid (see above) and this fluid is entrapped in
The consequences of gastrectomy for digestion are the layer of mucus. The alkaline mucus forms a barrier
discussed in Case 3.1: 4. that lines the stomach and protects it from damage by
acid and pepsin. Damage to the mucosal barrier results
in the development of ulcers. This topic is addressed in
Secretions of the mucous cell Chapter 4.

Mucus is a viscous sticky substance that contains glyco-

proteins known as mucins, which consist of about 80% Absorption in the stomach
carbohydrate, largely galactose and N-acetylglucosamine. Very few substances are absorbed in the stomach and the
The molecules are tetramers with a molecular weight of stomach is virtually impermeable to water. Aspirin and
approximately 2 million. The carbohydrate chains protect alcohol are the main substances that are absorbed at this
the molecule from digestion by pepsin. Gastric mucus location. Alcohol is lipid soluble and aspirin becomes
lubricates the pieces of food (in conjunction with salivary more lipid soluble when it meets the acid pH present in
mucus) enabling them to be moved about and churned the stomach (see Ch. 7). The consequences for absorp-
by the contractions of the stomach. The epithelial cells tion in the small intestine following gastrectomy are
secrete an opaque alkaline mucus which has a high discussed in Case 3.1: 5.

46 SYSTEMS OF THE BODY

 3

basic functions of the stomach

Case
3.1 Gastrectomy: 5

Intestinal absorption
The sensations of dizziness, palpitations and sweating expe- 200
rienced by the gastrectomized patient after meals indicate
activation of the sympathetic nervous system. We can now
consider the explanations for these sensations and attempt 150

Blood glucose (mg/100mL)

to understand why the symptoms might be alleviated if the
patient changed his eating habits.
If the stomach is removed, a normal-sized meal moves Normal
100
rapidly into the small intestine, due to the reduction in stor-
age capacity. This results in the absorption of nutrients at an
abnormally rapid rate. However, there may be insufficient
50
time for the meal to be completely digested and absorbed
before it is moved on along the intestines. Dumping
syndrome
Hypoglycaemia 0
0 30 60 90
If the meal has a high carbohydrate content, the absorption
Minutes after ingestion
of glucose can be so fast that the homeostatic mechanisms
for attenuating the increase in blood glucose concentration Fig. 3.9  Effect of eating an average-sized, high carbohydrate meal
during absorption are disturbed. Normally the blood glucose on the concentration of blood glucose in a normal adult (solid line)
rises to a maximum level at 30–60 min after the meal has been and in a patient who has undergone gastrectomy (dashed line).
ingested. An increase in blood glucose stimulates insulin secre-
tion from the pancreas into the blood. This hormone lowers Extracellular fluid volume
the blood glucose by promoting glucose uptake into muscle Another consequence of the rapid entry of material into the
and adipose tissue. Normally the blood glucose returns to nor- small intestine is a rapid loss of fluid into the gastrointestinal
mal after 1.5–2 hours (Fig. 3.9). The insulin concentration also tract that results in a reduced intravascular volume. This happens
returns to normal. This is normally a finely tuned feedback because the contents of the intestinal lumen become hyper-
control system (see Ch. 8). If the blood glucose concentration osmotic due to the breakdown of macromolecules in the food,
rises too rapidly however, the blood insulin concentration also being dissolved in an abnormally low volume of digestive juices.
rises rapidly to reach an abnormally high level in the plasma The presence of a hyperosmotic solution in the intestines results
(Fig. 3.9). This results in rapid clearance of the blood glucose in the transport of water from the blood, down its osmotic
but it can overshoot to an abnormally low level (hypoglycae- gradient into the lumen. Other, unknown, factors may also be
mia). Hypoglycaemia is associated with sweating and fainting, involved in fluid loss in this condition. The loss of water from the
which are seen after meals in a patient who has undergone body can result in a dangerous fall in the extracellular fluid (ECF)
gastrectomy. Salivary amylase is normally inactivated by acid volume. A concomitant fall in the intravascular volume results in
in the stomach (see Ch. 2), so after removal of the stomach, hypotension that will exacerbate the fainting sensation caused
the concentration of active amylase in the small intestine can by hypoglycaemia. Furthermore, the passage of hypertonic
be abnormally high. This enhances the rate of glucose pro- chyme through the small intestine into the large intestine will
duction in the lumen and uptake into the blood glucose. The impair water absorption in the colon resulting in diarrhoea.
hypoglycaemia that ensues could thereby be exacerbated. The symptoms that develop when a meal enters the small
Sympathetic nerves are stimulated by low blood glucose and intestine too rapidly are collectively known as ‘dumping
so hypoglycaemia causes symptoms associated with activation syndrome’. All of these symptoms can be prevented by redu-
of the sympathetic nervous system; palpitations, sweating, cing the size of meals and so restricting the transit of food
vasoconstriction and pallor. into the small intestine.

lumen is only slightly larger than that of the small intes-

Motility in the stomach
tine. The surface interior of the stomach is highly folded
into ridges. Upon being filled with food, the stomach
The most important function of the stomach is its action expands and the folds diminish. Thus the wall tension
to regulate the rate at which material enters the small
and the intraluminal pressure change only slightly.
intestine where digestion and absorption of most nutri-
ents occurs. The stomach is responsible for churning the
food and mixing it with gastric juice to produce a semi- Mixing and emptying
liquid mass known as chyme. The empty stomach in The contractions of the stomach that are responsible for
the adult has a volume of approximately 50 mL and its mixing the chyme and emptying it into the small intestine,

THE digestive SYSTEM 47

3
depend on the activity of the smooth muscle in the wall. Box 3.3  Factors that can trigger vomiting
basic functions of the stomach

The stomach, like the rest of the gastrointestinal tract, is

surrounded by layers of smooth muscle (Fig. 3.3). • Stimulation of sensory nerve endings in the stomach
During the first 30 min after a meal, waves of contrac- and duodenum (e.g. by solutions of copper sulphate
tion, known as peristalsis, cause weak ripples which and hypertonic sodium chloride)
proceed at approximately 1 cm/s over the body of the • Drugs, such as cytotoxic drugs (e.g. cisplatin used in
stomach pushing the food material towards the antrum. the treatment of cancer), and l-dopa used to treat
The muscle surrounding the antrum region is much Parkinson’s disease
thicker than that surrounding the rest of the stomach. • Endogenous substances produced as a result of
Gradually, the contractions become more intense, espe- radiation damage, infections or disease
cially in the antrum. This contractile activity is respon- • Touch receptors at the back of the throat
sible for churning the food material and mixing it with • Disturbances of the vestibular apparatus (known as
gastric juice. Eventually, a large part of the muscle in the motion sickness)
terminal antrum undergoes an intense concerted contrac- • Stimulation of the sensory nerves of the heart and
tion. This strong contraction is responsible for emptying viscera (uterus, renal pelvis, bladder, testicles)
material into the duodenum. Only a small spurt of mate- • A rise in intracranial pressure
rial is emptied at any one time. The antral contractions • Nauseating smells, sights and emotional factors acting
force the rest of the chyme back into the body of the through higher central nervous system centres
stomach where it undergoes further churning and mix- • Endocrine factors (e.g. increase in oestrogen
ing, becoming more and more fluid. concentration in morning sickness)
The pyloric sphincter separates the stomach from the • Migraine
duodenum. Although only a small amount of material is • Circulatory syncope.
ejected through the sphincter each time the antrum con-
tracts, immediately the food has entered the duodenum
the back-pressure helps to close the sphincter. Thus, the
function of the sphincter is to allow the carefully regu- postrema that resides in the floor of the fourth ventricle
lated emptying of gastric contents, and also to prevent near to the vagal nuclei that innervate the gastrointesti-
regurgitation of the duodenal contents that contain bile nal tract. The reflex response involves stimulation of the
into the stomach. The latter is important as the gastric respiratory and abdominal skeletal muscles as well as
mucosa is highly resistant to acid but may be damaged the smooth muscle of the gastrointestinal tract. A large
by bile. (The duodenal mucosa on the other hand, is number of different areas of the body have receptors that
resistant to bile but may be damaged by acid). Too rapid provide afferent inputs to the vomiting centre to trigger
emptying of gastric contents can lead to duodenal ulcers, vomiting. Box 3.3 lists the major stimuli that can trigger
whereas regurgitation of duodenal contents may possibly vomiting.
contribute to gastric ulcers.
Sequence of events
Vomiting Vomiting starts with a deep inspiration. This is followed
by closure of the glottis that protects the respiratory pas-
Vomiting is part of the protective role of the stomach as it sages and holds the diaphragm down as the lungs cannot
protects the body from ingested toxic substances. Thus, it let air out. Air and saliva are drawn into the oesophagus
augments the other protective mechanisms of the stom- that becomes distended. The soft palate is elevated to
ach including acid and pepsin secretion that inactivate prevent vomit entering the nasopharynx. Then expiration
ingested aerobic bacteria, and mucin secretion that pro- occurs against a closed glottis with simultaneous contrac-
tects the columnar epithelium. tion of the abdominal skeletal muscles. This increases
Vomiting or emesis is the forceful ejection of gastric both the intrathoracic and intra-abdominal pressures. The
contents, and sometimes, duodenal contents, through essential component of the vomiting reflex is relaxation
the mouth. It is a reflex that is usually preceded by a feel- of the lower oesophageal sphincter, without which the
ing of nausea. This can be accompanied by salivation, gastric contents cannot pass into the oesophagus. As the
sweating, pallor, a fall in blood pressure, pupillodilation, intrathoracic pressure is lower than the intra-abdominal
increased heart rate and irregular breathing. It is usu- pressure, relaxation of the lower oesophageal sphincter
ally also preceded by retching in which the gastric con- allows passive flow of gastric contents down the pres-
tents are forced into the oesophagus without entering the sure gradient. The importance of the abdominal muscles
pharynx. A series of retches of increasing strength often in vomiting is demonstrated by the fact that vomiting
precedes vomiting. can still be induced in an animal if the stomach has been
The vomiting reflex is controlled by the vomiting cen- replaced by a bladder.
tre in the reticular formation in the medulla oblongata Prior to vomiting, a number of cycles occur whereby
and the chemoreceptor trigger zone (CTZ) in the area the oesophagus is repeatedly filled and emptied, but as

48 SYSTEMS OF THE BODY

 3

basic functions of the stomach

Case Case
3.2 Excessive vomiting: 1 3.2 Excessive vomiting: 2

A 55-year-old woman was being treated for ovarian cancer

Acid-base and electrolyte disturbance
with a course of chemotherapy, using cisplatin, a cytotoxic
anti-cancer drug. A few days after her first chemotherapy Acid–base status
session, she became nauseous and could not stop vomiting. The measurements made on the patient’s blood included
Nausea and vomiting is a side-effect of treatment with the pH, HCO3 concentration, Pco2 and K concentration. If the
anticancer drug cisplatin, which binds to receptors in the vomiting were not suppressed the patient’s blood gas anal-
gastrointestinal tract and the Chemoreceptor trigger zone ysis would indicate a metabolic alkalosis; i.e. high pH, high
(CTZ). Persistent vomiting can become a chronic condition if [HCO3], Pco2 normal or mildly elevated. The disturbance
the therapy has to be continued. The loss of acid can have in acid–base balance is brought about because the HCO3
serious consequences for the acid–base status of the patient transported into the blood, from the secreting oxyntic cells
unless antiemesis is instigated. On her next visit to the hospi- in the stomach, would not be neutralized sufficiently by
tal, a sample of the patient’s blood was tested to assess her the H ions transported into the blood as a result of the
acid–base status and electrolyte concentrations. secretion of alkaline pancreatic juice, bile and intestinal
After consideration of the cellular mechanisms of hydro- juice (Fig. 3.8), which is not affected by persistent vomit-
chloric acid secretion in the stomach and the disturbances ing. Compensation for this alkalosis by the lungs and kid-
of acid–base homeostasis following gastrectomy, some of neys would become inadequate, due to the persistent loss
the consequences of persistent vomiting can be predicted. of H ions. (See the companion volumes on the Respiratory
These issues and the causes and treatment of chronic vom- and Renal Systems for a discussion of these compensatory
iting will be considered in Case 3.2: 2 and Case 3.2: 3. mechanisms.)

Electrolytes
Hypokalaemia (a low blood K concentration) may also be
present in this patient because K would be exchanged for
the hypopharyngeal sphincter is closed, gastric contents H in the kidneys (to partially correct the blood pH) and
cannot enter the mouth and they flow back into the stom- lost in the urine. Hypokalaemia affects nerve function (of
ach. Finally, a violent expulsive effort forces the material particular importance in the heart), and can lead to kidney
through the upper sphincter into the mouth. If the stom- damage. Alkaline K salts, e.g. K acetate, K citrate or K
ach still contains sufficient material, a second cycle can bicarbonate could be administered to correct the distur-
occur. Massive contractions of the duodenum can force bance in plasma K concentration.
intestinal contents into the stomach with the appearance
of bile in the vomit. This is not due to reverse peristalsis
but to the fact that when the stomach is relaxed, contrac-
tions of the duodenum will reverse the normal pressure digitalis, used in the treatment of cardiac conditions, and
gradient. by high concentrations of urea (uraemia) associated with
Excessive vomiting can occur as a side-effect of treat- renal failure. It is also probably involved in motion sick-
ment with certain drugs, such as the anti-cancer drug ness as removal of the area postrema in dogs has been
cisplatin. Case 3.2: 1 and Case 3.2: 2 discuss the conse- shown to prevent motion sickness from being induced.
quences of this problem for the acid–base and electrolyte Both the CTZ and the NTS also receive inputs from the
balance of the blood. visceral afferents (via the vagal nerves).

Control of vomiting Transmitters involved in vomiting

Figure 3.10 summarizes the major pathways involved The neurotransmitters in the areas of the brain that con-
in the vomiting reflex. The final common pathway trol vomiting are numerous. They include -aminobutyric
involves impulses from the vomiting centre to the skel- acid, acetylcholine, noradrenaline, dopamine, 5-hydroxyt-
etal and visceral smooth muscles. The vomiting centre is ryptamine, histamine, glutamate, substance P, endor-
a functional rather than an anatomical entity. It receives phins and neurophysins, but their precise roles are still
impulses from the chemoreceptor trigger zone (CTZ) unknown. The main stimulatory factors and their path-
and the nucleus tractus solitarius (NTS) as well as from ways of action are indicated in Figure 3.10. In some clini-
higher centres (which respond to repulsive sights, smells cal circumstances, for example after ingestion of a toxic
and emotional factors). The CTZ is ‘functionally’ outside substance, it is necessary to stimulate vomiting. The drug
the blood–brain barrier and it is affected directly by sub- used is usually ipecacuanha. Its active ingredients are
stances in the bloodstream such as the opioid analgesics emetine and cephaeline that act locally on receptors in the
morphine and apomorphine, and glycosides such as stomach and stimulate vomiting via the NTS.

THE digestive SYSTEM 49

3
basic functions of the stomach

SENSORY AFFERENTS Table 3.1  Antiemetic drugs and their actions

(Pain, smells, HIGHER CENTRES
emotions, sights) Receptor involved Drug(s) Used against
vomiting by

Histamine H1 Piperazine Motion

CTZ VOMITING CENTRE derivatives Morphine
D2 and 5-HT3 Muscarinic Muscarinic Hyoscine Motion
receptors receptors
Copper sulphate
Dopamine Phenothiazines Apomorphine
Gastrointestinal
NTS infections
VESTIBULAR NUCLEI Radiation
H1 and muscarinic
H1 and muscarinic receptors Cancer chemotherapy
receptors Oestrogen (morning
sickness)
Narcotics
VISCERAL
5-Hydroxy- (Ondansetron) Cancer chemotherapy
AFFERENTS
(gastrointestinal tract) tryptamine (5-HT3)
BLOOD Cannabinoid Nabilone Cancer chemotherapy
Drugs, toxins 5-HT3 receptors

Fig. 3.10  The major peripheral and central areas involved in the
control of vomiting and the receptors utilized. NTS, nucleus
tractus solitarius; CTZ, chemoreceptor trigger zone. Case
3.2 Excessive vomiting: 3

Mechanism and treatment

Vomiting, which can be induced by a number of stim- The receptors that respond to cisplatin to induce vomiting
uli, can be treated with various drugs, depending to some are present in the CTZ and the gastrointestinal tract. They
extent on the particular stimulus that induces it. Table 3.1 include 5-HT3 receptors and dopamine receptors in the
lists the major antiemetic drugs and their uses against chemoreceptor trigger zone (CTZ) and 5-HT3 receptors in
vomiting induced by different stimuli. All of these drugs the gastrointestinal tract.
can cause unwanted side-effects, especially drowsiness, A very effective antiemetic drug to treat this condition is
as they all have an inhibitory effect on the central nerv- the 5-HT3 antagonist ondansetron, which acts on the CTZ
ous system. The treatment of chronic vomiting which can (Table 3.1). Dopamine antagonists such as phenothiazines
be a side-effect of cancer chemotherapy is discussed in and cannabinoids such as nabilone are also effective. These
Case 3.2: 3. drugs probably act on the CTZ for their antiemetic effect.

50 SYSTEMS OF THE BODY

The stomach:
control 4
Chapter objectives
After studying this chapter you should be able to:

1. Understand the interplay of nervous and hormonal control of gastric

function, and how this is coordinated by food in the gastrointestinal
tract.

2. Understand how these control mechanisms result in coordinated

function of the digestive system.

3. Understand how dysfunction can result in mucosal ulceration and

how this can be diagnosed and treated.

4. Understand how dysfunction can result in secondary effects on the

gastrointestinal tract and on systemic acid–base balance.
4
approximately 36 min. Both peptides stimulate gastric
CONTROL MECHANISMS OF THE STOMACH

Introduction
acid secretion. The short half-life of the G17 form is con-
sistent with its main influence being via local receptors
Soluble substances in the food in the gastrointestinal tract in the stomach. The active part of the molecule is the car-
and the mechanical pressure exerted by the food on the boxy-terminal tetrapeptide sequence.
walls of the tract can stimulate or inhibit gastric secretion The active sequence is contained in the pentapep-
and motility. Nervous, paracrine and endocrine signals tide drug pentagastrin, a synthetic drug that consists of
are involved. Peptic ulcer disease is a common condition the C-terminal tetrapeptide to which a substituted
in which gastric acid damages the mucosa of the duode- -alanine has been added to stabilize the molecule. It
num or the stomach. In this chapter, the pathology and exhibits all the physiological actions of gastrin. Clinically,
complications of this disease are used to emphasize the it is administered as an alternative to histamine (see Ch. 3)
importance of the proper control of the functioning of the to test gastric secretion.
stomach (Case 4.1: 1).
A leading role in the coordination of gastrointesti-
nal functions is played by the hormone gastrin that is G cells and gastrin secretion
released from the stomach into the bloodstream during In normal individuals, most of the G cells, which secrete
a meal. It stimulates both secretion and motility in the gastrin, are found in the mucosa of the gastric antrum,
stomach. It also stimulates the blood supply and growth although some (20%) are present in the duodenal
of the gastric mucosa. In addition, it controls many func- mucosa. The G cells comprise less than 1% of the mucosal
tions of other regions of the gastrointestinal tract and its cells. In the human, these cells, together with other endo-
associated glandular organs. Gastrin is released from G crine cells, are found between the basal and neck regions
cells located mainly in the mucosa of the pyloric antrum, of the gastric glands (see Ch. 3). The mature cells are
and so these cells are ideally placed to respond to the replaced from immature precursor cells located in the
presence of ingested material in the stomach. Tumours isthmus of the antral glands. The turnover of the G cells
of ectopic G cells, known as gastrinomas, can give rise is slow (unlike that of the epithelial cells). It is stimulated
to the Zollinger–Ellison syndrome. This rare disease is by gastrin. G cells (Fig. 4.2) are ‘open’ APUD endocrine
characterized by over-secretion of gastrin, which results cells (see Ch. 1). In these cells, microvilli are present along
in excessive secretion of acid, and hypermotility of the their apical surfaces, which are in contact with the lumen
gastrointestinal tract. In this chapter the physiological of the stomach. This structural feature of the cell enables
and clinical importance of this hormone is illustrated by it to sample the gastric contents. Receptors present on the
discussion of the functional abnormalities that arise in luminal surface membrane sense chemical substances in
Zollinger–Ellison syndrome (Case 4.2: 1). food, known collectively as ‘secretogogues’, which regu-
late the release of gastrin (see below). Gastrin is stored in
secretory granules present along the basolateral border of
Control of gastric secretion the cell which lies in close proximity to the blood vessels.
It is released into the circulation at the basolateral mem-
The control of secretion of gastric juice involves extrinsic brane in response to neural, endocrine or paracrine stim-
and intrinsic nerves, hormones and paracrine mediators. uli, and by local factors in the lumen of the stomach.

Hormonal control Gastrin receptors

A variety of cell types possess specific surface receptors
Gastrin for gastrin. The oxyntic cell is the type that has been most
Gastrin is a hormone that is secreted from the G cells in studied. Interestingly, gastrin and cholecystokinin (CCK,
the stomach. It stimulates gastric juice secretion, and has a hormone secreted by the duodenal mucosa) have the
a general role in the preparation of the gastrointestinal same active carboxy-terminal tetrapeptide and act on the
tract for the digestion and absorption of food. It was the same receptors. There are two such receptors, the CCK-
first hormone to be discovered (Box 4.1). A receptor, present in the pancreas and the gall bladder,
and the gastrin-CCK-B receptor, present on the ECL cell
and the oxyntic cell. The two hormones exhibit different
Biologically active forms of gastrin
potencies at these receptors. CCK has a 10-fold higher
In the normal human, gastrin is produced mainly in the potency than gastrin at the CCK-A receptor, and gastrin
gastric antrum, although small amounts are produced is the more potent at the CCK-B receptor. This difference
in the proximal small intestine. Two major forms of gas- in binding affinities between gastrin and CCK at the two
trin exist, gastrin-34 (G34, composed of 34 amino acids) CCK receptors is the main reason for their different pat-
and gastrin-17 (G17, composed of 17 amino acids). In terns of biological activity. CCK exerts its main physio-
humans, over 90% of the gastrin present in the antral logical effects on the biliary tree and the pancreas where
mucosa is the G17 form. Gastrin-17 has a half-life in the CCK-A receptors predominate, whereas gastrin is more
circulation of approximately 6 min and G34 a half-life of potent in the stomach.

52 SYSTEMS OF THE BODY

 4

CONTROL MECHANISMS OF THE STOMACH

Case Case
4.1 Peptic ulcer disease: 1 4.2 Gastrinomas (Zollinger–Ellison
syndrome): 1
A 45-year-old man, from a family with a history of pep-
tic ulcer disease, visited his general practitioner and com- A 40-year-old woman who had been suffering, for several
plained of dull burning pain in his upper abdomen. This years, from intermittent abdominal pain and diarrhoea,
was associated with periodic nausea, vomiting, heartburn visited her general practitioner. She had previously been
and loss of appetite. He was a heavy drinker and smoker. diagnosed (by endoscopy) as having peptic ulcer disease,
Upon examination, the pain was found to be localized to and had been prescribed omeprazole and a short course
the epigastric region. The patient said that the pain was of antibiotics, but with no long-term relief of her symp-
worse when his stomach was empty and was eased by eat- toms. Consequently, she had undergone surgical division
ing a meal. He also complained of symptoms of hypersecre- of the vagal nerves to the stomach (a selective vagotomy).
tion of acid during the night. He often woke in the early Surprisingly, her symptoms persisted following the sur-
hours with a burning sensation behind his lower sternum. gery. Further tests were initiated to investigate the possi-
He had been taking antacids that afforded him some relief. bility that they were due to a gastrinoma. Her basal acid
The doctor sent him for an endoscopy. This showed the secretion and her acid secretion in response to an injection
presence of an ulcer in the proximal duodenum. He was of pentagastrin were investigated. This involved aspira-
advised to stop smoking and not to drink alcohol. He was tion of gastric juice. A radioimmunoassay for gastrin was
initially prescribed ranitidine, an H2 blocker, the preferred performed on a blood serum sample. She was restarted
treatment for ulcers at the time. However after 6 weeks, on a high dose of omeprazole to protect against further
the symptoms from the ulcer had not resolved. He was ulceration, and arrangements were made for her to have
then prescribed omeprazole, and symptomatic relief was a further endoscopy. Hypertrophy of the gastric rugae,
quickly obtained. Unfortunately, the symptoms returned and ulceration extending into the second part of the duo-
after approximately 8 months. Omeprazole treatment was denum, were seen. In the light of these observations, and
started again, but this time it was prescribed in combina- the abnormal plasma gastrin level found, a computer-
tion with a course of antibiotics. His symptoms disappeared, ized tomogram (CT scan) of her upper abdomen was per-
and by 2 years later he had suffered no further relapse. formed. This demonstrated a mass in the pancreas (fig. 4.1).
After considering the details of this case you should be
able to answer the following questions:
T
l Why did the general practitioner suspect from what the
patient said that he might have a duodenal ulcer rather
than a gastric ulcer?
l Which is the most common location for ulcers in the

duodenum? Why do they usually occur at that location?

l Which is the most common site for ulcers in the stomach

and why do they occur at that location?

l What is the mechanism of action of H receptor
2
antagonists such as ranitidine? Why are these drugs
L
usually effective in relieving the symptoms of peptic
ulcer disease? Why should they be administered at night
S
in this patient? K
l What is the mechanism of action of omeprazole?

l Why was the patient given a course of antibiotics?

Cellular actions of gastrin on acid secretion

Oxyntic cell
In the healthy individual the secretion of acid and intrin-
sic factor by the oxyntic cell are regulated in parallel,
so that stimulation of acid secretion is accompanied by
increased secretion of intrinsic factor. Gastrin stimulates Fig. 4.1  A CT scan showing a cross-section of the upper
abdomen. A large swelling in the head of the pancreas can be
acid secretion by two mechanisms: it stimulates the oxyn-
seen, suggestive of a tumour (T). The normal liver (L), spleen (S)
tic cell directly, and it stimulates it indirectly through and left kidney (K) are seen on the same image.
stimulation of the ECL cell to release histamine which in

THE digestive SYSTEM 53

4
Luminal
CONTROL MECHANISMS OF THE STOMACH

Case A
membrane
4.2 Gastrinomas (Zollinger–Ellison
syndrome): 1 (continued)

A laparotomy (abdominal operation) was performed and

the surgeon confirmed that a tumour was present in the
pancreas, and the tumour was removed. Subsequent his-
tological analysis of the resected specimen demonstrated
that the tumour was a gastrinoma. Removal of the tumour
cured the patient’s symptoms and her serum gastrin con-
centration declined to within the normal range.
After studying the details of this case we can consider
the following: Secretory vesicles
containing gastrin
l What abnormalities in blood gastrin levels, gastric acid
B C Lumen
secretion, and pepsinogen secretion, might we expect
to see in this patient? What changes might we expect
following surgical vagotomy? Somatostatin
l Why was hypertrophy of the gastric mucosa containing
present? secretory
l Why was ulceration seen in the second part vesicles
of the duodenum? Which other sites in the
gastrointestinal tract are likely to be ulcerated
in this condition?
l Which of the diagnostic tests used would have given Histamine containing
indications that the condition was Zollinger–Ellison secretory vesicles
syndrome and not simple gastric or duodenal
Fig. 4.2  (A) Gastrin-secreting (G) cell. (B) Histamine secreting (ECL)
ulceration? cell. (C) Somatostatin secreting cell.
l What is the rationale for treating this condition with a

high dose of omeprazole? Peptides,

+
l What are the explanations for the patient’s
amino acids Distension H
diarrhoea? Mechano R
l What are the physiological consequences of excessive
GRP
gastrin and acid production? ACh MR OX
GRP R
cell
G cell H2 R
CCK-B R
Box 4.1  Gastrin: the first hormone ACh
MR
Histamine
Gastrin was the first hormone to be discovered. The exist- ACh
ence of a substance that is released into the blood in
response to food in the stomach, and which circulates to ECL
MR
stimulate acid secretion, was first proposed by Edkins in cell
Gastrin ACh
1905. However, when it was realized that histamine, a sub- CCK-B R
stance present in abundance in gastric mucosa, stimulated
acid secretion, it was assumed that this was the main medi- Gastrin
ator. It was not until 30 years later that Grossman and his Vagus
colleagues demonstrated the existence of a blood-borne
factor that stimulated acid secretion. They isolated a pouch Gastrin Blood Gastrin
from the body of the stomach in a dog and transplanted it
into the neck region. They showed that food placed in the Fig. 4.3  Mechanisms of stimulation of acid secretion from the oxyntic
antrum, which remained in situ, stimulated acid secretion in cell by gastrin, histamine and neurotransmitters. ACh, acetylcholine;
the transplanted pouch. Increased secretion occurred even GRP, gastrin–releasing peptide; CCK-BR, cholecystokinin B receptor; H2R,
if the antrum was denervated, indicating that the stimulus histamine H2 receptor; MR, muscarinic receptor; OX, oxyntic.
was a blood-borne factor released from the gastric antrum;
that is, a ‘hormone’. In 1964, Gregory and Tracey isolated turn stimulates the oxyntic cell (Fig. 4.3). It binds to CCK-
the pure peptide hormone from hog stomach. It was subse- B receptors on the cell membranes in both types of cell.
quently called gastrin. The result of this stimulation is the incorporation of pro-
ton pumps into the canalicular membrane of the oxyntic

54 SYSTEMS OF THE BODY

 4
cell (see Ch. 3). Gastrin also stimulates the expression of the stomach stimulates gastrin release from the G cells

CONTROL MECHANISMS OF THE STOMACH

the gene for the proton pump in the oxyntic cell, thereby (Fig. 4.3). It probably also stimulates acid release by a
increasing its synthesis. gastrin-independent mechanism. This interaction of the
Gastrin also has trophic actions. It controls the growth neural and gastrin control mechanisms facilitates a rapid
and proliferation of a variety of cell types in the gastric response to food ingestion.
mucosa, including ECL cells and the precursors of oxyn-
tic cells. Hyperplasia of ECL cells and oxyntic cells occurs
in conditions where hypergastrinaemia is present (see Inhibitory control of acid secretion
Case 4.2: 2).
Feedback control via acid
ECL cell and histamine Gastric acid secretion is blocked if the contents of the
Gastrin binds with a high affinity to CCK-B receptors stomach become too acid (pH 3.0, or lower). This is a
on ECL cells, to cause the release of histamine (Fig. 4.3). negative feedback mechanism that prevents the gastric
Histamine acts in a paracrine manner on the oxyntic cell contents (and probably more importantly the duodenal
to release acid. The binding of gastrin to the ECL cell also contents) from becoming too acid. When the acidity of
stimulates histamine synthesis from histidine (see below). the stomach reaches pH 2.0 it is virtually impossible to
It is produced in large amounts by the gastric mucosa. stimulate gastrin release by any means. The inhibition is
It is produced by decarboxylation of histidine: indirect and is exerted via inhibition of gastrin release. In
conditions where achlorhydria (lack of acid secretion) is
histidine decarboxylase present (such as some types of pernicious anaemia), there
Histidine  → histamine  CO 2 are usually high levels of gastrin in the blood because

this feedback mechanism cannot operate. The inhibitory
Histamine acts on H2 receptors on the oxyntic cells to action of acid on gastrin secretion is due to its action to
release acid (Fig. 4.3) via a cyclic AMP-mediated mecha- stimulate the release of the hormone somatostatin from
nism. Its presence is necessary for the secretion of normal D cells in the mucosa. Somatostatin is a potent inhibitor
amounts of acid. Thus inhibition of the enzyme histidine of acid secretion; it inhibits gastrin secretion from G cells
decarboxylase reduces acid secretion. and histamine secretion from ECL cells. Furthermore,
the D cells exhibit gastrin-binding sites, and gastrin
Neural control of gastric secretion itself can stimulate somatostatin release from these cells.
However these binding sites are probably CCK-A recep-
The functions of the stomach are controlled by intrinsic tors which are more sensitive to CCK than to gastrin.
nerves in the internal nerve plexi of the enteric nervous Stimulation of somatostatin release via these receptors is
system and by extrinsic nerve fibres in the vagus nerve therefore probably normally due mainly to circulating
and sympathetic nerves (see Ch. 1). Axons of nerve fibres CCK (see below).
(in the intramural plexi) innervate both secretory cells and In both peptic ulcer disease and in Zollinger–Ellison
smooth muscle cells. In general activation of cholinergic syndrome, acid secretion is increased but gastrin levels
fibres stimulates gastric secretion and motility. Cases 4.1 are only increased in Zollinger-Ellison syndrome (Cases
and 4.2: 2 shows the arrangement of the vagal choliner- 4.1: 2 and 4.2: 2).
gic nerve trunks that innervate the stomach. Activation of
adrenergic fibres generally inhibits secretion and motility.
It should also be noted that a number of sensory Somatostatin
nerves leave the stomach and travel in the vagus nerve Somatostatin exists predominantly as the 14-amino-acid
and the sympathetic nerves. Sensory nerves in the stom- peptide somatostatin-14 in D-cells in the fundic and antral
ach also provide afferent paths of intrinsic reflex arcs, mucosa. It is released from cytoplasmic processes on the D
which travel in the intramural plexi of the stomach. This cells in the antrum in the vicinity of its target cell, the G-
provides some intrinsic control of smooth muscle con- cell (Fig. 4.5). It binds to somatostatin-2 (ST-2) receptors on
tractions and gastric juice secretion. the G cells. It acts primarily in a paracrine manner via dif-
fusion in the intercellular spaces, but it also acts systemi-
cally through its release into the local mucosal circulation.
Acetylcholine and gastrin-releasing peptide Somatostatin also acts on ECL cells to inhibit histamine
Acetylcholine released from cholinergic nerve fibres in release. These interactions are outlined for the antrum
local nerves can stimulate oxyntic cells to release acid, or region in Figure 4.5. Somatostatin also acts upon the oxyn-
G cells to secrete gastrin. Some fibres in the vagus nerve tic cells in the fundus to inhibit the release of acid directly.
also contain gastrin-releasing peptide (GRP), which Fundic D cells are ‘closed’ APUD cells (see Ch. 1) and
exists as two major forms, in which the active site is a do not respond to luminal acidity. Somatostatin appears
nonapeptide. The structurally similar peptide bombesin to exert a tonic inhibition of acid release in the fundus.
that has been extracted from the skin of the frog Bombina However, antral D cells are ‘open’ APUD cells, and they
bombina has similar actions. GRP released from nerves in respond to changes in H concentration in the stomach

THE digestive SYSTEM 55

4
CONTROL MECHANISMS OF THE STOMACH

Case
4.1 Peptic ulcer disease: 2

Causes and diagnosis

Individuals with duodenal ulcer disease often have a family however, the differential diagnosis between gastric and duode-
history of the condition. The duodenum is the most frequent nal ulcer cannot be ascertained on the basis of symptoms alone.
site for ulcer formation, the duodenal cap being the most vul- Figure 4.4 shows an X-ray of the stomach of a patient with
nerable area. Excessive secretion of acid and pepsinogen are a chronic gastric ulcer.
directly implicated in chronic ulceration of the duodenum. An endoscopy would demonstrate a gastric ulcer. In the
High H concentration can lead to the breakdown of the case of a suspected gastric ulcer it is important to ask whether
protective mechanisms of the mucosal barrier (see Box 4.3). the patient has lost weight and to take a biopsy of the ulcer-
Patients with simple duodenal ulcer usually have a high basal ated mucosa because there is a risk of malignancy, which is
acid output with normal levels of serum gastrin. In contrast, not seen in the case of a duodenal ulcer.
patients with gastric ulcer appear to have normal or slightly
low acid secretion (Table 4.1). In gastric ulcer the primary
defect may be a reduced ability of the mucosa to withstand A
damage by acid and pepsin (see Cases 4.1 and 4.2: 1).
An endoscopy can be carried out on patients with sus-
pected peptic ulcer to locate an ulcer and confirm that it is
not a tumour (which can present with similar symptoms).
The patient described in Case 4.1 demonstrated hypersecre-
tion of acid which is more typical of a duodenal ulcer than
a gastric ulcer. He also complained of heartburn and pain
when his stomach was empty. Eating provided relief because
food buffers the acid. Symptoms of hypersecretion at night
are supposedly more usually seen with a duodenal rather U
than a gastric ulcer but in practice there is often overlap of
symptoms between the two types. In the case of a duodenal
ulcer the symptoms usually last for a few weeks followed by
a remission.

Gastric ulcer
Although a family history is often present in duodenal ulcer
inheritance appears to be unimportant in gastric ulcer. In a
patient with gastric ulcer the pain is poorly localized but may be
perceived in the midline area. It occurs at any time but is often
worse during or after a meal. Physical examination does not Fig. 4.4  An X-ray of the stomach taken after ingestion of barium.
usually demonstrate epigastric tenderness. There is not usually The normal folds of the antrum (A) have been disrupted by the
nausea or vomiting and food does not ease the pain. In practice, chronic ulceration, giving rise to linear scarring around the ulcer (U).

Table 4.1  Acid and gastrin secretion in peptic ulcer disease and Zollinger–Ellison syndrome

Acid Rate of acid secretion Blood gastrin

(pmol/L)

Basal day Basal night Maximum

(mmol/h) (mmol/12 h) (mmol/h)

Normal 1–5 18 25 30
Gastric ulcer 1–5 8 25 30
Duodenal ulcer 4–10 60 40 30
ZES 45 120 55 650

Typical mean values are given for acid secretion and blood gastrin levels in normal subjects, and patients with simple gastric
ulcer, duodenal ulcer or Zollinger–Ellison (ZES) syndrome. Maximum acid output is elicited by injection of pentagastrin (6 g/kg).

56 SYSTEMS OF THE BODY

 4

CONTROL MECHANISMS OF THE STOMACH

Case
4.2 Gastrinomas (Zollinger–Ellison syndrome): 2

Causes and diagnosis

In 40% of patients with Zollinger–Ellison syndrome familial Diagnosis
inheritance has been recorded. The syndrome can be inher- The diagnosis of Zollinger–Ellison syndrome requires consider-
ited in an autosomal dominant fashion, so relatives may be ation of the results of a number of different procedures. Basal
affected. For this reason it is important to obtain a family his- acid secretion is dramatically elevated, and serum gastrin lev-
tory from patients diagnosed with the disease. els are often elevated over 10-fold, as a consequence of the
The gastrinomas present may be ectopic, commonly pre- uncontrolled secretion (Table 4.1). However, high basal acid
senting in the pancreas. They may be small and difficult to production by the stomach and high levels of gastrin in the
locate. In 60% of patients, the tumours are malignant. The blood are merely suggestive of the condition.
gastrinoma tumours secrete excessive amounts of gastrin The ‘secretin test’ has been used in the past to assist the
into the portal blood stream. The high serum gastrin lev- diagnosis of Zollinger–Ellison syndrome, but now that gastrin
els elicit massive secretion of acid from the oxyntic cells. It is levels can be measured directly and accurately by radioimmu-
the basal acid secretion (which occurs between meals) that is noassay, it is no longer often employed. The basis of the test
stimulated to the greatest extent by the high gastrin levels. depends on the fact that whereas secretin infusion normally
The secretion of gastrin from the gastrinomas (as with many inhibits acid secretion during the intestinal phase of diges-
other secretory tumours) is independent of secretogogues tion (by acting on the oxyntic cell directly and on the G cell),
such as peptides in the stomach. Thus secretion of acid dur- and normally has little effect on basal acid secretion between
ing a meal is not abnormally affected. Table 4.1 shows typical meals, it stimulates secretion of gastrin from ectopic gastrino-
values for the basal and maximum acid secretion (induced by mas; the so-called ‘paradoxical’ effect of secretin in Zollinger–
injection of pentagastrin), and serum gastrin levels in normal Ellison syndrome.
individuals, and in patients with gastric ulcer, duodenal ulcer, Radiological imaging (Fig. 4.4), particularly magnetic res-
or Zollinger–Ellison syndrome. The basal acid output is usually onance imaging (MRI) can detect lesions as small as 1 cm in
considerably elevated in Zollinger–Ellison syndrome. However, diameter. When malignant lesions are present, metastases
the maximum acid output measured after pentagastrin injec- are usually visible in the liver. Exploratory surgery is required
tion is not increased proportionately, unlike in normal indi- to confirm the lesion (and to remove benign tumours).
viduals or patients with peptic ulcer disease. The basal acid Malignant tumours are usually treated with proton pump
output is usually not less than 60% of the maximum output, inhibitors to simply control the symptoms of excessive acid
and is often the same as the maximum output. secretion.
In normal individuals, a low pH in the stomach lumen Note: Gastrin has trophic actions on the mucosa of the
inhibits acid secretion by inhibiting gastrin secretion from the gastrointestinal tract. It is a growth factor for the stomach
antral G cells (see below) but secretion by gastrinomas is inde- mucosa and in Zollinger–Ellison syndrome the high levels can
pendent of this feedback control. stimulate hypertrophy of the mucosa. The rugal folds may
Pepsinogen secretion is also stimulated by gastrin, so its become extremely thick. This can sometimes be seen in medi-
secretion is also usually abnormally high in Zollinger–Ellison cal imaging procedures such as the barium meal test.
syndrome.

lumen. During a meal, as the contents of the stomach less potent than gastrin this results in reduced acid
become increasingly acid, secretion from the oxyntic cell secretion, when gastrin is present in the circulation
declines, due to the action of somatostatin. The release l It is a potent antagonist of gastrin-stimulated acid
of somatostatin is inhibited when the luminal acid is
secretion, by its action on CCK-B receptors on D cells,
neutralized.
to release somatostatin, which in turn inhibits acid
secretion.
Other inhibitory factors
The duodenal hormone secretin also produces a pro-
Numerous peptides inhibit gastric acid secretion. Some of found inhibition of gastrin release and gastric acid secre-
these peptides are released from APUD cells by the pres- tion. It is released in response to the presence of food in
ence of chyme in the duodenum (see below). Importantly, the duodenum. It is a 27-amino-acid peptide which has
CCK, which is secreted in response to fat, causes inhibi- structural similarities to the pancreatic hormone glu-
tion of acid secretion in two ways: cagon. The most potent stimulus for secretin release is
It competitively inhibits gastrin-mediated stimulation
l acid in the duodenum. Secretin inhibits the secretion of
of acid release by binding to CCK-B receptors on the gastrin from G cells and the secretion of acid from oxyn-
oxyntic cell and the ECL cell. A high level of CCK tic cells. Other peptides which inhibit gastric acid release,
in the blood (if gastrin levels are high) results in include gastric inhibitory peptide (GIP, a 43-amino-acid
displacement of gastrin from its receptors, but as it is peptide) released in response to fat in the duodenum or

THE digestive SYSTEM 57

4
ileum, and the 28-amino-acid peptide vasoactive intesti- Finally, prostaglandins synthesized in the gastric
CONTROL MECHANISMS OF THE STOMACH

nal peptide (VIP), which is released into the circulation mucosa inhibit acid secretion. They function to protect
from nerve endings in the enteric nerves of the submu- the deeper mucosal layers from damage by acid (as dis-
cosal and myenteric plexi. VIP and GIP have considerable cussed below).
sequence homology (14 amino-acids) with secretin, and
they act on the same receptors as secretin on oxyntic cells
and G cells to inhibit acid release. The receptors for all Control of pepsinogen secretion
these hormones are denoted VIP receptors. Although the
primary effect of these peptides is to reduce gastric juice Pepsin is a proteolytic enzyme which is responsible for
secretion, tumours of APUD cells, such as VIPomas, cause only 15% of dietary protein digestion in the gastrointes-
increased motility, and consequently diarrhoea. Table 4.2 tinal tract and this role is dispensable (see Ch. 3). It is
summarizes the actions of some of the endogenous pep- important clinically however, because it exacerbates the
tides which inhibit acid production, and indicates their acid-induced ulceration of the stomach and duodenum
sites of release, and the likely mechanisms involved. (Cases 4.1 and 4.2: 1).

Pepsinogen
Lumen

+
H
Lumen
Ca2+ PKC PKA

IP3 DAG cAMP

D cell G cell
ST R
PLC AC G1
Somatostatin

ST R CCK-B R MR VIP R β-R ST R

ECL
Somatostatin cell Somatostatin
Gastrin, ACh VIP, Adrenaline, Somatostatin
CCK secretin noradrenaline

Fig. 4.6  Mechanisms of secretion of pepsinogen from the chief cell.

Somatostatin Blood Somatostatin CCK, cholecystokinin; ACh, acetylcholine; MR, muscarinic receptor;
VIP, vasoactive intestinal peptide; R, receptor; PKC, protein kinase C;
Fig. 4.5  Paracrine and endocrine mechanisms of feedback inhibition PKA, protein kinase A; DAG, diacylglycerol; AC, adenyl cyclase; IP3,
of acid secretion by somatostatin released in response to low pH in the inositol trisphosphate; -R, -adrenergic receptor; STR, somatostatin
antrum. STR, somatostatin receptor. receptor; G1, G protein.

Table 4.2  Gastrointestinal peptides that inhibit acid production in the stomach

Peptide Main stimulus Location Mechanism of action

Somatostatin Acid D cells (Stomach) inhibition of heritance and gastrin release

CCK Fat APUD CELLS (duodenum) Somatostatin release (CCK-B receptors)
Competes with gastrin (CCK-A receptors)
Enteric nerves
Secretin Acid APUD cells (duodenum) Inhibition of gastrin and acid release
GIP Fat APUD cells Inhibition of gastrin and acid release
Enteric nerves
VIP Distension of Enteric nerves Somatostatin
stomach

CCK, cholecystokinin; GIP, gastric inhibitory peptide; VIP, vasoactive intestinal peptide; ACh, acetylcholine.

58 SYSTEMS OF THE BODY

 4
Pepsinogen, the precursor of pepsin, is released from

CONTROL MECHANISMS OF THE STOMACH

Acid reduction therapy
the chief cell by acetylcholine, as well as by a number
of gastrointestinal hormones. Figure 4.6 illustrates
the various secretogogues and their receptors and the A variety of different classes of drugs can be effective in
second messenger systems involved in their actions. the treatment of peptic ulcer disease and other conditions
Acetylcholine released upon stimulation of the vagus such as gastrinomas and acid reflux. Figure 4.8 shows
nerve and local nerves is probably the most potent stimu- the sites of action of the different drugs which can inhibit
lus. It acts on muscarinic receptors on the chief cell mem- acid secretion in the stomach. The treatment of peptic
brane. H ions trigger the local cholinergic reflex that ulcer disease and gastrinomas with such drugs is dis-
stimulates the chief cells. They also enhance the effects of cussed in Cases 4.1 and 4.2: 1. Reduction of acid secretion
other stimuli on the chief cell. In addition H ions stimu- by drug therapy will increase the pH of the chyme and
late the release of secretin in the duodenum (see below) thereby reduce the activity of pepsin, and so also protect
and secretin also stimulates pepsinogen secretion. These the mucosa from its action.
effects of H may account in part for the correlation
between acid and pepsin secretion. Gastrin stimulates Antacids
pepsinogen secretion directly via CCK receptors, but the
most potent effect of gastrin on pepsinogen secretion is Antacids are weak bases that act by neutralizing gastric
its indirect action via acid secretion. acid (Fig. 4.8). Raising the pH of the stomach contents
Activation of muscarinic receptors, and CCK (CCK- results in suppression of the action of pepsin that exacer-
A and CCK-B receptors) on the chief cells, results in the bates ulceration due to acid. Thus, antacids can be used
generation of inositol trisphosphate and diacylglycerol. to relieve gastric pain caused by excessive acid secre-
The relative importance of these two intracellular mes- tion. Compounds that are commonly used include mag-
sengers has not yet been elucidated. Receptors for secre- nesium hydroxide, magnesium trisilicate, aluminium
tin, VIP, cholera toxin and prostaglandins are also present hydroxide. Sodium bicarbonate is a rapidly acting ant-
but these are linked to the adenyl cyclase-cAMP second acid, but it should not be used for long-term treatment in
messenger system. Pepsinogen secretion is decreased peptic ulcer disease as it is absorbed in the intestines and
by somatostatin, which inhibits adenyl cyclase in the may cause metabolic alkalosis. The release of CO2 from
chief cell. bicarbonate dissolved in the stomach chyme can also be
a problem as it causes belching (eructation).

Protective mechanisms in the mucosa H2 receptor antagonists

The mucosal barrier Histamine H2 receptor antagonists competitively inhibit

the actions of histamine at H2 receptors on the oxyntic cell,
The mucosa of the stomach and duodenum is protected
from acid damage by:
Secretion of alkaline fluid
l
Box 4.2  Non-steroidal anti-inflammatory drugs
and ulceration
Secretion of mucus. Surface mucous cells secrete
l

mucus in response to chemicals such as alcohol, and Ingestion of non-steroidal anti-inflammatory drugs (NSAIDs)
in response to contact with roughage in the food. such as aspirin (acetylsalicylate) can cause ulceration of the
Mucus neck cells are also stimulated by gastrin to gastric mucosa because they inhibit prostaglandin synthe-
secrete mucus sis by inhibiting the enzyme cyclooxygenase. Indeed a defi-
Adequate blood flow
l ciency of prostaglandins may be a contributing factor in
peptic ulcer formation. Aspirin is a weak acid and at low pH
The presence of growth factors which promote the
l
values it tends to exist in the unionized form. The union-
replacement of damaged cells ized acid is lipid soluble and it is readily absorbed across the
Prostaglandins, which maintain mucosal integrity
l lipid membranes of the stomach. Because prostaglandins
and cause decreased acid secretion and increased inhibit acid secretion, inhibition of prostaglandin synthesis
bi-ca­rbonate and mucin production and increased by aspirin results in increased acid secretion. This may result
blood flow, all of which modify the local inflammatory in ulceration in some individuals. The mechanism probably
response caused by high acidity. Non-steroidal also involves disruption of the normal body repair mecha-
anti-inflammatory drugs (NSAIDs) inhibit nisms including cell turnover, which prevents healing of
prostaglandin synthesis (see Box 4.2). small abrasions in the mucosa.
Interestingly however, this reduction in cell turnover by
In peptic ulcer disease the protective mechanisms are inad- aspirin is protective against cancer in the mucosa of the
equate. The mechanisms of ulcer formation in the stomach colon (see Ch. 11).
and the duodenum are described in Cases 4.1 and 4.2: 1.

THE digestive SYSTEM 59

4
thereby reducing acid secretion (Fig. 4.8). These drugs are drugs block the H/K ATPase proton pump, markedly
CONTROL MECHANISMS OF THE STOMACH

usually effective in relieving the symptoms of peptic ulcer inhibiting both basal and stimulated secretion of gastric
disease (Cases 4.1 and 4.2: 2). These drugs can inhibit acid acid. Omeprazole is a powerful proton pump inhibi-
secretion by up to 90% and promote healing of the ulcers. tor. It is a weak base which acts by blocking the H/K
The drugs used are cimetidine, ranitidine, famotidine and ATPase activity of the proton pump. It is inactive at neu-
nizatidine. Long-term maintenance with these drugs was tral pH, but it is activated in acid conditions (pH 3.0 and
widely used until effective treatment with proton pump below). Such conditions exist only in the canaliculi of the
inhibitors and antibiotics became available. oxyntic cell. The action of the drug is therefore restricted
to this location in the gastrointestinal tract thereby avoid-
Proton pump inhibitors ing the unwanted side-effects of disruption of Cl ion
transport, which could occur in other organs such as the
Proton pump inhibitors block the hydrogen ion pumps in lungs, pancreas and skin (sweating) with use of other
the oxyntic cell. They include omeprazole and lansopra- H transport inhibitors which are active in less acid
zole (Fig. 4.8 and Cases 4.1 and 4.2: 2). These powerful conditions.

Cases
4.1 Peptic ulcer disease and gastrinomas: 1
and
4.2
Ulceration of the mucosa secretion. The inhibition of somatostatin release results in
Peptic ulcers can occur in the stomach or duodenum. However, removal of its inhibitory effect on gastrin release and conse-
the most common location for ulcers is in the duodenum. There quently increases the rate of gastrin secretion. This stimulates
are differences in the mechanisms of ulcer formation depending more acid production. The trophic effect of gastrin to stimu-
on their location. In the duodenum, the primary defect appears late proliferation of the oxyntic and peptic cells in the gastric
to be hypersecretion of acid, but in the stomach the main defect mucosa could exacerbate the condition as this would result in
is probably a deficiency in the protective mucosal barrier. increased acid and pepsin secretion.

Duodenum Stomach
Duodenal ulcers usually occur at the duodenal cap, where The most common site in the stomach for ulcers to occur is the
the acidic chyme meets the duodenal mucosa, before it mixes antrum, where the oxyntic mucosa meets the pyloric mucosa,
with the alkaline secretions of the duodenum. The duodenum i.e. the acid acts on the mucosa that does not have the same
does not have the same protective mechanisms as the stom- protective mechanisms as the body and fundus.
ach mucosa. In individuals with duodenal ulcers there is often The stomach normally has a low permeability to acid due
a higher than normal basal secretion of acid, and an abnor- to the presence of the protective mucosal barrier. The barrier
mally high rate of maximum secretion in response to hista- is partly due to the presence of mucins but other factors such
mine stimulation. as adequate blood flow and the presence of growth factors,
Individuals with duodenal ulcer may have twice the aver- which promote the replacement of damaged cells, are also
age normal number of oxyntic cells in their mucosae. In addi- important. However, it should be noted that mucus does not
tion pepsinogen secretion is also usually high. The sensitivity form a continuous layer and the protection is due to a great
to gastrin, the hormone that stimulates acid secretion is also extent to the fact that the rate of acid production keeps
usually increased in these individuals. If acid concentrations pace with the buffering capacity of the food. Peptic ulcers
are high, local vasodilation initially allows mucus and bicarbo- (Fig. 4.4) form in the stomach due to the action of acid when
nate production to be maintained. the mucosal barrier is damaged and the stomach is unable to
The eventual consequence is that chyme with an abnor- protect itself and replace the damaged cells. Thus ulcers in
mally high level of acid and pepsin is passed into the duo- the stomach are not usually due to an increased rate of acid
denum where the mucosa is not protected, resulting in the secretion but rather to a defect in the ability of the mucosa to
formation of ulcers. withstand damage (which may be caused by substances such
Helicobacter pylori (H. pylori) has high urease activity. This as aspirin, ethanol and bile salts). In fact in some individuals
causes increased NH4 production from urea. This allows the with peptic ulcers, the rate of acid secretion may be lower
bacteria to colonize in the acid environment. The bacteria than normal. The decreased rate of acid secretion is caused
also release cytokines that are involved in the inflammatory in part by H ions leaking into the mucosa in exchange for
response. H. pylori has been implicated in causing hyper- Na. The H ions accumulate and the pH of the cells falls. This
secretion of gastric acid in duodenal ulceration. It does this results in cellular injury and cell death. The H ions also dam-
by inhibiting the secretion of somatostatin that inhibits acid age mucosal mast cells causing them to release histamine.

60 SYSTEMS OF THE BODY

 4

CONTROL MECHANISMS OF THE STOMACH

Cases
4.1 Peptic ulcer disease and gastrinomas: 1 (continued)
and
4.2
This exacerbates the condition by acting on the mucosal capil- Role of pepsin in ulceration
laries causing ischaemia and vascular damage. A small amount The presence of pepsin is implicated in acid-induced ulcera-
of blood loss (occult) is usually associated with the ulcer, and tion. This enzyme can digest damaged mucosa in the oesopha-
in chronic ulcers this will result in anaemia. Occasionally, the gus, stomach, and duodenum, when activated by the presence
ulceration can erode into a major vessel (commonly the gas- of acid. Disruption of the mucosal barrier will provide the
troduodenal artery behind the first part of the duodenum) opportunity for pepsin to digest the columnar epithelium and
and life-threatening bleeding can occur. promote ulceration. Thus, pepsin potentiates (rather than ini-
H. pylori has been implicated in gastric ulcer as well as duo- tiates) ulcer formation.
denal ulcer disease. It is responsible for breaking down the
gastric epithelial barrier in gastric ulcer disease. It penetrates
the barrier and releases digestive enzymes that digest the Gastrinomas
stomach wall. Local vasodilation initially allows mucus and The massive secretion of acid and pepsinogen in Zollinger–
bicarbonate production to be maintained. The entry of acid Ellison syndrome (Table 4.1) leads to widespread ulceration
into the mucosa damages mast cells, causing increased release of the upper gastrointestinal tract. In this disease, ulcers may
of histamine that results in inflammation. Other factors (PAF, occur in the oesophagus, the stomach and the duodenum. In
leukotrienes, etc.) that cause a reduction in blood flow may the duodenum they occur at the same sites where they are
be produced. H. pylori also increases gastric acid secretion by seen in simple duodenal ulcers, in which the first part of the
the mechanism described above. Thus, although an increase duodenum is the typical site. However, they may also occur at
in acid secretion cannot be measured in gastric ulcer disease more distal sites in the duodenum, because of the very low
it is probably increased, but in this case the acid leaks back pH, and the high pepsin content, of the chyme leaving the
across the defective epithelium. stomach.

Cases
4.1 Peptic ulcer disease and gastrinomas: 2
and
4.2
Treatment as well as reflux oesophagitis and gastrinomas. However, if the
treatment is withdrawn the ulcers usually reoccur.
Drug therapy
A variety of different classes of drugs can be effective in Triple therapy
the treatment of peptic ulcer disease. Currently antacids, H2 Combinations of omeprazole (see below) and antibiotics have
receptor blockers, proton pump inhibitors and antibiotics all proved to be extremely effective in the treatment and often
have a role to play. the cure of duodenal ulcers. In practice, ‘triple therapy’ consist-
Long-term treatment with antacids can produce healing of ing of a proton pump inhibitor and the antibiotics amoxicillin
duodenal ulcers but they are ineffective for healing gastric and either metronidazole or clarithromycin is often instigated.
ulcers. H. pylori is generally eradicated after 2 weeks of this regimen.
Patients often self-medicate with H2 blockers as they are
available without prescription and are effective in control- Surgery
ling the symptoms. They are most effective if taken at night Treatment with H2 antagonists or proton pump inhibitors and
because the hypersecretion of acid from the empty stomach antibiotics is highly effective for duodenal or gastric ulcers but
at night and its entry into the empty duodenum may be the surgery is sometimes necessary. Most bleeding ulcers require
most important factor in duodenal ulcer formation. When endoscopy to stop bleeding with cautery, or injection. Surgery
the stomach contains food, buffering of acid, by proteins for for peptic ulcer disease is usually restricted to patients with
example, and the mixing of acid in the chyme reduces the complications such as haemorrhage from a blood vessel at the
exposure of the mucosa to the acid. These drugs can inhibit base of an ulcer (usually the gastroduodenal artery which passes
acid secretion by up to 90% and promote healing of the behind the first part of the duodenum), and erosion through the
ulcers. However, if treatment is withdrawn in patients with stomach into the peritoneal cavity which results in perforation
duodenal ulcers the ulcers are likely to reoccur. and peritonitis due to leakage of duodenal contents into the
Proton pump blockers, such as omeprazole, are very power- cavity. If a peptic ulcer perforates, air leaks into the peritoneal
ful drugs for reducing acid secretion. They are usually the first- cavity. If the patient stands erect the air will float to a position
line therapy in controlling the symptoms of peptic ulcer disease under the diaphragm. This can be detected by a chest X-ray.
(Continued)

THE digestive SYSTEM 61

4
CONTROL MECHANISMS OF THE STOMACH

Cases
4.1 Peptic ulcer disease and gastrinomas: 2 (continued)
and
4.2
Prior to the development of effective drug treatment, sur- Posterior Anterior
right trunk left trunk
gery was the main treatment for chronic peptic ulcer disease.
It involved either division of the vagus nerve (vagotomy), or
antrectomy (resection of the stomach antrum). Vagotomy was Hepatic Coeliac Straight
performed to reduce vagal stimulation of acid secretion in the division division 1
branches
stomach. Unfortunately, this also resulted in impairment of Pyloric
gastric motility and emptying. To overcome this problem, divi- branch 2
2

sion of the pyloric muscle (pyloroplasty) was also performed.

2 2
In the 1970s highly selective vagotomy, which preserved the
2 2
function of the pyloric muscle, was developed (Fig. 4.7). This 2
2
2
circumvented the need for a pyloroplasty.
2
A more radical approach sometimes used was surgical
removal of the antrum (antrectomy) that was performed in
order to remove the G cells and so reduce gastrin stimulation
of acid secretion. As gastrin has trophic actions to maintain
the gastric mucosa, patients who have undergone resection Branches
of the antrum have low circulating gastrin concentrations and Branches to antrum to body
may display atrophy of the oxyntic glandular mucosa. (Crow’s foot) and fundus

Fig. 4.7  Arrangement of the vagal innervation of the stomach. 1.

Gastrinomas Site of vagus nerve in a vagotomy; 2. sites of nerve section in a highly
The recognized treatment for Zollinger–Ellison syndrome is selective vagotomy.
first to control the overproduction of acid by treatment with
a proton pump inhibitor, such as omeprazole. This enables
the ulcers to heal and controls the diarrhoea. Patients usually
survive for many years with pharmacological treatment alone. However, many patients with Zollinger-–Ellison syndrome
When the ulcers are under control, surgery to remove a gas- (approximately 25%) have multiple endocrine neoplasia type
trinoma can be attempted to try to effect a cure. 1 (MEN 1), which may preclude surgical intervention.

Omeprazole has few unwanted side-effects, although However, the drug pirenzepine is a relatively specific
there remains concern about lowering acid secretion too M1 receptor antagonist that probably acts on postsynap-
drastically, because of the resultant elevation of serum tic nerves in parasympathetic ganglia, to block the stimu-
gastrin levels, which in theory could be mitogenic (and lation of oxyntic cells.
therefore tumour-promoting) because acid is a potent
inhibitor of G cell proliferation, and because of this, the
chronic administration of a proton pump blocker such Antibiotics
as omeprazole results in proliferation of G cells and ECL
cells. For this reason, if omeprazole treatment is suddenly Over the last few years, evidence has accumulated that
discontinued, rebound hyperacidity can result. chronic infection of the gastric mucosa by the bacterium
Helicobacter pylori is causally involved in potentiating
peptic ulcer disease. These bacteria are present in the
Muscarinic receptor antagonists stomach in many individuals but only a minority develop
peptic ulcer disease. The reasons for this are unknown.
Anticholinergic drugs that bind to muscarinic M2 recep- Over 80% of patients with gastric or duodenal ulcers are
tors on the oxyntic cell and the ECL cell can antagonize infected with it. It is a spiral Gram-negative bacterium
the effects of vagal nerve stimulation and reduce gastric which can survive in the low pH environment in the
acid secretion (Fig. 4.8). Most muscarinic M2 antagonists stomach. The action of this organism leads to impairment
are less effective than H2 receptor antagonists or proton of the function of the protective mucosal barrier. It is sen-
pump blockers, although they can have beneficial anti- sitive to a large number of antibiotics but those that pen-
spasmodic effects on gut smooth muscle. Furthermore etrate the submucosa where the microorganisms reside,
muscarinic receptors are present at many locations within such as clarithromycin and metronidazole, are the most
the gastrointestinal tract and outside it, and for this rea- effective. Eradication of H. pylori by antibiotic therapy
son, parasympathetic side effects, including effects on the prevents ulcer recurrence and so prevents the need for
cardiovascular system, are common with these drugs. long-term treatment.

62 SYSTEMS OF THE BODY

 4
Box 4.3  H. pylori and peptic ulcers: history

CONTROL MECHANISMS OF THE STOMACH

Stomach Antacids H+ Omeprazole
lumen
The role of bacterial infection in peptic ulcer disease was
+
H disputed for many years, in spite of some compelling evi-
CCK-B R pump PG R dence. The first recorded use of antibiotics to treat peptic
ulcers was by Lykoudis, a Greek general practitioner, in
G cell OX cell
Gastrin 1958. In 1982 Warren and Marshall, two Australian doc-
antagonists M3 R H2 R tors, rediscovered this role for bacteria. They proposed that
(proglumide) peptic ulcer disease and gastritis were caused by coloniza-
MR
tion with H. pylori. This hypothesis was not well-received
CCK-B R Prostaglandin by the drug companies, so Marshall performed an experi-
agonists
ment upon himself to demonstrate the role of H. pylori. He
ECL (misoprostol)
H2 receptor drank a culture of organisms extracted from a patient and
cell
antagonists soon developed gastritis. His symptoms disappeared after
MR (cimetidine,
2 weeks but he treated himself with antibiotics to kill the
ranitidine) NSAIDs remaining bacteria at the urging of his wife, as halitosis
is one of the symptoms of infection. In 1997, a campaign
Anticholinergic
was launched to educate healthcare providers about the
drugs (hyoscine)
link between H. pylori and peptic ulcer disease. In 2005,
Fig. 4.8  Drugs that inhibit or neutralize acid secretion, and their Warren and Marshall were awarded the Nobel Prize for
targets. OX, oxyntic cell; M R, muscarinic receptor; H2 R, histamine H2 their discovery.
receptor; CCK-B R, cholecystokinin-B receptor; PG R, prostaglandin
receptor; NSAIDs, non-steroidal anti-inflammatory drugs.

Short-term treatment with antibiotics combined with the sheets of smooth muscle. The muscle therefore exhib-
symptomatic relief by a proton pump inhibitor is now its contractile activity even in the resting state (see Ch. 1).
the standard treatment for peptic ulcer disease (Box 4.3). This contractile activity can be increased or decreased in
amplitude and frequency by factors that control the elec-
Other possible drug treatments trical activity of the smooth muscle cell membranes.
The electrical changes are of different shape and
Prostaglandins, which are synthesized in the gastric amplitude in different regions of the stomach. The mem-
and intestinal mucosa, can also be effective in reduc- brane potential is relatively stable in the fundus region,
ing acid secretion. In particular, prostaglandins of the E but a slow wave can be recorded in the rest of the stom-
(PGE) and I (PGI) series can be administered to protect ach. This slow wave is of relatively small amplitude in
the deeper mucosal cells from damage. PGE1 and PGE2 the body of the stomach but its amplitude progressively
and stable analogues such as misoprostol also inhibit increases in regions closer to the pylorus. The frequency
the histamine-mediated stimulation of acid secretion of the slow waves remains the same, approximately
(Fig. 4.8). In practice, their use has been superceded by 3/min, in the different regions because they are driven
proton pump inhibitors in the prevention of gastric dam- by the same pacemaker cells (see Ch. 1). In gastric
age from chronic use of non-steroidal anti-inflammatory smooth muscle, there is a threshold potential for action,
drugs (NSAIDs), such as aspirin (see Box 4.2). potential generation and contraction of the muscle. When
Antagonists of gastrin have been developed (Fig. 4.8). the membrane potential during the slow wave exceeds
An example is proglumide. However, these compounds the threshold, contraction occurs (Fig. 4.9). The greater the
are not potent enough for clinical use. Finally, agonists depolarization and the longer the membrane potential
of somatostatin and duodenal peptides such as secre- remains above the threshold, the more action potentials
tin could theoretically be useful in peptic ulcer disease, are generated and the greater the tension developed.
but at the present time suitable stable analogues of such In the antrum the action potentials exhibit an initial
drugs are not yet available. rapid depolarization phase, followed by a long plateau
phase (Fig. 4.9). The rapid depolarization phase is caused
by Ca2 entry into the cells through voltage-gated chan-
nels and the plateau phase is due to entry of both Ca2
Control of motility in the stomach and Na through slower voltage-gated channels. The
influx of Ca2 leads to muscle contraction (see Ch. 1).
In the stomach, the pacemaker cells are located in the In the terminal antrum, action potential spikes occur on
longitudinal muscle in the greater curvature region of the the plateaus of the slow waves. Trains of action poten-
fundus. The basal electrical rhythm (spontaneously oscil- tials that occur during the plateau phase elicit vigorous
lating membrane potential) generates action potentials contractions in the antrum and these can lead to gastric
in the pacemaker cells and these are transmitted through emptying.

THE digestive SYSTEM 63

4
Box 4.4  Postoperative gastric stasis
CONTROL MECHANISMS OF THE STOMACH

Tension (g) A B C
1 After surgical procedures, motility in the stomach is inhib-
0 ited. This is known as gastric stasis. If severe, it can result
in acute gastric dilatation (Fig. 4.10). It is a condition
that can last for several days. It may be due to activation
Threshold for
depolarization (mV)

of the sympathetic nervous system, i.e. excessive release of

contraction
-50 noradrenaline (Fig. 4.9). Biopsies of the human antrum of
Membrane

such patients have been investigated electrophysiologi-

cally. The action potentials recorded have a shorter plateau
-70
phase during repolarization. This leads to less tension being
0 2 4 6 8 10 0 2 4 6 8 10 12 0 2 4 6 8 10
generated, and the stomach dilates. Because the pylorus is
Time (seconds) Time (seconds) Time (seconds)
closed, the gastric juice accumulates in the stomach. It can
be easily relieved by passing a fine tube (a nasogastric tube)
Fig. 4.9  Control of smooth muscle contraction in the stomach into the stomach via the oesophagus, which allows free
antrum. (A) Electrical recordings of the membrane potential in the
drainage of the gastric juice and air from the stomach. The
absence of chemical mediators. (B,C) Effects of gastrin and nor-
condition is self-limiting and usually resolves over 48 h.
adrenaline, respectively, on the membrane electrical changes and
the contractile force.

Table 4.3  Endogenous factors which control smooth muscle

tension
S
Factor Location Stimulus Receptor

Depolarization (increased muscle tension)

Stretch Stomach Distension
Ach Nerves Distension, Muscarinic
peptides
Gastrin Stomach Peptides, CCK-B LB
distension
Hyperpolarization (decreased muscle tension)
NA, Nerves Stress (e.g. -adrenergic
adrenaline exercise)
ATP Nerves Chewing, taste, Purinergic
smells, etc.
CCK Duodenum Fat CCK-A?
Secretin Duodenum Acid VIP
VIP Enteric nerves Distension VIP
GIP Duodenum Fat VIP
Fig. 4.10  A plain abdominal X-ray showing dilated loops of
large bowel (LB) and a massively dilated stomach (S) containing
ACh, acetylcholine; NA, noradrenaline; VIP, vasoactive intestinal
food residue.
peptide; GIP, gastric inhibitory peptide; CCK, cholecystokinin.

Stretch or distension of the stomach walls increases the during exercise and therefore the motility of the gastroin-
tension (the myogenic reflex, see Ch. 1). Increased levels testinal tract is decreased. Stimulation of purinergic fibres
of circulating gastrin or stimulation of the vagus nerve in the vagus during the cephalic phase of gastric control
also lead to a greater force of contraction. This effect is (see below) also inhibits muscle contraction. These nerves
due to an increase in the amplitude and duration of the release ATP which hyperpolarizes the smooth muscle
slow wave depolarization (Fig. 4.9). membranes. Table 4.3 summarizes the effects of endog-
Stimulation of the adrenergic sympathetic nerves to enous factors on smooth muscle electrical potential and
the stomach or increasing levels of CCK, secretin or GIP muscle tension.
(see below) in the blood results in hyperpolarization of After stomach surgery, the motility of the stomach is
the membrane, fewer action potentials, and relaxation of reduced, a phenomenon which may be attributed to cat-
the muscle (Fig. 4.9). Sympathetic nerves are activated echolamine release (Box 4.4).

64 SYSTEMS OF THE BODY

 4
3. The intestinal phase: due to food material in the

CONTROL MECHANISMS OF THE STOMACH

Control of the pyloric sphincter
intestines, mainly the duodenum and upper jejunum.
The mucosal and muscle layers of the stomach and duo- In practice of course, for much of the time during a meal,
denum are discontinuous due to the presence of a ring ingested material is present at different locations at the
of connective tissue on the duodenal side of the pyloric same time.
sphincter, but the myenteric plexi of the pylorus and duo- The effects of hypersecretion of acid in peptic ulcer
denal bulb are continuous. The basal electrical rhythm of disease and gastrinoma on gastrointestinal functions are
the duodenum is faster (approx. 10/min) than that of the described in Cases 4.1 and 4.2: 3.
stomach. The duodenal bulb contracts rather irregularly
because it is influenced by the basal electrical rhythm of
both the stomach and the duodenum. However, the activ- The cephalic phase
ity in the antrum and duodenum is coordinated, and when
the antrum contracts, the duodenal bulb is relaxed. The Secretion
pylorus is densely innervated by parasympathetic (vagal) During the cephalic phase, gastric acid and pepsino-
and sympathetic nerve fibres. The sympathetic nerves gen secretion is activated by the thought, sight or smell
release noradrenaline, which acts on adrenergic receptors of food, and by food in the mouth. The mechanisms of
to increase the constriction of the sphincter. Relaxation of control of gastric secretion during the cephalic phase
the sphincter is due to impulses in peptidergic fibres in the are summarized in Figure 4.11. Emotions also influence
vagus that release VIP. After non-selective vagotomy this gastric secretion. The response to the sight and smell of
constriction is unopposed, and the outlet of the stomach food is a conditioned reflex; a learned response based on
can be obstructed. Interestingly there are also excitatory previous experiences of eating food. The release of acid
(cholinergic) fibres in the vagus nerve, activation of which at the sight and smell (approach) of food was first dem-
increases constriction of the sphincter. However, as the onstrated by sampling of the gastric contents through a
sphincter relaxes when the stomach empties, activation of gastrostomy (fistula) in subjects who could not swallow
the inhibitory fibres predominates during stomach empty- food and had therefore been provided with a permanent
ing. Finally, CCK causes constriction of the pyloric sphinc- fistula so that food could be placed directly in the stom-
ter in physiological concentrations that cause gall bladder ach. Emotions were found to elicit increased or decreased
contraction. Therefore, CCK is probably also one of the acid secretion. This was shown by Wolff and Wolff, phy-
physiological regulators of the sphincter. sicians who studied a patient with a closed oesophagus
who was provided with a gastrostomy. They showed that
hostility and resentment tended to increase gastric secre-
tion whilst depression tended to reduce it.
Control of gastric function by food The taste and the touch of food in the mouth also elic-
its secretion of gastric juice (before the food reaches the
stomach). This is a non-conditioned reflex. It was studied
Motility in the stomach is controlled partly by blood
by the physician Janowics, in a patient who had had a
glucose levels. When the blood glucose concentration
gastrostomy because she could not swallow food. It was
falls during fasting, gastric smooth muscle is stimulated.
found that if the patient placed some food in her mouth
Peristaltic contractile activity increases, but not gastric
and chewed it, there was an increased secretion of gastric
emptying. These contractions can be strong enough to
juice. Furthermore, food that the patient enjoyed elicited
cause ‘hunger pains’. They are due to impulses in the
a more copious secretion than food which she merely
vagus nerve that is sensitive to low blood glucose.
tolerated. The secretion in response to palatable food is
Acid is secreted at a low rate even when the stomach
known as ‘appetite juice’. This gives some physiologi-
is empty. The basal rate is approximately 10% of the max-
cal justification for starting a meal with a savoury course
imum rate. However, the basal rate is not constant as it
(hors d’oeuvre).
shows a diurnal variation: it is lowest in the morning and
The gastric juice secreted during the cephalic phase
highest in the evening.
is rich in pepsinogen, but also contains some acid. The
When a meal is eaten, the mechanisms which control
secretion of both pepsinogen and acid is due to impulses
the secretion of gastric juice and the motility and empty-
in the vagus nerve. Stimulation of the nerves releases
ing of the stomach interact in a complex manner to coor-
acid both directly from the oxyntic cell and indirectly via
dinate the functions of this organ. The control of gastric
the release of gastrin (Fig. 4.11). Less than half the acid
function during a meal can be conveniently divided into
produced in response to a meal is secreted during the
three main phases depending on the location of the food:
cephalic phase. Vagotomy (section of the vagus nerve,
1. The cephalic phase: occurs before the food reaches the see Cases 4.1 and 4.2: 1) reduces the secretion of gastric
stomach. It is a response to the approach of food (i.e. juice mainly because its effect during the cephalic phase
smell, sight of food), or food in the mouth. is abolished. When acid is secreted during the cephalic
2. The gastric phase: occurs in response to food when it phase, that is while the stomach is still empty, there is
reaches the stomach. very little protein present in the stomach to buffer the

THE digestive SYSTEM 65

4
CONTROL MECHANISMS OF THE STOMACH

Cases
4.1 Peptic ulcer disease and gastrinomas: 3
and
4.2

Effects on gastrointestinal function Thus, in Zollinger–Ellison syndrome, the excessive acid secre-
tion may lead to defective absorption of lipids and other
Peptic ulcer disease
nutrients. The consequences are defective lipid absorption,
Stomach function deficiency of essential fatty acids required for healthy nerves
High acidity in the stomach normally causes the release of and deficiency of vitamin A (required for night vision), vitamin
somatostatin that inhibits the release of gastrin to reduce D, required for Ca2 absorption (see Ch. 8) and Ca2 homeos-
the secretion of acid in the stomach. In peptic ulcer disease tasis, and vitamin K, required for effective blood clotting.
H. pylori inhibits somatostatin secretion and the rate of gas-
trin secretion could consequently increase. This would stimu- Pernicious anaemia
late more acid production. Gastrin also has a trophic effect Vitamin B12 is poorly absorbed in the ileum at low pH values for
to stimulate proliferation of the oxyntic and chief cells in the reasons that are not yet understood. As a consequence of this,
gastric mucosa which exacerbates the condition by causing pernicious anaemia can develop in Zollinger–Ellison syndrome.
increased acid and pepsinogen secretin.
Excess acid in the duodenum normally causes the release of Diarrhoea
secretin, which inhibits the secretion of gastric acid, but these
Diarrhoea is usually a prominent symptom in Zollinger–Ellison
effects are overwhelmed by the high acid secretion in peptic
syndrome. It is present in approximately 65% of cases. There
ulcer disease.
are a number of causes:

Gastrinomas l Elevated gastrin concentrations in the blood cause massive

Digestion and absorption volumes of secretion from the stomach, pancreas, liver and
In the patient with gastrinomas diarrhoea is a frequent symp- intestines. The absorptive capacity of the small intestines
tom. This is due to hypersecretion and hypermotility, secondary and colon is consequently overwhelmed, and diarrhoea
to chronic gastrin stimulation. Such patients can also suffer from results. This is probably the major mechanism involved in
steatorrhoea; fat in the faeces. Normally, almost all neutral fat causing diarrhoea in this condition
ingested is digested and absorbed in the small intestine (see Ch. l Impaired digestion and malabsorption of nutrients (see

8). Therefore steatorrhoea is an indication of malabsorption of above) results in the chyme becoming highly concentrated
fat. The excessive acid production in Zollinger–Ellison syndrome and therefore hyperosmotic. In the colon, undigested
can lead to fat malabsorption for two reasons: nutrients ferment to produce a further increase in osmotic
particles. Water is consequently transported from the
1. Pancreatic lipase (and other enzymes) are active at neutral blood into the lumen of the intestines, down the osmotic
or slightly alkaline pH values and are reversibly inactivated gradient, and ‘osmotic diarrhoea’ results
at acid pH values, so digestion of food is reduced. l As gastrin increases, smooth muscle contractility and high

2. Effective absorption of the monoacylglycerol and long- circulating levels can result in increased gastrointestinal
chain fatty acid products of lipid digestion, and lipid- motility. This will reduce intestinal transit time and cause
soluble vitamins (A, D, K and E), depends on them being diarrhoea.
sequestered in micelles (see Ch. 8). Micelle formation will
only take place at neutral or alkaline pH values, so again, The mechanisms involved in diarrhoea are discussed more
fat absorption is reduced. fully in Chapter 7.

acid. Therefore a small amount of acid will produce a depression, fear and sadness also inhibit it. The mecha-
marked fall in pH. This results in the feedback control nism is probably via impulses in inhibitory purinergic
mechanism coming into operation, whereby acid secre- fibres in the vagus nerve. The activity in these nerve
tion is inhibited. The secretion of pepsinogen during the fibres causes relaxation of stomach smooth muscle and
cephalic phase is due both to direct stimulation of the inhibits gastric emptying. At the same time, the pyloric
chief cells by the vagal impulses, and to the release of sphincter is constricted. The latter effect is probably also
gastrin, which also stimulates the chief cells. due to impulses in cholinergic fibres in the vagus nerve.
This delay in the emptying of the stomach permits the
stomach initially to store a greater volume of material,
Motility and so allows time for the digestive processes to oper-
Motility in the stomach smooth muscle is reduced dur- ate. Interestingly, aggression and anger increase gastric
ing the cephalic phase. The sight, smell, taste and touch motility but the mechanisms involved have not yet been
of food in the mouth all inhibit gastric emptying. Pain, elucidated.

66 SYSTEMS OF THE BODY

 4
Peptides,

CONTROL MECHANISMS OF THE STOMACH

Sight, smell of food, Lumen amino acids Acid
food in the mouth
+ +
+ + -
Vagus G cell D cell
Somatostatin
nerve
Local
neurone +
ACh
+ Gastrin
G cell Mechano + Vagus
receptor nerve
(distension) ECL
cell
Gastrin
ACh

+ ACh
Histamine
ECL
cell
+ +
OX cell

ACh + + Chief cell

Histamine

+ +
OX cell +
H Pepsinogen
+ Chief cell
Fig. 4.12  Gastric phase of control of gastric secretion, OX, oxyntic
cell, ECL, enterochromaffin-like cell.
+
H Pepsinogen

Fig. 4.11  Cephalic phase of control of gastric secretion.

Motility
During the gastric phase, the stomach empties at a rate
that is proportional to the volume of material within it.
The gastric phase
This is due partly to the effect of distension; the chyme
stimulates pressure receptors in the wall of the stomach,
Secretion which trigger impulses in nerves in the internal nerve
Food placed directly into the stomach through a gastric plexi. It is probably also due to the direct effect of stretch-
fistula (gastrostomy) elicits an increase in both acid and ing the smooth muscle (the myogenic reflex, see Ch. 1).
pepsinogen secretion. The gastric phase accounts for more There is also a vagal mechanism involved in the response
than 50% of the acid secreted during a meal. The con- to distension, but in the gastric phase (unlike the cephalic
trol of secretion during the gastric phase is summarized phase), impulses in the vagus nerve increase peristalsis
in Figure 4.12. The amount of secretion depends on the and gastric emptying. In this case it is the cholinergic nerve
chemical content of the food, and its volume. Secretion of fibres in the vagus that are activated. However, excessive
gastric juice is in response to chemicals in the food and to distension inhibits contractility (see Ch. 1) thereby allow-
distension of the walls of the stomach by food. The prod- ing a longer time for the digestive processes to operate.
ucts of protein digestion, especially peptides and amino Gastrin release into the blood in response to peptides and
acids (in particular tryptophan and phenylalanine), and amino acids also causes potentiation of peristalsis.
caffeine (present in tea, coffee, coca cola), and alcohol, Gastric emptying is brought about by strong periodic
stimulate gastric secretion. These chemical substances in contractions of the antrum, potentiated by gastrin, and
the food, or ‘secretogogues’, are sensed by APUD cells acetylcholine in the vagus nerve. The pyloric sphincter
which behave as chemoreceptors or ‘taste’ cells. The G relaxes when the antrum contracts and allows a portion
cells sense peptides and amino acids. Distension, another of the gastric chyme into the duodenum. The relaxation
stimulus that increases acid secretion, is detected by pres- of the sphincter is probably due to impulses in peptider-
sure receptors or nerve endings in the mucosa. Distension gic nerve fibres which release VIP, in the vagus nerve.
is not as powerful a stimulant as the chemical constituents
of food. A low pH in the stomach causes inhibition of acid
secretion, although pepsinogen secretion is stimulated. The intestinal phase
The D cells sense H ions. The regulation of gastric secre-
tion in this phase is via coordinated neural, hormonal and The intestinal phase of gastric function is largely inhibi-
paracrine mechanisms. The neural signals are conducted tory. Gastric secretion and motility are both inhibited. In
in extrinsic nerves of the vagus nerve, and in intrinsic the duodenal phase, the food is mixed with the diges-
nerves of the enteric nerve plexi. tive secretions of the pancreas and liver. The inhibition of

THE digestive SYSTEM 67

4
Duodenum Stomach
CONTROL MECHANISMS OF THE STOMACH

Cases
4.1 Peptic ulcer disease and
Acid Fat and gastrinomas: 4
4.2

Acid–base balance
Oxyntic cell
– Peptic ulcer disease
APUD
– Acid secretion in the stomach is accompanied by secretion
cells Smooth
of bicarbonate into the blood that makes the blood alkaline
muscle
– (the ‘alkaline tide’, see Ch. 3). This is normally neutralized
– by the acid secreted into the blood when alkaline bicarbo-
nate secretions (pancreatic juice, bile, intestinal secretions)
Secretin CCK Secretin CCK are produced. The acid secretions are increased in duode-
nal ulcer disease and the consequent raised blood pH will
take longer to be neutralized by respiratory and renal com-
Secretin Secretin
Blood pensatory mechanisms. However, these mechanisms usually
CCK CCK maintain the pH within normal parameters.

Fig. 4.13  Intestinal phase of gastric control.

Gastrinomas
In Zollinger–Ellison syndrome there is excessive secretion of
gastric emptying by food in the duodenum enables the acid, due to the high levels of circulating gastrin, which can
duodenal contents to be processed before more material lead to a pronounced alkaline tide. Gastrin not only stim-
enters it from the stomach. ulates acid secretion in the stomach, it also stimulates the
production of alkaline juices from the duct cells of the liver
and pancreas. Furthermore, acid in the duodenum stimu-
Secretion lates alkaline pancreatic juice and bile secretion via secretin
Although food in the duodenum is largely inhibitory as (see Chs 5 and 6), which would normally result in an ‘acid
far as gastric secretion is concerned, there is an early stim- tide’. However, the exaggerated alkaline tide resulting
ulatory phase in response to slight distension of the duo- from the copious acid secretion seen in Zollinger–Ellison
denum, probably due to the release of gastrin from APUD syndrome may overwhelm these homeostatic mechanisms.
cells in the walls of the duodenum. However, appropriate The respiratory and renal mechanisms may be inadequate
stimulation of the duodenum inhibits gastric secretion. to compensate for this effect, so metabolic alkalosis occurs.
Inhibitory stimuli include distension of the duodenum,
fats and peptides in the chyme, increased acidity, and
hypertonic solutions. All of these stimuli cause the release
of hormones from APUD cells. This phase of control of Control of the pH of the gastrointestinal tract helps to
secretion is summarized in Figure 4.13. maintain the pH of the blood within normal limits (see
Acid in the duodenal chyme causes the release of secre- Ch. 3). The effects of hypersecretion of acid on acid–base
tin, and fat in the duodenal chyme causes the release of balance are described in Cases 4.1 and 4.2: 4).
CCK and GIP into the blood, and these hormones all inhibit
secretion of gastric juice (see above). This is a feedback
mechanism that prevents the duodenal contents becoming Motility
excessively acid. It is important for several reasons:
Motility in the stomach can be influenced by food in
l Digestive enzymes, which act in the small intestine the duodenum, food in the ileum and food in the colon.
require neutral or acid pH values for optimum activity Distension of the duodenum inhibits gastric motility via
two mechanisms:
l Micelle formation, which is necessary for fat digestion
and absorption in the small intestine (see Ch. 8) will 1. A quick enterogastric reflex which employs
only take place at a neutral or slightly alkaline pH nerve fibres in the vagus nerve and an unknown
neurotransmitter.
l The duodenum is the most common site for ulcer
formation in the digestive tract and acid is the prime 2. A slower humoral mechanism involving the release of
cause of ulceration in this region. The reduction of hormones from the walls of the duodenum into
acid secretion begins when the pH of the duodenal the blood. These hormones are collectively known
contents falls to 5.0, and it is complete at a pH value of as enterogastrones. They include CCK and secretin
approximately 2.5. (Fig. 4.13).

68 SYSTEMS OF THE BODY

 4
When food material reaches the ileum, the emptying of There is also a neural reflex response when the chyme

CONTROL MECHANISMS OF THE STOMACH

the stomach is delayed. This is a neural reflex initiated enters the colon; distension of the colon activates pres-
by activation of mechanoreceptors in the walls of the sure receptors which triggers impulses in internal nerves
ileum, which trigger action potentials in nerve fibres in to delay gastric emptying.
the internal nerve plexi. Interestingly, when food enters
the stomach the motility of the ileum is increased. Thus the
ileogastric reflex operates in both directions.

THE digestive SYSTEM 69

Pancreas: Exocrine
Functions 5
Chapter objectives
After studying this chapter you should be able to:

1. Describe the macroscopic and microscopic anatomy of the pancreas

and relate these to its function.

2. Describe the components of exocrine function of the pancreas and

apply this knowledge in understanding the pathological conditions
of acute and chronic pancreatitis and cystic fibrosis.
5
EXOCRINE FUNCTIONS OF THE PANCREAS

Introduction Anatomy and morphology

The pancreas contains exocrine tissue that secretes pan- The pancreas is an elongated gland that lies in the abdom-
creatic juice, a major digestive secretion, and endocrine inal cavity. It can be divided into three regions: the head,
tissue that secretes the hormones insulin and glucagon. the body and the tail (Fig. 5.1). The head is an expanded
The hormones are important in the control of metabolism portion that lies adjacent to the C-shaped region of the
and their roles in the absorptive and postabsorptive met- duodenum to which it is intimately attached by connective
abolic states will be discussed in Chapter 9. This chapter tissue, and to which it is connected by a common blood
will be mainly concerned with the exocrine secretions supply. The body and tail extend across the midline of the
of the pancreas, their functions, and the mechanisms body toward the hilum of the spleen. The pancreatic duct
whereby the secretory processes are controlled. (duct of Wirsung) extends through the long axis of the
Pancreatic juice finds its way into the duodenum via gland to the duodenum. Pancreatic juice empties from this
the pancreatic duct that opens into the duodenum at the duct into the duodenum via the ampulla of Vater. In some
same location as the common bile duct (Fig. 5.1). Entry individuals, there is also an accessory pancreatic duct.
of both pancreatic juice and bile into the duodenum is Bile in the common bile duct from the liver also enters the
controlled by the sphincter of Oddi. The smooth muscle duodenum at the ampulla of Vater, by passing through the
of the sphincter is contracted between meals so that the head of the pancreas. This is why inflammation (pancrea-
junction is sealed. When a meal is being processed in the titis) and tumours (pancreatic cancer) involving the head
gastrointestinal tract, the sphincter muscle relaxes and of the pancreas are commonly associated with jaundice, as
allows the pancreatic juice and bile into the small intes- a consequence of blockage of the common bile duct.
tine. The control of the sphincter of Oddi is discussed in
Chapter 7. Pancreatic exocrine dysfunction may be due
to disorders of the pancreas itself, or to blockage of the Exocrine tissue
ducts which prevents the exocrine secretions reaching the
duodenum. Duct blockage may also result in impaired The exocrine units of the pancreas are tubuloacinar glands
bile flow from the liver, which can result in jaundice. that are organized like bunches of grapes (Fig. 5.3), in a
In the small intestine, pancreatic juice, bile and the similar manner to the units in the salivary glands. The
juices secreted by the walls of the intestines, mix with the exocrine units surround the islets of Langerhans, the
fluid (chyme) arriving from the stomach (see Fig. 7.1). endocrine units of the pancreas. For this reason, destruc-
Pancreatic juice provides most of the important digestive tive diseases such as chronic pancreatitis involve impair-
enzymes. In addition, by virtue of its bicarbonate content, ment of both exocrine and endocrine function. A thin
it helps to provide an appropriate neutral or alkaline pH layer of loose connective tissue surrounds the gland. Septa
in the intestinal lumen for the enzymes to act on their extend from this layer into the gland, dividing it into lob-
nutrient substrates. The functional importance of the ules and giving it an irregular surface. Larger areas of
pancreas to the digestive processes can be illustrated by connective tissue surround the main ducts and the blood
the problems arising in chronic pancreatitis (Case 5.1: 1) vessels and nerve fibres that penetrate the gland. Small
and cystic fibrosis (Case 5.2: 1) conditions in which pan- mucous glands situated within the tissue surrounding the
creatic tissue is destroyed. pancreatic duct secrete mucus into the duct.

Cystic duct Common bile duct

Head

Body

Duct
Tail
openings
Duodenum Pancreas
Sphincter
of Oddi

Duodenum Main pancreatic duct

Accessory pancreatic duct

Fig. 5.1  The pancreas and its innervation and blood supply.

72 SYSTEMS OF THE BODY

 5

EXOCRINE FUNCTIONS OF THE PANCREAS

Case
5.1    Chronic pancreatitis: 1

A 40-year-old man who had been a heavy drinker for many

years, went to see his general practitioner. He had made two
previous visits over the past year complaining of recurrent
episodes of abdominal pain. Although the pain had been
intermittent at first, it was now continuous. The doctor ascer-
tained that the pain originated in the epigastrium, and radi-
ated through to the back. The patient had lost a considerable
amount of weight since his last visit. The doctor noticed that
A
he was mildly jaundiced. Arrangements were made for the
patient to be admitted to hospital for tests. A
An X-ray examination, and serum and urine analyses were
B
performed. The patient’s stools were collected over 3 days. C
These were pale-coloured and bulky, indicating a high fat D D
content (steatorrhoea). He was told to abstain from food the
next morning so that a glucose tolerance test (see Chapter 9)
could be performed.
The blood tests showed increased bilirubin and alkaline
phosphatase. The glucose tolerance test showed an abnor-
mally high and prolonged rise in serum glucose, and urine
analysis confirmed the presence of glucose (glycosuria), indi-
cating that the patient was diabetic. The presumptive diag-
nosis was chronic pancreatitis. The patient was prescribed Fig. 5.2  CT scan: cross-section of the abdomen showing a
pethidine to control the pain. He was advised to abstain swollen pancreas caused by pancreatitis (A) lying posteriorly on
completely from alcohol, and to eat regular meals. Figure 5.2 the abdominal wall. The spleen (B), lower border of liver (C) and
shows a CT (computerized tomography) scan of the abdomen kidneys (D) are also seen.
of an individual with chronic pancreatitis. The swollen pan-
creas can be clearly seen. Examination of the details of this l What is the basis of the glucose tolerance test and why has
case gives rise to the following questions: diabetes mellitus developed in this patient?
l Why did the patient appear jaundiced?

l Is the primary defect in chronic pancreatitis known? l Why were the patient’s serum bilirubin and alkaline

l What might the X-ray have revealed? phosphatase abnormally high?

l What could be the cause of the condition in this patient? l What are the main physiological consequences of this

l How are the exocrine and endocrine functions of the disease and how can the condition be treated or managed?
pancreas impaired in chronic pancreatitis?
l What did the high faecal fat content indicate? These questions will be addressed in this chapter.

Endocrine tissue Glucagon and insulin, the hormones produced by the

 and  cells, respectively, are taken up by the local blood
The endocrine units, or islets of Langerhans, are most vessels to act systemically. Somatostatin acts locally in a
numerous in the tail region of the pancreas. They consist paracrine manner to inhibit the secretion of the  and 
of clusters of cells which are surrounded by the pancre- cells, as well as the exocrine secretions of the acinar and
atic acini (Fig. 5.3). The islets vary considerably in size. duct cells. Pancreatic polypeptide acts in a paracrine
As with all endocrine tissue, the hormones they produce manner to inhibit the exocrine secretions of the pancreas.
are secreted into the blood. The major endocrine cell Oxygenated blood is supplied to the pancreas by
types present are: , , D and PP cells, which secrete glu- branches of the coeliac and superior mesenteric arteries.
cagon, insulin, somatostatin, and pancreatic polypeptide, The pancreatico-duodenal artery lies between the duode-
respectively (for more information, see Ch. 9). Different num and the head of the pancreas. The close proximity
types of endocrine cells can be distinguished under of these structures means that it would be hazardous to
the electron microscope by the different appearance remove the pancreas without the duodenum, because the
of the granules within them. The islet cells have the gen- main arterial supply would inevitably be damaged.
eral features of APUD cells (see Ch. 1). In addition, there The blood drains from the pancreas via the portal vein to
are a few (5%) small ‘clear’ cells with as yet no clearly the liver. This arrangement is important for the transport
defined function. of pancreatic hormones to the liver where they contribute

THE digestive SYSTEM 73

5
EXOCRINE FUNCTIONS OF THE PANCREAS

Case Intercalated
5.2   Cystic fibrosis: 1 Pancreatic
ducts
lobule

A 12-year-old boy who was suffering from cystic fibrosis Extralobular

was taken to the outpatient clinic for his regular check-up. duct
Interlobular
Cystic fibrosis is an inherited autosomal recessive disorder.
ducts
The primary defect is a mutation in the gene that encodes
the cystic fibrosis transport regulator (CFTR). The CFTR is
A Main
responsible for cyclic-AMP-regulated Cl conductance in the
collecting
membranes of secretory cells of epithelia. The defect causes duct
impaired Cl transport that is predominantly a problem in
the wet surfaces of the respiratory tract, but also causes
severe problems in the pancreas. It is also manifest in the Islet of
reproductive tract and sweat glands. The boy’s condition Langerhans
had been diagnosed soon after birth and he had both respi-
ratory tract and pancreatic involvement. He had been asked
to bring a sample of his stool. This was pale-coloured, poorly
formed and oily in appearance. It was sent to the laboratory
for analysis to assess his pancreatic function. His exocrine Acinar cell
pancreatic insufficiency was being treated with a pancreatic
enzyme preparation and the anti-ulcer drug ranitidine. Duct cell
After studying the above details, we can attempt to
answer the following questions: B

l How is the inherited defect manifest in the pancreas?

l Which abnormalities of pancreatic function result from
this pathology?
Microvilli
l Why was the boy’s stool pale coloured?

l Which tests would be performed on the stool sample? Zymogen granules Tight junction
l Would there be any abnormalities in the acid–base (zonulae adherens)
Mitochondrion
status of this patient?
Rough Golgi apparatus
l Why was the child being treated with an enzyme
endoplasmic
preparation and would there be any problem with reticulum Nucleus
giving such a preparation by mouth?
l Why is the boy being treated with ranitidine?

C Lumen

Fig. 5.3  (A) A lobule of the pancreas indicating the duct system. (B)
to the control of energy metabolism, a topic discussed in The relationship of an exocrine unit and an islet of Langerhans. (C) An
Chapter 9. The acini and ducts are surrounded by sepa- acinar cell.
rate capillary beds. Some of the capillaries that supply the
islets converge to form efferent arterioles which then enter
further capillary networks around the acini. This arrange- The duct that drains the acinus is known as an inter­
ment is important for the paracrine control of pancreatic calated duct. These empty into larger intralobular ducts.
exocrine secretion. The intralobular ducts in each lobule drain into a larger
Cholinergic preganglionic fibres of the vagus nerve extralobular duct that empties the secretions of that lob-
enter the pancreas. These synapse with postgangli- ule into still larger ducts, and the latter converge into the
onic cholinergic nerve fibres which lie within the pan- main collecting duct, the pancreatic duct.
creatic tissue and innervate both acinar and islet cells. The acinus is a rounded structure consisting of mainly
Postganglionic sympathetic nerves from the coeliac and pyramidal epithelial cells (Fig. 5.4). These cells secrete the
superior mesenteric plexi innervate the pancreatic blood digestive enzymes of the pancreatic juice. They display
vessels as well as the acinar and duct cells. polarized features that are common to secretory cells
(Fig. 5.3). The nucleus of the acinar cell is situated at the
base of the cell. The cytoplasm in the basal region can be
Histology of the exocrine tissue stained with haematoxylin or basic dyes due to the pres-
ence of rough endoplasmic reticulum, the site of produc-
Figure 5.3 shows the structure of a pancreatic lobule. tion of the digestive enzymes. Small mitochondria are
The exocrine units of the pancreas, or pancreatins, each situated throughout the cell. The apical portion of the cell
consist of a terminal acinar portion and a duct (Fig. 5.4). contains the Golgi apparatus, and numerous zymogen

74 SYSTEMS OF THE BODY

 5
from the spaces. They also have gap junctions that permit

EXOCRINE FUNCTIONS OF THE PANCREAS

the transmission of membrane electrical changes between
the cells. These ducts lead into the intralobular ducts that
are lined with cuboidal or low columnar epithelium.
Acinar cell
Larger ducts contain interlobular connective tissue cells
Enzyme
and APUD cells.

Pancreatic juice

The pancreatic juice entering the duodenum is a mixture

of two types of secretion: an enzyme-rich secretion from
Centrocinar cell the acinar cells and an aqueous alkaline secretion from
HCO3- the ducts. Thus, if the ducts are ligated near the acini,
which results in acinar cell degeneration, the secretion of
the alkaline component of the juice is largely unaltered,
but the secretion of enzymes is markedly reduced. The
alkaline secretion originates largely from the centroaci-
nar cells and the duct cells of the intralobular and small
interlobular ducts. These relationships are illustrated in
Duct cell HCO3-/Cl- Figure 5.4.
exchange

Alkaline secretion

Fig. 5.4  Secretory unit showing the cellular locations of the different
Composition
secretions.
The cells of the upper ducts secrete an isotonic juice
which is rich in bicarbonate but contains only traces of
granules that contain the pancreatic enzymes or their enzymes. There is a continuous resting secretion of this
precursors. The apical region therefore stains with acid juice, but it can be stimulated up to 14-fold during a
dyes such as eosin. Microvilli extend from the apical sur- meal. It contains Na, K, HCO3, Mg2, Ca2, Cl and
face of the acinar cell into the lumen. The apical poles of other ions present in concentrations similar to those of
neighbouring cells are joined by tight junctions, known plasma. It therefore resembles an ultrafiltrate of plasma,
as zonulae adherens. These junctions separate the fluid but is alkaline by virtue of its high HCO3 content.
in the lumen of the acinus from the fluid in the intercellu-
lar spaces that bathes the basolateral surfaces of the cells. Functions
The tight junctions are impermeable to macromolecules,
such as digestive enzymes, in the luminal fluid, but per-
The pancreatic juice arriving in the duodenum is mixed
mit the exchange of water and ions between the inter-
with the chyme by contractions of the smooth muscle of
stitial spaces and the lumen of the acinus. Disruption of
the small intestine. The function of the alkaline pancre-
these junctions may be an aetiological factor in the devel-
atic secretion, together with the other alkaline secretions
opment of chronic pancreatitis. Gap junctions between
(bile and intestinal juices) that act in the small intestine,
neighbouring cells allow rapid changes in membrane
is to neutralize the acid chyme arriving from the stom-
potential to be transmitted between the cells. They also
ach. This is important for several reasons:
permit the exchange of low molecular weight molecules
(1400 kDa mass) between cells. l The pancreatic enzymes require a neutral or slightly
The intercalated duct begins within the acinus. This is alkaline pH for their activity
a unique feature of secretory glands. The upper duct cells l The absorption of fat depends on the formation in
within the acinus are known as centroacinar cells (Fig.
the intestinal lumen of micelles, a process which only
5.4). These stain lightly with eosin. They are squamous
takes place at neutral or slightly alkaline pH values
cells with a centrally placed nucleus. These cells are con-
tinuous with those of the short intercalated duct that lies l It protects the intestinal mucosa from excess acid
outside the acinus and drains it. The intercalated ducts which can damage it, leading to the formation of
are lined by flattened squamous epithelial cells. The ulcers. This (peptic) ulceration most commonly
neighbouring duct cells are joined by tight junctions, as in occurs in the first part of the duodenum, before the
the acinus. These separate the duct lumen from the inter- acidic chyme has mixed with the alkaline pancreatic
cellular spaces and function to exclude large molecules juice.

THE digestive SYSTEM 75

5
Lumen of duct Box 5.1  Post-surgical pancreatic fistula
EXOCRINE FUNCTIONS OF THE PANCREAS

Resting duct cell

In post-surgical conditions, a patient may be provided with
Aggregates of CFTR a fistula that drains the pancreatic juice to the outside
(Cl- channels) (usually via a fine plastic tube). This can protect the joins
in the bowel from the damaging effects of the pancreatic
Tubulovesicles enzymes. In this situation the patient incurs considerable
+
with H pumps losses of HCO3 resulting in a metabolic acidosis. This is usu-
ally compensated for by renal excretion of H and respi-
ratory mechanisms (hyperventilation to reduce CO2 in the
blood). The latter compensatory mechanisms are discussed
in the companion volumes The Respiratory System and The
Renal System.
Stimulation of duct cell
The fistula may be in direct communication from the
(increase in intracellular cAMP)
main pancreatic duct to the skin, in which case the fluid
Disaggregation and will not contain significant quantities of activated enzymes.
activation of CFTR Alternatively, the fistula may communicate from the duode-
num to the skin and then the digestive enzymes in the fluid
Tubulovesicles move to will have been activated and can then cause a significant
the basolateral membrane amount of skin excoriation and damage. This will result in
considerable management problems until the fistula closes.
Secreting duct cell Somatostatin analogues are administered in this situation
Cl- HCO3- Cl-
to reduce the secretions.
Secretion of Cl- via C FTR Fluid and electrolyte losses in these patients can be dif-
channels ficult to manage because the patient may have a restricted
Secretion of HCO3- in
Cl- H+ + HCO3- Cl- oral intake. Replacement via intravenous infusion is then
exchange for Cl- at the luminal
membrane necessary.
+ -
H + HCO3
+
c.a. Secretion of H via the pumps
which have fused with the
CO2 + H2O basolateral membrane The HCO3 ions are secreted across the luminal mem-
H+
brane by Cl/HCO3 exchange, and the H ions are
secreted into the blood. Thus for every HCO3 ion that
CO2 is secreted into the duct lumen one H ion is secreted
into the blood. Therefore the blood flowing through the
Fig. 5.5  Cellular mechanisms involved in the production of HCO3
and H in a duct cell. c.a., carbonic anhydrase; CFTR, cystic fibrosis
pancreas becomes transiently acid when it is secreting
transport regulator. HCO3. The H ions in the blood help to neutralize the
‘alkaline tide’ produced during a meal by the secreting
stomach (see Ch. 3), by combining with plasma HCO3 to
produce CO2. In conditions where a patient is provided
Cellular mechanisms of secretion with a pancreatic fistula, loss of HCO3 must be carefully
monitored (Box 5.1).
The mechanisms involved in the production of intra­ The exchange mechanism in the centroacinar and
cellular HCO3 in the centroacinar and upper duct cells upper duct cells, whereby HCO3 is secreted in exchange
are illustrated in Figure 5.5. The initial intracellular step for Cl, obviously depends on the presence of Cl in the
involves the reaction of CO2 with water. Secreted H fluid in the lumen. This is achieved by flux of Cl ions
ions react with HCO3 ions in the blood perfusing the out of the cell into the lumen via a chloride conduct-
gland and this generates CO2, some of which diffuses ance channel known as the cystic fibrosis transmem-
into the duct cell. More than 90% of the HCO3 in pan- brane conductance regulator (CFTR) which is regulated
creatic juice is derived from blood CO2. In the cell, the by cyclic AMP. It is a defect in the CFTR that results in
CO2 combines with intracellular water to generate car- impairment of the secretory process and disruption of
bonic acid, in a reaction catalysed by carbonic anhydrase pancreatic function in cystic fibrosis (Case 5.2: 1). Immu­
II, an enzyme present in the centroacinar and upper nocytochemical studies using fluorescent antibodies
duct cells. The carbonic acid dissociates to give HCO3 against the CFTR have shown that it is localized to the
and H. Whilst bicarbonate is being secreted the partial apical region of centroacinar and intralobular duct cells.
pressure of CO2 (pCO2) in the cells is lower than in the The CFTR is coupled to the HCO3/Cl exchanger.
blood as it is being used up in the production of HCO3 The CFTR Cl channel is present in clusters in the api-
ions, and the higher the rate of secretion the greater the cal plasma membranes. When the gland is stimulated (by
downhill gradient for diffusion of CO2 into the cell. secretin or by an increase in cAMP), the channel clusters

76 SYSTEMS OF THE BODY

 5
disaggregate (Fig. 5.5) increasing the number of open HCO3 and Cl ions with increasing rates of flow. There

EXOCRINE FUNCTIONS OF THE PANCREAS

channels. The channel is regulated in two ways: is a reciprocal relationship between the concentrations
of the two ions. The concentration of HCO3 increases
1. Via phosphorylation and dephosphorylation by with increasing flow rate and the concentration of Cl
protein kinase A and a phosphatase respectively, decreases. The sum of the concentrations of the two ions
serving as a molecular switch involved in the gating is kept constant by the action of the ion exchange pumps.
of the channel. As the HCO3 concentration increases, the juice becomes
2. Via activation of the channel by hydrolysis of ATP and more alkaline.
other nucleotides. The changes in the ionic composition of the juice with
rate of flow are due to the presence of transport systems in
The main features of the ion transport relationships the membranes of the duct cells. The primary alkaline juice
in the pancreatic duct cell are shown in Figure 5.5. It has secreted at the tops of the ducts is modified as it passes
been observed, using electron microscopy, that when the down the ducts by transport systems in the cells lower
cell is not being stimulated it contains numerous tubulo­ down in the extralobular ducts, and in the main ducts. At
vesicles in its apical cytoplasm. The membranes of these high flow rates, the time the juice spends in contact with
vesicles contain proton pumps that are ATPases. When the cells is not sufficient for appreciable modification via
the cell is stimulated, the tubulovesicles are translocated HCO3/Cl exchange and other processes to take place.
to the basolateral surface and their membranes fuse Therefore the composition of the juice produced at high
with the basolateral plasma membrane. Thus, the proton flow rates resembles that of the primary secretion more
pumps are incorporated into the membrane. Then H closely than juice secreted at low flow rates.
ions are actively pumped out of the cell into the intersti-
tial fluid in the lateral spaces, and from there they dif-
fuse into the plasma. Electron microscope studies have Pancreatic enzymes
shown that stimulation of secretion involves a change in
the shape of the cell. This is associated with expansion of The enzymes released from the pancreatic acinar cells
the basolateral plasma membranes as the membrane of the comprise the major enzymes involved in the digestion of
vesicles fuse with it. The fusion of the membranes is an foodstuffs. Many of these are secreted as inactive precur-
active process that derives its energy from the breakdown sors. The acinar cells contain zymogen granules, which
of ATP that is catalysed by the ATPase of the pumps. are the locus of storage of enzyme or enzyme precursor
Cl ions are secreted by the cells into the lumen via protein. The enzyme precursors produced by the acinar
the CFTR (Fig. 5.5). Na and K ions reach the pancreatic cells include those of the proteolytic enzymes, trypsin,
juice by the paracellular route (between the cells), trav- chymotrypsin, carboxypeptidase and elastase, and that
elling down the electrochemical gradient. Water flows of phospholipase A. Lipase, -amylase, ribonuclease, and
down the osmotic gradient (created by the ion transport) deoxyribonuclease are secreted as active enzymes. The
either transcellularly or paracellularly, from the lateral release of enzymes as inactive precursors ensures that
spaces. A Na/K-ATPase pump in the lateral borders of the activated enzymes do not autodigest the pancreatic
the cell transports Na out of the cell and this maintains tissue.
a low intracellular concentration and high extracellular The importance of the pancreatic enzymes for nutri-
concentration of Na ions. A Na/H exchange mecha- tion can be illustrated by consideration of the impairment
nism also operates at the basolateral pole of the cell to of function and the treatments employed in chronic pan-
keep the intracellular pH stable, but this mechanism is creatitis and cystic fibrosis (Case 5.1: 3 and 4 and Case
probably not activated during secretion. 5.2: 3 and 4).
Failure of the secretory mechanism is seen in chronic
pancreatitis (Case 5.1: 2) and in cystic fibrosis, in which
there is an inherited defect in the gene which encodes the Secretion of enzymes and precursors: cellular
CFTR (Case 5.2: 2). As water transport would normally mechanisms
follow the ion transport (down the osmotic gradient), the
defective ion secretion in these conditions results in a vis- The mechanism of secretion in the acinar cell is illus-
cous fluid in the ducts with a high concentration of pro- trated in Figure 5.9. This scheme was first discovered by
tein in the pancreatic ducts which can block the lumen. Palade in the 1970s. He was awarded the Nobel Prize for
This results in secondary pancreatic damage. the work. The enzymes or precursors are synthesized on
the rough endoplasmic reticulum of the cell. The mole-
cules are then released into the cisternae of the endoplas-
Variation in composition with rate of flow mic reticulum. Buds containing the enzymes or enzyme
precursors break off the cisternal membranes and the
The concentration of bicarbonate in the pancreatic juice buds coalesce in the region of the Golgi complex to form
that enters the duodenum ranges from 25 to 150 mM. The ‘condensing vacuoles’. The vacuoles migrate towards the
electrolyte composition of the juice varies with the flow luminal membrane. If the cells are stained for zymogen
rate. Figure 5.8 shows the changes in concentrations of the vacuoles can be seen to be more and more densely

THE digestive SYSTEM 77

5
EXOCRINE FUNCTIONS OF THE PANCREAS

Case
5.1   Chronic pancreatitis: 2

Defect and causes

The primary malfunction in chronic pancreatitis is defective inherited forms of the disease have been described. The inci-
ductal secretion of bicarbonate and water, which results in a dence of the disease is low, being approximately 30/100 000 in
high protein concentration in the pancreatic juice in the ducts. the UK. Onset is usually in middle age. The disease is approxi-
The protein precipitates and forms plugs, with consequent mately three times more common in males than females. Most
dilatation of the proximal ducts. A high pressure is generated alcoholic patients already have sustained permanent struc-
behind the blockages causing pain. Secondary back-pressure tural and functional damage to the pancreas by the time of
may lead to disruption of the ductal epithelium and result their first attack of abdominal pain. Moreover, morphological
in destruction of the pancreatic tissue. This can lead to an changes are evident at post-mortem examination in many alco-
inflammatory and fibrotic process in and around the pancre- holics who had no symptoms of pancreatic disease during life.
atic tissue. This in time leads to pancreatic insufficiency due It is not known how alcohol causes chronic pancreatitis. It
to destruction of islet cells and acinar glands. The pancreas may promote the precipitation of proteins in the pancreatic
lies in close proximity to the coeliac plexus and inflammation secretion.
around these autonomic nerves results in chronic back pain.
Chronic pancreatitis is characterized by progressive dam-
age to the pancreas with permanent destruction of pancre-
atic tissue. Exocrine and endocrine pancreatic insufficiency
usually follow. However, owing to the tremendous reserve A B
of pancreatic tissue, the insufficiency may be subclinical and
tests of pancreatic function may be necessary to reveal it. C
The histopathology indicates irregularly distributed fibrosis,
reduced number and size of islets of Langerhans, and vari-
able obstruction of pancreatic ducts of all sizes. Protein pre-
cipitation initially occurs in the lobular and interlobular ducts,
leading to the formation of plugs that calcify by surface accre-
tion. Concentric lamellar protein precipitates appear in the
major pancreatic ducts and these also calcify to form stones.
A specific protein, called stone protein, a normal constitu-
ent of pancreatic juice, which has a high affinity for Ca2, is
the major protein present in the stones. The calculi contain
calcium bicarbonate or hydroxyapatite (calcium phosphate
and calcium bicarbonate). The stones can be seen in X-rays
(Fig. 5.6). The chronic inflammation may extend to adjacent
organs, including the duodenum, common bile duct, stomach Fig. 5.6  Plain abdominal X-ray showing calcified stones in the
antrum and transverse colon. pancreatic duct (A), from a patient with chronic pancreatitis
In up to 80% of patients with chronic pancreatitis, there is a secondary to alcoholism. Gas in the left colon (B) and overlying
history of excessive alcohol intake but rare autosomal dominant stomach (C) are also seen.

stained as they approach the surface. At the luminal from the extracellular spaces or release from intracellular
membrane the membranes that surround the ‘zymogen’ stores.
granules fuse with the cell membrane and the vesicles
break open to release their contents, a process known
as exocytosis. The different enzymes are packaged Activation of enzyme precursors
together in each zymogen granule and they are probably
released together in constant proportions. The zymogen The enzyme precursors secreted by the acinar cells are
granule membrane is rapidly recycled from the surface activated in the lumen of the duodenum and jejunum.
membrane. Trypsinogen is converted to trypsin plus a short pep-
It is exocytosis, rather than the synthesis or sequestra- tide, in a reaction catalysed by enterokinase, an enzyme
tion of the enzyme proteins that is under physiological present in the brush border of the epithelial cells of the
control by hormones and neurotransmitters. Exocytosis is small intestine. Once a small amount of activated trypsin
triggered by an increase in intracellular Ca2. The rise in has been formed it can catalyse the conversion of more
intracellular Ca2 when the cell is stimulated is via influx trypsinogen to trypsin. Trypsin is a powerful proteolytic

78 SYSTEMS OF THE BODY

 5
enzyme that can convert chymotrypsinogen, procarboxy­ of activated trypsin which may find its way into the

EXOCRINE FUNCTIONS OF THE PANCREAS

peptidase, proelastase and prophospholipase A to their ducts, by complexing with it
activated forms. Thus once a small amount of trypsin is l Another pancreatic factor, enzyme Y, which is
formed a catalytic chain reaction occurs (Table 5.1).
activated by traces of active trypsin degrades
In acute pancreatitis, a condition which can be life-
zymogen, thus exercising a protective function
threatening, activated enzymes are present in the pancre-
atic ducts leading to destruction of the pancreatic tissue l The alkaline pH (8.0–9.5) and low Ca2 concentration
(Box 5.2). Various mechanisms exist to prevent this: in pancreatic secretions promote the degradation
rather than the activation of trypsinogen.
The pancreas normally secretes a polypeptide known
l

as Kazal inhibitor that inhibits any small amounts

Table 5.1  Activation of enzyme precursors in the small intestine

Precursor Active enzyme

Trypsinogen trypsin  peptide

enterokinase,
 trypsin
→
Chymotrypsinogen chymotrypsin  peptide
trypsin
→
Proelastase elastase  peptide
trypsin
→
Procarboxypeptidase carboxypeptidase  peptide
trypsin
→
Prophospholipase A phospholipase A  peptide
trypsin
→

Case
5.2   Cystic fibrosis: 2

Defect and diagnosis

In the pancreas, the defect in the CFTR is associated with
defective secretion of chloride into the ducts, and there-
fore reduced water transport so that the fluid in the ducts
becomes viscous. This leads to the formation of protein-rich
plugs which can obstruct the proximal intralobular ducts,
resulting in secondary pancreatic damage (a process similar
to that which occurs in chronic pancreatitis, see Case 5.1: 2).
Thus, the digestive enzymes do not reach the duodenum. The
tests performed on the stool sample would show a high fat B
content. Chymotrypsin or trypsin content would also be high.
Over 80% of patients have steatorrhoea due to pancreatic
dysfunction and meconium ileus (obstruction of the small
A
intestine by impacted material) is common in the newborn
(Fig. 5.7).
The same process of mucous plugging results in blockage
of the bronchioles. This leads to recurrent respiratory infec-
tion and eventually to respiratory failure. These broncho-
pulmonary and gastrointestinal manifestations usually alert
the clinician to the possibility that the child has cystic fibrosis.
The condition can be diagnosed by DNA analysis or the pres-
ence of a high Na concentration (over 60 mmol/L) in sweat.
Fig. 5.7  Plain abdominal X-ray taken from a baby with cystic
The latter is due to the impaired Cl transport in the secretory
fibrosis. The meconium stool has obstructed the bowel and can
cells of the sweat glands as water transport into the sweat
be seen in the caecum (A). The proximal small bowel loops have
depends on the setting up of an osmotic gradient. dilated (B) and are filled with gas.

THE digestive SYSTEM 79

5
160
EXOCRINE FUNCTIONS OF THE PANCREAS

Case
– 5.1   Chronic pancreatitis: 3
HCO3
120
Impairment of functions
Concentration (mmol/L)

Both exocrine and endocrine secretions of the pancreas are

impaired in chronic pancreatitis.
80
The blockage of the secretory ducts and loss of acinar tis-
sue lead to a decrease in both alkaline juice and enzymes.
The reduced alkaline secretion leads to: (1) reduced activ-
40 ity of enzymes in the small intestine which results in mal-
absorption and weight loss; (2) impaired micelle formation
Cl – (essential for adequate lipid absorption) which leads to
0 steatorrhoea (high fat content in the stools); (3) possibly
0 0.2 0.4 0.6 0.8 1.0 1.2 duodenal ulceration as a consequence of the high acidity.
Secretion rate (g/10 min) Destruction of islet tissue can lead to decreased secre-
tion of the hormones insulin and glucagon, which are both
Fig. 5.8  Variation in the composition of pancreatic juice with respect
involved in the control of glucose metabolism. Insulin low-
to Cl and HCO3, with rate of flow.
ers the blood glucose by increasing the uptake of glucose
into tissues whilst glucagon increases blood glucose by
stimulating glucose release from the liver (see Ch. 9). Thus,
Control of secretion the two hormones have opposite effects on blood glucose
concentration, although the effect of insulin is dominant.
The control of the exocrine secretion of the acinar and Insulin is normally released from the pancreas in
duct cells of the pancreas is via peptides such as the hor- response to an increase in blood glucose concentration dur-
mones secretin, cholecystokinin (CCK) and vasoactive ing a meal. The glucose tolerance test measures the insulin
intestinal peptide (VIP), and somatostatin which acts response to ingestion of a glucose solution (see Fig. 9.4).
mainly as a paracrine factor, and neurotransmitters. The insulin response is impaired early in chronic pancreati-
tis, i.e. the time taken for the increased blood glucose to
return to normal is prolonged. Overt diabetes eventually
Hormonal control develops in many patients.
Chronic progressive jaundice may also occur in chronic
The major hormones involved in stimulating secretion pancreatitis. This is due to fibrosis around the lower end
are secretin, which stimulates the secretion of the alkaline of the common bile duct as it passes through the head
aqueous component, and cholecystokinin (CCK) that stim- of the pancreas. The fibrosis prevents the access of bile
ulates the secretion of the enzyme component. These hor- to the small intestine resulting in a raised serum bilirubin
mones are produced by the APUD cells in the duodenal due to reflux of bile constituents into the systemic circula-
mucosa (see Ch. 1) in response to food constituents in the tion. Raised serum alkaline phosphatase is also seen as this
duodenal chyme (see below). As secretion of the two com- enzyme is released by damaged cells lining the biliary tree.
ponents of pancreatic juice is controlled by separate regu- In chronic pancreatitis, there may also be coexisting alco-
latory mechanisms, the composition of the juice entering holic liver disease, making it difficult to determine whether
the duodenum can vary with respect to its enzyme pro- the jaundice is primarily due to disease of the pancreas or
tein content. It can contain between 1% and 10% protein. to cirrhosis of the liver. Thus a liver biopsy and histological
CCK and gastrin compete for the same receptor on the assessment of the tissue may also be required.
acinar cell (Fig. 5.12). CCK, gastrin and acetylcholine all
increase enzyme protein synthesis and secretion via:
l Increase in phosphatidylinositol turnover
l Increase in intracellular Ca2 concentration. of pancreatic secretion. It acts in a paracrine manner to
inhibit the release of the exocrine alkaline and enzyme
Secretin and VIP act on the acinar cell to increase the secretions, as well as the pancreatic hormones insu-
intracellular levels of cAMP (Fig. 5.12). This increase in lin and glucagon. In addition, it inhibits the release of a
cAMP by secretin and VIP potentiates the effect of CCK, gas- number of gastrointestinal hormones, including CCK,
trin and acetylcholine. Thus the enzyme secretion is greater secretin and gastrin. Circulating somatostatin probably
when the two types of secretogogue are acting together. augments the actions of locally released somatostatin. It
originates from a number of sites in the body, including
various locations in the gastrointestinal tract. Pancreatic
Somatostatin somatostatin is predominantly the tetradecapeptide
Somatostatin, which is present in D cells in the islets form, S-14. The release of this hormone is stimulated by
of Langerhans of the pancreas, is a powerful inhibitor CCK, gastrin and secretin. Analogues of somatostatin

80 SYSTEMS OF THE BODY

 5

EXOCRINE FUNCTIONS OF THE PANCREAS

Case Case
5.2   Cystic fibrosis: 3 5.2   Cystic fibrosis: 4

Impairment of functions Treatment

In cystic fibrosis, the primary defect in the pancreas is a lack There is currently no cure for this condition. Genetic screen-
of Cl secretion leading to defective bicarbonate secretion. ing is usually offered to couples with a family history of the
The secretion of enzymes is not initially affected but the block- condition. Some 90% of affected individuals survive into
age of the ducts prevents them reaching their site of action in their teens and most will now survive into middle age. Lung
the small intestine. Thus digestion and absorption are impaired or heart–lung transplantation can be successful in prolong-
leading to malnutrition if the condition remains untreated. ing and improving the quality of life. Genetic engineering
Undigested fat is passed out of the intestines and appears in offers hope for a cure in the future. However, even if the
the stools, accounting for their pale colour (steatorrhoea). CFTR gene could be stably transfected into the secretory
Although the secretion of bicarbonate is impaired abnor- epithelial cells, there would be a need for repeat treatment
malities in the patient’s acid–base status may not be present as the cells are continuously being shed and replaced by
as secretion of both alkaline and acid digestive juices are new ones. This problem might one day be overcome if the
affected. gene could be transfected into the progenitor (stem) cells.
Later in the disease, the pancreas may become damaged and Although the pulmonary problems dominate the con-
there may be a deficiency of the pancreatic hormones insulin dition in most cases, the management of the pancreatic
and glucagon. As insulin is the dominant hormone, diabetes insufficiency is necessary to maintain overall nutrition
mellitus may develop (as in chronic pancreatitis, see Case 5.1: 3). and growth. The treatment is the ingestion of a pancre-
atic enzyme preparation by mouth. This should be done
throughout a meal to ensure optimum mixing of the
enzymes with the food. The dosage is determined by the
Case
5.1   Chronic pancreatitis: 4
level of fat in the stools (steatorrhoea). The enzymes are
usually administered in enteric-coated form that renders
them resistant to degradation by acid in the stomach. The
Physiological consequences, treatment and coating is susceptible to degradation in the alkaline envi-
management ronment of the small intestine, the enzymes consequently
The main consequences of malabsorption and diabetes melli- being released at their usual site of action. Degradation
tus are malnutrition and weight loss. Lack of alkaline secretion of the enzymes by gastric acid can still be a significant
can lead to alkalosis because the ‘alkaline tide’ in the blood problem but this can be minimized by concomitant treat-
which results from gastric acid secretion during a meal (see Ch. ment with an H2 receptor antagonist such as ranitidine or a
3) is normally partially neutralized by the ‘acid’ tide resulting hydrogen pump inhibitor such as omeprazole.
from the secretion of alkaline juice by the pancreas. However,
in chronic pancreatitis, the alkalosis is normally compensated
by respiratory and renal mechanisms (see the companion vol-
such as octreotide are used clinically to inhibit pancreatic
umes: The Respiratory System and The Renal System).
enzyme secretion (Box 5.3).
Treatment is usually non-surgical in uncomplicated chronic
pancreatitis. The need for complete abstention from alco-
hol is emphasized. Pain relief is initially via treatment with a Nervous control
non-steroidal anti-inflammatory drug (NSAID) such as aspirin,
and then, if necessary, via opiates. Nutritional support in the The nervous control of pancreatic secretion is via both
form of simple nutrients (amino acids, glucose, fatty acids) parasympathetic and sympathetic nerves. Stimulation of
may be advised. Oral pancreatic extract can be prescribed cholinergic fibres in the vagus nerve enhances the rate of
to replace the pancreatic enzymes. Usually, the extract is secretion of both enzyme and alkaline fluid. Stimulation
enriched with lipase as the secretion of this enzyme tends of the sympathetic nerves inhibits secretion, mainly by
to decrease more rapidly than that of proteolytic enzymes. reducing the blood flow to the gland (via vasoconstric-
The enzyme preparation can be administered together with tion of the arterioles) that decreases the volume of juice
an anti-ulcer drug (proton pump inhibitor) to reduce acid secreted. However, stimulation of the sympathetic nerves
production by the stomach, as this inactivates the enzymes. to the pancreas depresses the enzyme content of the
Alternatively, the enzymes can be administered in the form secretion as well as the volume of juice secreted.
of granules within which the enzymes are enclosed in a pH-
dependent polymer. The protective coating dissolves only
Control of secretion during a meal
when the pH is more alkaline than 6.0, i.e. not in the stom-
ach, but hopefully in the duodenum or upper jejunum. The control of the secretion of pancreatic juice during a
The metabolic complications of diabetes are discussed in meal depends on the volume and composition of the
Chapter 9. If diabetes is present, it is treated with insulin. food. Ingested material present at different locations
within the gastrointestinal tract affects the control of the

THE digestive SYSTEM 81

5
EXOCRINE FUNCTIONS OF THE PANCREAS

Release of enzymes

Luminal
Lumen
membrane
of acinus

Golgi
Bud complex

Bud coalescing Zymogen granule

close to Golgi
complex
Condensing vacuole

Bud containing zymogen

Rough endoplasmic reticulum

Cisternae

Fig. 5.9  Mechanism of enzyme secretion in the acinar cell.

secretions in different ways. The control during a meal which occurs in the control of salivary secretion that is
can accordingly be divided into three phases (see Ch. 1), described in Chapter 2.
according to the location of the food or chyme:
Gastric phase
1. The cephalic phase: due to the approach of food or the
The presence of food in the stomach stimulates the secre-
presence of food in the mouth.
tion of pancreatic juice via a hormonal mechanism.
2. The gastric phase: when food is in the stomach.
Activation of chemoreceptors in the walls of the stom-
3. The intestinal phase: when food material is in the
ach by peptides, and the activation of mechanoreceptors,
duodenum.
causes the release of the hormone gastrin from G cells,
into the local circulation. Stimulation of cholinergic nerves
is also involved in this phase of control. During the gas-
Cephalic phase tric phase the secretion of both the enzyme-rich and the
The sight and smell of food, or other sensory stimuli alkaline components of pancreatic juice is increased.
associated with the impending arrival of food, elicit
increased pancreatic secretion via a ‘conditioned’ reflex. Intestinal phase
The presence of food in the mouth stimulates secretion
via a ‘non-conditioned’ reflex. The control during this The intestinal phase of control is the most important phase
phase is therefore nervous. It is mediated by impulses in of the response to food. Food material in the duodenum
cholinergic fibres in the vagus nerve. The juice secreted stimulates both the alkaline and the enzyme-rich compo-
is mainly the enzyme-rich secretion, containing very lit- nents of pancreatic juice. The alkaline component of pan-
tle HCO3. creatic juice is secreted in response mainly to acid in the
In response to vagal stimulation, the acinar cells also duodenal contents. Acid stimulates the release of secretin
secrete kallikreins, which catalyse the production of from APUD cells in the walls of the intestine and this hor-
bradykinin, a vasodilator. This results in increased blood mone stimulates the duct cells to secrete the alkaline fluid.
flow to the pancreas, and increased volume of secretion. This is a feedback control mechanism that helps to control
The mechanism involved in this effect is similar to that the pH of the duodenal contents.

82 SYSTEMS OF THE BODY

 5
Box 5.2  Acute pancreatitis

EXOCRINE FUNCTIONS OF THE PANCREAS

Acute pancreatitis is a condition in which the pancreatic tis-
sue is destroyed by digestive enzymes. Most attacks of this
acute disease (approximately 75%) are mild but in some more
severe cases the condition can result in haemodynamic insta-
bility and multi-organ failure. The physiological mechanisms
underlying acute pancreatitis are not completely understood.
A
It is characterized by the presence of activated enzymes in the B
pancreatic ducts. The consequence of this is autodigestion of
the pancreatic tissue.
In acute pancreatitis activated trypsin in the ducts of the
pancreas proteolytically activates more trypsinogen and other
proteolytic enzyme precursors (chymotrypsinogen, proelastase
and procarboxypeptidase) and prophospholipase A.
The active enzymes digest the pancreatic tissue. When the
walls of the acini on the surface of the pancreas are digested,
the enzymes leak into the abdominal cavity and a generalized
peritonitis results. In 5% of cases, the condition is extremely
serious and the blood vessels are digested by pancreatic
Fig. 5.10  Ultrasound scan of the biliary tree, showing a calcified
elastase resulting in internal bleeding, and eventually ischae-
stone in the common bile duct (A) which is dilated around the
mia (due to hypotension) and anaemia. The condition is then
stone. The adjacent gallbladder is also seen (B).
known as haemorrhagic necrotizing pancreatitis, which has
an 80% mortality rate.
It is not known how activated digestive enzymes appear
in the pancreatic ducts in acute pancreatitis, but one possi-
bility is that it is due to reflux of intestinal chyme containing
activated enzymes, into the pancreatic duct. The condition is
often associated with the presence of gallstones in the bile
ducts. It is likely that small gallstones lodge at the ampulla
of Vater and prevent the closure of the sphincter of Oddi.
This process may allow duodenal juice containing activated
enzymes to reflux into the pancreatic duct. Alcohol abuse, B
A
infections, pancreatic tumours and treatment with certain
drugs may also have a causative role in acute pancreatitis.
D
The diagnosis of acute pancreatitis depends on the pres-
ence of high concentrations of -amylase in the blood. This C C
enzyme, together with others, leaks from the lysed pancre-
atic cells into the blood. -Amylase may also be present in the
urine because it is not adequately reabsorbed in the kidney
tubules. An ultrasound scan (Fig. 5.10) of the abdomen may
reveal the presence of biliary gall stones. CT scanning (Fig.
5.11) enables the extent of necrosis to be assessed.
Hypocalcaemia may also be present. This is partly due to Fig. 5.11  CT scan of the same patient as Fig. 5.10, showing the
loss of albumen, with bound Ca2, in the protein-rich exu- calcified stone at the lower end of the common bile duct (A) lying
dates from the pancreas. This exudation also causes a rise in within a swollen head of the pancreas (B). The kidneys (C) and
the haematocrit due to loss of plasma volume. spleen (D) are also visible.

The enzyme-rich juice is released during the intestinal the quantity of enzymes present in the intestines, and
phase in response to fat and peptides in the food. The fats may have some protective function.
and peptides cause the release of CCK from the walls of Secretin exerts a permissive effect on the secretion of
the duodenum into the blood. CCK stimulates the acinar enzymes; it does not stimulate enzyme secretion on its
cells to secrete enzymes. Trypsin in the duodenum inhib- own, but it enhances the effect of CCK. Similarly, CCK
its the release of enzymes via inhibition of CCK release. exerts a permissive effect on the secretion of the alkaline
This is another feedback control mechanism, which limits fluid by secretin. Stimulation of the vagus nerve causes the

THE digestive SYSTEM 83

5
Box 5.3  Somatostatin analogues
EXOCRINE FUNCTIONS OF THE PANCREAS

Increase in
ACh M Analogues of somatostatin such as octreotide are used clin-
PI turnover
ically to inhibit pancreatic enzyme secretion in acute pan-
+ CCK Increase in creatitis, and following pancreatic surgery. Reducing the
gastrin CCK-A
Ca2+ Increased secretion of digestive enzymes allows the pancreas to heal
+ Secretin enzyme more safely following injury (whether due to inflammation
VIP Increase in secretion
VIP or surgery). Octreotide is an octapeptide which contains the
cAMP
tetrapeptide sequence which is known to be essential for
somatostatin activity. Somatostatin itself, when injected,
has a short half-life (4 min). However, octreotide injected
subcutaneously, has a half-life of approximately 100 min
Fig. 5.12  Cellular mechanisms of control in the acinar cell. M,
and its action is therefore relatively long-lasting. This is
muscarinic receptor; Pl, phosphatidylinositol.
important in the clinical setting as somatostatin is only
effective if given as a continuous infusion, whereas ana-
logues such as octreotide are effective if given as a bolus
release of mainly the enzyme-rich secretion, but if the vagi
two or three times per day.
are sectioned, the alkaline secretion elicited in response to
secretin is reduced by 50%, indicting a functional overlap
between the effects of vagal stimulation and secretin. Thus
the vagal mechanism may enhance the effect of secretin.

84 SYSTEMS OF THE BODY

Liver and biliary
system 6
Chapter objectives
After studying this chapter you should be able to:

1. Understand the role of the liver in the digestive process and the
excretion of waste metabolites and toxic substances.

2. Understand the relationship between the structure of the

hepatobiliary tract and its function in the secretion and storage of
bile.

3. Understand the mechanisms of secretion of the important

components of bile, and their recycling via the enterohepatic
circulation.

4. Understand the mechanisms of control of bile secretion and its

release into the duodenum.
6
Liver and biliary system

Introduction

The numerous functions of the liver can be divided into

two broad categories:
1. Those concerned with the processing of absorbed
materials and synthetic reactions Liver

2. Those concerned with secretion and excretion. Left hepatic duct

This chapter is concerned with the secretory and excre-
tory roles of the liver. The processing of absorbed nutri- Right hepatic duct
ents and the role of the liver in the control of energy
Cystic duct
metabolism are discussed in Chapter 9.
The most important exocrine functions of the liver are:
Common bile duct
l The provision of bile acids and alkaline fluid
for the digestion and absorption of fats, and for
the neutralization of gastric acid in the intestines Gallbladder Pancreatic duct

l The degradation and conjugation of waste products Ampulla of Vater

of metabolism
Sphinctor of Oddi
l The detoxification of poisonous substances
l The excretion of waste metabolites and detoxified Smooth muscle fibres Duodenum
substances in bile
Detoxified substances and waste metabolites are
l
Fig. 6.1  Anatomical arrangement of the liver, gall bladder and biliary
eliminated from the body either in the bile, via the
tract.
gastrointestinal tract, or via secretion from the liver
into the blood for subsequent excretion by the kidneys.

The liver has enormous reserves of function, and nor-

mal homeostasis can be maintained even after three The gall bladder is surrounded by smooth muscle.
quarters of it have been removed. Clinical manifestation Between meals, when the gall bladder smooth muscle is
of liver disease therefore implies considerable damage relaxed, the sphincter of Oddi is closed, preventing the
to the organ. bile from entering the small intestine. Consequently, the
Gallstones form in the gall bladder and biliary tract as bile passes into the gall bladder where it is stored and
a consequence of various derangements of the hepatobil- concentrated. Contraction of the gall bladder forces the
iary system. The problems encountered in a patient with bile into the common bile duct. At the same time the smooth
gallstone disease are given in this chapter to illustrate muscle in the sphincter of Oddi relaxes, and the sphinc-
many of the roles of the liver in secretion and excretion. A ter opens to allow the bile to enter the duodenum. Food
second case history involving a patient who had taken an in the duodenum is the main stimulus for gall bladder
overdose of paracetamol is used to emphasize the impor- contraction.
tant role of the liver in the detoxification of drugs.

Anatomy and morphology of the liver

Overview of the functioning of the
hepatobiliary system The liver is the largest single organ in the body. In the
adult it comprises approximately one-fiftieth of the body
The anatomical arrangement of the liver, gall bladder and weight. In the infant it is proportionately even larger. It
biliary tract is shown in Figure 6.1. The liver is continu- consists of right and left lobes (Fig. 6.2A), the right lobe
ally secreting substances both into the blood, and into being six times the size of the left in the adult.
the bile. Bile is both a secretory fluid and an excretory The liver is composed of lobules (Fig. 6.2B). In the
medium. In the human, it is stored between meals in the centre of each lobule is the central canal, in which lies
gall bladder, where it is concentrated. During a meal it is a hepatic vein, which is a tributary of the inferior vena
released from the gall bladder and enters the cystic duct cava. Columns of liver cells (hepatocytes) and sinusoids
that in turn drains it into the common bile duct. The bile radiate out from the central canal. Several portal tracts
enters the small intestine at the level of the duodenum. lie at the periphery of each lobule. Each tract (or ‘portal
Its entry into the small intestine is controlled by a smooth triad’) contains a bile duct, a branch of the portal vein,
muscle sphincter: the sphincter of Oddi. and a branch of the hepatic artery.

86 SYSTEMS OF THE BODY

 6
Right Left The liver has a double blood supply: the hepatic

Liver and biliary system

artery supplies the liver with oxygenated blood from the
Inferior vena cava Hepatic vein lungs, and the portal vein supplies it with nutrient-rich
blood from the intestines (see Ch. 1). The arterial blood
comprises approximately 20% of the total blood supply
of the liver and the portal venous blood, approximately
80%. The arterial blood and the portal venous blood
mix together in the liver sinusoids. The sinusoidal blood
drains away via the hepatic veins to the vena cava. This
direction of flow is determined by the relatively higher
pressure of the blood in the portal vein compared to the
central vein.
In liver cirrhosis, scar tissue replaces normal healthy
tissue. This scar tissue distorts the normal structure
and regrowth of liver cells and blocks the flow of blood
Common bile duct through the organ. This disease is described in Box 6.1.
The liver is covered by a fibroconnective tissue cap-
sule known as the capsule of Glisson, from which thin
connective tissue septa enter the organ to divide it into
A lobes and lobules. The capsule is covered by peritoneum,
except in an area known as the ‘bare area’ which is in
Central vein direct contact with the diaphragm.
Sinusoid The secretory system of the liver begins with minute
tubules, the canaliculi. These are formed by oppositely
Hepatic aligned grooves in the contact surfaces of adjacent hepa-
triad tocytes (Figs 6.2C, 6.3). The membrane of each liver cell
Hepatic
lobule Hepatic contributes to several bile canaliculi. Bile secreted into
portal vein the canaliculi flows in the opposite direction to the flow
Hepatic of blood in the sinusoids. The canaliculi drain into termi-
artery nal bile ductules. The ductules converge to form intralob-
Interlobular Bile
septum ular ducts, and these converge to form interlobular ducts,
ductule
which in turn converge to form the right and left hepatic
Bile canaliculus bile ducts. These converge outside the liver to form the
Hepatocytes common hepatic bile duct.
B
Lipocyte
Kupffer cell
Histology

Endothelial The major type of cell in the liver is the hepatocyte that
cell is an epithelial parenchymal cell. The hepatocytes are
Reticulin Space arranged in plates which branch and anastomize to form
fibre of Disse a three-dimensional lattice (Fig. 6.2). Between the plates
are the blood-filled sinusoids. In this respect the liver
Microvilli
resembles an endocrine gland. There is usually only one
Lysosome layer of hepatocytes between the sinusoids.
Actin Tight The sinusoidal spaces differ from blood capillaries in
fibres junction that they are of greater diameter and their lining cells are
Canaliculus not typically endothelial. The basal lamina around the
Microvilli
Gap
sinusoids is incomplete and this enables direct access of
junction the plasma to the surface of the hepatocyte. This allows
Nucleus
active metabolic exchange between the blood and the
Desmosome
cells (Fig. 6.2C). The perisinusoidal space is an intersti-
tial space that contains reticular and collagenous fibres.
A few mesenchymal cells called lipocytes produce the
C
fibres. Two main cell types are present in the sinusoidal
Fig. 6.2  (A) The biliary drainage of the two lobes of the liver. lining. These are endothelial cells and Kupffer cells. They
(B) Lobular structure of the liver, illustrating the biliary secretory system lie in a mesh of fine reticular fibres. The endothelial cell
and the dual blood supply. (C) Features of the hepatocyte, and its has small elongated nuclei and greatly attenuated cyto-
relationship to adjacent cells and the sinusoid. plasm. The cytoplasm may interdigitate with cytoplasmic

THE digestive SYSTEM 87

6
Box 6.1  Liver cirrhosis Hepatocyte
Liver and biliary system

Sinusoid
Canaliculus
In cirrhosis of the liver scar tissue replaces normal healthy
tissue and blocks the flow of blood from the portal vein
through the organ. This leads to reduced synthesis of pro-
teins and other molecules by the liver and reduced oxida- Nucleus
tive capacity. Metabolism of bile constituents, and drug
detoxification, and secretion and excretion of bile constitu-
ents become inadequate to maintain health.
Liver cirrhosis has many causes, including:
Hepatocytes
• Chronic alcoholism. Cirrhosis does not usually develop Canaliculus
until after more than 10 years of alcohol abuse. This
is a major cause of liver cirrhosis in the western world
• Chronic hepatitis C, B or D. Hepatitis C virus causes
low-grade damage, which over the course of many Fig. 6.3  Early secretory system of the liver. Inset: canaliculus
years can lead to cirrhosis. This is a major cause of (in cross-section) formed by adjacent hepatocytes.
liver cirrhosis. It was commonly transmitted by blood
transfusion before routine testing for hepatitis C virus
was available. Hepatitis B virus is the most common extensive cytoplasm, with processes that extend into, and
cause of liver cirrhosis in the third world but is less sometimes across, the sinusoidal space. They increase in
common in more developed countries number when required for phagocytosis, possibly by dif-
• Autoimmune disease: the immune system attacks the ferentiation of the endothelial type of cell.
liver causing inflammation and tissue damage which
can eventually lead to cirrhosis Hepatocytes
• Inherited diseases including 1-antitrypsin deficiency,
haemachromatosis, Wilson’s disease, galactosaemia The hepatocyte is a polygonal cell with a clearly defined
and glycogen storage diseases cell membrane, which is closely apposed to the cell mem-
• Drugs, toxins and infections. Severe reactions branes of adjacent hepatocytes (Figs 6.2C, 6.3). The mem-
to prescription drugs, prolonged exposure to branes of adjacent cells are partially separated to form
environmental toxins, parasitic infection (with a bile canaliculus. The plasmalemma of adjacent hepa-
schistosomes) can also cause liver cirrhosis. tocytes shows irregularities with tight junctions, spot
desmosomes and gap junctions. These separate the canal-
The signs and symptoms of liver cirrhosis include fatigue, iculus from the rest of the intercellular space (Fig. 6.2C).
weight loss, nausea, abdominal pain, spider-like blood ves- The plasma membrane of hepatocytes is specialized
sels on the skin, oedema of the legs and abdomen (ascites), in certain regions. Adjacent to a sinusoidal blood space
jaundice (see Box 6.2), gallstones (see Case 6.1: 1–6), itch- the hepatocyte is separated from the wall of the sinu-
ing (due to bilirubin being deposited in the skin) and a soid by the perisinusoidal space (the space of Disse) and
tendency to bleed easily (due to reduced clotting factor at this location the plasma membrane of the hepatocyte
synthesis in the liver). has numerous long microvilli. Vesicles and vacuoles are
The treatment of liver cirrhosis depends on the cause of present in the subadjacent cytoplasm (Fig. 6.2C). The
the condition and the complications experienced. The dam- microvilli provide a large surface area for absorption and
age cannot be reversed but the progression of the disease secretion.
can be arrested or delayed by, for example cessation of The nuclei in different hepatocytes show consider-
alcohol abuse or medication to treat infections and other able variation in shape and size and in some cases the
causes. When liver damage is so pronounced that the liver cells are binucleate. Clumps of basophilic material are
stops functioning, a transplant is necessary. The survival present in all cells. There are numerous small mitochon-
rate after liver transplantation is over 90% now that effec- dria throughout the cytoplasm of the hepatocyte. The
tive immune-suppression drugs are available. structure of all hepatocytes is broadly similar but the
cytoplasm of the cells shows a gradual variation with
the distance of the cell from the periphery. The differ-
ences are related to the differences in functional activity
processes from adjacent cells of the same type or another of the peripherally and centrally positioned cells. The
type. They contain few organelles but numerous pinocy- hepatocytes closest to the afferent blood supply, the ‘peri­
totic vesicles. They also contain large fenestrae that are not portal’ cells, are exposed to the highest concentrations
closed by a diaphragm. Kupffer cells are phagocytic and of nutrients and oxygen and those in the central region,
often contain degenerating red cells, pigment granules, the ‘perivenous’ cells, near to the efferent outflow, are
and iron-containing granules. They have large nuclei and exposed to the lowest concentrations. The periportal

88 SYSTEMS OF THE BODY

 6
Canaliculus

Liver and biliary system

Bile
Common
Bile salts Toxic metabolites acid-dependent
bile duct and
secretion
duodenum Hepatocyte

Cellular and
Oxidation paracellular
transport of water
Biotransformation
Gluconeo-
genesis Alkaline secretion
Glycolysis
Glycogen Duct cell
Ketogenesis
deposition
Fat deposition
Bile salt
conjugation
Bile canaliculus
Fig. 6.5  Sites of secretion of the two component secretions of bile.

Bile salts
Portal Toxic Hepatic
O2 the canaliculus. Contractions of the canaliculi can be
vein substances vein
Nutrients
stimulated by extracellular ATP. The contractions involve
Blood capillary actin–myosin interaction as in smooth muscle cells. They
probably pump bile towards the ducts. Atony (lack of
Fig. 6.4  Major functions of periportal and perivenous hepatocytes.
contractile function) of the canaliculus causes cholestasis
(reduced bile flow).
cells are the most active in the uptake from the blood of The junctions of the bile canaliculus with the bile
bile salts and in the secretion of many bile constituents ducts at the periphery of a lobule consist of an interme-
into the canaliculi as well as in oxidative metabolism diate structure called the ductules or canals of Hering.
and gluconeogenesis (Fig. 6.4). After feeding, glycogen Here the hepatocytes that form the canaliculus are grad-
is deposited first in the periportal cells. It is only after a ually replaced by smaller cells with dark nuclei and
heavy carbohydrate meal that the more centrally located poorly- developed organelles. These are the ductule cells.
perivenous cells store glycogen. Moreover, when the They are underlain by a distinct basal lamina. The lumen
blood sugar concentration falls, glycogen is removed first of the ductule eventually joins that of a bile duct in the
from the perivenous cells. The perivenous cells, which portal area.
are exposed to depleted plasma, are the more active in
biotransformation reactions and the secretion of poten-
tially toxic xenobiotic and endobiotic substances. They Extrahepatic ducts
are also more active in glycolytic and ketogenic reactions.
The extrahepatic ducts are lined by tall columnar epi-
Under certain conditions fat is deposited in the hepato-
thelium (Fig. 6.5) that secretes mucus. There is a layer of
cytes and it appears first in the more centrally disposed
connective tissue beneath the epithelium, with numerous
cells. Thus the cytosol of a given hepatocyte exhibits dif-
elastic fibres, mucous glands, blood vessels and nerves.
ferences in composition at different times in relation to
In the common bile duct there is also a layer of smooth
feeding and whether fat or glycogen has been deposited.
muscle cells. These cells are sparse in the upper region
of the duct but form a thicker layer of oblique and trans-
The canaliculus verse fibres in the regions of the sphincter of Oddi near
The lumen of the canaliculus is approximately 0.75 m the duodenum (see below).
in diameter. Microvilli project from the canalicular mem-
brane into the lumen, providing a large surface area for Bile
secretion. Membranes of adjacent hepatocytes are joined
by tight junctions near the canaliculus (Fig. 6.2C). These
junctions are leaky and permit paracellular exchange
Composition and functions
between the plasma and the canaliculus. Bile is secreted at a rate of 250–1000 mL/day in the adult.
The canaliculus is involved in transport of substances It is isosmotic with blood plasma. It is a composite of two
into the lumen, but it is also a contractile structure. Actin different secretions; one originating in the hepatocytes,
filaments are present in the microvilli, and both actin and and the other in the cells that line the bile ducts (Fig. 6.5).
myosin fibres are present in the cytoplasm surrounding The two secretions mix together in the ducts.

THE digestive SYSTEM 89

6
Secretion of the duct cells
Liver and biliary system

Table 6.1  Comparison of the concentrations of some substances

The secretion from the duct cells is a watery alkaline fluid in hepatic and gall bladder bile
that is rich in bicarbonate. It comprises approximately
25% of the total bile volume. Its function is, first, to Constituent Hepatic bile Gall bladder bile
provide an appropriate pH for the process of micelle for- electrolytes (mM) (mM)
mation (see below), which requires a neutral or slightly
alkaline environment. Second, it contributes (together with HCO3 28 10
pancreatic juice and intestinal secretions) to the neutraliza- Cl 100 25
tion of stomach acid in the intestinal chyme. This is impor- K 
5 12
tant both for micelle formation and digestive enzyme
action in the small intestine (see Ch. 8). In addition the neu- Na 145 130
tralization of acid in the duodenum protects the mucosa Ca2 5 23
from ulceration. The secretion contains Na, K, Cl and Organic molecules
HCO3 ions. Its composition is similar to that of alkaline Bilirubin   0.7 5.1
pancreatic juice. At basal rates of secretion the ionic com-
Cholesterol 2.6 16.0
position resembles that of plasma. However as the flow
increases upon stimulation (by a meal) the Cl concen- Lecithin 0.5 3.9
tration decreases and the HCO3 concentration increases. Bile salts 26.0 145.0
This is due to the presence of a Cl/HCO3 exchange
mechanism in the duct cells. HCO3 ions are extracted Loss of gall bladder bile via a fistula can quickly deplete K
from the bile and Cl is added to it, a process similar to reserves, unless replacement therapy is started.
that involved in the secretion of alkaline juice from the
pancreatic duct cells (see Ch. 5). At high flow rates, the bile of haemoglobin. Bile also contains numerous other com-
is not in contact with the duct cells for sufficient time to pounds that are extracted from the blood, metabolized
allow appreciable modification to take place and there is by the liver, and excreted. Many of these substances are
proportionately less bicarbonate extracted, resulting in a potentially toxic endogenous or exogenous substances
more alkaline bile. Thus, the secretion becomes more alka- such as steroid hormones, drugs and environmental tox-
line at flow rates higher than the basal level. ins that have been detoxified and conjugated in the liver.
The volume of the alkaline secretion, unlike the secre- Conjugation serves to increase the polarity of a substance
tion produced by the hepatocytes, is not directly deter- and therefore its solubility in water (see below). Bile
mined by the concentration of bile salts in the blood. It remains isosmotic with plasma at different rates of flow.
has been termed the ‘bile acid-independent’ component This implies that an increase in secretion of bile acids and
of bile. The control of this secretion during a meal, like metabolites by the liver is accompanied by an increase in
that of alkaline pancreatic juice and the alkaline fluid water secretion resulting in an increase in bile volume.
secreted from Brunner’s glands in the duodenum, is This is known as the choleretic effect.
via the release into the blood of the hormone secretin,
from the walls of the duodenum. This occurs mainly in
response to the presence of acid in the duodenum. The
Biliary lipids
hormone circulates to stimulate all of these alkaline secre-
tions. As it is released in response to acid chyme in the
The structures of the major lipids present in bile are shown
duodenum this mechanism provides a feedback control
in Figure 6.6. The bile acids are derivatives of cholest-
of the pH of the intestinal contents.
erol and contain the cyclopentanoperhydrophenanthrene
nucleus. One, two or three alcohol groups are attached to this
Secretion from the hepatocytes nucleus and there is a short hydrocarbon chain ending in a
The hepatocytes secrete a primary juice into the canal- carboxyl group (Fig. 6.6). Primary bile acids (cholic acid and
iculi. It contains a number of inorganic monovalent and chenodeoxycholic acid) are synthesized by the liver hepato-
divalent ions, and various organic substances (Table 6.1). cytes. Secondary bile acids (deoxycholic acid and lithocholic
The latter include lipids; bile acids, lecithin and choles- acid) are formed by dehydroxylation of primary bile acids in
terol, all of which are sequestered together in micelles. the intestines, by bacteria (Fig. 6.6). The bile acids are usu-
Bile secretion is a major route whereby cholesterol is ally conjugated in the hepatocyte, with amino acids, largely
lost from the body. The bile acids are essential for the glycine or taurine. The ratio of glycocholates to taurocho-
effective digestion and absorption of dietary fats. There lates is normally approximately 3:1 but the exact propor-
are also some proteins in bile, including albumin, poly- tions depend on the relative availability of the two amino
meric immunoglobulin A (pIgA) that protects the biliary acids. The conjugated primary and secondary bile acids
tract and the upper intestines from infection, and some are reabsorbed actively in the ileum (see Ch. 8). However,
plasma-derived enzymes. Bile also contains bile pig- bile acids may be deconjugated by bacteria in the small
ments, chiefly bilirubin, that have been conjugated with intestine and colon. Some of the unconjugated bile acids
glucuronic acid. The pigments are breakdown products are absorbed by passive diffusion. Bile acids synthesized

90 SYSTEMS OF THE BODY

 6
OH

Liver and biliary system

+
Na Bile salt
COO- COO-
Primary
bile acids Sinusoidal
membrane
Bile
HO OH HO OH Na+
salt
Cholic acid Chenodeoxycholic acid

Na+ Bile salt + protein

(bacterial (bacterial
enzymes) enzymes)
Bile salt - protein
Na+ (Bile acid
synthesis and
OH conjugation)
- -
COO COO ATPase ATPase
Secondary
bile acids Bile
salt
HO HO
Canalicular membrane
A Deoxycholic acid Lithocholic acid
Fig. 6.7  Uptake and secretion of bile acid in the hepatocyte.
O
R C O CH2
O Bile salts are secreted into the canaliculus against a con-
R' C O CH O siderable electrochemical gradient. The transport across
CH2 O P O CH2 CH2 N+(CH3)3
the canalicular membrane is Na-independent. The energy
–
may be partly derived from the membrane potential which
O Phosphatidylcholine is approximately 40 mV (negative inside the cell), but an
B
ATPase-dependent pump that is specific for bile acids is
present in the canalicular membrane and this is the major
mechanism for bile salt transport across this membrane
(see Fig. 6.7). It is distinct from the Na gradient-driven
bile acid uptake transporter in the sinusoidal membrane.
Bile acids are held in micelles in bile. They can be con-
centrated several-fold in hepatocyte bile as they are still
held in micellar form. Bile acids are powerful detergents,
HO and their sequestration in micelles may reduce their
C Cholesterol detergent and cytotoxic actions.
The major phospholipid in bile is a phosphatidylcho-
Fig. 6.6  (A) Structure of primary and secondary bile acids and their line (lecithin) with a unique fatty acid pattern: palmitic
modification by intestinal bacteria. (B) Structure of phosphatidylcholine
acid forms the outer ester bond and either oleic acid or
(R, palmitic acid; R, oleic or linoleic acid). (C) Structure of cholesterol.
linoleic acid the inner ester bond (Fig. 6.6). The immedi-
ate source of this phospholipid is a preformed pool in
de novo in the liver, and absorbed unconjugated bile acids, the liver cell membranes. The cholesterol in bile is also
are reconjugated in the liver. In physiological fluids bile mainly derived from a preformed pool but an appreci-
acids form salts with Na and K ions. able proportion is derived via de novo synthesis in the
Uptake of bile salts from the blood into the hepatocyte liver. The cholesterol in bile is not esterified to any sig-
is an active process that occurs against a concentration nificant extent (Fig. 6.6).
gradient (Fig. 6.7). It derives its energy from a Na/K- Inside the hepatocytes the phospholipid and cholesterol
ATPase that pumps Na out of the cell and involves a probably exist as components of membranes of intracel-
Na/bile salt cotransporter system located in the sinu- lular vesicles. The membranes of these vesicles are incor-
soidal membrane. The process is driven by the electro- porated into the plasma membrane by fusing with it. The
chemical gradient for Na set up by the pumping out rate of secretion of phospholipid and cholesterol appears
of Na ions. Another mechanism for bile acid transport, to be linearly related to the rate of bile salt secretion. Bile
which involves a transporter with a wider specificity, salts are secreted into the canaliculus first. The detergent
has also been characterized. The different bile salts com- action of these may be responsible for removing the other
pete with each other indicating that they share the same lipids from the canalicular membrane. The ratio of cho-
transporter. Inside the hepatocyte the bile salts bind to lesterol to phospholipid is fairly constant (approx. 0.3 in
protein, thereby keeping the intracellular concentration the human). Some biliary phospholipid and cholesterol is
of free bile salts low. These proteins may be involved in present in bile in vesicles. These vesicles can incorporate
transport of the bile acids through the cell. bile salts and are gradually converted to micelles.

THE digestive SYSTEM 91

6
Liver and biliary system

OH
CO.NH.CH2.CH2.SO3H
12
Taurocholic acid
3 7
HO H HO

3OH, 7OH, 12OH - Trihydroxy-5β-cholan - 24 oyl taurine

Chemical structure

12
OH CONH CH2 CH2 SO3H
H
7 B Primary micelle in water
OH

OH Three-dimensional structure

Hydrophobic surface

12
7 SO3
3
Hydrophilic surface

A Amphiphilic shape C Mixed micelle

Fig. 6.8  (A) Electrical polarity of a conjugated bile acid. (B) Primary micelle, composed of bile salts, showing orientation of the amphiphilic
lipid in the micelle. (C) Mixed micelle, containing bile acid and phospholipid, illustrating surface net negative charge and outer shell of cations
(mainly Na ions).

Micelle formation chains forming the hydrophobic domain that resides in

the core region of the micelle and the phosphorylcho-
Bile salts are essential for the formation of micelles in line group the hydrophilic domain which projects into
bile. The bile salt molecule is amphiphilic; the roughly the shell region (Fig. 6.8). The mixed micelle can hold
planar ring system is hydrophobic and forms one side more cholesterol than the primary micelle. In the pres-
of the molecule. The alcohol groups, the carboxyl group, ence of phosphatidylcholine larger micelles tend to form
and the peptide bond of the bile acid, all project from the than in its absence. It is therefore known as a ‘swelling’
other side, imparting a net negative charge, and there- amphiphile. Cholesterol, which is extremely insoluble in
fore a hydrophilic nature to that side of the molecule water, resides in the core of the micelle. As the net charge
(Fig. 6.8). A micelle has a hydrophilic shell region and on all micelles is negative they repel each other, thereby
a hydrophobic core region. Newly formed (primary) preventing coalescence, and inducing the formation of
micelles are initially composed of bile salt molecules. a stable suspension. The negatively charged micelle col-
The bile salts orientate themselves in the micelle with lects an outer shell of cations, mainly Na ions. A micelle
the hydrophobic side in the core and the hydrophilic is disc-shaped, and its thickness approximates that of a
side in the shell (Fig. 6.8). Primary micelles can sequester lipid bilayer.
very little cholesterol. However, they take up phos- If the concentration of bile acids is too low for micelles
pholipid to form mixed micelles. Phosphatidylcholine is to form, cholesterol precipitates out and gallstones form
also an amphiphilic molecule; the long chain fatty acyl (Case 6.1: 1–3).

92 SYSTEMS OF THE BODY

 6
Two properties of bile salts determine whether they

Liver and biliary system

will not form. Most bile acids have Krafft points well
will participate in micelle formation: below body temperature, although the secondary bile
1. The Krafft point, which is the temperature below acid lithocholic acid has a high Krafft point and is
which micelles composed of the particular bile acid incapable of forming micelles at body temperature.

Case
6.1 Gallstone disease: 1

An obese middle-aged woman explained to her general Examination of the details of this case provokes the follow-
practitioner that she had suffered several attacks of severe ing questions:
‘gripping’ pain in the upper abdomen. However, there were
l What would an ultrasound scan show in gallstone disease?
no abnormal physical signs at the time she was seen by
How could the findings explain the cause of the patient’s
the doctor. Upon questioning she said that the attacks had
pain?
started after meals. The pain built up gradually to a maxi-
l How can the abnormal appearance of the patient’s stools
mum and lasted for several hours. Her description of the
be explained? What abnormalities of the digestive process
location of the pain indicated that it was epigastric, and in
does it indicate?
the right upper quadrant of the abdomen. She also said that
l How can the yellowing of the sclera (a symptom of
during a recent severe attack her husband had remarked that
jaundice) be explained?
the ‘whites’ of her eyes (the sclera) had appeared yellow. In
l How would the composition of the bile entering the
addition the patient had noticed that her urine became dark
duodenum differ from normal after cholecystectomy?
in colour, and her stools were pale and greasy-looking and
Would cholecystectomy have deleterious consequences for
tended to float in the lavatory pan. The doctor suspected that
the normal functioning of the body?
the patient was suffering from gallstones. This was subse-
l What is the composition of gallstones? Why do they form?
quently confirmed by an ultrasound scan, and the patient was
l How can gallstone disease be treated?
referred to a surgeon for a cholecystectomy (surgical removal
of the gall bladder). These issues will be addressed later in this chapter.

Case
6.1 Gallstone disease: 2

Detection and cause of pain

Gallstones (biliary calculi) are hard masses that can be present
in the gall bladder or the bile ducts (Fig. 6.9). They can be
classified broadly into two types:

1. Those composed largely of cholesterol

2. Those composed largely of bile pigment.
Gallbladder
Both types may be calcified, but usually are not. Cholesterol
stones tend to be large (often in excess of 1 cm in diameter),
and several may be present in one individual. The attacks of
Stones
pain (biliary cholic) experienced following meals are due to
transient obstruction of the cystic duct when the gall blad-
der contracts. The pain in this patient is due to the pressure
of the bile behind the stone. However, most individuals with
gallstones are asymptomatic, and require no treatment.
Gallstones that are sufficiently calcified (20% of all gall-
stones) can be detected by plain abdominal radiography. Fig. 6.9  An ultrasound scan showing a distended gall bladder
and radio-opaque stones within the lumen.
These may be cholesterol stones with a calcified shell, or pig-
ment stones composed mainly of calcium bilirubinate. Pure
cholesterol stones are radiolucent and cannot be detected gallstone detection rate of over 90%. It also allows evaluation
using this technique. of the thickness of the gall bladder wall; an abnormally thick
The simple rapid technique of ultrasonography is usually wall indicates a diseased gall bladder, usually secondary to
employed to reveal gallstones (Fig. 6.9). This provides an overall chronic inflammation, but occasionally due to a carcinoma.

THE digestive SYSTEM 93

6
Liver and biliary system

Case
6.1 Gallstone disease: 3

Gallstones: composition, formation and of bile salts or water in the gall bladder, thereby encouraging
occurrence the cholesterol to precipitate out in the bile.
Women tend to have a higher cholesterol: phospholipid
Many compounds can precipitate in bile to form stones, but
ratio than men which may account for the fact that four
approximately 80% are formed from cholesterol, with a vari-
times more women than men suffer from gallstones. Genetic
able Ca2 content. The rest are composed largely of bile pig-
and racial factors also appear to be important. Cholesterol
ments and Ca2 salts.
gallstones are also found in diseases of the ileum, such as
Cholesterol stones Crohn’s disease (see Ch. 8), which lead to reduced bile salt
If the concentration of bile acids or phospholipids relative reabsorption.
to cholesterol in the bile falls, cholesterol will not be held in
micelles. The bile then becomes supersaturated with cholesterol, Pigment stones
and this tends to precipitate out as microcrystals. These micro­ Pigment stones are usually of small diameter (a few m), and
crystals coalesce to form gallstones. Some cholesterol stones are dark brown or black in colour. When they occur, they are usu-
composed purely of cholesterol. In these cases the stones tend ally multiple. They contain 40–95% pigment and less than
to be large, solitary and pale yellow in colour. Smaller choles- 20% cholesterol. They constitute approximately 20% of all
terol stones can form and these are often of mixed composition gallstones. They can form if there is an overload of unconju-
but usually contain more than 70% cholesterol. These are also gated bilirubin resulting from haemolytic anaemia, burns or
pale yellow and are usually multiple. They are of variable size crush injury. A high incidence of pigment gallstones is seen in
and are laminated, with a dark central nucleus. The cholesterol patients with haemolytic states (such as sickle cell anaemia).
crystals deposit around this nucleus, and then become hardened The bile becomes supersaturated with unconjugated bilirubin
by the precipitation of organic salts. and it precipitates out. The free bilirubin combines with cal-
Cholesterol gallstones tend to develop when there is a high- cium in the bile to form insoluble calcium bilirubinate. This
ratio of cholesterol to bile acids or lecithin in the bile. This can forms the nidus of a stone, and degradation products of
be due to high cholesterol secretion, as a consequence of a high bilirubin aggregate on this core to form pigment stones. A
fat diet, or to congenital hypercholesterolaemia. They may also deficit in the conjugating ability of the liver can also result
form if there is reduced bile acid secretion, as a consequence of in the formation of pigment gallstones. In addition, infect-
bile acid malabsorption in the ileum, or reduced lecithin secre- ing organisms that contain -glucuronidase, an enzyme that
tion. The bile acid pool in an individual is fairly constant (see deconjugates bilirubin glucuronide, can be responsible. Until
below) but in people with gallstones it tends to be smaller than recently a form of the disease where highly calcified pigment
average. Gallstone formation may happen at night as bile acid stones were present occurred in oriental countries (notably
secretion falls (even further) and when blood concentrations are Japan). It was caused by infestation of the biliary duct with
low (see below). The ratio of cholesterol to bile salts and lecithin parasites that contain this enzyme. Its incidence has dimin-
is raised by a high-fat diet, as fats are converted to cholesterol in ished as hygiene and nutrition have improved. Unfortunately,
the liver. Interestingly, gallstones are common in South American however, as the diet has become ‘westernized’ the incidence
women whose diet includes diosgenin-rich beans, because of cholesterol gallstones has increased. There is also a ten-
diosgenin increases cholesterol secretion. Inflammation of the dency for pigment stones to form in patients with cirrhosis of
gall bladder may also contribute by increasing reabsorption the liver due to stasis in the biliary tract.

2. The critical micellar concentration, which is the increase in its content of osmotic particles is followed by
minimum concentration of a particular acid required increased secretion of fluid (the choleretic effect). When
for micelle formation. The critical concentration is biliary lipids are secreted into bile however, micelle
usually well below the concentration of bile acids formation enables bile to be highly concentrated with
present in bile, and micelles easily form. respect to its lipid constituents without the enormous
increase in volume that would accompany an equivalent
Micelle formation is also dependent on the phospholipid
secretion of water-soluble molecules.
concentration, and on the ionic strength and pH of the
medium: neutral or alkaline conditions are a prerequisite.
The alkaline secretion from duct cells has an important Conjugation of metabolites and drugs
role in this respect.
Micelle formation determines the volume of bile A number of other anions (mostly in conjugated form),
secreted. An individual micelle may be composed of in addition to bile acids, appear in bile. Their concentra-
20 or so molecules of lipid but it constitutes only one tions may be 10–1000 times that of their precursors in the
osmotic particle. Thus a simple chemical analysis of the plasma, indicating that active transport mechanisms exist
composition of bile does not indicate its osmolarity. Bile for the removal of their precursors from the blood, or for
is in osmotic equilibrium with blood plasma and any their secretion into the canaliculus. Some of these anions

94 SYSTEMS OF THE BODY

 6
PHASE 1 PHASE 2 Bilirubin + 2UDP-glucuronate

Liver and biliary system

(Uridine diphosphoglucuronate)
(enzyme) (enzyme)

Organic Oxidation, Conjugation Glucuronyl transferase

anion reduction, products -
hydrolysis, COO COO-
products HC HC
HCOH HCOH
Excretion in
HCOH HCOH
urine and bile
A HCOH HCOH
HCO HCO
O O
Oxidation Conjugation
CO CO
Paracetamol CH2 CH2
Phenacetin Paracetamol
glucuronide
CH2 CH2
M V M M M V
+ UDP
Excretion
O N C N C N C N O
B mainly in urine
H H H H2 H H H

(Bilirubin diglucuronide) (Uridine diphosphate)

Hydroxylation Conjugation Fig. 6.11  Conjugation of bilirubin in the hepatocyte.

7-hydroxy- 7-O-
Chlorpromazine
chlorpromazine chlorpromazine i­ nactivates many biologically active amines, including
glucuronide adrenaline and serotonin. Reduction reactions are less
common, but one important clinical example is the inacti-
vation of the anticoagulation drug warfarin.
Phase 2 involves conjugation of the anion with a more
Excretion strongly ionizable group that introduces a negative
mainly in bile charge, or increases the negative charge, on the molecule,
C
making it more hydrophilic. The most common phase 2
Fig. 6.10  Biotransformation of anions in the hepatocyte. (A) General reaction involves the production of glucuronides. These
scheme involving two phases. (B) A drug (phenacetin) which is glucuronidation reactions are all catalysed by UDP-
metabolized in the liver, secreted into the blood, and excreted in the glucuronyl transferase (Fig. 6.10). Steroid hormones, thy-
kidney. (C) A drug (chlorpromazine) which is metabolized in the liver roid hormones, bilirubin and many drugs are converted
and excreted in the bile. to glucuronides in the liver. The formation of bilirubin
diglucuronide is described below and is illustrated in
are of endogenous origin, such as bile pigments or ster- Figure 6.11. However, many compounds are conjugated
oid hormones, and others are xenobiotics such as drugs to form sulphates, in the presence of glutathione. Others
or toxins, or their metabolites. Many of these organic are conjugated to amino acids or to certain hexoses.
anions undergo biotransformation in two phases in the These transformations enable the organic anion that is
liver cells. Figure 6.10 shows a general scheme for these generated to be handled by anion transporters (see below)
reactions. Phase I metabolism makes the molecule more in the canalicular membrane. The conjugates are usually
polar. It can be from oxidation, reduction or hydrolysis. more water soluble and less toxic than their precursors,
The most common type of phase 1 reaction is oxidative. although some (e.g. 7-O-chlorpromazine glucuronide)
These oxidative reactions are catalysed by a complex may be more toxic, and as a consequence may damage
enzyme system, known as the mixed function oxygen- the biliary system, or act as carcinogens (especially in the
ase system, present in the endoplasmic reticulum. The lower part of the duct system). Furthermore, some con-
most important enzyme in this system is cytochrome jugated drugs become less hydrophilic after being acted
P-450, a haem protein which is part of the electron trans- upon by bacteria in the colon. They may then be absorbed
fer chain, that catalyses an intermediate hydroxylation by passive absorption in the colon and recycled via the
step in phase 1 oxidative reactions. liver (the enterohepatic circulation), in which case they
Some drug oxidation reactions involve specific can be difficult to eliminate from the body. Their toxicity
enzymes. Ethanol oxidation, for example, is catalysed is thereby increased. In liver diseases such as cirrhosis,
by alcohol dehydrogenase, and monoamine oxidase in which the hepatocytes are damaged, there may be an

THE digestive SYSTEM 95

6
increase in the half-life of a drug because the capacity of Transport of organic ions
Liver and biliary system

the liver to metabolize and secrete it is decreased.

Transport into the hepatocyte
Organic ions are transported in the blood largely by high
Determinants of preferential excretion into bile affinity binding to albumin and consequently the concen-
trations in plasma of the free ions are low. However, the
Some organic anions are excreted preferentially via the amount of material extracted in a single pass through the
bile and some via the urine. The processing of two impor- liver is often greater than that in free solution. The mech-
tant drugs to glucuronides is indicated in Figure 6.10. anism for this is unknown.
One of these, the analgesic drug phenacetin, is converted Uptake of ‘cholephilic’ anions by the hepatocyte
to paracetamol glucuronide, which is secreted by the involves membrane carrier proteins with high affinity
liver into the blood to be excreted mainly by the kidney. binding sites. Competition studies indicate that the car-
The other, the antipsychotic drug, chlorpromazine, is riers are shared by several anions. Thus bilirubin, sul-
converted to 7-O-chlorpromazine glucuronide, which is phonamides, salicylates and sulphobromophthalein share
excreted mainly in the bile. In the human, small organic the same carrier. This carrier is known as the organic
anions of molecular mass less than 500 Da are excreted anion transporter (oatp). Transport of anions via this
exclusively by the kidney while bigger anions are pref- mechanism is energy requiring and can be against enor-
erentially excreted into bile. Conjugation with glucuronic mous concentration gradients. It involves a chloride anti-
acid or glutathione serves to increase the molecular mass port system.
of a substance by 176 Da and 306 Da, respectively and
conjugation may therefore increase the likelihood of
secretion of the anion into bile. The reason for this dis- Transport into bile
criminatory threshold for excretion in bile is unknown Transport of anions across the canalicular membrane
but the anion transporters in the canalicular membrane into the bile can be against a 100-fold concentration
(see below) may show molecular size specificity. Another gradient. The membrane potential difference, which is
possibility is ‘molecular sieving’ by tight junctions approximately 40 mV, intracellular negative, can only
between the hepatocytes; according to this hypothesis, account for transport of organic anions against a three-
all anions are secreted into the canaliculus but the small fold concentration gradient. At least three specific ATP-
ones leak back into the plasma across the tight junctions. dependent active transport mechanisms are present in
Many drugs are toxic to the liver in high doses; one the canalicular membranes for the transport of organic
of these is paracetamol. Case 6.2: 1 describes the conse- ions (Fig. 6.12). The ATP-dependent transporters and the
quences of an overdose of this drug. The reasons for its membrane potential-dependent transporter are distinct
toxicity at high concentrations in the blood are described proteins. The membrane potential-dependent transporter
in Case 6.2: 2, and the possible treatments are described is a glycoprotein. One of the ATP-dependent transport-
in Case 6.2: 3. ers is responsible for transport of bile acids and has been

Case
6.2 Paracetamol overdose: 1

A teenager who had just failed her examinations was dis- After the transplant operation, the patient’s serum bilirubin
covered unconscious in her bed and rushed into hospital. An levels, prothrombin time and serum albumen were monitored
empty bottle of paracetamol tablets was found in her bed- to determine the progress of her recovery.
room and it seemed likely that she had ingested a whole bot- After studying the details of the above case history we can
tle of tablets. Her stomach was washed out as soon as she ask the following questions:
arrived in casualty. The girl’s blood paracetamol levels were
monitored for 12 h and from the results it was predicted that l Why are high blood levels of paracetamol toxic to the liver?
she might suffer liver damage. She was given intravenous l Why did the patient suffer a relapse after she appeared to
acetylcysteine over the following 20 h. After about 48 h she have recovered?
seemed to have recovered, but then she became aggressive l Why did the patient appear jaundiced after her relapse?

and 2 days later she started to vomit, and became delirious. l How can the patient’s aggressive behaviour be explained?

At the time of her relapse, she had become jaundiced, her l Why were the patient’s serum prothrombin and

liver was tender, and her serum transaminase levels and pro- transaminase levels excessively high, and what is the
thrombin levels were found to be extremely high. These find- significance of this finding?
ings indicated that acute hepatic necrosis was present and it l Why was the patient treated with intravenous

was decided that her best chance of survival would be to have acetylcysteine?
a liver transplant. Luckily a suitable donor liver was available. l Why was a liver transplant necessary?

96 SYSTEMS OF THE BODY

 6
Metabolism of bilirubin

Liver and biliary system

described above. Another is known as the canalicular
multiorganic anion transporter (cMOAT). It transports Bilirubin, which is reddish-orange in colour, is the major
many organic anions including bilirubin glucuronide, bile pigment produced by breakdown of either hae-
and conjugates of various xenobiotics. It does not trans- moglobin or myoglobin in the reticuloendothelial sys-
port unconjugated bilirubin. The jaundiced mutant (Tr-) tem. Figure 6.13 shows the formation of bilirubin from
rat that exhibits hyperbilirubinaemia is deficient in this haem, the porphyrin moiety of haemoglobin. Some of the
transporter. A similar defect is present in Dubin–Johnson intermediate product, biliverdin, a green pigment, is also
syndrome in the human. The third transporter is actu- usually present in bile, and in bile that has been stored
ally a group of phosphoglycoproteins (Pgps), known as the bilirubin reoxidizes to form biliverdin, and the bile
P-transporters, which bind ATP. They transport mainly tends to turn green. (These pigments are bound to albu-
hydrophobic, neutral compounds, and organic cati- min in the circulation.)
ons, into bile. One P-transporter, known as the multi- Free bilirubin from the blood enters the liver cells via
drug transporter 3 (mdr-3), transports many cationic an anion transporter that exchanges it for Cl. Inside the
drugs across the canalicular membrane including certain cell, it is bound to specific cytoplasmic proteins, known
peptides and anti-cancer drugs such as daunomycin. as ligandins (or Y and Z proteins). It is then conjugated
Interestingly the expression of the P-transporters is tem- to glucuronic acid to form bilirubin diglucuronide, in a
porarily increased after partial hepatectomy. reaction catalysed by glucuronyl transferase (Fig. 6.11).

Case
6.2 Paracetamol overdose: 2

Toxicity
Liver dangerous if there is underlying liver disease (as can be the
Paracetamol has potent analgesic and antipyretic actions but its case in an alcoholic).
anti-inflammatory actions are weaker than those of many other The hepatotoxic effects of paracetamol metabolites take
non-steroidal anti-inflammatory drugs (NSAIDs). It is given more than 24 hours to inflict significant damage to hepato-
orally. A therapeutic dose of paracetamol is normally metabo- cytes. That is why the patient had a relapse after she appeared
lized in the liver by conjugation to form soluble glucuronide or to have recovered. She appeared jaundiced after her relapse
sulphate derivatives that can be excreted in the urine. Its half- because the damaged liver could not excrete bilirubin in the
life in the blood is 2–4 h. It may act therapeutically by inhibiting bile. Consequently, it accumulated in the blood. The bilirubin
a central nervous system-specific cyclo-oxygenase isoform such in the blood would be predominantly unconjugated bilirubin
as COX-3, although this has not yet been proved. because of the widespread damage to the liver cells where it
High toxic levels of paracetamol cause nausea and vomiting. is normally conjugated.
A dose of approximately 10 g of paracetamol is sufficient to The excessively high concentrations of serum transami-
cause toxicity. The damage to the liver is due to the conjugat- nase in the patient’s blood and prolonged prothrombin clot-
ing enzymes becoming saturated, that results in the drug being ting time are other manifestations of liver damage because
converted by mixed function P-450 oxidases to N-acetyl-p-benzo- transaminases are inappropriately released from dying hepa-
quinone imine (NAPBQI). The latter compound causes cell death by: tocytes and liver cell failure results in reduced production of
clotting factors such as prothrombin. Determination of these
l Depleting intracellular glutathione, causing oxidative parameters enables the extent of the liver damage to be
stress. When glutathione is depleted, intermediate assessed, and its progress monitored.
metabolites build up and these also contribute to
hepatocyte cell death
Other tissues
l Binding to cell proteins to produce NAPBQI protein The patient’s aggressive behaviour was due to encephalopa-
adducts thy that can accompany hepatic necrosis. The encephalopathy
l Increasing lipid peroxidation and membrane permeability is due to high concentrations of toxic substances in the blood
l Oxidizing SH groups on Ca2-ATPases resulting in sustained as a result of the inability of the liver to detoxify and excrete
increases in intracellular Ca2 and activation of Ca2 them. These cross the blood–brain barrier to damage the cen-
activated proteases. tral nervous system. An EEG (electroencephalogram) can be
used to monitor the encephalopathy.
Note: Alcohol ingestion should be avoided if paracetamol Paracetamol and other NSAID can also cause nephrotoxicity
has been taken for a headache because alcohol is an enzyme and renal failure. This occurs mainly in patients with diseases
inducer and therefore it enhances the formation of toxic where glomerular filtration is compromised, such as heart or
metabolites of paracetamol. Thus, the combination of a nor- liver disease. This effect is due to ischaemia in the kidneys
mally safe dose of paracetamol and a high level of blood alco- because NSAIDs such as paracetamol inhibit the synthesis of
hol can lead to liver damage. This combination is particularly prostaglandins, which are vasodilators.

THE digestive SYSTEM 97

6
Liver and biliary system

Case
6.2 Paracetamol overdose: 3

Treatment Transplantation
A liver transplant was necessary in this patient because,
Drugs
although the ability of the liver to recover function is well rec-
Intravenous acetylcysteine was administered to the patient ognized, if over 80% of the hepatocytes have been irrevers-
because paracetamol can be conjugated to form sulphates, ibly damaged, sufficient function will not be recovered. This
as well as glucuronides. The sulphation reaction requires glu- degree of damage would have been present in this case.
tathione. Acetylcysteine increases glutathione synthesis in Determination of prothrombin time, and serum albumen
the liver and this increases the conjugation of paracetamol and bilirubin concentrations enables the function of the trans-
to paracetamol sulphate, which can be excreted. Glutathione planted liver to be assessed and monitored. The production of
itself is not administered because it does not readily pene- clotting factors and albumen is seen within hours. As the new
trate the liver. If the patient is seen soon after ingesting the liver becomes functional, the bilirubin levels gradually fall
paracetamol overdose (within 12 h) the liver damage may be because the liver regains its ability to sequester it from the
prevented by this treatment. blood and excrete it into the bile. The process of excreting
Note: Forced diuresis or renal dialysis would not have the bilirubin takes several weeks. Thus, prothrombin time and
been useful in this patient because these procedures do not albumen levels are sensitive tests for monitoring early trans-
increase the excretion of paracetamol or its metabolites as plant function.
the compounds bind tightly to tissues.

M V

Hepatocyte Hepatocyte HC CH
N
Anions M M
N Fe N Haem
V V
N
Anions
HC CH
Anions
P M
cMOAT
O2 + NADPH
Anions +
H2O + NADP
Bile canaliculus Haem oxygenase
Bile acids Fe3
+

CO

Organic cations M V M P P M M V
Bile Biliverdin
acids pgps
O N N N N O
H H H
Organic
cations
+
NADPH - H
Biliverdin reductase
NADP

Fig. 6.12  Organic ion transporters in the canalicular membrane

of the hepatocyte. cMOAT, canalicular multiorganic anion transporter; M V M P P M M V
pgps, P-transporters which transport organic cations into bile. Bilirubin

O N N N N O
The glucuronide is more soluble than free bilirubin. Some
H H H H
of the bilirubin diglucuronide escapes into the blood
and may be excreted by the kidney, but most is excreted Fig. 6.13  Formation of bile pigments from haem. M, methyl;
actively via the cMOAT transporter system into bile. V, vinyl; P, propionyl; CO, carbon monoxide.

98 SYSTEMS OF THE BODY

 6
Box 6.2  Jaundice and its causes

Liver and biliary system

INTESTINES LIVER

Jaundice becomes obvious when the plasma bilirubin con-

Bilirubin Bilirubin
Glucuronide Glucuronide centration exceeds 34 mol/L. It can be classified into three
types, depending on the location of the defect that causes it:
Portal blood 1. Prehepatic (or haemolytic) jaundice. Excessive
haemolysis of red blood cells and haemoglobin
Deconjugation Bilirubin Conjugation breakdown to bilirubin can exceed the capacity of
Glucuronide
the liver to excrete it. This type of jaundice is most
frequently associated with haemolytic anaemia of
various types. The bilirubin present in the plasma is
Bilirubin Bilirubin Bilirubin largely unconjugated as it has not been taken up and
conjugated by the liver.
Reduction 2. Intrahepatic (or hepatocellular) jaundice. A variety
of defects in the liver itself can also give rise to
Urobilinogen Urobilinogen Urobilinogen hyperbilirubinaemia. These include decreased uptake
of bilirubin into hepatocytes, defective intracellular
protein binding or conjugation, or disturbed secretion
into the bile canaliculi. This type of jaundice is most
Partial
oxidation commonly seen in acute hepatitis. Although the primary
failure is due to hepatocyte damage that results in
Stercobilinogen accumulation of unconjugated bilirubin, there is also
URINE secondary biliary stasis that provides a mixed picture
with secondary accumulation of conjugated bilirubin.
In Crigler Najjar disease there is an inherited defi-
ciency of glucuronyl transferase and high concentrations
FAECES of unconjugated bilirubin are present in the plasma,
causing jaundice. The affected individuals may develop
Fig. 6.14  Metabolism and fate of bile pigments in the intestines. kernicterus (deposits of pigment in the brain) that can
cause nerve degeneration. Exposure to light degrades
the pigment, and children born with this disease can be
treated by phototherapy. Gilbert’s syndrome is another
If bilirubin subsequently becomes deconjugated in the bil- condition in which unconjugated bilirubin accumulates
iary system, pigment gallstones may form (see Case 6.1: 3). in the blood. In this case glucuronyl transferase activity
is reduced by approximately 70%. This results in mild,
Fate of bile pigments in the gastrointestinal tract intermittent jaundice that normally does not require
treatment. Conjugation of some drugs is also usually
After delivery to the intestines most conjugated bilirubin impaired in these conditions.
is eliminated in the faeces. This is because the intestinal At birth, infants have little ability to conjugate bilirubin
mucosa is not very permeable to the conjugated metabo- but it develops within the first few weeks of life. Thus some
lite. However, some may be deconjugated by the action babies are jaundiced soon after birth, as unconjugated
of bacteria in the intestines and the free bilirubin formed bilirubin is not readily excreted. This condition is known as
can be absorbed to some extent, by passive diffusion into physiological jaundice of the newborn. Exposure to light can
the portal blood because it is more lipid-soluble than con- be employed in these infants to deplete the excess bilirubin.
jugated bilirubin. It is then returned to the liver (via the 3. Post-hepatic (or obstructive) jaundice. Blockage of the
enterohepatic circulation, see below). Intestinal bacteria intrahepatic or extrahepatic bile ducts by, for example,
can also convert bilirubin to colourless derivatives known gallstones, also causes jaundice as the bile is refluxed
as urobilinogens, which can also be absorbed into the por- into the blood. This is commonly referred to as post-
tal blood. These are mostly excreted in the bile but some hepatic or obstructive jaundice (Case 6.1: 4). In this case
are excreted in the urine. Urobilinogen remaining in the the bilirubin is largely conjugated.
gut is partially reoxidized to stercobilinogen, the reddish-
brown pigment responsible for the colour of the faeces.
Figure 6.14 outlines the fate of excreted bile pigments.
Failure of the body to excrete bile pigments results Proteins in bile
in accumulation of the pigments in the blood plasma
(hyperbilirubinaemia), causing jaundice. This is manifest Most proteins in bile are plasma proteins, although
as yellowing of the skin, sclera and mucous membranes. some are derived from cells of the hepatobiliary system.
Box 6.2 describes this condition and its causes. The plasma proteins are mostly synthesized in the liver

THE digestive SYSTEM 99

6
disrupted and the secretory vesicles are misdirected
Liver and biliary system

Case
6.1 Gallstone disease: 4
to the canalicular pole of the cell. The release of some
plasma membrane-derived enzymes, such as alkaline
phosphatase, into bile is promoted by bile salts. This
Obstructive jaundice enzyme has no known function in bile but raised alkaline
The yellowing of the patient’s sclera was due to high con- phosphatase in plasma is used as a biochemical marker
centrations of conjugated bilirubin in the blood. Bile backs of liver disease. It is usually elevated in any form of
up in the hepatobiliary system when there is a blockage of cholestasis, including biliary cholic.
the bile duct and is refluxed into the blood. Thus, in this
case, the plasma bilirubin has been conjugated by the
liver cells. The presence in the blood of abnormally high The gall bladder
concentrations of conjugated bilirubin or certain other
constituents of bile, such as the enzyme alkaline phos- Anatomy and histology
phatase, indicates hepatobiliary disease. The non-clearance
of bilirubin from the body may not in itself be particularly The gall bladder is a pear-shaped sac. In the human
damaging. However, when jaundice is present it is likely adult it is approximately 8 cm long and 4 cm wide, but
that many other potentially toxic materials have also accu- it is capable of considerable distension. It is lined by a
mulated in the blood as a consequence of their reflux from mucous membrane that is thrown into numerous folds
the bile or impaired secretion from the hepatocyte. This can (rugae) when the gall bladder is contracted (Fig. 6.15). As
lead to impaired mental function and malaise. the gall bladder fills with bile the folds flatten out. The
The patient’s urine was dark-coloured because the cystic duct conveys the bile to the hepatic duct (Fig. 6.1).
bilirubin conjugates in the blood are water-soluble, and are The wall of the gall bladder is composed of three layers,
therefore excreted by the kidney. Unconjugated bilirubin the mucous membrane, the muscularis, and the adventi-
binds tightly to albumen. Therefore, in healthy individu- tia (or serosa, see Fig. 6.15). The epithelium of the mucous
als, not much bilirubin is excreted in the urine. Conjugated membrane is composed of high columnar cells with
bilirubin binds much less tightly to albumen and when the basally located nuclei. The apical (luminal) borders of the
conjugate is present in high concentrations in the blood, cells are provided with microvilli, consistent with their
some of it is filtered in the glomerulus of the kidney and is absorptive function. They resemble the absorptive cells of
only partially reabsorbed in the tubules. Thus excretion of the small intestine. Beneath the epithelial cells is the lamina
bilirubin glucuronide by the kidney (bilirubinuria) reflects propria, which is a coat of loose connective tissue. Around
the presence of bilirubin conjugates in the blood. When the the mucous membrane is a thin coat of smooth muscle, the
bile ducts are blocked, bile pigments cannot gain entry to muscularis externa. Most of the smooth muscle fibres run
the gastrointestinal tract and consequently, the faeces are obliquely but some run circularly and some longitudinally.
pale and clay-coloured (acholic). Many elastic fibres are present within the connective tissue
between the muscle fibres. Outside this muscle layer is an
outer coat of dense fibroconnective tissue, the adventitia
and secreted into the blood, but some plasma proteins (or serosa) that is covered by peritoneum.
are normally present in bile, including unaltered active At the neck of the gall bladder, the mucous membrane
enzymes and antibodies. is thrown into a spiral fold that has a core of smooth
Some proteins exhibit relatively low bile:plasma con- muscle (Fig. 6.15). This extends into the cystic duct and
centration ratios. Two non-specific pathways exist for is known as the spiral valve. Its function may be to pre-
protein transport in hepatocytes: vent sudden changes in the filling and emptying of the
gall bladder.
l Paracellular sieving. This pathway is responsible for
secretion of smaller proteins
l Pinocytosis (membrane vesiculation) followed by
Functions
transport of the pinocytotic vesicles and exocytosis.
The functions of the gall bladder are to store and concen-
This pathway does not discriminate in relation to
trate bile, and to deliver it into the small intestine during
molecular size.
a meal. In the human adult, it has a capacity of 30–60 mL.
There are also receptor-linked pathways for the secre- Gall bladder bile is an isotonic solution but some of its
tion of some proteins. One example is immunoglobulin A components are highly concentrated (Table 6.1). The
(IgA) that is transported by receptor-mediated vesicle endothelial cells actively reabsorb Na ions from the bile,
transport in the duct cells. This protein provides immu- by exchange for K ions. The Na ions are pumped into
nological protection for the biliary and intestinal tracts. the lateral spaces between the epithelial cells. Anions,
Excessive secretion of these molecules across the largely Cl and HCO3, follow passively, down the elec-
canalicular membrane can occur when the intracellu- trochemical gradient. The extraction of HCO3 ions tends
lar microtubular guiding system which directs the vesi- to make the gall bladder bile less alkaline. Thus gall blad-
cles which house them to the sinusoidal membrane is der bile is less concentrated with respect to Na, Cl and

100 SYSTEMS OF THE BODY

 6

Liver and biliary system

H2O H
+
Na+ HCO3
-
Cl
-

Tight H+ Na+ HCO3- Cl-

junction

Lateral
space
Corrugated surface H2O
K+
Na+

Cl-
HCO3-
Fig. 6.16  Transport of ions in the gall bladder.
Spiral valve

the gall bladder. The ions and water then pass through the
basement membrane into the blood capillaries (Fig. 6.16).
Table 6.1 compares the composition of gall bladder bile
Cystic duct with hepatic bile. Ca2 ions are not absorbed by the gall
bladder to any appreciable extent and Ca2 is therefore
Common hepatic duct concentrated in gall bladder bile. K ions are also concen-
trated. The organic constituents are highly concentrated
in gall bladder bile, but it remains isosmotic with plasma.
The bile pigments in hepatic bile impart a golden-brown
colour to it, but gall bladder bile is almost black because
the pigments are more concentrated. Bilirubin, bile acids,
Common bile duct lecithin and cholesterol are 5–10 times more concentrated
A in gall bladder bile than in hepatic bile.
Bile may be lost from the body if there is a fistula
Epithelium between the common bile duct and the skin, as may
be provided as a complication of biliary surgery. This
Lamina propria
results in impaired fat absorption in the small intestine.
Loss of significant amounts of K ions (present in high
Muscularis externa concentrations in gall bladder bile) can also occur, and
replacement with KCl has to be instigated in the clinical
management of patients with such fistulae.
Gallstones can form in the gall bladder or the ducts,
causing obstruction of the passage of bile into the duo-
denum. As micelles are important for fat digestion and
Adventitia (serosa) absorption, this can lead to fat malabsorption (Case 6.1: 5).
(The condition can sometimes be managed by the oral
administration of bile acids, see Case 6.1: 6.)
B Peritoneum

Fig. 6.15  The gall bladder. (A) Structural features. (B) Layers of the
Gall bladder contraction
gall bladder wall. The gall bladder exhibits muscle tone and contrac-
tions even in the interdigestive period. It also contracts
between meals to deliver bile intermittently into the duo-
HCO3, than hepatic bile. The pumping of Na out of the denum. The contractions coincide with the migrating
endothelial cell at the basal surface keeps its concentration myoelectric complex of the small intestine (see Ch. 7).
low inside the cell, and this provides the driving force for These fasting contractions may cause mixing of the bile,
Na ions to enter the cell via the apical membrane (down reducing the likelihood of cholesterol crystals accumulat-
their concentration gradient). Transport in the apical mem- ing and forming gallstones.
brane occurs partly via exchange for H ions and partly The major stimulus for gall bladder contraction after
by symport with Cl ions. As a consequence, water is a meal is a high blood level of CCK, the hormone that is
transported passively, down the osmotic gradient, out of released in response to fat in the duodenum. It acts on

THE digestive SYSTEM 101

6
Liver and biliary system

Case
6.1 Gallstone disease: 5

Fat malabsorption bile acids are not delivered to the small intestine and as a
The pale colour of the patient’s stools was due to the absence consequence, lipids are not absorbed. Fat malabsorption
of bile pigments (see below), and the greasiness was due to causes flatulence and diarrhoea. The duration of the time
the presence of abnormally large quantities of unabsorbed period over which fat malabsorption is present in gallstone
fat. Elimination of excessive amounts of fat is known as stea- disease before it is treated is usually relatively short and for
torrhoea. The fat caused the faeces to float, and to smell that reason, fat-soluble vitamin deficiency is unusual, except
abnormally offensive because it had been fermented by bac- in the case of vitamin K as body stores of vitamin K are very
teria in the colon. limited. Deficiency of this vitamin leads to deranged blood
Bile acids play an important role in the digestion of lipid, coagulation.
and in the absorption of lipid- and fat-soluble vitamins (vita- Restriction of dietary fat reduces steatorrhoea, but then
mins A, D, E and K). Consequently, in severe cholestasis such vitamin K supplements are required to prevent failure of
as when the common bile duct is obstructed by gallstones, blood clotting.

Case
6.1 Gallstone disease: 6

Treatment absorbed, so dehydration does not occur. One consequence

is that bile acids may enter the small intestines more rapidly,
Surgery and therefore, a higher proportion may be eliminated from
In gallstone disease, where stones are present in the gall blad- the body. However, this reduction in the bile acid pool is nor-
der, surgical removal of the gall bladder is often performed mally rectified by increased synthesis in the liver.
using ‘keyhole’ surgery (Fig. 6.17). If a gallstone is present
in the biliary duct, sphincterectomy can be employed. This Lithotripsy
involves passing an endoscope down through the mouth into A non-invasive treatment for gallstones, involving the use of
the duodenum (Fig. 6.18). The sphincter of Oddi can then be ultrasonic vibrations, known as lithotripsy, can be performed.
divided to allow the stone to be removed.
The digestive processes are not seriously impaired after
removal of the gall bladder because hepatic bile simply flows
directly into the duodenum. A greater volume of uncon-
centrated bile enters the intestines, but the extra fluid is

L G E
I I

C
C

Fig. 6.17  Gall bladder surgery being performed laparoscopically.

The gall bladder (G), divided cystic duct (C) and cystic artery (A) are Fig. 6.18  This X-ray shows an endoscope (E), which has been passed
seen, with the liver (L) lying behind. (I) Instruments for lifting and into the duodenum. Contrast has been injected (retrograde) into a
dividing the gall bladder structures. dilated common bile duct (C), which contains a calculus (S).

102 SYSTEMS OF THE BODY

 6

Liver and biliary system

Case
6.1 Gallstone disease: 6 (continued)

In this procedure, focused ultrasound waves are used to dis- even more effective. These particular bile acids are effective
rupt the gallstones and the fragments formed are carried in because they increase cholesterol sequestration in micelles
the bile into the small intestines and subsequently eliminated and (unlike cholic acid and deoxycholic acid) they do not
from the body. Lithotripsy is not widely employed because suppress bile acid synthesis. Ursodiol also inhibits cholesterol
the stone fragments can get lodged in the common bile duct, absorption in the intestine and decreases the synthesis of chol­
resulting in obstructive jaundice. (Kidney stones are more esterol in the liver. This causes reduced plasma cholesterol lev-
commonly treated using this technique.) els, and for this reason, ursodiol has also been considered for
the treatment of coronary heart disease.
Treatment with bile acids The main side-effect of bile acid treatment is diarrhoea,
Gallstones can be treated by oral administration of bile secondary to incomplete absorption of the ingested bile salts.
acids. Cholesterol supersaturation in bile in patients with Small gallstones disappear relatively quickly with bile acid
gallstones is usually due to a diminished bile acid pool. The treatment. However, it is the large stones which are usually
ingested bile acids are absorbed in the ileum and taken up responsible for the symptoms of gallstone disease, and so
by the liver and then secreted in the bile (Fig. 6.19). Thus if alleviation via this means takes a long time. Moreover, most
a bile acid is fed in substantial amounts, the bile acid pool individuals with gallstones present with acute symptoms,
is expanded. This enables more cholesterol to be retained in which are often associated with a dysfunctional gall bladder.
micelles, rather than precipitating in the bile. The bile acids Therefore the use of bile salt therapy is limited. Furthermore,
slowly dissolve the gallstones over a period of time, usually life-long therapy with bile salts would be required to prevent
several months. Chenodeoxycholic acid (Fig. 6.6) can be effec- the stones recurring.
tive. Ursodeoxycholic acid (ursodiol), a derivative of chenode- Thus cholecystectomy remains the primary choice for the
oxycholic acid that is relatively abundant in polar bear bile, is removal of gallstones.

CCK-A receptors on the smooth muscle of the gall blad- contract, the ducts shorten and become wider to increase
der. Gastrin, a related peptide, released by the stomach the flow of the digestive juices through them. The main
antrum in response to peptides also stimulates gall blad- stimulus for relaxation of the sphincter muscle is CCK.
der contraction. In addition, distension of the stomach Thus when the levels of CCK increase in the blood dur-
antrum stimulates contraction via a nervous reflex. The ing a meal, the gall bladder contracts and the sphincter of
gastric mechanisms involved in the control of bile release Oddi relaxes, and bile enters the duodenum. These events
are presumably preliminary to the emptying of chyme act in concert to allow bile to enter the small intestine when
from the stomach. a meal is being processed in the gastrointestinal tract.
Vasoactive intestinal peptide (VIP), pancreatic
polypeptide (PP), and stimulation of the sympathetic
nerves to the gall bladder, all cause gall bladder relaxa- The enterohepatic circulation of bile acids
tion. Bile acids in the duodenum also inhibit gall bladder
contraction (a feedback control). Conjugated bile acids are secreted by the liver, released
into the duodenum, and eventually absorbed in the ileum
into the portal blood. They are then taken up by the liver
The sphincter of Oddi and secreted again. This cycle is repeated over and over
again. This is known as the enterohepatic circulation of
The hepatic bile duct penetrates the wall of the duode- bile acids. The secretion of the bile acid-dependent frac-
num, at the same location as the pancreatic duct. Part of tion of bile from the hepatocytes is not controlled to any
the way through the duodenal wall, the hepatic duct and great extent by hormones or nerve impulses originat-
the pancreatic duct fuse. The lumen of the fused duct is ing in the gastrointestinal tract, although CCK may be a
relatively wide and this region is known as the ampulla weak stimulus. The normal stimulus for increased secre-
of Vater. It opens into the lumen of the duodenum, tion of bile salts is a high bile salt concentration in the
and at the opening are the duodenal papillae. Circular blood (Fig. 6.19). The bile salts are secreted more or less
smooth muscle is associated with the ampulla and with continuously but the rate of secretion increases when the
the regions of the hepatic and pancreatic ducts that are blood concentration increases. The concentration in the
associated with it (Fig. 6.1). This constitutes the sphincter portal blood normally increases after a meal when the bile
of Oddi. The closure of this sphincter prevents bile from acids have been absorbed.
entering the intestine. As a result, the bile that is formed Thus, food in the gastrointestinal tract indirectly controls:
while it is closed is diverted into the gall bladder. In addi-
tion there are smooth muscle fibres that run in paral- l The secretory process, as bile acids do not enter the
lel with the bile and pancreatic ducts. When these fibres duodenum in any appreciable amounts until the gall

THE digestive SYSTEM 103

6
Control of the hepatobiliary system during a meal
Liver and biliary system

Food in the Storage in the Uptake and

duodenum gallbladder secretion
by the liver Bile is secreted at a rate of between 250 and 1500 mL/day
in the human adult. Several different functions of the
hepatobiliary system are under physiological control;
secretion of alkaline fluid from the ducts, the secretion
CCK release Increased bile of bile from the hepatocytes, contraction of the smooth
acid concentration muscle in the wall of the gall bladder to release the stored
in portal blood
bile, and relaxation of the smooth muscle in the sphincter
of Oddi, which allows the bile into the duodenum.
Contraction of
The control of alkaline bile secretion (like that of
the gallbladder
Absorption into gastric juice and pancreatic juice) during a meal can be
portal blood divided into three phases according to the location of the
ingested material:
Transport of
Bile enters bile acids to 1. The cephalic phase, which is the response to the
the duodenum the ileum approach of food or the presence of food in the
mouth.
Fig. 6.19  The enterohepatic circulation of bile acids. 2. The gastric phase, which is the response to food in the
stomach.
3. The intestinal phase, which is the response to food in
the duodenum.
bladder contracts and the sphincter (of Oddi) relaxes, The bile acid-dependent fraction is secreted more or less
when they can subsequently be absorbed in the ileum continuously, but the gall bladder usually only contracts
into the portal blood, to stimulate secretion forcefully during a meal. Thus although secretion is con-
l Access of bile to the chyme in the intestines, by tinuous, bile acids usually only enter the gastrointestinal
stimulating gall bladder contraction and sphincter tract in appreciable amounts during a meal, i.e. when
(of Oddi) relaxation via CCK release into the blood. they are required.
Most of the pool of bile salts may be recycled twice dur-
ing a meal, and between 3 and 14 times a day depend- Cephalic phase
ing on the number of meals taken and the fat content of
the meals. Fat in the chyme elicits CCK release which The cephalic phase is mediated via impulses in nerve
stimulates gall bladder contraction and sphincter relaxa- fibres in the vagus nerve. It is due to the sight and smell
tion. As bile acids are important for lipid digestion and of food, and the activation of taste and touch receptors
absorption (see Case 6.1: 5), this control constitutes a pos- by food in the mouth. In this phase there is an increase
itive feedback mechanism. The uptake of bile acids from in the secretion of alkaline bile from the duct cells, which
the intestines enables small gallstones to be successfully would presumably minimize the effects of increased acid
treated by oral administration of a bile acid, as this will secretion in the stomach during the cephalic phase. Weak
be secreted by the liver to increase the concentration in contractions of the gall bladder and relaxation of the
the bile and dissolve the stones (see Case 6.1: 6). sphincter of Oddi also occur.
The total bile acid pool (approx. 3.0 g in the adult) is
kept constant. The rate of synthesis is normally very low Gastric phase
because most of the conjugated bile acids that enter the
small intestine are actively reabsorbed and returned to Peptides, caffeine or alcohol in food in the stomach, and
the liver (Fig. 6.19). Normally only a small proportion, distension of the stomach walls cause increased release
approximately 10%, is lost in the faeces. The liver keeps of gastrin from the pyloric antrum and activation of
the size of the pool constant by synthesizing an amount nerve fibres in the vagus nerve. These influences stimu-
equivalent to that lost. De novo synthesis is a response to late alkaline juice secretion from the bile ducts and weak
low levels of bile acids in the blood. If for any reason bile contractions of the gall bladder.
acids are not reabsorbed in the intestines (e.g. disease of
the ileum) then de novo synthesis of bile acids increases.
However, if the enterohepatic circulation is interrupted Intestinal phase
(e.g. after resection of the terminal ileum), the rate of syn- The intestinal phase is the most important of the three
thesis is not sufficient to compensate for the loss via the phases for the control of both the secretion of alkaline
faeces. The result is malabsorption of fats and fat-soluble bile and the contraction of the gall bladder. It is mediated
vitamins. The commonest cause of this is Crohn’s disease largely via the peptide hormones secretin and CCK that
of the terminal ileum (see Ch. 8). are released from the walls of the duodenum into the

104 SYSTEMS OF THE BODY

 6
blood. Secretin is released in response mainly to acid in contraction of the gall bladder is weak. CCK also causes

Liver and biliary system

the chyme. It acts on receptors on the duct cells to stimu- relaxation of the sphincter of Oddi, thereby enabling the
late the release of alkaline bile. Its action is potentiated bile to flow freely into the duodenum. Bile acids exert a
by CCK. negative feedback control on gall bladder contraction
CCK is the most potent stimulus for gall bladder con- and sphincter relaxation, by inhibiting the release of CCK
traction. The most potent stimulus for CCK release is from the duodenum.
fat in the duodenum: when fat is not present in a meal,

THE digestive SYSTEM 105

The small intestine 7
Chapter objectives
After studying this chapter you should be able to:

1. Describe the structure of the small intestine and the major cell types
present in the mucosa.

2. Understand the processes of water and electrolyte secretion and

absorption in the small intestine.

3. Understand the mechanisms of diarrhoea, its consequences and

treatment.

4. Describe the motility of the small intestine, and its control.

7
secretin and CCK from endocrine (APUD) cells in the
The small intestine

Introduction
walls of the duodenum. Secretin stimulates secretion of
alkaline pancreatic juice, alkaline bile, and alkaline intes-
In the human, most digestion and absorption occurs in the tinal juice. CCK stimulates secretion of enzyme-rich pan-
small intestine. Digestion in the stomach is dispensable and creatic juice. It also causes contraction of the gall bladder
it is only preparatory. Pancreatic juice and bile from the liver and relaxation of the sphincter of Oddi, which promotes
enter the duodenum (Fig. 7.1). Intestinal juice is secreted the entry of bile and pancreatic juices into the duodenum
along the entire length of the intestine from glands in the
wall. In the normal individual, digestion is substantially
complete when the chyme passes into the colon. The small
intestine normally also absorbs over 95% of the water which Case
enters the gastrointestinal tract. There is considerable reserve 7.1 Cholera: 1
of function, and two-thirds of the small intestine can be
removed without serious impairment of the quality of life.
An elderly man was carried by his son into a hospital,
Absorption is the central process of the digestive sys-
which was situated in a remote region of Bengal. The man
tem and all other physiological processes that occur in
appeared emaciated. He said he had initially been vomiting
the gastrointestinal tract subserve it. In this chapter we
and suffering from abdominal distention. Now he was suf-
shall deal with the absorption of water and monovalent
fering from copious diarrhoea. The duty doctor noted that
ions. Digestion and absorption of other nutrients will
the man’s skin lacked turgor. The man’s pulse was barely
be dealt with separately. We shall also consider how the
detectable but his pulse rate was rapid (100 b.p.m.). The
contractile activity of the intestines mixes and propels the
younger man was also suffering from diarrhoea, but he was
food towards the ileum.
less severely affected. The doctor suspected that they were
The importance of water and electrolyte absorption in
both victims of the latest cholera epidemic. Such epidemics
the intestines is illustrated in this chapter, by the prob-
are not uncommon in the region because of contamination
lems encountered in cholera, a condition in which there
of food and drinking water with the bacterium Vibrio chol-
can be a massive loss of fluid from the body (Case 7.1: 1).
erae. The elderly man was provided with electrolyte fluid
via an intravenous drip. His plasma and urine K and HCO3
Intestinal phase of digestion concentrations were monitored. He was also given intrave-
nous tetracycline for 2 days. The younger man was given
When chyme enters the small intestine from the stom- some packets containing a mixture of salt (NaCl) and sugar
ach, it causes the release into the blood of the hormones (glucose) and a supply of clean drinking water. He was told
to dissolve the salt and sugar in clean water from the hos-
pital supply and to drink large quantities of the solution
Liver over the next few days. He was given tetracycline to take
by mouth. Both patients had recovered within a few days.
We shall address the following questions:

l What causes cholera?

Smooth
muscle
l Why were the patients treated with tetracycline?
l Why was it necessary to monitor the patient’s plasma

and urine K and HCO3 concentrations?

l How would the patients’ acid–base status have changed?
Pancreas
l What adjustments in respiratory and renal function

Gallbladder Pancreatic duct would be taking place in response to the changes in

Common bile duct acid–base status?
Sphincter of Oddi
l How does the V. cholerae bacterium cause diarrhoea?

l Could other treatments counteract the effect of the

toxin on the crypt cells?

l What is the rationale for treating people suffering from

cholera with (a) oral fluid containing NaCl and glucose

Duodenum and (b) intravenous fluid? What is the likely composition
Pyloric Food (chyme) of the intravenous fluid?
Stomach sphincter l Why was the elderly man’s pulse (a) feeble and

Fig. 7.1  Structures involved in the duodenal phase of digestion. (b) rapid?
l What adjustments in cardiovascular and renal function
Pancreatic juice and bile from the liver enter the duodenum during
the intestinal phase. The entry is controlled by the pressure generated would take place in response to the hypovolaemia?
when the gall bladder contracts and by relaxation of the sphincter of l Are changes in intestinal motility involved in this

Oddi. These juices, and juices from the intestinal walls, mix with the condition?
acid chyme arriving from the stomach.

108 SYSTEMS OF THE BODY

 7
(Fig. 7.1). At the same time, these hormones inhibit gas- part of the duodenum are two papillae. The major duo-

The small intestine

tric emptying which enables processing of the contents denal papilla is the location of the duct where the bile
of the small intestine to occur before the next portion of and pancreatic juice empty into the duodenum via the
chyme enters from the stomach, and prevents the intes- ampulla of Vater. The opening of the ampulla is control-
tinal chyme from becoming too acid. The latter is impor- led by the sphincter of Oddi (Fig. 7.1). An accessory pan-
tant because the action of pancreatic enzymes and lipid creatic duct, present in most individuals, opens at the tip
absorption require an alkaline or neutral pH. of the lesser papilla.
The chyme also stimulates contraction of the smooth The surface of the duodenum is folded. The folds
muscle of the intestines, which mixes the intestinal con- are known as plicae circularis (circular folds). Most are
tents and propels it towards the ileum. The intestinal phase crescent-shaped, and do not disappear when the intestine
of the control of digestion is summarized in Table 7.1. is distended. The mucosa of the small intestine is covered
with tiny projections, known as villi. These are tongue-
shaped in the duodenum.
Anatomy and structure Two types of glands are present in the duodenal
mucosa. At the base of the villi are tubular invaginations
In the adult human, the small intestine consists of that reach almost to the muscularis mucosae, known as
approximately 6 m of 3.5 cm diameter tubing that is coiled intestinal glands or crypts of Lieberkühn (Fig. 7.3). The
in the abdomen. It leads from the stomach to the colon submucosa of the duodenum contains coiled compound
(Fig. 7.2). The duodenum comprises the first 25 cm or so. tubular mucous glands known as glands of Brunner that
This region differs from the rest of the small intestine in secrete an alkaline fluid rich in mucus. These glands are
having no mesentery. The adjacent region is the jejunum more numerous in the proximal region of the duodenum.
that comprises approximately 40% (2.5 m) of the small They usually open at the base of the intestinal glands.
intestine. The remaining distal part is the ileum. The lon-
gitudinal smooth muscle in the wall is normally partially
Jejunum and ileum
contracted (tone). After death, when it is relaxed, the
small bowel reaches a length of approximately 7.5 m.
No anatomical feature separates the jejunum from the
ileum. The structure of the jejunum and ileum is basi-
Duodenum cally similar to that of the duodenum. However, there is
a gradual decrease in diameter, and in the thickness of
The duodenum has an essential role in mixing digestive the wall, and in the number of mucosal folds, with dis-
juices, derived from the liver and pancreas, and its own tance from the duodenum (Fig. 7.4). The folds are absent
wall with the food. It forms an arc ending in a sharp bend, altogether from the terminal ileum. In addition the villi
the duodeno-jejunal flexure. The head of the pancreas gradually become less numerous, smaller, and more
lies within the arc, with which it shares a blood supply finger-like, with distance from the duodenum. Numerous
via the pancreatico-duodenal artery (Fig. 7.2). At approx-
imately two-thirds of the way down the descending

Stomach
Duodenum
Table 7.1  Control of secretion and motility during the
intestinal phase Mesentery

Effect Hormone

Pancreas
Secretion
Duodenojejunal
Duodenal (alkaline) Stimulation Secretin flexure
Bile (alkaline) Stimulation Secretin
Jejunum
Bile (hepatocyte) None
Pancreatic juice (alkaline) Stimulation Secretin
Pancreatic juice (enzyme-rich) Stimulation CCK
Smooth muscle
Stomach Relaxation CCK, secretin Ileum
Ascending
Gallbladder Contraction CCK colon Vermiform appendix
Sphincter of Oddi Relaxation CCK Caecum

Intestinal Contraction Various Fig. 7.2  Anatomical arrangement of the small intestine and
associated structures.

THE digestive SYSTEM 109

7
lymph nodes, called Peyer’s patches are present in
The small intestine

the mucosa and submucosa of the ileum. The junction

Villi between the ileum and the large intestine is the ileocaecal
junction. It consists of a ring of thickened smooth mus-
cle, known as the ileocaecal sphincter (see Ch. 10), which
reduces reflux from the colon.
The jejunum and ileum are on a mesentery. This con-
tains the arterial blood vessels (branches of the superior
Lamina propria mesenteric artery), and the veno-lymphatic drainage ves-
sels, which are supported in fatty connective tissue, and
is covered by mesothelium.

Blood supply

At rest, approximately 10% of the cardiac output flows to

Crypt
the intestine. The blood vessels in the jejunum and ileum
are derived from the superior mesenteric artery. Numerous
Muscularis mucosa arterial branches form an extensive network in the submu-
cosa that supplies the wall of the intestine (Fig. 7.5).
Nerves, hormones and local paracrine factors control
Fig. 7.3  Structure of the submucosa of the small intestine, showing
the intestinal circulation. Stimulation of the sympathetic
the relationship of the glands to the villi.
nerves (which follow the arteries) causes vasoconstric-
tion and reduced blood flow, enabling a redistribution of
blood away from the intestine. This is particularly impor-
D J
tant during low cardiac output states such as shock, or
during exercise when extra blood is required for skeletal
muscle. In the blood vessels of the villi, the vasoconstric-
tion is relatively short-lived. This is due to vasodilator
S
metabolites, such as adenosine, which accumulate during
the vasoconstrictor response.
The splanchnic blood flow increases by 50–300%
during a meal (functional hyperaemia). Distension of
the walls of the intestine and substances present in the
chyme stimulate the blood flow. Other stimuli include
products of carbohydrate and lipid digestion in the prox-
imal small intestine, and bile acids in the distal ileum.
Gastrin, CCK, secretin, serotonin and histamine all have

Ileum

Fig. 7.4  An X-ray of the small bowel taken 2 h after ingestion of Vessels
barium. The mucosal outline of the jejunum (J) is clearly seen, showing
the dense mucosal folds that maximize the surface area. The stomach Fig. 7.5  A photograph of the vascular arcade in the ileum, showing
(S) and duodenum (D) are also visible. the multiple arterial anastomoses in the mesentery.

110 SYSTEMS OF THE BODY

 7
the capacity to increase blood flow, and may be involved Ch. 1). Beneath the serosa is the muscularis externa that

The small intestine

in this response during a meal. consists of two layers of smooth muscle, an outer lon-
The nutrients absorbed across the absorptive cells are gitudinal coat and an inner circular coat. Preganglionic
transported to the liver in the portal veins (Ch. 6). parasympathetic nerve fibres of the vagus nerve synapse
with the cells of the terminal ganglia in the myenteric
plexus. The postganglionic nerves stimulate muscle con-
Countercurrent exchange in the villi traction and gland secretion (see Ch. 1). Postganglionic
The blood vessels of the villi (Fig. 7.6) constitute a coun- sympathetic nerve fibres arising largely from the prever-
tercurrent exchange system, whereby there is net diffu- tebral ganglia mostly innervate their target effector cells
sion of dissolved substances across the interstitium from directly. The submucosal plexus contains a few parasym-
the venule to the arteriole, or vice versa, depending on pathetic ganglia of the vagal nerve, but postganglionic
which limb has the higher concentration. Thus oxygen sympathetic fibres from the superior mesenteric plexus
tension is higher in the ascending arterial blood because form the major proportion of the extrinsic nerves present.
it is extracted from the blood in the capillaries, and it dif- Beneath the submucosa is the muscularis mucosae
fuses from the ascending to the descending limb. This which consist of two thin layers of muscle with some
results in a lower oxygen tension at the tips of the villi elastic tissue. The inner muscle layer consists of circu-
than at their bases. The relative hypoxia at the tip has larly disposed fibres and the outer layer longitudinally
been causally implicated in the shedding of the epithelial disposed fibres. The muscularis mucosae permit local-
cells from the tips of the villi. In hypovolaemic shock, a ized movement of the mucous membrane. Small bundles
situation where hypotension is present, the reduced per- of muscle fibres extend from it to the epithelium. Some
fusion pressure together with increased smooth muscle of the fibres end on the epithelial basement membrane.
relaxation that accompanies it, leads to a reduced oxy- Beneath the muscularis mucosa in the lamina propria is
gen supply. This can cause the tips of the villi to become a layer of connective tissue that supports the epithelium
severely hypoxic. During hypovolaemic shock this can and contains collagen, reticular fibres and some elastic
lead to ulceration of the intestines, which can develop fibres. It also contains blood capillaries and lymph cap-
within hours of the onset of hypovolaemia. Such acute illaries that are situated close to the epithelial surface,
ulcers are seen in patients who have suffered severe especially in the villi (Fig. 7.6). It also contains numerous
burns, especially children, and after major haemorrhage, lymphatic nodules. Lymphocytes and plasma cells gain
such as a leaking aortic aneurysm. access to this layer across the epithelial membrane. These
cells protect the tissue against bacteria that enter across
the epithelial membrane. The plasma cells produce IgA
Structure of the intestinal wall immunoglobulins. The innermost layer is the epithelium
which is described below.
The wall of the small intestine has the same basic struc-
ture as other regions of the gastrointestinal tract (see
The villus

Capillary The villus is regarded as the unit of absorption. Its length

varies between 0.5 and 1.5 mm, depending on its loca-
Lacteal tion in the small intestine. The structure of the villus is
depicted in Figure 7.6. Each villus contains a blood cap-
illary network and a blind-ended lacteal (or lymph ves-
sel). It is covered by simple columnar epithelium. Most
Venule of these cells have numerous cytoplasmic extensions,
Arteriole
known as microvilli at the luminal surface. The microvil-
lous surface of the intestine is known as the brush border.

Histology

The mucosa of the small intestine is simple columnar epi-

thelium. Four cell types are present:
Artery 1. Absorptive cells that produce digestive enzymes and
absorb nutrients from the chyme
Vein 2. Goblet cells that produce mucus which lubricates the
surface and protects it from mechanical damage
Lymph duct
3. Granular cells (cells of Paneth) that produce enzymes
Fig. 7.6  Structural features of the villus. and protect the intestinal surface from bacteria

THE digestive SYSTEM 111

7
4. APUD cells that produce peptide hormones which apparatus. They synthesize enzymes, such as lysozyme,
The small intestine

regulate secretion and motility in the gastrointestinal and sequester them in zymogen granules, from which
tract, liver and pancreas. The general function and they are released into the lumen by exocytosis.
structure of APUD cells are described in Chapter 1. There are also oligomucous cells that contain few
mucus globules in the crypts. These are the precursors of
The four cell types arise from undifferentiated cells in the goblet cells. They can divide but they lose this ability
the crypts of Lieberkühn. The granular and endocrine when they become distended with mucus after migrating
cells remain at the bottom of the crypts but the absorp- up the villus.
tive and goblet cells slowly migrate up the sides of the Endocrine cells comprise about 1% of the cells in the
villi, to the tips. Figure 7.7 shows the cell types and their crypts. They have a narrow apex, and a wide basal region
typical locations in the mucosa. The cells that migrate that is packed with dense argentaffin granules. These
are eventually shed from the tips. The process of migra- cells produce hormones such as secretin, CCK, somato-
tion from the crypts to the tips of the villi occurs over statin or endorphins. Others produce serotonin.
3–6 days in the human. Thus, most of the intestinal epi- There are a few caveolated cells, characterized by
thelium is renewed every few days. The columnar cells invaginations of the cell membrane extending into its
mature as they travel towards the tips of the villi, and cytoplasm (caveolae). They have long microvilli that con-
their functions change. There is a gradual transition tain long bundles of straight filaments that extend into
from base columnar cells in the crypts (Fig. 7.7) to villous the cytoplasm, and filaments encircling the apical region.
columnar cells; their size increases progressively as they Their role is unknown.
ascend the walls of the crypts and villi, and their content
of free ribosomes decreases, while their content of rough
endoplasmic reticulum increases. Intestinal secretions

An alkaline fluid containing electrolytes, mucus and

Cell types water, is secreted throughout the length of the small
Villous epithelium intestine. The precise composition of the secretion, and
the mechanisms that control it, vary from one region
About 90% of the cells covering the villi are the absorp- to another. It is secreted by the immature cells in the
tive columnar cylindrical cells. Most of the rest are gob- crypts of Lieberkühn. The mechanisms involved are out-
let cells, but 0.5% are endocrine cells. The absorptive lined in Figure 7.8. The key step is the active transport
cells have abundant cytoplasm and mitochondria but of Cl across the basolateral membrane of the cell. Cl is
few ribosomes. They have a thick striated microvillous actively transported into the cell via a co-transporter pro-
border and convoluted lateral cell membranes. Figure 7.7 tein that transports Na, K and 2Cl. The transport of
shows the structure of an absorptive cell, and the struc- Na down its electrical gradient is the driving force for
ture of microvilli. The rough endoplasmic reticulum and the operation of this transporter. The K is transported
Golgi saccules are well-developed in columnar cells at back out via K channels in the same membrane. This K
the base of the villi but less prominent in cells at the tips flux maintains the electrical potential difference (cytosol
of the villi. The columnar cells produce a cell coat that is negative) across the cell membranes. This potential dif-
composed of glycoproteins, but the cells at the base of the ference contributes to the driving force for the baso­
villi are more active in this respect than the other cells, lateral influx of Na across the basolateral membrane,
as is consistent with their well-developed Golgi saccules. and also for Cl transport across the luminal membrane.
Some of the glycoproteins present are enzymes involved Cl is transported into the lumen via the cystic fibrosis
in the digestion of nutrients such as disaccharides (see transport regulator (CFTR, see Ch. 5) which is an electro-
Ch. 8). They act in situ but are also active after being shed genic Cl channel in the luminal membrane. Na is then
into the lumen. transported into the lumen between the cells, down the
electrochemical gradient produced by the extrusion of
Cl from the cell. The opening time of the CFTR chan-
Crypt epithelium
nel is prolonged by increased cAMP. Therefore secretion
The base of the crypt contains approximately equal num- by the crypt cells is stimulated by substances that elevate
bers of small columnar cells and Paneth cells. The small cAMP, such as vasoactive intestinal peptide (VIP) and
columnar cells have sparse cytoplasm containing few prostaglandins. Ca2-mobilizing agents such as acetyl-
mitochondria and little rough endoplasmic reticulum choline potentiate the actions of these substances. The
and a small Golgi apparatus. However, they contain mechanism of action of cholera toxin is also via increas-
numerous free ribosomes, consistent with their active ing intracellular cAMP. In this case it causes a massive
protein synthesizing function. They have smooth lateral secretion of fluid (Case 7.1: 2). There is a defect in the
membranes and are relatively undifferentiated. These are CFTR channel in cystic fibrosis (see Ch. 5). The first man-
the stem cells that give rise to the other cell types. ifestation of cystic fibrosis can be postnatal constipation
Paneth cells are highly differentiated, possessing abun- (meconium ileus) that is directly related to absence of the
dant rough endoplasmic reticulum and a prominent Golgi CFTR channel.

112 SYSTEMS OF THE BODY

 7
Absorptive Goblet cell

The small intestine

Microvilli cell

Cell Terminal web

membrane
Ribosome
Rough
endoplasmic Mitochondrion
reticulum

Golgi
apparatus
Nucleus
Intercellular
space

Glycocalyx Actin filaments Small

columnar cell

Paneth cell
Cell
membrane
Undifferentiated cell Endocrine cell

Myosin Terminal
filaments web

Paneth cell APUD (endocrine) cell Goblet cell Crypt columnar cell
(stem cell)

Zymogen
granules

Mucus
globules

Dense
granules

C D E F

Fig. 7.7  Cell types in the intestinal epithelium. (A) Absorptive columnar cell. (B) Structure of microvilli of the absorptive cell. (C) Paneth cell. (D)
Endocrine cell. (E) Goblet cell. (F) Undifferentiated columnar cell. (G) Localization of the different cell types in the epithelium of the crypts and the villi.

THE digestive SYSTEM 113

7
Structure Relative increase
The small intestine

- +
Lumen Cl H2O Na
in surface area

Simple
CFTR 1
cylinder
Tight
junction
Lateral 3
Folds of
space
Kerkring
Na+
ATP
K+

Villus 30
Coport

Na+ K+
K
+
2Cl
- Basement membrane

Microvilli 600

Fig. 7.9  Adaptation of the small intestine for absorption. Comparison

Fig. 7.8  Mechanism of secretion of electrolytes and water by the of the surface area of a segment of the small intestine with a simple
immature cells of the crypts of Lieberkühn. cylinder of the same length and diameter.

Control of secretion in the small intestine Absorption

Secretion in the small intestine can be controlled by hor- Most substances are absorbed in the proximal small intes-
mones, paracrine factors and nervous activity. Gastrin, tine and most of the contents of the small intestine have
neurotensin, serotonin, histamine, prostaglandins, and a normally been absorbed by the time the chyme reaches
number of other hormone and paracrine factors stimulate the middle of the jejunum. However, a few substances
the epithelial cells directly. The cells are innervated by such as vitamin B12 and bile salts (see Ch. 8) are actively
secretomotor neurones, mainly from ganglia in the sub- absorbed in the ileum.
mucosal plexus but also from ganglia in the myenteric
plexus. The submucosal neurones release ACh, VIP, sub-
Surface area of the small intestine
stance P and serotonin, and probably other transmitters,
to stimulate secretion. Parasympathetic nerves inner- The rate of transport of materials across the small intes-
vate neurones in the enteric nerve plexi. They enhance tine is proportional to its surface area. The surface area
secretion via ACh release onto neurones in the plexi. of the small intestine is vast. This organ is therefore well-
Parasympathetic tone contributes to the basal secretion. adapted for absorption. Its area is approximately 600
Reflexes triggered by distension of the lumen of the small times greater than that of a simple cylinder of the same
intestine, and the presence of various substances (glu- length and diameter, by virtue of the presence of mucosal
cose, acid, bile salts, ethanol, cholera toxin) in the intes- folds, villi and microvilli (Fig. 7.9). When the surface area
tinal chyme, stimulate secretion. These reflexes involve is reduced, malabsorption of many substances ensues. In
intrinsic and extrinsic (parasympathetic nerves). coeliac disease, for example, which is characterized by
Noradrenaline inhibits secretion in two ways: it acts flattened villi, and therefore reduced surface area, there
directly on the epithelial cells (via -adrenoreceptors), is malabsorption of many nutrients, including protein,
and it acts on neurones in the submucosal ganglia to resulting in malnutrition (see Ch. 8). The children who
inhibit secretory nerves that stimulate the epithelial cells. present with this condition have weight loss, diarrhoea
Somatostatin acts humorally on the crypt cells, as an and a failure to thrive.
inhibitory neurotransmitter. It is released from the enteric
secretomotor nerves, and from the nerve fibres that
Barriers to absorption
innervate the crypt cells. It inhibits secretion by decreas-
ing the levels of cAMP in the epithelial crypt cells. The There are a number of barriers to transport from the
effect of somatostatin to inhibit secretion has led to use of intestinal lumen to the blood: the unstirred layer, the
its analogues such as octreotide in the treatment of secre- luminal plasma membrane, the cell’s interior, the basola-
tory diarrhoea, and to reduce fluid loss from small bowel teral plasma membrane, the intercellular space, the base-
(ileocutaneous) fistulae. ment membrane of the capillary and the cell membranes

114 SYSTEMS OF THE BODY

 7

The small intestine

Case
7.1 Cholera: 2

Causes, mechanism of action and changes in electrolyte and acid–base balance

Causes Hypermotility
The V. cholerae bacterium present in contaminated water and Hypermotility of the small intestine can result in water and
food produces a toxin that elicits a massive secretion of fluid electrolytes being delivered rapidly into the colon. It can be
and electrolytes. The effect is produced mainly in the proximal delivered so fast that the colon may not be able to absorb it
small intestine. Epidemics in the Indian subcontinent usually before it is lost in the faeces. This mechanism is also involved
occur in the early summer before the monsoon breaks. The bac- in conditions such as cholera, as distension of the intestines
teria are harboured in the gall bladder in asymptomatic carriers, by the large volumes of secreted fluids stimulates peristaltic
which may comprise up to 5% of the population in this region. activity, which propels the fluid rapidly along the intestines.
Treatments with antibiotics such as tetracycline or chloram-
phenicol is effective but should be regarded as ancillary to
Changes in electrolyte and acid–base
rehydration therapy (see below). Thus, for example, tetracy-
balance
cline treatment decreases the average duration of the disease
by 60%. Secretions of the small intestines contain large amounts of
Anticholera vaccines have been developed, but these are of HCO3, Na and Cl ions. K is absorbed during a meal, down
limited use during epidemics because it takes 2–3 weeks for the concentration gradient set up by the absorption of water (see
them to become effective. below). However, when the concentration of K in the lumen is
Bacteria are normally destroyed by gastric acid in the stom- reduced below approximately 25 mM the concentration gradient
ach, normally providing some protection. Increased suscepti- favours net secretion into the lumen. This occurs via the paracel-
bility to the disease is seen in individuals with achlorhydria or lular pathway. In diarrhoea, the luminal contents become diluted
those who have had a partial gastrectomy. with respect to K and it is therefore transported into the lumen.
Considerable losses of K can occur, leading to hypokalaemia.
As HCO3 is secreted into the lumen, H is transported into
the blood, which becomes transiently acid. Excessive loss of
Mechanisms of cholera toxin action HCO3 in secreted intestinal fluid causes a severe acidosis. The
Hypersecretion transient acidity in the blood is normally neutralized by the
There is an increased secretion of Cl, Na and water into alkaline tide that accompanies the secretion of acid in the stom-
the crypts of Lieberkühn in patients with cholera. The chol- ach (see Ch. 3). If there is excessive loss of alkaline fluid from
era toxin is an 84 000 kDa protein produced by V. cholerae. the gastrointestinal tract however, the acidity in the blood is
It binds to monosialoganglioside (Gm1) receptor molecules in proportionately increased and it cannot be buffered. This met-
the brush border membrane of the crypt cells, mainly in the abolic acidosis will be partially compensated in the short term
proximal intestine. This results in activation of adenyl cyclase, by an increased rate and depth of breathing which results in
which causes an increase in cAMP in the cells. The increase in CO2 being blown off from the body. Longer-term adjustments
cAMP causes activation of the CFTR Cl channels in the brush are brought about by reabsorption of HCO3 in the tubules of
border resulting in an increase in the secretion of Cl. Na the kidney, and excretion of H (see the companion volumes:
and water secretion increase as a consequence. Cholera vic- The Respiratory System and The Renal System).
tims sometimes produce up to 20 L of watery stool per day. K is required for cell growth and division, enzyme action,
Treatment with somatostatin analogues such as octreotide cell excitability, muscle contraction, acid–base balance and vol-
which inhibit secretion by decreasing the levels of cAMP coun- ume regulation. Hypokalaemia (reduced serum K concentra-
teracts the effect of cholera toxin. tion) causes hyperpolarization of cell membranes and reduces
The intramural nerves are also involved in the mechanisms the excitability of neurones, cardiac muscle, and skeletal muscle.
of the toxin action because substances that block nerve activ- Severe hypokalaemia can cause paralysis, cardiac arrhythmias,
ity reduce the effects of the toxin. However, the precise neu- decreased ability to concentrate urine, and death, which is usu-
ral mechanisms involved are unclear. ally due to cardiac arrest.

of the endothelial cell of the capillary or lymph vessels. membranes involved, for example the membranes of
The luminal border of the enterocyte is the effective bar- the endothelial cells, is via simple passive diffusion.
rier for the absorption of many substances but for some However, for transport across others, special mechanisms
substances it is the basolateral border or the endothe- such as active transport, facilitated diffusion or pinocyto-
lial cell membrane. Transport across some of the plasma sis (endocytosis) exist.

THE digestive SYSTEM 115

7
Potential difference across the small intestine membrane. The cell membrane can be regarded as a sea
The small intestine

of lipid with proteins embedded in it. Lipid–soluble sub-

A potential difference exists across the wall of the small
stances dissolve in the lipid and diffuse rapidly through
intestine, the serosal side being positive with respect to
the membrane. Examples of lipid–soluble substances
the mucosal side. In the case of a charged ion, transport
transported by this route are alcohols and long–chain
is the net effect of the forces due to the concentration gra-
fatty acids.
dient and the potential difference (see Ch. 1). Thus net
transport of anions from the lumen can occur passively
down the electrochemical gradient. Absorption of drugs
The size of the potential difference varies along the
length of the small intestine. The magnitude of the potential Lipid soluble drugs
difference is determined by the active transport of electro- The importance of lipid solubility is illustrated in Table
lytes, in particular Na, which occurs against the electrical 7.3, where the rates of absorption of a selection of bar-
gradient (see below). The magnitude of the potential differ- biturate drugs are compared. Compounds with the high-
ence is increased in the presence of glucose that stimulates est lipid solubility are absorbed at the fastest rate. Thus
the active transport of Na. Table 7.2 compares the poten- hexethal, the compound with the greatest lipid solubility
tial difference in different regions of the small intestine in chloroform/water coefficient of those listed is absorbed
the presence and absence of glucose in the lumen. four times as fast as barbital even though it has the great-
est molecular size.
Routes of absorption
Weak electrolyte drugs
The rate of absorption of a substance by passive diffusion
is determined by its ionization and its lipid solubility. A weak electrolyte exists as the undissociated molecule in
Substances can be absorbed via two routes: water-filled equilibrium with the dissociated ion products. The equilib-
pores, and the lipid membrane. rium for a weak acid can be represented by the equation:

Pore route HA ↔ H+ A

Water-soluble substances, with low molecular diameter where HA represents the undissociated weak acid, and
can diffuse through water-filled pores in the cell mem- A the anionic component. The undissociated molecule
brane. The pore diameter in the small intestine varies is lipid soluble but the ions are not. Thus the undissoci-
between 40 and 340 nM. Bulk fluid movement drags ated molecule is transported rapidly through the lipid
small solute molecules through the pores in the moving
stream of fluid (solvent drag). Thus if water absorption
is increased by any means (e.g. hormonal influences),
then the rate of passage of the dissolved substances is Table 7.3  Effect of lipid solubility on the absorption of
barbiturates
increased. Examples of small soluble substances that are
absorbed by this route are urea, creatinine, some mono­
Compound Chloroform/ Absorbed
saccharides (mannitol, xylose, fucose) and ions.
water (%)
coefficient
Lipid route
The rapid rate of absorption of many substances can only NH CO CH2CH3 0.7 12
be explained by their passage through the lipid of the cell CO C

NH CO C2H5
Table 7.2  Potential difference in different regions of the small Barbital
intestine in the presence and absence of glucose
NH CO CH2CH2CH2CH3 11.7 24
Potential difference (Vm)
CO C
Upper jejunum Mid-intestine Lower ileum NH CO C2H5
Butethal
Glucose 2.9   4.7 3.8
absent NH CO CH2CH2CH2CH2CH2CH3 100 44
Glucose 7.3 11.1 7.4 CO C
present
NH CO C2H5
The potential difference rises in the presence of glucose, thereby
Hexethal
increasing the passive transport of anions into the cells.

116 SYSTEMS OF THE BODY

 7
membrane. Removal of the undissociated acid from the place. Excessively increased motility can reduce the pro-

The small intestine

equilibrium causes more of the undissociated molecule to portion of a substance that is absorbed. Some drugs, for
form. This then diffuses across the membrane. In this way example, muscarinic antagonists, can slow motility, and
the substance can be rapidly absorbed. The rate of trans- others such as metoclopramide can increase it.
port will depend on the proportion present in the undis- Particle size and formulation of a drug can be significant
sociated form, i.e. it will depend on its pK and the pH of factors in the rate of absorption. Capsules, or tablets can be
the solution in which it is dissolved. Thus in situations given a resistant coating, which enables them to remain
where the proportion of unionized molecule is increased intact for some hours, thereby delaying absorption. A sus-
the rate of absorption will be high. Many drugs are weak tained absorption can sometimes be achieved by including
electrolytes. For a weak acid the rate of absorption can be a mixture of slow and fast release particles in a capsule.
increased if the pH of the solution is lowered below the Chemical properties that can cause reduced absorption
pK value because the equilibrium will be shifted to the rate include the ability to bind strongly to Ca2 in milk
left. The opposite applies to a weak base which has a high for example. Liquid paraffin, which is lipophilic, retards
pKa. Figure 7.10 illustrates this for two drugs: 5-nitrosali- the absorption of lipid–soluble vitamins.
cylic acid, an aspirin derivative, which is a weak acid, and
quinine, which is a weak base. In the upper small intes-
tine, the pH of the chyme tends to be slightly acid, thereby Absorption into the blood or lymph
favouring the absorption of weak acids. Furthermore,
some weak acids such as aspirin can be absorbed in the Some substances are absorbed solely by passive diffu-
acid environment of the stomach (see Ch. 3). sion. Others are absorbed by both passive and specialized
mechanisms: at a rapid rate by a specialized mechanism,
Strong electrolyte drugs and at a slow rate by passive diffusion (see Ch. 1).
A substance that is absorbed into the blood or lymph
Strong acids (pKa 3.0) and bases (pKa 10) are very can be transported across the luminal and basolateral
poorly absorbed. Clinically important drugs such as the membranes of the enterocyte and, if it is transported into
muscle relaxants tubocurarine and hexamethonium that the blood, it crosses the membranes of the endothelial
are strong bases, have to be administered intravenously. cells of the capillary. In many cases a given substance is
However for others, such as the aminoglycoside antibiot- transported across each membrane by a different mecha-
ics, their poor absorption is an advantage because they nism. A good example is the transport of Na that is by
can be used to sterilize the gut before intestinal surgery, carrier-mediated facilitated diffusion across the brush
without producing systemic effects. border, by active transport across the basolateral border
(see below), and via passive diffusion across the endothe-
Factors that affect gastrointestinal absorption of lial membranes of the capillaries.
drugs Some substances are preferentially absorbed into the
blood capillaries of the villi, and some into the lacteals
In most cases, approximately 75% of a drug is absorbed (Fig. 7.6). Two properties determine whether a given sub-
within 1–3 h, but the rate of absorption can be altered by stance is absorbed into the blood or the lymph; its size,
local factors, including changes in intestinal motility or and its lipid solubility. Large molecules, particles, and
splanchnic blood flow. lipid–soluble substances, are transported into the lymph.
In many diseases gastrointestinal motility is slowed Most lipids are sequestered in chylomicrons prior to
and this increases the time over which absorption takes transport into the lymph, and certain intact proteins can
be absorbed in trace amounts in some individuals (see
Ch. 8). Most other substances, that is, small, water-soluble
100 substances, are absorbed into the blood. Transport across
the endothelial cells of blood and lymph vessels is always
50 passive and occurs down a concentration or electrochemi-
cal gradient. Substances that are absorbed into the lymph
Absorption (%)

20 eventually gain access to the blood via the thoracic duct.

10 The reasons for a particular substance being preferentially
5-nitrosalicylic acid Quinine absorbed into the blood or lymph are outlined below.
5

Absorption into the blood

2
Both capillaries and lymph vessels are freely perme-
0 2 4 6 8 10 12 able to low molecular weight water-soluble substances.
pH However, there is an extensive network of capillaries in
Fig. 7.10  Effect of pH on the absorption of weak electrolyte drugs each villus but only a single lacteal and therefore there
in the small intestine. Absorption of a weak acid, 5-nitrosalicylic acid is a greater surface area available for transport into the
(pKa 2.3), and a weak base, quinine (pKa 8.4). blood than into the lymph, and a greater blood volume.

THE digestive SYSTEM 117

7
Furthermore, blood flow is much greater (approx. 500 highly permeable. The colon is permeable to water but
The small intestine

times faster) than lymph flow. This ensures the rapid less so than the small intestine.
removal of the transported substances, which are carried The transport of water in the small intestine can occur
away via the rapidly flowing blood and helps to main- either from the lumen to the blood or from the blood to
tain a favourable concentration gradient for transport. the lumen. Net transport is down the osmotic gradient
Thus, most (95%) low molecular weight, water-soluble and it will occur in whichever direction the osmotic forces
substances are absorbed into the blood. determine. It will be secreted into the lumen if the chyme
is hypertonic to plasma and absorbed into the blood if it
is hypotonic. The chyme entering the duodenum from
Absorption into the lymph the stomach is usually initially hypertonic. Rapid gastric
The endothelial cells of the blood capillary contain pores emptying, as may occur after surgery, results in the con-
(fenestrae) with diameters in the range 20–50 nM. They tents of the small intestine being abnormally hypertonic.
also have a basement membrane. The pores are large This causes an influx of water into the small intestine. If
enough to admit large molecules, but they cannot cross excessive, this can cause severe diarrhoea.
the basement membrane, and are therefore excluded The digestion of complex nutrients in the duodenal
from the blood capillary. Lipids are delivered to the chyme results in a further increase in osmolarity. The pre-
lateral spaces as components of large protein–bound vailing osmotic forces result in the secretion of water in
particles (chylomicrons), which are excluded from the this region, and the intestinal contents normally become
capillaries for the same reason. isotonic with plasma in the duodenum.
The endothelial cells of the lacteals lack a basement In the jejunum and ileum, water is absorbed from the
membrane. They do not contain pores, but when they are lumen into the blood down the osmotic gradient pro-
viewed under the microscope the endothelial cells appear duced as a result of the absorption of nutrients in these
to be displaced relative to each other at their lateral bor- regions. More water absorption occurs in the jejunum
ders (as though movement can occur between adjacent than the ileum. The chyme remains isotonic throughout
cells). It seems likely therefore that transient gaps form the jejunum and ileum where water is absorbed as a con-
between adjacent cells. Large molecules or particles are sequence of the absorption of other substances.
probably transported to the lymph between the cells via A major determinant of the osmotic gradient in the
these gaps. Peristalsis and the pumping action of the villi small intestine is the active transport of Na ions (see
(see below) aid absorption into the lacteals, probably by below). Cl ions are absorbed passively down the elec-
promoting the formation of the gaps. trochemical gradient as a consequence of Na absorp-
tion. In addition the absorption of other ions, for example
K, by passive diffusion, depends on the concentration
Transport of water and electrolytes in different gradients set up as a consequence of water absorption.
regions of the small intestine Moreover, some sugars and amino acids are absorbed
by symport mechanisms with Na. Thus, all of these pro­
The cells at the tips of the villi are specialized for water cesses are interdependent and they will therefore be con-
and ion transport while those in the crypts produce net sidered together. Figure 7.11 shows the consequences of
secretion of water and ions. However, the rate of trans- failure of membrane transport in the small intestine.
port varies along the length of the intestines because the
villi are larger and the brush border surface is greater
per unit area in the proximal region of the small intes- Absorption of sodium, chloride and potassium
tine than the distal region (see above). Thus, the fluxes Na transport occurs throughout the length of the small
of water and nutrients tend to be greater in the jejunum intestine. The transport of sodium across the epithelial
than the ileum, except where localized special transport cells of the small intestine is by both passive diffusion
mechanisms exist. The surface area in the colon is less and active special mechanisms. The mucosal surface of
than in the small intestine and therefore less net transport the small intestine is electronegative with respect to the
occurs in the colon. Flux of ions and water occurs both serosal surface, favouring the passive transport of Na
through the cells and across the tight junctions between into the lumen. The electrochemical gradient is largely
them. The tight junctions are leakier in the proximal due to the secretion of Cl into the lumen (Fig. 7.8).
small intestine than the distal regions. This also results The passive flux of Na is via the paracellular pathway.
in a greater paracellular flux per unit area in the jejunum However, the permeability for Na decreases along the
than the ileum. The result is that most absorption occurs small intestine, being highest in the duodenum and low-
in the proximal small intestine. est in the ileum, due to the gradual decrease in both the
brush border surface area and in the leakiness of the tight
junctions from jejunum to ileum.
Absorption of water Most Na is transported from the lumen of the
Water transport in the gastrointestinal tract is largely a small intestine into the blood by active mechanisms. This
function of the small intestine (see Ch. 1). The stomach involves the transcellular route. It is usually transported
is almost impermeable to water but the small intestine is in the absence of a chemical gradient as the chyme in the

118 SYSTEMS OF THE BODY

 7

The small intestine

Facilitated Facilitated
+
Na Glucose Na+ Amino acid
Lumen
J

+
Na Glucose Na+ Amino
acid

Facilitated
Na+ + Amino acid
K
Active Glucose
Facilitated

Fig. 7.12  The secondary active transport of Na via the Na/glucose
and Na/amino acid co-port systems in the absorptive cells of the
Fig. 7.11  A plain abdominal X-ray showing obstruction to the small proximal small intestine.
bowel. The jejunum (J) has become grossly dilated and filled with air
(A) and fluid, due to failure of membrane transport.

set-up by the operation of the Na/K ATPase pump in

small intestine is normally isotonic with plasma, but it is the lateral border of the cell (see Fig. 7.12 and Ch. 8).
obviously transported against the small electrochemical The net rate of absorption of Na is highest in the
gradient present. The processes involved are illustrated jejunum because the glucose and neutral amino acid
in Figure 7.12. The key process is the active transport transporters are situated mainly in this region. Sugars
of Na out of the cell, across the lateral border via a and amino acids produce a lesser stimulation of Na
Na/K ATPase pump, which simultaneously pumps absorption in the ileum where the transporters are less
K into the cell. This maintains the low concentration numerous.
of Na within the cell. The Na concentration gradient The active transport of Na out of the cell across the lat-
set up by this pump is the driving force for the trans- eral border increases its concentration in the lateral spaces.
port of Na from the lumen of the intestine into the cell. Cl and other monovalent anions are transported down
This diffusion across the luminal brush border of the cell the electrical gradient created, mainly via the paracellular
is therefore down the concentration gradient. However, pathway, through the tight junctions, into the lateral spaces.
transport across this membrane occurs at a faster rate than This occurs in the duodenum, jejunum and ileum, although
it would by simple passive diffusion. This is because the the proportion transported via this route is greater in the
Na ions are transported on carrier proteins in the brush duodenum, where the tight junctions are leakiest.
border membrane. One of these carriers is the Na The accumulation of ions within the lateral spaces cre-
dependent/glucose transporter (SGLT 1, see Ch. 8). It ates an osmotic gradient, and water is transported down
only functions if glucose, or galactose (which competes this osmotic gradient, via the paracellular pathway, into the
with glucose), is present in the lumen. The transporter spaces. The spaces expand during a meal because of this
has a binding site for glucose and a binding site for Na. increase in osmolarity. The transport of water out of the
Both binding sites must be occupied for the transport lumen results in concentration of the chyme. This increases
process to take place, and then both Na and the hexose the concentration, and therefore the concentration gradient
are transported into the cell via this co-port system (see for ions such as K. These are then transported passively
Fig. 7.12 and Ch. 8). The transport of Na and glucose between the cells into the lateral spaces. Thus, the trans-
by this means is inhibited by the presence of high con- port of many substances ultimately depends on the active
centrations of K in the lumen. This is because K occu- transport of Na out of the epithelial cells.
pies the Na binding site to inhibit the transport process. Na can also be actively absorbed in exchange for
Inside the cell, where there is a high concentration of K, H that is secreted into the lumen, i.e. via a N/H


the displacement of Na from the carrier by K, may be exchange mechanism. This anion exchange operates in
responsible for Na being released into the cell’s cyto- the lower small intestine and the colon. It is the major
plasm. The transport of hexoses, including glucose, is route for active Na transport in the ileum, where the
described in more detail in Chapter 8. glucose and amino acid transporters are less numer-
Neutral amino acids also stimulate Na absorption via a ous than in the jejunum, and in the colon. However, the
co-port system involving transporter molecules. This mech- ileum and colon can absorb Na against a higher poten-
anism also depends on the Na concentration gradient tial difference than can the jejunum. The anion exchange

THE digestive SYSTEM 119

7
mechanism is illustrated in Figure 7.13. The H secreted Diarrhoea can be classified as four types, according to
The small intestine

into the lumen reacts with HCO3 to form carbonic acid. the mechanism responsible: secretory diarrhoea, diarrhoea
The HCO3 arises via transport out of the cells because due to defective ion transport, osmotic diarrhoea and
of the operation of a Cl/HCO3 exchange mechanism diarrhoea due to increased intestinal motility. However,
whereby Cl is absorbed in exchange for HCO3. Thus several or all of these mechanisms may co-exist.
active transport of Na and Cl is coupled in this way.
The carbonic acid formed in the lumen is hydrolysed to Secretory diarrhoea
give CO2 and water. CO2 is lipid soluble and it diffuses
across the membranes of the cells into the blood. In this In secretory diarrhoea, the secretions of the small intestine
way H and HCO3 are effectively reabsorbed. are so copious that the capacity of the colon to reabsorb the
excessive water is overwhelmed. Food poisoning caused by
bacteria (e.g. V. cholera or Escherichia coli) causes this type of
Control of absorption diarrhoea. The bacteria produce toxins that bind to recep-
tors in the membranes of the secreting crypt cells to increase
Various factors are involved in the control of water and intracellular cAMP, which stimulates a massive secretion
electrolyte absorption by the cells near the tips of the villi. (see Case 7.1: 2). The treatment of this condition by rehydra-
These include endocrine, paracrine and nervous influences. tion therapy is described in Case 7.1: 3. The massive secre-
Glucocorticoids stimulate electrolyte and water absorp- tion of fluid in cholera can cause hypovolaemia (Case 7.1: 4).
tion in both the small and large intestines, probably by
causing an increase in the expression of the Na/K-
ATPase pumps in the basolateral membrane of the epi- Case
thelial cell. Opioids (acting on -opioid receptors) also 7.1 Cholera: 3
stimulate water and electrolyte absorption. Somatostatin
stimulates electrolyte and water absorption in the ileum Rehydration therapy
and colon. Noradrenaline also increases Na absorption, Individuals suffering from cholera are treated with (1) intra-
probably following its release from sympathetic nerves venous fluid and electrolytes, or with (2) oral fluid, salt and
on to enteric nerves that innervate the absorptive cells. sugar, depending on the severity of their symptoms.
Absorption can be inhibited by inflammatory mediators
such as histamine and prostaglandins that are released Intravenous rehydration
from cells of the gastrointestinal immune system. The intravenous fluid would consist of water containing
electrolytes in concentrations that are isotonic with plasma.
Diarrhoea The massive fluid loss can lead to dehydration, hypovolae-
mia, renal failure and death. Particular attention is paid to
Diarrhoea is defined clinically as a loss of fluid and solutes K and HCO3 replacement as excessive losses of these ions
from the gastrointestinal tract in excess of 500 mL/day. can have rapid and dangerous consequences.
The causes are infectious agents, toxins, drugs, food, or
anxiety. The mechanisms responsible for loss of fluid can Oral rehydration therapy
operate in the small intestine or the colon. The discovery of the co-port mechanisms for Na transport
in the small intestine revolutionized the treatment of food
poisoning due to V. cholerae or E. coli, where excessive fluid
H2CO3 CO2 + H2O
loss and dehydration can occur. Prior to the discovery of the
co-port mechanisms, approximately 50% of individuals suf-
fering from cholera died, due to collapse of the extracellu-
H+ HCO3- lar fluid volume (ECF). Treatment was by administration of
Lumen large quantities of salt solution, a regimen that was only
partially effective. Oral rehydration therapy with a solution
of glucose and common salt has dramatically reduced the
Na+ Cl-
death rate. The solution used should be isotonic or hypot-
onic, as a hypertonic load will create an osmotic gradient for
CO2 the transport of more water into the lumen. Inflammation
and damage to the mucosa are not normally present and
Na+ the digestion and absorptive mechanisms are not affected.
K+ Therefore glucose can be replaced with table sugar (sucrose)
as it is digested to glucose (and fructose). Replacement of
CO2 glucose with starch can also be effective because digestion
of each starch molecule results in numerous glucose diges-
Fig. 7.13  The active transport of sodium and chloride ions via the tion products, and it can therefore be ingested as a dilute
Na/H exchange and Cl/HCO3 exchange systems, respectively, in solution that does not constitute a great osmotic load.
the small intestine.

120 SYSTEMS OF THE BODY

 7
Excessive activation of intrinsic neurons in pathologi- A defect in ion transport can also result in failure to

The small intestine

cal conditions may also cause secretory diarrhoea. Some absorb water. In congenital chloridorrhoea, for exam-
of these neurons release VIP that increases intracellular ple, the Cl/HCO3 exchanger is absent from the brush
cAMP. Others release transmitters such as acetylcholine border membrane (see Case 7.2: 1 and 2). A congenital
or substance P that cause increased intracellular Ca2, defect in the Na/H exchanger has also been described.
which can also mediate excessive secretion from the In these conditions the defective exchanger protein is
crypt cells. lacking in the jejunum, ileum and colon. In the duode-
num and jejunum, the glucose and amino acid co-port
mechanisms promote Na and water absorption, but
Defective ion transport these transporters are not present in the ileum or colon.
As active transport of Na is a major determinant of the Therefore it is impairment of Cl transport in distal
osmotic transport of water from the lumen into the blood, regions of the gastrointestinal tract that results in diar-
the presence of inhibitors of Na transport will inhibit rhoea in these congenital transporter deficiencies.
water transport to cause diarrhoea. Bile acids inhibit Na
absorption in the colon, if they are not absorbed in the
terminal ileum. Furthermore, fat malabsorption results in Osmotic diarrhoea
fermentation of lipids in the colon to produce toxins that The presence of hypertonic fluid in the intestinal lumen
inhibit Na absorption. Inflammatory mediators such as can cause osmotic diarrhoea. High concentrations of salts
histamine and prostaglandins released from cells of the such as SO42, Mg2 and PO43, which are only slowly
gastroimmune system that inhibit Na absorption may absorbed in the intestine can be responsible. Magnesium
be involved in the secretory diarrhoea of inflammatory sulphate solution is commonly used as a laxative. The
bowel disease and Crohn’s disease. However, noradrena- osmotic gradient set-up favours water transport into the
line can increase absorption, and in diabetes when sym- lumen. Absorption disorders can also give rise to osmotic
pathetic neurodegeneration is present, diarrhoea can be diarrhoea. If nutrients that are normally absorbed in the
a problem.

Case
Case 7.2   Congenital chloridorrhoea: 1
7.1   Cholera: 4
A premature infant who was born with a distended abdo-
Hypovolaemia: cardiovascular and renal men, developed diarrhoea soon after birth. The chloride
adjustments content of the fluid on the infant’s napkin was extremely
high (95 mmol/L). The child appeared dehydrated and during
Cause of feeble rapid pulse rate the first week of life, blood analyses showed that she was
In hypovolaemic conditions the blood volume is reduced, hyponatraemic, hypochloraemic and hypokalaemic. Later,
and the cutaneous veins collapse, leading to reduced she developed a metabolic alkalosis, and her faeces were
venous return. This results in a reduced end-diastolic vol- acid. Fortunately she was quickly diagnosed as having con-
ume in the left ventricle, leading to a reduced cardiac out- genital chloridorrhoea. In this rare condition the Cl/HCO3
put (see the companion volume The Cardiovascular System). exchanger is absent from the luminal membranes of the
This is manifest clinically as a low pulse, and collapsed jejunum, ileum and colon. Initially intravenous electrolyte
peripheral veins. Reduced baroreceptor stimulation leads replacement therapy was instituted, but after a few weeks,
to reduced vagal tone and increased sympathetic tone, electrolyte replacement therapy (a solution of KCl and NaCl)
and this causes an increase in heart rate, and an increase in could be given orally.
contractility of the myocardium. The increased sympathetic Perusal of this case history could provoke the following
activation also leads to general venoconstriction leading questions about this condition:
to increased venous return. The reduced blood flow to the
intestinal mucosa can be so severe as to lead to necrosis of l Why are abnormally high amounts of Cl lost in the
the tissue, due to a decreased oxygen supply. faeces?
l How does this defect result in diarrhoea?

Adjustments in function to correct the l Is the fluid loss likely to be due to the absence of the

reduced ECF exchanger in the small intestine or the large intestine, or

The major adjustments however, are those brought about both?
by changes in renal function. The kidneys respond to the l Why did alkalosis develop in the child and why were the

decrease in ECF volume by decreasing the urine output. child’s faeces acid?
The mechanism involves sympathetic vasoconstriction in the l What is the basis of oral replacement therapy with KCl

kidney, and retention of Na ions and water, as a result of and NaCl?
increased release of aldosterone and antidiuretic hormone l Why was it not necessary to include glucose in the oral

(ADH), respectively. replacement fluid?

THE digestive SYSTEM 121

7
The small intestine

Case
7.2   Congenital chloridorrhoea: 2

Defect and consequences

In this condition, the inherited defect is an absence of the Na into the blood in exchange for H. The K was low
C/HCO3 exchanger in the brush border membrane in the because K is transported into the lumen down its concentra-
small intestine and in the colon. The exchanger transports Cl tion gradient. If water accumulates in the lumen, as in diar-
out of the lumen, in exchange for HCO3 (Fig. 7.13). The Na/ rhoea, this gradient will favour transport into the lumen, as
H exchanger is normal in this condition, but eventually the the contents become more dilute.
acidity of the luminal contents inhibits the Na/H exchange Thus the oral replacement therapy given will correct the
mechanism as well. hyponatraemia (low blood Na concentration), the hypoka-
laemia (low blood K concentration) and the hypochloraemia
Diarrhoea (low blood Cl concentration).
If the exchanger protein is absent, Cl transported across the The transport of water as a consequence of the Na/glu-
gut wall is reduced, and Cl is lost in the faeces. The high con- cose co-port mechanism in the upper small intestine is not
centrations of electrolytes present in the lumen cause water affected in this condition, and it is probably operating opti-
to be transported into the lumen by osmosis (osmotic diar- mally. As the mechanisms that are defective are the Cl/HCO3
rhoea). The absence of the exchanger in the jejunum is less exchanger and the Na/H exchanger that operate mainly in
important than its absence in the ileum and colon, because the distal small intestine and colon, the presence of glucose in
water is transported as a consequence of Na/glucose and the solution administered would serve no purpose.
Na/amino acid co-port mechanisms in the jejunum. These co-
port systems are not numerous in the ileum and not present Metabolic alkalosis
in the colon. So the osmotic forces in the ileum and colon The exchanger protein that is absent in congenital chloridor-
cause water malabsorption. rhoea transports Cl into the blood in exchange for HCO3
that is transported into the lumen. If the exchanger is absent,
Treatment HCO3 accumulates in the blood and causes alkalosis. The Na/
The child was treated by administration of NaCl and KCl solution H exchange system transports Na into the blood in exchange
for the following reasons: the child’s plasma Cl concentration for H, which is transported into the lumen. This is normally
was low because of the absence of the Cl/HCO3 exchanger, neutralized by the HCO3 transported into the lumen in
and the Na concentration was low because of the conse- exchange for Cl, but in this case the HCO3/Cl exchanger is
quent inhibition of the Na/H exchanger which transports absent in the membranes and H would be lost in the faeces.

small intestine cannot be absorbed for any reason, the that increase motility in the colon (as well as inhibiting
osmotic pressure in the lumen is increased. Furthermore, Na transport, see above).
when these nutrients enter the large intestine they may The treatment of diarrhoea is outlined in Box 7.1.
be fermented by colonic bacteria so that each molecule
is degraded to a number of products, thereby increasing
the osmolarity even further. The volume of water trans- Motility in the small intestine
ported into the lumen as a consequence may be too great
for the colon to reabsorb it, and diarrhoea results. An The smooth muscle of the small intestine performs two
example of such a condition is lactase deficiency in which major functions. First, it is responsible for a thorough
lactose (milk sugar) cannot be digested. This sugar enters mixing of the digestive juices arriving from the liver
the colon unchanged, but it is fermented by colonic bacte- and pancreas with the chyme received from the stom-
ria to smaller products. This causes an increased osmotic ach. Second, it is responsible for moving the contents,
potential (see Ch. 8). usually slowly, but sometimes rapidly, along the 5 m
separating the stomach from the colon. This enables one
meal to make way for the next. However, it is important
Hypermotility of the intestines
that the food is retained in each location for sufficient
Where hypermotility of the intestines is present, water time to allow mixing, digestion and absorption of food
and electrolytes may be delivered to the colon at a rate substances.
that is too fast for the water to be absorbed in the colon. Smooth muscle contracts spontaneously, even during
The causes of intestinal hypermotility are not clear, but fasting, although the contractions increase in strength
in cases of malabsorption, colonic bacteria may ferment and frequency after food has been ingested. The fine local
unabsorbed nutrients to produce toxins that increase and temporal control of intestinal motility in the different
motility. One example is lipid malabsorption, where segments of the intestine is integrated by nervous and
lipids are fermented to produce hydroxylated fatty acids hormonal mechanisms.

122 SYSTEMS OF THE BODY

 7
Box 7.1  Treatment of diarrhoea muscle fibres from the stomach cross the pyloric sphinc-

The small intestine

ter region to the duodenum (see Ch. 4). The frequency of
Oral rehydration therapy contractions in the duodenum (approx. 12/min) is higher
than in the stomach. Every fifth contraction of the muscle
Severe acute diarrhoea requires maintenance of fluid and
in the duodenal bulb is augmented by a contraction of the
electrolyte balance, with occasional use of antibiotics.
antrum due to the transmission of the slow waves via the
Maintenance of fluid and electrolyte balance is of para-
fibres crossing the sphincter. This acts to prevent the duo-
mount importance. The use of oral rehydration therapy
denal contents flowing back into the stomach.
(fluid containing NaCl and glucose) is described in Case 7.1: 3.
There is also a regular type of spontaneous contrac-
This treatment is particularly important in small children
tion, known as the moving myoelectric complex (MMC,
with diarrhoea, in whom the fluid and electrolyte loss can
see below), which moves distally down the intestine.
rapidly become life-threatening.
Transmitters released during the progression of the
Antibiotics MMC (see below) may be responsible for augmenting
Antibiotics can be useful in the treatment of diarrhoea in other types of spontaneous muscle activity. In addition
enteritic conditions such as amoebic dysentery, typhoid and cate­cholamines such as noradrenaline released from sym-
cholera, which are caused by bacteria and protozoa. Milder pathetic nerves, and adrenaline released into the blood,
types of bacterial and viral enteritis generally resolve with- during fasting and in times of stress, can reduce the tone
out being treated. Campylobacter is a common infection of the smooth muscle.
that causes diarrhoea (in developed countries) and this can
be treated with erythromycin. However, in many under­
developed regions of the world enteritis is usually caused
The migrating myoelectric complex (MMC)
by viruses. In fasting individuals there are cycles of smooth muscle
contractions with an average frequency of approximately
Antimotility drugs
1.5 h. These are the MMCs. Each cycle involves contrac-
Antimotility drugs, including opiates, codeine and lopera- tion of several adjacent segments of the small intestine,
mide, can be used to treat diarrhoea. These increase the and it lasts approximately 10 min. The contractions occur
tone and rhythmic activity of the intestine, but decrease its sequentially in adjacent groups of segments. They actu-
propulsive activity. They also inhibit secretion in the intes- ally begin in the stomach and migrate via the proximal
tine. They are not usually used in infective diarrhoea. small intestine ‘aborally’ towards the colon (Figure 7.14).
Absorbents In the fasting state, the periodic sweeping of the contents
Absorbents such as kaolin, chalk and charcoal are also used towards the colon may clean the intestine of residual
to decrease diarrhoea, but their mechanism of action is not food and secretions. It may also prevent the migration of
entirely clear. They may act by adsorbing microorganisms colonic bacteria into the ileum. As one sweep reaches the
and toxins, by altering the intestinal flora in some way, or terminal ileum, another starts in the duodenum. MMCs
by coating and protecting the intestinal mucosa. also occur when a meal is being processed, but then
they are more frequent, and less ordered. Presumably
Non-steroidal anti-inflammatory drugs they then assist in sweeping the digested contents of the
Agents that reduce secretion or increase absorption can lumen towards the colon.
also reduce diarrhoea. Non-steroidal anti-inflammatory
drugs such as aspirin and indometacin are effective. The
mechanism is probably due to inhibition of prostaglandin Mixing and propulsion during a meal
synthesis.
Segmentation mixes the contents of the lumen when a
meal is being processed, while peristalsis is responsible
Types of motility for propelling the chyme along towards the colon.

Spontaneous contractions Segmentation

The smooth muscle of small intestine displays spontaneous
activity even when a meal is not present in the gastroin- Segmentation involves contraction of rings of circular
testinal tract. This activity is tonus. Spontaneous contrac- muscle situated at intervals along a region of the small
tions of smooth muscle occur in the absence of stretch, intestine (Fig. 7.15A). The contractions remain stationary.
hormones or nervous activity due to the uneven ampli- These rings of muscle then relax, and then adjacent seg-
tude of the oscillating membrane potential (see Ch. 1). ments contract. The overall effect is a continuous rhythmic
The inherent mechanisms of tone and rhythmicity may be division and subdivision of the intestinal contents that
augmented by a background of transmitters such as ace- results in a thorough mixing of the chyme in the lumen.
tylcholine released from nerves in the vicinity. This slow Segmentation increases in frequency and strength when
wave activity of the smooth muscle in the duodenum is chyme enters the duodenum. It occurs more frequently
influenced by that in the stomach. Some longitudinal in the duodenum (approx. 12 contractions/min) than

THE digestive SYSTEM 123

7
The small intestine

A
Feeding
Jejunum

Ileum

Time (h)

B
Jejunum

A
Ileum

Time (min)

Fig. 7.14  The moving myoelectric complex. (A) Contractile activity.

(B) Electrical activity.

in the jejunum or ileum (approx. 8 contractions/min).

This is appropriate because the need for mixing is great-
est in the duodenum, where the alkaline pancreatic juice
and bile mix with acid chyme from the stomach to pro-
vide the appropriate neutral or slightly alkaline condi-
tions necessary for digestion and micelle formation.
Rhythmic (concertina-like) back and forth movements
also occur, but may simply be as a result of segmenta-
tion. At any one time, a group of segments contract
and this is followed by a period of rest. In the jejunum B
segmentation occurs as bursts of contractions that last
approximately 1 min, followed by an interval when the con- Fig. 7.15  Motility in the small intestine. (A) Segmentation.
(B) Peristalsis.
tractions are weak or absent. This pattern is known as the
minute rhythm.
Contraction of a ring of smooth muscle forces the
chyme forwards and backwards, but because segmen- followed by relaxation of these rings of muscle, causing
tation is more frequent in the proximal regions, the a wave of contraction that propels the chyme towards
chances of the material being pushed towards the colon the colon (Fig. 7.15B). In the human, after a meal has
are greater than it being pushed towards the stomach. been eaten, peristaltic activity in the small intestine is
Thus although segmentation is responsible for mixing infrequent and of low strength. Furthermore, each wave
the chyme, it also aids propulsion of the chyme towards of contraction travels only about 10 cm. It is for this rea-
the colon. son that resection of segments of the intestine do not
interfere with propulsion. However, there are occa-
sional waves of intense contraction, known as peristal-
Peristalsis tic rushes, which travel the entire length of the small
intestine. Both the short and the long waves are respon-
Peristalsis involves the sequential contraction of adja- sible for moving the chyme along the intestine towards
cent rings of smooth muscle in the aboral direction, the colon.

124 SYSTEMS OF THE BODY

 7
Contraction of the muscularis mucosae are blocked at a particular level the MMC does not prop-

The small intestine

agate past the block.
In addition to the above types of motility due to contrac-
tions in the circular and longitudinal layers of muscle,
sections of the muscularis mucosae undergo irregular Hormonal control
contractions. These contractions assist in the mixing of
the chyme. In addition the villi contract in an irregular Many peptide hormones are secreted by the stomach
fashion. Contractions of the villi are most frequent in the and small intestine in response to activation of pres-
proximal small intestine. They squeeze the lacteals in the sure receptors and chemoreceptors to control motility.
centre of the villi, thereby emptying them of lymph and Gastrin, which is released into the blood in response to
enhancing intestinal lymph flow. peptides in the stomach, and secretin and CCK, released
in response to acid and fat respectively in the intestinal
chyme, all increase intestinal motility if injected.
Control of motility Motilin, a peptide that is released from the walls of
the duodenum and jejunum into the blood when the
intestinal chyme becomes alkaline, increases peristalsis
Certain basic patterns of contractile activity may be pro-
if injected into the blood. It seems likely that when the
grammed into the neural circuitry of the intrinsic nerve
acid in the chyme has been neutralized and the nutrients
plexi. However, motility in the small intestine is under
in the chyme have been digested that chyme becomes
physiological control by various factors, including
more alkaline, because alkaline juices are still being
stretch, intrinsic nerves of the intramural plexi, extrin-
produced. A resulting increase in blood concentration
sic autonomic nerves, paracrine factors and circulating
of motilin would then cause the chyme to be moved
hormones.
on. Interestingly the plasma levels of motilin oscillate
An intrinsic property of smooth muscle is reflex con-
in phase with the MMCs, indicating that this hormone
traction in response to stretch of the muscle, without the
may be involved in initiating the MMC. This possibil-
involvement of nerves or hormones (see Ch. 1). This is
ity is supported by the fact that intravenous injections of
known as the myenteric reflex. However, reflex contrac-
motilin initiate MMCs that strongly resemble those that
tile activity due to activation of pressure receptors and
occur naturally. Another view is that motilin is released
chemoreceptors in the walls of the intestine is probably
as a result of the MMC but then helps to coordinate the
more important when a meal is being processed by the
events involved in it.
small intestine.
Another peptide hormone released from the small
intestine when food material is present is enterogluca-
Nervous control gon. It is released in response to glucose and fat in the
chyme. This hormone inhibits peristalsis, and its role
Activation of the intrinsic nerves in the intramural plexi may be to allow time for the absorption of glucose and
can control segmentation and short peristaltic waves by fat before the chyme is moved on towards the colon.
influencing the basal electrical rhythm, in the absence Endogenous opioids may inhibit intestinal motility and
of extrinsic nerves and hormones. However, extrinsic as a consequence constipation is one of the most common
parasympathetic and sympathetic nerves synapse with side effects of opiate therapy used for pain relief.
intrinsic nerves in the nerve plexi. The extrinsic nerves
mediate long-range reflexes and both extrinsic nerves and
hormones modulate the activity in intrinsic nerves. Reflex control
Segmentation and peristalsis are increased by activation
of parasympathetic nerves, and inhibited by stimulation Activation of pressure receptors by distension of the
of sympathetic nerves. Activation of the sympathetic walls is involved in the reflex control of intestinal motil-
nervous system, during stress for example, results in ity. A bolus of food placed in the small intestine will
release of adrenaline into the circulation and this also cause the smooth muscle behind it (in the orad direction)
inhibits motility. Sympathetic activation also causes to contract, and that in front of it, to relax. Furthermore,
marked vasoconstriction of the gastrointestinal blood ves- over-distension of the walls of one part of the intestine
sels (see Ch. 1). by food results in relaxation of the rest of the intestine
Many transmitters, in addition to acetylcholine and the (the intestino-intestine reflex). The pressure receptors
catecholamines, can influence intestinal motility. These are probably near the longitudinal muscle layer. The
include peptides, amines and nucleotides. The peptides afferent and efferent limbs of this reflex involve activa-
include VIP, somatostatin, VIP, substance P and opioids. tion of extrinsic autonomic nerves, and would therefore
Peptides may be released from nerves and APUD cells to be absent in a patient with a bowel transplant.
influence the gastrointestinal contractility. Trauma of other organs outside the gastrointestinal
The initiation and propagation of the MMC depends tract, such as the kidneys and gonads, leads to inhibition
largely on enteric neural activity. If the enteric neurones of intestinal motility (atonic bowel, or paralytic ileus).

THE digestive SYSTEM 125

7
This inhibition ultimately involves activity in the sym- sphincter (Ch. 10). It is approximately 4 cm long in the
The small intestine

pathetic splanchnic nerve. Various regions of the central adult human. Relaxation and contraction of the sphinc-
nervous system have been implicated in the control of ter controls the rate of entry of material into the colon. It
intestinal motility in such conditions. These include the may have a role in preventing the movement of bacteria
cerebellum and pituitary. However, the precise role of the from the colon to the ileum. This sphincter is normally
central nervous system and the pathways involved are closed, but when peristalsis occurs in the last portion of
still largely unknown. the ileum in response to food in the stomach (the ileogas-
tric reflex), distension of the ileum causes reflex relaxa-
Gastroileal reflex tion of the sphincter muscle. This allows a small amount
of chyme to enter the large intestine. The rate of entry is
When food is present in the stomach, motility increases appropriately slow as it enables salt and water absorp-
in the ileum, and the ileocaecal sphincter relaxes. This is tion from the chyme in the colon to take place before the
known as the gastroileal reflex. Conversely, distension next portion of chyme enters. Relaxation of the smooth
of the ileum decreases gastric motility (emptying) in the muscle of the sphincter is coordinated by activity in the
stomach (the ileogastric reflex). The gastroileal reflex nerves in the intramural plexi.
appears to be mainly under the control of external nerves
to the intestinal mucosa, but gastrin, released into the
blood in response to food in the stomach, may augment Drugs that affect intestinal motility
the response.
Drugs that increase intestinal motility include purgatives,
which accelerate the movement of chyme through the
Ileocaecal sphincter gastrointestinal tract, and drugs that increase segmenta-
tion but not peristalsis. Purgatives can be used to treat
The last portion of the ileum is separated from the colon constipation. The treatment of constipation is discussed
by a ring of smooth muscle known as the ileocaecal in Box 7.2.

Box 7.2  Treatment of constipation

Purgatives (laxatives) can be used to treat constipation. These treat constipation. They have a rapid onset laxative effect,
can be substances that stimulate secretion and motility, sub- within a few hours of administration.
stances that cause a relative osmotic diarrhoea, emollients, The concept of osmotic diarrhoea consequent to carbohy-
which alter the consistency of the faeces, or bulk-forming drate malabsorption in brush border diseases, such as lactase
agents. deficiency, has been exploited by the pharmaceutical industry
in the development of lactulose that is now commonly used
Secretory laxatives
to treat constipation. Lactulose, a disaccharide composed of
Secretory laxatives cause an increased secretion of fluid and fructose and galactose, is not digested in the small intestine.
electrolytes by the mucosa into the lumen of the intestines. It is digested to its component monosaccharides, by bacteria
This results in fluid accumulation and watery chyme that in the colon. These are then fermented to lactic and acetic
flows rapidly through the intestines. They include castor oil, acid that act as osmotic laxatives.
the active ingredient of which is ricinoleic acid. Others are
cascara, aloe, senna and fig syrup, all of which are naturally Emollients
occurring anthraquinone derivatives, and phenolphthalein, Emollients are non-absorbable substances that coat and lubri-
bisacodyl and danthron, which are synthetic agents. Senna cate the faeces. This accelerates their movement through the
and cascara contain derivatives of anthracene (such as emo- intestines, and softens the rectal contents. Examples of emol-
din) bound to sugars to form glycosides. Hydrolysis of these lients are didactyl sodium sulphosuccinate and liquid paraffin.
glycosides by bacteria in the colon releases the active anthra- Liquid paraffin can interfere with the absorption of fat-
cene derivatives. These are absorbed to act on the myenteric soluble vitamins, and for this reason it is now seldom used.
plexus. This results in stimulation of secretion and motility.
Bulk-forming agents
These agents can cause abdominal cramps due to excessive
Bulk-forming agents, such as bran and methylcellulose, are
stimulation of smooth muscle. Prolonged usage can result in
generally the preferred treatment for constipation as they
dependence, loss of normal intestinal function, and even an
are free from side-effects, inexpensive, and probably the
atonic colon.
most acceptable and natural of the alternatives. They consist
Osmotic laxatives of nondigestible cellulose fibres that become hydrated in the
Osmotic laxatives are poorly absorbed solutes that cause the intestines. This decreases the viscosity of the luminal contents
volume of chyme to increase by transport of water down the to increase their flow through the intestines. Hydration causes
osmotic gradient into the lumen. Salts such as Epsom’s salts them to swell, providing bulk, with consequent activation of
(MgSO4) or Mg(OH)2, which act in this way can be used to the defaecation reflex (see Ch. 10).

126 SYSTEMS OF THE BODY

 7
Drugs that increase motility as antiemetics (via their actions on the central nervous

The small intestine

system, see Ch. 3) prior to procedures such as diagnos-
Drugs that increase intestinal motility include muscarinic tic radiography or duodenal intubation. Domperidone,
receptor agonists such as bethanechol, and anticholines­ a dopamine D2 receptor antagonist can also be used to
terases such as neostigmine. Such drugs that increase seg- increase intestinal motility. It probably enhances motil-
mentation without increasing propulsive activity can be ity by blocking 1adrenoreceptors, rather than dopamine
used for disorders of motility in the gastrointestinal tract, receptors, thereby decreasing the relaxant effect of sym-
such as paralytic ileus (paralysis of the ileum) that can pathetic activation of these receptors.
occur following intestinal surgery. They can also be used

THE digestive SYSTEM 127

Digestion and
absorption 8
Chapter objectives
After studying this chapter you should be able to:

1. Explain the mechanisms of digestion and absorption of complex

nutrients, vitamins and minerals.

2. Understand the consequences of malabsorption in intestinal diseases.

8
Digestion and absorption

Introduction Case
8.1 Coeliac disease: 1
Most digestion and absorption occurs in the small intes-
tine. The transport of water, monovalent ions and drugs A 25-year-old woman visited her doctor and complained of
was discussed in Chapter 7. In this chapter, the digestion diarrhoea and flatulence. She also said she had recently lost
of complex nutrients, and the absorption of the products a considerable amount of weight, and she felt weak and
of digestion, as well as the absorption of vitamins and exhausted most of the time. She also suffered from back
minerals will be considered. pain. Upon questioning she said her faeces were bulky,
The consequences for nutrition, of disease of the greasy and foul-smelling.
small intestine will also be addressed in this chapter. As She recalled that she had had persistent diarrhoea
absorption of different nutrients can occur in different throughout childhood but the symptoms had disappeared
regions of the gastrointestinal tract, the regions affected during adolescence. She was referred to a gastroenterolo-
by the disease process determine which nutrients will be gist. The consultant arranged for blood and faecal analyses.
poorly absorbed. Coeliac disease (Case 8.1: 1, 2 and 3), The faecal tests confirmed the presence of steatorrhoea.
which usually affects the proximal small intestine, and The blood tests indicated that she had iron-deficiency anae-
Crohn’s ileitis (Case 8.2: 1, 2 and 3), which usually affects mia, folate-deficiency and Ca2 deficiency. Her blood elec-
the terminal ileum, will be used to illustrate some of the trolyte concentrations and prothrombin clotting time were
general principles of absorption, as well as the specific within the normal range. The consultant suspected coeliac
problems encountered as a consequence of malabsorp- disease and arranged for an endoscopy (telescopic visuali-
tion of the nutrients that are normally absorbed in the zation of the duodenum) to be performed. A biopsy of the
affected regions. mucosa, taken at the examination, showed flattening of the
villi and excessive plasma cells in the submucosa. A further
blood test, to measure the concentrations of transglutami-
Absorption nase antibodies was performed and this showed a high titre
of the antibodies. In view of these findings the consultant
Most nutrients are absorbed at a slow rate by passive diffu- told the patient to exclude wheat, rye and barley flours (but
sion throughout the small intestine. However, many impor- not oat flour) from her diet, and to try to ensure that it was
tant nutrients are absorbed at a faster rate by processes nutritionally balanced. She was prescribed iron, folate and
which involve saturatable mechanisms (see Ch. 1). The vitamin D supplements. This diet was not easy to follow as
proximal small intestine, i.e. the duodenum and jejunum, so many food products contain the flours, but after a few
is the location of most of these special mechanisms, as most weeks the patient had vastly improved. She had gained
substances are absorbed predominantly in those regions. weight and was no longer feeling constantly tired.
Figure 8.1 shows the approximate sites of absorption of After reading this case history we can address the follow-
many important nutrients. The important divalent cati- ing questions:
ons, Ca2 and Fe2, are absorbed mainly in the duodenum
and jejunum. Hexoses, including glucose, galactose and l What is the basic defect in this condition?
fructose, are also absorbed in the duodenum and jejunum, l If the duodenum and proximal jejunum were the
as are amino acids, small (di- and tri-) peptides and some regions of the small intestine involved, which nutrients
water-soluble vitamins. Fatty acids, ­ monoacylglycerols are likely to be malabsorbed? Why was iron-deficiency
and fat-soluble vitamins are also absorbed in the duode- anaemia present? Why was the patient’s clotting time
num and jejunum. Cholesterol is absorbed throughout measured? Is milk intolerance likely to be a complication
the small intestine. Vitamin C is absorbed in the proximal in this condition? Why was her blood investigated for
ileum. Vitamin B12 and bile salts are absorbed predomi- transglutaminase antibodies?
nantly in the terminal ileum. Water and monovalent ions l Why was steatorrhoea present in this patient?

are absorbed throughout the small and large intestines. The l What problems result from deficiencies of these

defects in absorption seen in coeliac disease and Crohn’s nutrients?

disease which affect different regions of the small intestine, l How would a defect in CCK and secretin release from the

are described in Case 8.1: 2 and Case 8.2: 2. duodenum affect the functioning of the digestive system?
l What are the likely causes of diarrhoea in coeliac

disease?
Absorption of important nutrients l Why were the patient’s blood electrolyte concentrations

measured?
Carbohydrates

The average daily intake of carbohydrate in the human (animal starch), in meat and liver. These polysaccharides are
adult is probably between 250 g and 800 g/day. The useful composed entirely of D-glucose subunits linked together
carbohydrate in the food is largely vegetable starch in pota- mainly by -1,4 glycosidic linkages. In the human, over
toes, bread, pasta and rice, and to a lesser extent glycogen 90% of the starch in the diet is digested and absorbed. The

130 SYSTEMS OF THE BODY

 8

Digestion and absorption

Case
8.2 Crohn’s disease: 1

A 17-year-old young man complained to his general prac- emergency operation was then performed to remove the
titioner that he had been suffering from abdominal pain, affected part of the ileum (which was causing the obstruc-
diarrhoea, weight loss and feelings of lassitude. The doctor tion). Following the operation he made a good recovery. He
examined him and found that his abdomen was distended. He resumed a normal diet and regained the weight he had lost.
ascertained that the pain was in the central and right lower Later in life he developed symptomatic gallstone disease that
quadrant. He suspected acute appendicitis, and the patient required the removal of his gall bladder (cholecystectomy).
was admitted to hospital. An abdominal operation was Upon consideration of the details of this case we can
arranged. The surgeon observed that the appendix appeared address the following questions:
normal. However, a short length of the terminal ileum was
reddened, thickened and oedematous. These features indicate l What is the basic defect in Crohn’s disease and what causes
Crohn’s disease of the terminal ileum. No further surgery was it? Which parts of the gastrointestinal tract can be affected
performed. Following the operation, blood and faecal samples in this disease?
were obtained for analyses. The patient was allowed a few l How is the condition diagnosed? Which blood and faecal

days to recuperate and was then sent home. He was prescribed analyses would have assisted the diagnosis?
codeine for the pain, and diphenoxylate (Lomotil) for the l What could account for the symptoms of weight loss and

diarrhoea, and he was started on oral steroids to reduce the lassitude? Which nutrients are poorly absorbed in Crohn’s
inflammation. He was advised to keep to a nutritious diet. disease? Why were diarrhoea and steatorrhoea present?
The acute symptoms gradually settled, but he suffered sev- Why was the patient started on iron supplements? Why
eral relapses over the next few years. He required iron sup- was he given intramuscular vitamin B12?
plements and intramuscular injections of vitamin B12. He l Why was the patient maintained on parenteral nutrition

developed steatorrhoea. for a while? What was the likely composition of the
The patient eventually suffered an intestinal obstruc- intravenous fluid used?
tion. He was maintained on intravenous parenteral nutrition l What are the likely causes of the intestinal obstruction?

for 2 weeks and during this time the symptoms diminished, l What could be the cause of the gallstone disease that

but they returned when he resumed normal nutrition. An developed later in life in this patient?

Oesophagus

Ethanol Stomach

Duodenum
Ca+, Fe2+, glucose, galactose, fructose,
amino acids, di- and tri-peptides, fatty acids,
monoglycerides, fat-soluble vitamins, water-soluble vitamins Jejunum

Cholesterol
Vitamin C
Monovalent ions,
Ileum
water
Bile salts
Vitamin B12

Colon

Fig. 8.1  Sites of absorption of important nutrients in the gastrointestinal tract.

remainder passes into the colon where it may be utilized by it is not digestible in humans and other non-ruminants
colonic bacteria. because the subunits are linked by -1,4 glycosidic bonds
Cellulose is another polysaccharide, which is com- that cannot be hydrolysed by the enzymes in the diges-
posed of glucose subunits, present in the diet. However, tive tract. Therefore it passes into the colon. Nevertheless,

THE digestive SYSTEM 131

8
Digestion and absorption

Case
8.1 Coeliac disease: 2

Defect and treatment

Coeliac disease is common in Northern Europe with an inci- cannot be replaced quickly enough by stem cell division in the
dence of possibly 1 in 250. (It is rare in Africa.) Genetic and crypts, and many of the cells present are immature and there-
environmental factors are involved. fore do not absorb nutrients effectively.

Defect Treatment
The disease is due to an abnormal reaction to gluten, a con- Treatment of coeliac disease involves the individual following
stituent of wheat flour. Gluten damages the enterocytes, a gluten-free nutritious diet. The gliadin peptides that cause
causing atrophy of the villi, and malabsorption. The duode- the abnormal reactions are present in wheat, rye and barley
num and proximal jejunum are usually more severely affected but not oats. The latter is therefore safe for individuals with
than the ileum. The damage is due to an abnormal immune coeliac disease.
response to gliadins (especially -gliadin), components of glu-
ten. It is a T-cell-mediated disease. Antibodies to the enzyme
V P
transglutaminase, which is released in tissues during inflam-
mation, are present in 98% of affected individuals. The
mechanisms involved in the damage have not yet been fully
characterized but there is evidence that deamidation of glia-
din by transglutaminase generates a recognition site for CD4
T lymphocytes; the locally activated lymphocytes trigger pro-
duction of cytokines which then cause the damage. In addi-
tion transglutaminase antibodies have been shown to affect
the differentiation of epithelial cells, possibly by interfering
with the action of the enzyme.

Diagnosis
Determination of the serum concentration of transglutaminase
antibodies is a useful tool in the diagnosis of coeliac disease.
The diagnosis of coeliac disease also requires a biopsy, usu-
ally of the duodenum, which would show flattened villi, crypt
Fig. 8.2  Section through the jejunal mucosa in a patient
hyperplasia, infiltration with lymphocytes and plasma cells and
with coeliac disease, showing flattened villi (V), and plasma cell
reduced cell differentiation. Figure 8.2 shows a section through
infiltrates (P).
the jejunal mucosa in a patient with coeliac disease. The cells

cellulose is an important source of dietary fibre, providing Structure of starch and glycogen
bulk that stimulates intestinal motility, and prevents con-
stipation (see Ch. 10). In ruminants, cellulose is degraded
The molecular weight of vegetable starch ranges from a
by bacterial cellulases that hydrolyse the -1,4 glycosidic
few thousand to 500 000. It consists of two components:
linkages to produce D-glucose, which is absorbed.
There are appreciable amounts of disaccharides, 1. Amylose in which the glucose subunits are linked
including sucrose (table sugar), lactose (milk sugar) and together in straight unbranched chains via -1,4
maltose (malt sugar), in Western diets. The only free glycosidic linkages (Fig. 8.4A).
monosaccharide likely to be present in the diet is glucose,
2. Amylopectin which consists of branched chains, with
which is added to ‘high energy’ drinks and foods.
the branches occurring at approximately every 30th
Dietary carbohydrate is utilized to provide energy for
glucose residue. -1,4 linkages are present within the
muscular and secretory activity and other metabolic func-
chains and -1,6 linkages occur at the branch points
tions. It is not ‘essential’ as a source of energy as calories
(Fig. 8.4B).
can also be provided by fat and protein. However, a few
carbohydrate substances, such as inositol, are ‘essential’ Glycogen has a structure similar to amylopectin but the
vitamin components of the diet, as they either cannot be molecular weight is usually greater, between 270 000 and
synthesized in the body, or cannot be synthesized at a rate 100 000 000, and it has a more branched structure, the
which is rapid enough to meet the body’s requirements. branches occurring every 8–10 glucose residues.

132 SYSTEMS OF THE BODY

 8

Digestion and absorption

Case
8.2 Crohn’s disease: 2

Defect, diagnosis and treatment

Crohn’s disease is most commonly diagnosed in young adults. diseased segments become grossly thickened. This can give rise
The highest frequency is seen in Caucasians, and in the Western to obstruction. As the inflammation resolves, areas of second-
world. In the UK, it affects approximately 50/100 000 of the ary scarring (fibrosis) in the wall of the bowel also constitute
population. The cause is unknown, but it is probably multifac- obstructive regions. The mucous membrane appears ‘cobble-
torial. As it is an inflammatory disease, infectious organisms, stoned’ due to longitudinal fissures and transverse oedema-
including the measles virus and Mycobacterium pseudotuber- tous folds. Aggregations of inflammatory cell infiltrates may
culosis, have been variously implicated. Autoimmunity has also be present, and the mesenteric lymph nodes may be enlarged
been suspected because there is an association with known due to reactive hyperplasia. Granulomas (aggregates of epi-
autoimmune conditions such as arthritis and eczema. Inherited thelial macrophages surrounded by a cuff of lymphocytes) may
factors are also implicated because of the high concordance in be present in the lymph nodes and the bowel wall.
monozygotic twins, and in families. Crohn’s disease in children The formation of enteric fistulae is a further feature of
can lead to growth retardation and delayed sexual develop- the disease. Fistulae may extend between different loops of the
ment, probably because of poor nutrition. bowel (enteroenteric fistulae), or between the bowel and the
skin (enterocutaneous fistulae, especially in the perianal areas).
Defect Gastrointestinal bleeding can also occur. This is usually mild but,
Crohn’s disease is an inflammatory disorder that can affect any because it is chronic, it can lead to iron-deficiency anaemia. There
region of the gastrointestinal tract, from the mouth to the is also an increased incidence of malignant neoplasms in patients
anus. However, the terminal ileum is the commonest site to with Crohn’s disease, especially in the small and large bowel. This
be affected (Crohn’s ileitis, Fig. 8.3). In the mouth, aphthous may be related to the long-term damage to the bowel mucosa.
ulcers of the buccal mucosa and tongue are seen. At the anus,
skin tags, fissures and fistulae may be present. The disease is Diagnosis
characterized by remissions and relapses. Macroscopically, The diagnosis of Crohn’s disease is difficult because all the
the intestines appear red and swollen. Normal areas of tissue salient features are seen in other disorders. A combination
are usually present between the damaged areas. Because the of histology, endoscopy and radiology is usually employed.
inflammatory process involves all layers of the intestinal wall, Evidence from blood analyses, including leukocytosis, elevated
sedimentation rate, and thrombocytosis, is indicative of an
active inflammatory process. Radiological evidence of the sites
of involvement, and the chronic remitting course of the
patient’s illness, also assist the diagnosis. However, a definitive
diagnosis requires histological assessment of the bowel and
identification of granulomata.

Treatment
CH The management of patients with this disease includes:
OMA
ST l Treatment of the symptoms (diarrhoea, pain)
J l Treatment with anti-inflammatory and immunosuppressive
agents
l Surgical treatment where there are complications such as

luminal obstruction
l Management of the patient’s nutritional status, including

supplementation of the diet

l Parenteral nutrition when necessary.

A
Total parenteral nutrition
Intravenous feeding can be used in extreme cases to rest the
bowel and allow healing. The fluid administered would con-
tain amino acids, glucose and lipid in amounts sufficient to
meet the protein and energy needs of the individual, and elec-
trolytes, vitamins and minerals in amounts sufficient to meet
Fig. 8.3  An X-ray of the ileum, taken 15 min after ingestion of
barium in a patient with Crohn’s ileitis. Three narrowed segments the estimated daily requirements. In patients with Crohn’s dis-
of ileum are visible (strictures A). The normal mucosal folds of the ease total parenteral nutrition can lead to positive nitrogen
proximal jejunum are also seen (J). balance, weight gain and temporary remission of symptoms.

THE digestive SYSTEM 133

8
CH2OH CH2OH
Digestion and absorption

H H H H H
H H
OH H H H
O
α-1, 6 glycosidic bond
H OH OH OH
CH2OH CH2 CH2OH
6
CH2OH H H H H H H H H
H H H
H 5 OH OH H OH H OH H
4 H Glucose O
OH H 1
OH 3 2 H OH H OH H OH
A H OH B α-1, 4 glycosidic bond

Fig. 8.4  (A) Structure of glucose showing the conventional numbering system for the carbon atoms. (B) Portion of an amylopectin molecule
showing -1,4 and -1,6 glycosidic linkages.

α - amylase unbranched oligosaccharides and branched oligosac-

charides (-limit dextrins) are formed. Thus a mixture of
products is produced (Fig. 8.5).
Amylose Maltotriose Maltose Glucose
A Salivary amylase starts the digestion of starch. It con-
tinues to act for up to half an hour in the interior of the
food bolus after it has arrived in the stomach. It is even-
tually inactivated at the low pH produced by the gas-
tric acid when it penetrates the food bolus. It can digest
α - amylase up to 50% of the starch present in food. Pancreatic juice
that contains a second -amylase is released into the
duodenum when a meal is present in the digestive tract.
Pancreatic amylase continues the digestion of starch and
glycogen in the small intestine. It is produced in larger
Amylopectin α - limit dextrins
amounts than salivary amylase. The -amylases from the
B
two sources have similar catalytic properties, despite hav-
Fig. 8.5  Degradation of (A) amylose, and (B) amylopectin, by ing different amino acid sequences. They both require Cl
-amylases. The filled circles indicate glucose subunits with -1,6, for optimum activity and both act at neutral or slightly
glycosidic linkages. alkaline pH values.

Role of brush border enzymes

Digestion of carbohydrate
Intestinal isomaltase (-1,6 glycosidase) splits -1,6 link-
In the gastrointestinal tract there are several enzymes ages in the branched poly- and oligosaccharides produced
that degrade starch and glycogen. These include the by amylase action in the small intestine. The combined
-­amylases secreted by the salivary glands and the pan- action of -amylase and -1,6 glycosidase can degrade
creas, and isomaltase and glucoamylase, which are integral amylopectin and glycogen to a mixture of maltose and
components of the intestinal absorptive cell membranes. glucose, but other enzymes in the brush border speed
Maltose, sucrose and lactose can also be degraded to their up and complete the process of starch digestion. These
component monosaccharides by enzymes situated in the are glucoamylase, which degrades small unbranched oli-
brush border of the upper small intestine (see below). gosaccharides, and maltase and isomaltase, which degrade
maltose and isomaltose, respectively. All of these enzymes
have access to the mixture of polysaccharides, oligosaccha-
-Amylases rides and disaccharides in the chyme during a meal.
-Amylases split the -1,4 glycosidic linkages in amy- The enzymes available to digest disaccharides are:
lose to yield maltose and glucose, but they do not act on l Maltase that degrades maltose to glucose
maltose, a disaccharide composed of two glucose sub­ l Sucrase that degrades sucrose to glucose and fructose
units linked by an -1,4 linkage. In theory -amylase will l Lactase that degrades lactose to galactose and glucose
ultimately degrade a solution of amylose to maltose, and
(Fig. 8.6).
glucose which can be released from the ends of the chains
(Fig. 8.5). Intermediate oligosaccharides (dextrins) are Sucrase and isomaltase are synthesized as a single
formed in the process. -Amylases also attack amylo- polypeptide chain inside the cell, and this is inserted
pectin and glycogen at their -1,4 linkages. Intermediate intact into the plasma membrane. Pancreatic protease

134 SYSTEMS OF THE BODY

 8
CH2OH CH2OH CH2OH CH2OH

Digestion and absorption

OH Maltase OH OH
OH OH OH + OH
HO HO HO
OH OH OH OH
A Maltose Glucose Glucose

CH2OH CH2OH
CH2OH CH2OH CH2OH
Sucrase OH
OH HO OH + HO
HO CH2OH HO OH
OH HO OH HO
B Sucrose Glucose Fructose

CH2OH CH2OH CH2OH CH2OH

HO OH Lactase HO OH OH
OH OH OH + OH
HO
OH OH OH OH
C Lactose Galactose Glucose

Fig. 8.6  Degradation of disaccharides by brush border disaccharidases. (A) Maltose, (B) sucrose, (C) lactose.

Glucose
cleaves the polypeptide chain at a site between the active
centres of the two enzyme moieties, but they remain non-
covalently associated in the membrane. When sucrase is Lumen
incorporated into artificial membranes, it binds sucrose Galactose Na+ Fructose
Lactose Sucrose
at one face and releases glucose and fructose on the
other side of the membrane. This has led to speculation
* * *
that it is both a hydrolytic enzyme and a transport mol- Lactase SGTL1 GLUT5 Sucrase
ecule. The other brush border enzymes do not appear to
behave in this way. These disaccharidases are all present
in the brush border of the enterocyte, and it seems that Fig. 8.7  Disaccharidases and hexose transporters in the brush border
the digestion of disaccharides and small oligosaccha- membrane. The enzymes reside in the brush border in close proximity
rides actually occurs in the membrane itself. This has to the hexose transporters. Disaccharides and oligosaccharides are
been inferred from the fact that after administration of degraded in the membrane by the enzymes, and the products are
either transferred to other enzymes for further degradation or, in the
a solution of a disaccharide to an animal, very little free
case of monosaccharides, to the appropriate transporter.
glucose can be detected in the lumen, yet the disaccha-
ride molecules are too large to diffuse through the pores
in the membrane, and disaccharide molecules cannot
be detected in the blood. It seems likely that the brush D-fructose, the products of digestion of starch, sucrose
border enzymes occupy positions in the membrane that and lactose. Both L-hexoses and D-hexoses are absorbed
are adjacent to the hexose carriers. The release of mono­ slowly by passive diffusion in the gastrointestinal tract.
saccharides occurs on the surface of the membrane and However, the plasma membrane of cells is relatively
these are then transferred to the adjacent carrier mol- impermeable to polar molecules such as monosaccharides
ecule for transport into the cell (Fig. 8.7). Inherited dis- and the transport of these sugars into the enterocyte by
orders of brush border enzymes are described in Box 8.1. passive diffusion is therefore slow. Glucose, galactose and
These defects result in carbohydrate malabsorption and fructose are absorbed by saturatable mechanisms, mainly
diarrhoea. in the duodenum and jejunum. This is accomplished by
membrane-associated transporters located in the brush
border and basolateral membranes of the mature entero-
Monosaccharide absorption cytes. These bind the sugars and transfer them across the
cell membranes and deliver them to the interstitial fluid
The most abundant monosaccharides in dietary carbo- in the lateral spaces, from where they are taken up into
hydrate are the hexoses, D-glucose, D-galactose, and the adjacent capillaries to enter the portal blood.

THE digestive SYSTEM 135

8
Box 8.1  Carbohydrate malabsorption syndromes: brush border diseases
Digestion and absorption

Brush border membrane disease is a collective term for condi- in populations such as Mediterranean and Oriental races
tions in which there is an absence of, or a marked decrease in that do not normally consume milk after childhood,
the activity of a functional brush border membrane protein. with the result that the enzyme is not present in their
These diseases are usually genetic. Sufferers may also exhibit intestines. If milk is ingested in these individuals they
disorders of reabsorption in the kidney proximal tubules. experience the symptoms of lactose intolerance. A rare
Several brush border diseases exist where the defect results congenital form of lactase deficiency exists; feeding
in malabsorption of a specific carbohydrate. Intolerance of infants with this condition with normal milk causes
that carbohydrate in the diet develops. The unabsorbed sugar diarrhoea. The problem can be overcome by feeding
passes into the colon where some of it is fermented by bacte- artificial milk in which lactose has been replaced by
ria. The remaining unaltered sugar and its bacterial fermenta- sucrose or fructose. There is a rise in H2 elimination
tion products cause osmotic diarrhoea (see Ch. 7). The clinical in the breath of affected individuals: the result of the
symptoms of carbohydrate malabsorption are abdominal dis- metabolism of the unabsorbed lactose by bacteria in the
tension, gassiness, borborygmi, nausea, cramping, pain and colon.
diarrhoea. In some of these conditions, there is also a high • Sucrase–isomaltase deficiency. Individuals with this
incidence of ulceration of the mouth. Carbohydrate malab- inherited brush border enzyme disease are intolerant of
sorption is diagnosed by an oral tolerance test that involves sucrose and isomaltose.
administration of the suspected sugar by mouth, and meas- • Glucose/galactose malabsorption. In this condition,
urement of the sugar in the blood and faeces. If the individual there is a genetic defect in the Na-dependent glucose/
is intolerant of the sugar, it appears in the faeces, but it (or its galactose transporter, SGLT1. Ingestion of glucose or
normal digestion products) cannot be detected in the blood. galactose produces the symptoms of brush-border disease.
Confirmation is by examination of a jejunal biopsy to see if Treatment involves omitting these sugars, as well as
the appropriate enzyme or carrier protein is absent from the lactose (which is degraded to glucose and galactose) from
mucosa. the diet. Fructose is absorbed normally via the GLUT5
Brush border diseases that have been characterized include: transporter.

• Lactase deficiency. This is a common brush border Certain amino acid malabsorption diseases are also brush
disorder that is usually expressed in adolescence or border diseases. These are described in Box 8.2. A congeni-
early adulthood. The enzyme, lactase, is induced by its tal disease where the Cl/HCO3 exchanger is absent from
substrate, lactose, in individuals who consume milk. the membranes of the jejunum, ileum and colon (congenital
There is generally a high incidence of lactase deficiency chloridorrhoea) is described in Chapter 7.

Pentoses are smaller than hexoses but they are absorbed inherited disorder where the SGLT1 is absent from the
at a slower rate than glucose, galactose and fructose, brush border has been described (see Box 8.1).
indicating that they are probably absorbed by passive
diffusion.
Hexose transport
The uptake of glucose across the enterocyte plasma mem-
Hexose transporters brane involves the binding of glucose to the Na/glucose
There are two types of hexose transporter in mammalian cotransporter SGLT1, as described in Chapter 7. SGLT1 is
cells; Na/glucose co-transporters which are involved present only in mature enterocytes in the upper regions
in the secondary active transport of glucose, and Na- of the villi. Galactose also binds to this carrier, but fruc-
­independent facilitative hexose transporters. Two forms tose does not. Glucose and galactose transport into the
of the Na-dependent transporter have been identified. epithelial cell is via secondary active transport. The
These are SGLT1 and SGLT2, but only SGLT1 is present energy required is derived from the coupling of sugar
in the small intestine. There are at least five functional transport to the transport of Na down the concentration
isoforms of facilitative transporter (GLUT1, GLUT2, and electrical gradients from the lumen into the cell. Both
GLUT3, GLUT4 and GLUT5). All mammalian cells Na ions and the sugar are transported into the cell on
express at least one of these transporters. The most stud- the SGLT1 transporter. This represents a major route for
ied is GLUT4, an insulin-sensitive glucose transporter the uptake of both the sugar and Na into the enterocyte.
present in muscle and adipose tissue (see Ch. 9). GLUT1, Thus the uptake of glucose is stimulated by the presence
GLUT2 and GLUT5 are all present in the enterocyte. of Na in the intestinal chyme. The affinity of the carrier
Figure 8.8 shows the structures of the SGLT1 and GLUT1 for glucose increases as the luminal Na concentration
transporters, and their conformations in the membrane. increases. The Km of SGLT1 in the presence of Na is less
The two molecules exhibit many similar features. The than 0.5 mM, but in its absence it is greater than 10 mM.
specificity of the transporters is shown in Table 8.1. An The absorption of glucose is illustrated schematically

136 SYSTEMS OF THE BODY

 8
248 45

Digestion and absorption

NH2

COOH

1 2 3 4 5 6 7 8 9 10 11 12 13 14 664

1 2 3 4 5 6 7 8 9 10 11 12

NH2
473
A Cytosol

COOH
B Cytosol

Fig. 8.8  Structure of SGLT1 and GLUT1 hexose transporters. (A) A model of the human Na/glucose transporter, SGLT1. The transporter has
664 amino acid residues. There are 12 membrane-spanning hydrophobic domains each composed of 21 residues arranged in an -helix.
N-linked glycosylation is present at residue 248 (asparagine) in a hydrophilic loop on the exoplasmic face between membrane spans 5 and 6. This
may be the site which binds the hexose molecules. There is another large hydrophilic exoplasmic loop between the 11th and 12th membrane
domains. The –NH2 and –COOH termini are on the cytoplasmic side of the membrane. (B) A model of the GLUT 1 transporter. The model depicted
represents GLUT1 that has 473 amino acid residues. A total of 12 hydrophobic membrane-spanning domains are connected by hydrophilic
segments. A large exoplasmic loop present between the 1st and 2nd membrane domains contains a potential N-glycosylation site at residue 45
(asparagine), where glucose might bind. A large cytoplasmic loop is located between the 6th and 7th transmembrane domains. The –NH2 and
the –COOH termini are both on the cytoplasmic side of the membrane. The facilitative transporters GLUT1, GLUT2, GLUT3, GLUT4 and GLUT5
are structurally related to this protein.

SGLT1 GLUT5
Table 8.1  Specificity of transporters for hexoses in the enterocyte facilitated facilitated
diffusion diffusion
Transporter Glucose Galactose Fructose Glucose,
+
2Na galactose Fructose
SGLT1   
GLUT1   
Lumen * * *
GLUT2   
GLUT5   
+
2Na Galactose Fructose
Glucose
GLUT1
in Figure 8.9. Each carrier molecule binds two Na ions Glucose facilitated
and one glucose molecule. The glucose concentration in Metabolism diffusion
the cell may be higher than that in the lumen but the cou-
pling of the transport of glucose with that of Na, enables Na+
Glucose
glucose to be transported into the cell against a concen- K+
tration gradient. ATPase pump *
Fructose does not bind to SGLT1 in the brush border. It active
is transported into the enterocyte, down its concentration transport
gradient by GLUT5 (which does not transport glucose, Glucose
GLUT2 Galactose
Fig. 8.9). The separate pathways for glucose and fructose
facilitated Fructose
transport into the enterocyte can be inferred from the fact diffusion
that normal fructose absorption is present in patients with
inherited glucose-galactose malabsorption (see Box 8.1), Fig. 8.9  Transport of hexoses in the enterocyte. The Na/glucose
and this provides the rationale for the treatment of this cotransporter (SGLT1) and the facilitative GLUT5 fructose membrane
condition with fructose. GLUT5 is present only in mature transporter reside in the brush border membrane, and GLUT1, GLUT2,
enterocytes on the tips and sides of the villi in the jejunum. and the ATPase pump in the basolateral membrane.
Some glucose is utilized by the cell for its energy
requirements. The transport of the remaining glucose, this low-affinity transporter allows the rate of glucose
galactose and fructose across the basolateral membrane transport through the basolateral membrane to increase
is accomplished by the GLUT2 transporter, which has in proportion to the glucose concentration, which var-
a low-affinity for glucose (Km 23 mM). The presence of ies from 5 mM (the normal value) to 20 mM. GLUT1 is

THE digestive SYSTEM 137

8
Digestion and absorption

Case
8.1 Coeliac disease: 3

Malabsorption and its consequences

Malabsorption l Anaemia and fatigue due to iron and folate malabsorption
In coeliac disease, the damaged villi and loss of enterocytes
l Osteomalacia as a result of vitamin D and Ca2
leads to a reduced surface area for absorption of fat and malabsorption, and the formation of Ca2 soaps from
other nutrients that are normally absorbed in the proximal fatty acids (which prevents their absorption)
l Bleeding from nose, gastrointestinal tract, vagina and
small intestine. Malabsorption is exacerbated if damage to
APUD cells in the duodenum results in deficiency of CCK and ureters, as a result of increased clotting time, due to
secretin, as these control secretion of pancreatic juice and vitamin K deficiency. The blood loss would exacerbate
bile, the major digestive juices in the gastrointestinal tract. the iron-deficiency anaemia.
Steatorrhoea (loss of fat in the faeces) was present in the
patient due to fat malabsorption. Iron-deficiency anaemia Diarrhoea
was present due to iron malabsorption as iron is absorbed in The patient’s blood electrolyte concentrations were measured
the proximal small intestine. because there can be a severe loss of electrolytes in diarrhoea
The absorption of hexoses, amino acids, fat, fat-soluble vita- (see Ch. 7).
mins, folate and Ca2 ions could also be impaired as they are Diarrhoea in this condition is due to:
all absorbed in the proximal small intestine.
l High concentrations of unabsorbed nutrients in the
Consequences chyme which cause osmotic diarrhoea
l The delivery of large amounts of fat into the colon
The consequences of malabsorption in this condition, if it is
left untreated, are: which results in the production of hydroxylated fatty acids
by colonic bacteria. These can act as cathartics
l Milk-intolerance, due to lactase deficiency, as this enzyme
l Weight loss and fatigue due to malabsorption of fuels such
as carbohydrates and fat, and malabsorption of amino is present in the enterocyte of the brush border in the
acids required for synthetic reactions proximal small intestine (see Box 8.1).

also present in enterocytes but its function is unclear. It Glucose transport into the blood can also be regulated
is a high-affinity transporter that functions close to the by blood glucose concentrations. Transport of glucose
Vmax even at normal blood concentrations. It may par- across the brush border membrane, but not the basolateral
ticipate in the release of glucose at the basolateral border. membrane, is stimulated by low blood sugar (hypogly-
However, in other tissues, such as the kidney tubules, caemia). The mechanism may involve an increase in the
where it is present in the basolateral membranes its func- concentration of circulating glucagon, a hormone which
tion appears to be to provide the cells with a source of stimulates cAMP formation in the cell. This hormone is
metabolic energy derived from the blood. Its function in released into the blood during starvation (see Ch. 9).
the enterocyte may therefore be to provide glucose from Paradoxically, in diabetes, chronic hyperglycaemia
the blood for metabolism during periods of fasting when (high blood sugar) also stimulates intestinal glucose
it is not being absorbed from the intestinal lumen. The transport. This is partly due to an increased surface area
locations of the different transporters in the enterocyte for absorption, resulting from an increase in the number
are illustrated in Figure 8.9. of enterocytes. However, glucagon levels are also high in
Malabsorption of carbohydrate is a feature of coeliac diabetes and this may stimulate glucose transport by the
disease that involves damage to the mucosa of the proxi- same mechanism as during starvation. In addition there
mal small intestine (see Case 8.1: 3). is also an upregulation of the GLUT2 transporter in the
basolateral membrane in diabetic hyperglycaemia.
Physiological regulation of hexose absorption
The transport of hexoses by the enterocyte can be regu- Protein
lated by diet. Thus a diet high in glucose or fructose
results in upregulation of the GLUT2 transporter in the In the Western hemisphere, the amount of protein in the
basolateral membrane, and increased transport of hex- average diet exceeds that required for nutritional balance.
oses into the blood. Thus blood glucose levels are regu- The dietary requirement for protein in the human adult
lated in part by alterations in the absorptive capacity of is between 30 and 50 g/day. Protein is required to supply
the enterocyte. the eight ‘essential amino acids’ which the body cannot

138 SYSTEMS OF THE BODY

 8
O O O O Proteins

Digestion and absorption

NH CH2 C NH CH C NH CH C NH CH CO trypsin
CH3 CH2 CH2 chymotrypsin
carboxypeptidases A
OH carboxypeptidases B
elastase
Amino
acid: Glycine Alanine Serine Phenylalanine Oligopeptides
Fig. 8.10  Part of a peptide chain showing three peptide linkages.
Dipeptides
Tripeptides
synthesize, or cannot synthesize rapidly enough, and Amino
acids
to replace nitrogen lost in the urine. In addition to that
which is ingested, 10–30 g of protein (enzymes, mucins,
etc.) is secreted into the digestive tract each day. An addi- Lumen
tional 25 g or so is derived from epithelial cells that have Oligo- Amino-
peptidase peptidase
been shed into the lumen. Most of this protein is digested
and absorbed. Approximately 10–20 g, derived from cell Carrier Carrier
debris and colonic microorganisms, is eliminated in the
Dipeptides
faeces each day.
tripeptides
dipeptidase
Digestion tripeptidase
Amino
Proteins are high molecular weight substances composed acids
of up to 20 different amino acids, joined together in pep-
tide linkages (see Fig. 8.10). In the adult, most protein Fig. 8.11  Digestion of proteins and peptides, and absorption of di-
is degraded in the digestive tract to small peptides and and tri-peptides and amino acids in the enterocyte.
amino acids. This is accomplished by a variety of pro-
teolytic enzymes. These can be divided into two catego-
ries, endopeptidases and exopeptidases. Endopeptidases 2. Chymotrypsin, which prefers linkages where the
cleave peptide bonds in the centre of the peptide carboxylic group is provided by an aromatic amino
chains, the initial products being mostly large peptides, acid.
which are subsequently degraded to oligopeptides. 3. Elastase, which degrades elastin.
Exopeptidases cleave bonds at the ends of the peptide
chain, splitting off amino acids one by one, in a stepwise Pancreatic juice also contains two carboxypeptidases
manner: carboxypeptidases act at the C-terminal, and (A and B). Carboxypeptidase A has the highest specifi-
aminopeptidases at the N-terminal. Enzymes that specifi- city for bonds where the C terminal amino acid is basic,
cally attack dipeptides and tripeptides are also present. such as lysine or arginine. The pancreatic enzymes are
The combined actions of these enzymes digest proteins secreted as inactive precursors that are converted to the
to small peptides and amino acids. active enzymes in the duodenum (see Ch. 5). They all
have slightly alkaline pH optima. At least 50% of the pro-
tein ingested is normally degraded in the duodenum.
Digestion in the stomach A number of peptidases reside in the brush border or
Pepsin is an endopeptidase which is secreted by the the cytosol of the enterocyte. They are most abundant in
stomach as an inactive precursor, pepsinogen, which is the cells in the jejunum. The active sites of these enzymes
activated by gastric juice (see Ch. 3). It favours peptide face the intestinal lumen and they act in situ, upon con-
linkages where aromatic amino acids are present. It is tact with the protein in the chyme. Enterocyte peptidases
responsible for the digestion of only approximately 15% also act in the lumen where they are present as compo-
of dietary protein. Protein digestion is not impaired nents of disintegrating cells that have been shed from the
in the absence of pepsin because other proteases are tips of the villi. One of the brush border enzymes is leu-
available. cine aminopeptidase. Others are oligopeptidases, which
degrade small peptides, such as tetrapeptides. There is
also a dipeptidyl aminopeptidase that removes dipep-
Digestion in the small intestine tides from the N-terminal of proteins.
The products of proteolytic digestion are tetrapep-
Pancreatic juice contains three endopeptidases (Fig. 8.11):
tides, tripeptides and dipeptides, and some amino acids.
1. Trypsin, which prefers peptide linkages where the Tripeptides, dipeptides and amino acids are transported
carboxylic acid group is provided by a basic amino into the epithelial cells. The dipeptides and tripeptides
acid. are degraded to amino acids by cytosolic tripeptidases

THE digestive SYSTEM 139

8
Facilitated Facilitated
Digestion and absorption

diffusion aa aa Na+ diffusion Table 8.2  Carriers involved in amino acid absorption in the
Lumen enterocyte

Location Carrier Na- Amino acid

dependence specificity

Brush border B Yes Neutral

Brush border B0, Yes Neutral, basic and
cystine
Brush border Imino Yes Imino (proline,
hydroxyproline)
Brush border XAG Yes Acidic
aa Na+ Brush border  Yes , mainly taurine
K+ Brush border b0, No Neutral, basic and
cystine
Na+
Brush border y No Basic
aa
K+ Basolateral asc No Small neutral
Facilitated Active border
diffusion transport Basolateral y No Basic
border
Fig. 8.12  Amino acid carrier mechanisms in the brush border and
basolateral border of the enterocyte. aa, amino acid. Basolateral L No Large, hydrophobic
border neutral

and dipeptidases in the endothelial cells. These relation-

ships are represented in Figure 8.11.
Five of the known amino acid transport systems in the
brush border are Na-dependent co-porters, which oper-
Absorption of protein products ate in a manner resembling that of the SGLT1 glucose
transporter (see above and Ch. 7). The pumping of Na
Mechanisms exist in the digestive tract for the absorption ions across the basolateral membrane produces concen-
of both small peptides and amino acids. In addition traces tration and electrical gradients that favour Na transport
of intact protein are absorbed in some human adults. into the cell. This provides the driving force for the oper-
ation of the co-transporters in the brush border. These are
therefore secondary active transport mechanisms. The
Amino acids other two brush border transporters do not require the
presence of Na ions in the lumen. The specificities of
The transport of amino acids across the membranes of the transporters are shown in Table 8.2.
the enterocytes into the blood can occur via passive dif- Three transporters in the basolateral border are col-
fusion, facilitated diffusion or active transport (Fig. 8.12). lectively responsible for the facilitated diffusion of neu-
Relatively hydrophobic amino acids, such as tryptophan, tral and basic amino acids into the lateral spaces (see
are transported to an appreciable extent by passive dif- Fig. 8.12). These transporters are present in many differ-
fusion. Only the L-isomers of amino acids are absorbed ent types of cell. Acidic amino acids such as glutamate
by facilitated diffusion and active transport. They are and aspartate are utilized by the enterocyte as energy
absorbed in the jejunum and the upper ileum. Carrier substrates, and do not appear to be transported out of the
systems for amino acids exist in the brush border and cell by specific carrier mechanisms. The basolateral mem-
the basolateral border (Table 8.2). At least seven specific brane also expresses carriers that transport amino acids
transport systems are present in the brush border mem- from the fluid in the lateral spaces into the enterocyte,
brane, and at least three are present in the basolateral where they are used for protein synthesis. These systems
membrane. The transport of most amino acids occurs require the presence of Na ions in the intercellular fluid.
against a concentration gradient, and therefore depends Malabsorption of amino acids is a feature of coeliac dis-
on active mechanisms. Each carrier is shared by a group ease due to damaged mucosa and the consequent loss of
of amino acids. Those that share the same transport transporters from the epithelial cells (see Case 8.1: 3).
mechanism compete with each other for a binding site
on the carrier protein. Table 8.2 shows the membrane
locations of the transporters that have been character- Absorption of small peptides
ized. The relationships were first discovered as a result of
studies of patients with amino acid carrier deficiencies. The dipeptide and tripeptide products of protein diges-
These diseases are described in Box 8.2. tion are transported into the enterocyte by secondary

140 SYSTEMS OF THE BODY

 8
Box 8.2  Amino acid malabsorption diseases Dipeptide,

Digestion and absorption

Tripeptide H+ H+
Lumen
The existence of different transport systems for amino acids
was first deduced from the study of rare amino acid mal-
absorption diseases. In these autosomal recessive diseases, H H+ Na+
a group of amino acids are either poorly absorbed or not Dipeptide Tripeptide
absorbed at all, while amino acids that are not in that group
are well absorbed. In these conditions, there is an absence Dipeptidase Tripeptidase
or deficiency of a specific amino acid transporter. The
defect is usually present in both the small intestine and the Amino
proximal tubules of the kidney, and the amino acids that acids
cannot be transported can appear in the urine.
These diseases include: + ATP Na+
K

• Hartnup’s disease. In this condition, the transport of Amino

neutral amino acids is defective, and neutral amino acids
acids appear in the urine. In this case the defect is in Fig. 8.13  Transport and metabolism of small peptides in the
the Na-dependent neutral amino acid B transporter. enterocyte.
Children with this condition exhibit skin changes,
cerebellar ataxia and mental disturbances
• Cystinuria. In this condition, the defect can be in
either the Na-dependent transporter or the
Absorption of protein
Na-independent transporter, both of which transport
basic amino acids (arginine, lysine, ornithine) and
Traces of intact protein can be absorbed in some adults. A
cystine (see Table 8.2). In cystinuria, these amino acids
foreign protein antigen that enters the circulation may pro-
appear in the urine. There is a tendency for kidney
voke the formation of antibodies and the subsequent entry
stones to develop in this condition, probably because
of that same protein may cause allergic symptoms. Intact
the dipeptide cystine is poorly soluble
protein can be absorbed in neonatal rodents, but it is not
• Familial iminoglycinuria. In this condition, there is a
clear whether it can also be absorbed to any appreciable
defect in the IMINO transport system leading to impaired
extent in the human infant. However, the absorption of
absorption of the imino acids, proline and hydroxyproline.
antibodies present in the maternal colostrum or milk may
contribute to the passive immunity of neonates. Inhibitors
In the above diseases, amino acids that are not absorbed
of proteolytic enzymes (which prevent protein degrada-
via the amino acid transporters can still be absorbed as
tion in the digestive tract) may be present in milk or colos-
components of small peptides. Therefore supplements of
trum, and so facilitate the absorption of whole proteins.
dipeptides and tripeptides that contain the essential amino
acids that cannot be absorbed as the free amino acids can
be provided in the diet. This also explains why the amino Minerals and trace elements
acids can appear in the urine (as a result of similar defects
in the kidney tubules), even although they cannot be Chemical analysis of the human body has revealed the
absorbed as the free molecules. presence of over 20 elements. Some, such as oxygen, car-
bon, hydrogen and nitrogen, are abundant as constitu-
ents of organic molecules, or, in the case of oxygen and
hydrogen, as components of water. Some elements are
active transport. The driving force for this system is the present in only trace amounts. Many enzymatic reactions
electrochemical gradient set up by the active pumping of will only take place if minute quantities of a particular
H ions across the brush border into the intestinal lumen. ion are present. Therefore these substances are required
The small peptides are transported across the brush bor- in the diet.
der via a H-dependent co-porter (Fig. 8.13). This trans- The cations required by the body are sodium, potas-
porter is specific for peptides that contain L-amino acids, sium, calcium, iron, magnesium, manganese, copper,
and has a very low affinity for peptides that consist of molybdenum and zinc, and the anions are chloride,
more than three amino acids. Most of the small peptides iodide, fluoride, phosphates and selenate.
transported into the cell are hydrolysed by intracellular The body requires Ca2 for a number of physiologi-
dipeptidases and tripeptidases (Fig. 8.13). Dipeptides cal processes, including bone and teeth formation, syn-
and tripeptides are absorbed at a more rapid rate than aptic transmission in the nervous system and glandular
amino acids. Thus, an amino acid can be absorbed at a secretion. PO43 is required for bone and teeth forma-
faster rate from the intestinal chyme if it is a component tion, acid–base balance and many other functions. Iron is
of a dipeptide or a tripeptide than if it is present as the required for the synthesis of respiratory pigments such as
free amino acid. haemoglobin, the respiratory pigment of red blood cells

THE digestive SYSTEM 141

8
that transports oxygen to the tissues of the body. Mg2 is
Digestion and absorption

Facilitated diffusion
required for nerve function, and as a co-factor for many Calcium
enzyme reactions. Copper and zinc ions and many oth- Ca2+ 1,25 (OH)2 vit D3
binding protein
ers are essential co-factors for enzyme reactions, and are
required in trace amounts. Lumen *
Many ions, including Mg2, SO42 and PO43, are
absorbed slowly in the small intestine by passive dif-
fusion, although there also appears to be an additional Ca2+ Ca2+
active transport mechanism for Mg2 in the ileum.
Special mechanisms exist for the transport of Ca2 and Calbindin
Fe2. Moreover, the absorption of these two ions is regu-
lated according to the needs of the body. Deficiencies of ATPase pump
Ca2 and Fe2 can occur in coeliac disease in which the active Ca2+
proximal small intestine is damaged (see Case 8.1: 3). transport

1,25 (OH)2 vit D3

Calcium Parathyroid hormone

The average adult diet probably contains 1–6 g of Ca2. Fig. 8.14  Ca2 transport in the absorptive cell.
In addition, approximately 0.6 g enters the tract as a
component of secretions. Of this 2.2 g total, only 0.7 g is
absorbed. Thus after subtraction of the amount entering (CaBP). This protein binds two Ca2 ions per molecule. In
the tract from non-dietary sources, the net amount enter- the cell free Ca2 is in dynamic equilibrium with protein
ing the body per day is only approximately 100 mg. bound calcium. The binding of Ca2 to protein enables
Ca2 ions can be absorbed along the entire length of high amounts of Ca2 to be transported into the cell with-
the small intestine. Its absorption is via both passive and out insoluble Ca2 salts being formed inside the cell.
active mechanisms. When its concentration in the chyme The process of calcium absorption in the small intes-
is low (5 mM) most absorption of Ca2 ions is via active tine is stimulated by a derivative of vitamin D3. This vita-
transport, but when its concentration is high, an appre- min can be ingested in the food (see below), or it can be
ciable proportion is absorbed by passive diffusion. This formed in the skin from 7-dehydrocholesterol, under the
is a consequence of the rate-limiting property of active influence of sunlight. Vitamin D3 is converted to 1,25-
transport. Ca2 can be absorbed against a 10-fold concen- dihydroxy vitamin D3 via reactions that occur in the
tration gradient, but the rate of absorption is still 50 times liver and kidneys. This vitamin behaves as a hormone in
slower than that of Na. the body, and it circulates via the blood to control Ca2
The mechanism for the secondary active transport of metabolism and homeostasis in various tissues. It is a
Ca2 ions in the enterocyte is illustrated in Figure 8.14. steroid molecule that binds to nuclear receptors in the
They are pumped out of the cell across the basolateral bor- enterocytes of the small intestine to stimulate the syn-
der by primary active transport involving a Ca2-ATPase. thesis of the brush border and cytosolic binding proteins.
This pump is phosphorylated by a protein kinase, which It also stimulates the synthesis of the basolateral Ca2-
is stimulated by a complex of Ca2 and calmodulin in the ATPase pump. Vitamin D deficiency leads to calcium
cell. The phosphorylation of the pump increases both its malabsorption that can cause rickets in children and
enzymatic and its transport activities. In addition, there osteomalacia in adults (see Box 8.3).
is a Na/Ca2-exchanger present in the basolateral bor- Absorption of Ca2 ions is also stimulated by para­
der. Na is transported down its concentration gradient thyroid hormone, another hormone that is intricately
into the cell in exchange for Ca2. These two mechanisms involved with Ca2 homeostasis in the body. The mecha-
keep the concentration of free Ca2 in the cell cytosol nism of action of parathyroid hormone in the small intes-
very low. The exchanger mechanism is the more effec- tine is not clearly understood, although one effect is to
tive mechanism at high levels of extracellular Ca2, and stimulate the formation of 1,25-dihydroxy vitamin D3.
the Ca2-ATPase mechanism at low levels. The concentra- These control mechanisms enable the body to maintain a
tion gradient set up as a consequence of the extrusion of balance between the absorption and utilization of Ca2.
Ca2 at the basolateral border provides the driving force Excess absorption results in increased Ca2 excretion in
for Ca2 transport into the cell across the brush border the urine, which can lead to precipitation of insoluble
(secondary active transport). Ca2 in the chyme binds salts such as calcium oxalate, which can lead to the for-
to a carrier protein in the brush border membrane that mation of urinary tract stones.
transports it into the cell by facilitated diffusion, down its Bile salts indirectly facilitate the absorption of Ca2
concentration and electrical gradients. The carrier protein ions by promoting the formation of micelles in the lumen
is known as the intestinal membrane calcium-binding of the small intestine (see Ch. 6, and below). This is
protein (IMcal). Inside the cell Ca2 is bound to another partly because vitamin D is fat soluble and its absorption
protein, known as calbindin or calcium binding protein depends on micelle formation, and partly because bile

142 SYSTEMS OF THE BODY

 8
Box 8.3  Rickets and osteomalacia Fe2+

Digestion and absorption

Calcium deficiency is usually due to vitamin D deficiency, Fe3+
either through dietary deficiency or lack of exposure to Fe2+ H+ DMT1 Haem-Fe2+
sunlight. It can also be due to a diet low in calcium. In Lumen
addition, it can be a consequence of anticonvulsant ther- Ferrireductase
apy (phenytoin and phenobarbital) that affects vitamin D
metabolism. Malabsorption of vitamin D occurs in Crohn’s
disease (see Box 8.7) and coeliac disease (see Case 8.1: 3). HO-1 Haem-Fe2+
The deficiency leads to rickets in children and osteomala-
cia in adults. The main defect is inadequate mineralization
of bone matrix (see the companion volume The Endocrine Fe2+ Biliverdin + CO
System). In affected individuals there is a tendency to frac-
tures, muscle and bone tenderness, and occasionally tetany.
In children with rickets, lower limb deformities may occur. Hephaestin
Ferritin
It has been shown in animals with rickets caused by vita- store Fe2+ Fe3+
min D deficiency, that their brush border membranes are
Ferroportin
deficient in IMCal transporter molecules. The transporter
Fe2+
is induced by the vitamin, and if vitamin D3 is adminis-
tered to these animals, the binding protein appears in the
brush border within 90 min of the vitamin being ingested.
Treatment of the diseases is via supplementation of the diet Blood Fe3+-transferrin Fe3+
with vitamin D and increased exposure to sunlight (which
increases the synthesis of the active form of the vitamin,
Fig. 8.15  Iron transport in the absorptive cell. HO-1, haemoxidase-1.
1,25-dihydroxy vitamin D3).

Some 30–50% of the iron present in haem is released

in the stomach lumen. Iron tends to form insoluble
salts help to hold fatty acids in the micelles, thereby pre- complexes with anions such as hydroxide, phosphate,
venting them from forming insoluble Ca2 soaps which oxalate and bicarbonate that are only slowly absorbed.
cannot be absorbed. Thus, bile salt deficiency can result in It also forms insoluble complexes with tannins, phytins
negative Ca2 balance. Another consequence of calcium and fibre in the food. These complexes are more solu-
soap formation is that Ca2 is not then available to pre- ble at low pH and their absorption is stimulated by the
cipitate oxalic acid, a constituent of certain foods such as presence of gastric acid. Furthermore, various compo-
rhubarb. As a consequence, in bile salt deficiency where nents of food such as ascorbate (vitamin C) form soluble
calcium soaps are formed, oxalic acid can be absorbed up complexes with iron, thereby facilitating its absorption.
to five times more rapidly than normal. Calcium oxalate Fe2 has a lower tendency than Fe3 to form insoluble
kidney stones can also develop as a consequence because complexes and is better absorbed. Fe3 is only poorly
of the high levels of oxalate in the blood. absorbed. Ascorbate and gastric acid also reduce Fe3 to
Calcium absorption is facultatively regulated to meet Fe2. Removal of the stomach can lead to the develop-
the needs of the body. The ability to absorb Ca2 ions, via ment of iron deficiency anaemia as a consequence of the
secondary active transport is increased by calcium dep- absence of gastric acid (see Ch. 3). Approximately half
rivation. Young and growing people absorb Ca2 more of the total amount of iron absorbed is present in haem.
rapidly than do mature and elderly people. Lactating Figure 8.15 illustrates these processes. Absorption of iron
women require Ca2 for milk production, and they absorb occurs mainly in the proximal small intestine.
Ca2 avidly.
Haem absorption
Iron The haem molecule consists of a porphyrin moiety con-
taining bound iron. It is absorbed intact into the entero-
Iron is required by the body as a component of hae- cyte, probably via a membrane carrier. Once inside the
moglobin and myoglobin and as a co-factor in various cell the Fe2 ions are liberated from the molecule in a
enzyme-catalysed reactions. Approximately two-thirds of reaction catalysed by haem oxygenase (HO-1). Carbon
the body iron is present in haemoglobin. Iron is ingested monoxide (CO) and the green bile pigment biliverdin
in several forms. The major component in normal meat- are the other products of this reaction. The free Fe2 pro-
eating individuals is haem, the product of proteolytic duced is thereafter processed in the same way as inor-
degradation of haemoglobin and myoglobin in the intes- ganic Fe2 absorbed from the lumen. Some intact haem
tines. Ferrous (Fe2) and ferric (Fe3) salts are usually may be transported into the circulation but the mecha-
present in the food. nism involved is unknown.

THE digestive SYSTEM 143

8
Non-haem iron absorption Box 8.4  Iron-deficiency anaemia
Digestion and absorption

An enzyme, ferrireductase, on the extracellular surface of

the enterocyte reduces Fe3 to Fe2 (Fig. 8.15). The Fe2 is Chronic iron deficiency results in iron-deficiency anaemia, a
absorbed by combination with the divalent metal trans- condition in which the synthesis of the respiratory pigment
porter, DMT1, which co-transports H into the cell. In haemoglobin is reduced.
the cell a large proportion of the liberated Fe2 enters a In iron-deficiency anaemia the red blood cells are char-
store, ferritin, but some is transported across the basola- acteristically small (microcytes) and contain a low concen-
teral membrane via a transporter, ferroportin. The Fe2 is tration of haemoglobin (hypochromia). In iron-deficiency
then oxidized to Fe3 by a ferroxidase enzyme known as anaemia the haemoglobin concentration is below 130 g/L in
hephaestin. In the blood, the Fe3 combines with plasma men and below 115 g/L in women. The prevalence is 2–5%
transferrin that transports it to the tissues. The major in adult men and postmenopausal women in the developed
stores of iron, apart from the small intestines are liver, world. Tiredness is a prominent symptom of the condition
spleen and bone marrow. because the reduced capacity of the red cells to carry oxy-
In ferritin Fe2is stored in combination with apoferri- gen results in the body’s requirement for oxygen not being
tin, a -globulin. The Fe2 is surrounded by apoferritin met. Treatment is by oral administration of iron salts such
subunits. When iron ingestion is increased, more iron is as ferrous sulphate.
stored in the mucosal cells, partly because iron stimulates In iron-deficiency anaemia, the expression of ferropor-
the synthesis of apoferritin, and so absorption into the tin in the enterocyte is increased. This causes an increase in
blood is minimized. The Fe2 in ferritin is a storage pool the capacity of the cell to absorb iron. There is a reduced
that is not usually absorbed. It is lost when the cells are expression of hepcidin in the liver in iron deficiency.
shed from the villi. The cells disintegrate in the intestinal Hepcidin circulates in the blood and signals the require-
lumen and the liberated iron is eliminated in the faeces. ment for an increase in iron absorption in the intestine.
Ferritin is the principal storage form of iron in tissues. It Iron-deficiency anaemia may be of dietary origin, due
contains approximately 27% of the body’s iron. to menstrual blood loss, or malabsorption of iron in condi-
tions such as coeliac disease (see Case 8.1: 3), chronic blood
loss (as in Crohn’s Disease (see Case 8.2: 3). ‘Silent’ chronic
Regulation of iron absorption bleeding from the gastrointestinal tract is also a feature of
all gastrointestinal cancers, and for this reason any adult
The recommended dietary intake of iron in the adult is with unexplained iron deficiency should be investigated for
10 mg/day for males and 15 mg/day for females of men- tumours of the large bowel, stomach and oesophagus.
strual age. Normally, less than 10% of dietary iron is
absorbed. In the normal adult very little iron is required
because most of the iron released from erythrocytes at
the end of their lifetime is recycled. The adult male or the villi where they become mature, which takes approxi-
post-menopausal female loses approximately 0.6 mg/day mately three days. The message to increase the rate of iron
and women of menstrual age approximately 1.2 mg/day absorption would therefore be given to the dividing cells in
(averaged over the monthly cycle). However, the pro- the crypts, which cannot absorb iron until they are mature.
portion that is absorbed is tightly regulated to meet the However there is recent evidence to indicate that the mes-
body’s needs. The amount of iron absorbed in the small sage is given directly to the mature enterocytes. Thus the
intestine is approximately equal to the amount lost. Thus lag phase between blood loss and increased absorption
its rate of absorption is increased when more iron is of iron remains to be fully explained, but it may be due to
required, for example after a haemorrhage (see below). the time taken for the events that regulate the expression
In iron-deficient conditions (in which haemoglobin syn- of the humoral factor, hepcidin, a peptide molecule that is
thesis is impaired, see Box 8.4), there is an increased expres- synthesized in the liver. Circulating hepcidin appears to
sion of the transporter proteins DMT1 and ferroportin, and signal the iron requirements of the body to the intestine by
hephaestin, in the enterocyte (see Fig. 8.15). However, the influencing the expression of ferroportin in the basolateral
rate of iron export from the enterocyte appears to be the membrane of the enterocyte. In iron deficiency the expres-
main (rate-limiting) regulatory step indicating the primary sion of ferroportin is increased and in conditions of iron
role played by the rate of expression of ferroportin. overload it is decreased. The expression of hepcidin itself
Conversely, mucosal cells that are loaded with iron (in the liver) may be partly regulated via the concentration
have a reduced ability to take up iron. This prevents the of transferrin-bound iron in the bloodstream.
absorption of excessive amounts, which can be toxic. In
hereditary haemochromatosis, the gene mutation leads to
prolonged and excessive absorption of iron (see Box 8.5). Water-soluble vitamins
The amount of iron absorbed in the small intestine
increases following a haemorrhage, but not until 3 days The water-soluble vitamins required by the body are
after the haemorrhage has taken place. This delay was vitamin C (ascorbate), which prevents scurvy, and is
until recently believed to be due to the time taken for the present largely in fresh fruit, and components of the vita-
absorptive cells to migrate from the crypts to the tips of min B ‘complex’, including thiamine, riboflavin, biotin,

144 SYSTEMS OF THE BODY

 8
Box 8.5  Haemochromatosis of the Na/K ATPase in the basolateral border provides

Digestion and absorption

the gradient for Na transport into the cell.
Mucosal cells that are loaded with iron normally have a
reduced ability to take up iron. This prevents the absorption of Folic acid
excessive amounts, which would be toxic. Haemochromatosis
is a relatively common disorder that develops when there is Folic acid (pteroylmonoglutamic acid) is formed by
prolonged excessive absorption of iron. It may also be due deconjugation of polyglutamate that is the form of the
to excessive dietary intake. It is characterized by excessive vitamin present in food. The deconjugation takes place
deposits of ferritin and haemosiderin (iron binding proteins) in the brush border. It is catalysed by a zinc-activated
in tissues. It can result in pigmentation of the skin (bronze enzyme, folate conjugase, which is maximally active at
diabetes), pancreatic damage (causing diabetes mellitus), cir- pH 5.0. Pterylmonoglutamate is transported across the
rhosis of the liver, and (as a consequence) a high incidence of apical membranes by a folate/OH-exchange mechanism
hepatic carcinoma. Hereditary haemochromatosis is an auto- but its transport out of the enterocyte is by an unknown
somal recessive congenital disorder in which the mutant gene mechanism. Pteroylglutamate is converted to the active
is HFE, on the short arm of chromosome 6. It is characterized derivative tetrahydrofolate by folate reductase. It is then
by a high rate of iron absorption in the presence of elevated, converted to 5,10-methylene-tetrathydrofolate that is
rather than depleted, body stores. The total body stores required for DNA synthesis. Folate deficiency leads to
are usually between 20–40 g as opposed to 3–4 g in healthy macrocytic anaemia because DNA synthesis in the bone
individuals. In this condition, the mucosal regulatory mech- marrow is impaired.
anism is impaired, but the mechanisms involved are unclear.
HFE, the protein product of the gene, is involved in the
regulation of iron absorption, possibly via the regulation of Vitamin B12
the expression of hepcidin, the molecule that normally reg-
ulates iron absorption in the enterocyte. Expression of the Vitamin B12 exists as four metabolically important forms
hepcidin gene is decreased in hereditary haemochromato- in food: cyanocobalamin, hydroxocobalamin, deoxyade-
sis, and this facilitates iron overloading. nosylcobalamin and methylcobalamin, which are mostly
Treatment of haemochromatosis is by phlebotomy; bound to protein. This vitamin is required for red cell
removal of blood is done as often as is required to maintain maturation. For this reason pernicious anaemia develops
low iron stores, as assessed by the concentrations of iron in vitamin B12 deficiency. The dietary requirement for
and iron-binding proteins in the blood, and transferrin sat- vitamin B12 is close to the maximum absorptive capacity,
uration levels. A potential treatment for haemochromatosis but large quantities of the vitamin are stored in the liver
is administration of a proton pump inhibitor that reduces and these stores would normally be sufficient for at least
acid secretion in the stomach, thereby inhibiting the reduc- three years if the vitamin ceased to be absorbed (as after
tion of Fe3 to Fe2. gastrectomy, see Ch. 3). Some is lost in the bile secreted
by the liver, although most of this is reabsorbed.
The cobalamins are released from their protein com-
plexes, in the stomach, by the action of pepsin and acid.
pantothenic acid, niacin, pyridoxine, inositol, choline, They are then rapidly bound to cobalamin-binding glyc-
folic acid and cobalamins (vitamin B12). In the main, oproteins known as R proteins (haptocorrin) that are
members of the B complex are found together in nature. secreted in saliva and gastric juice. These complexes are
Furthermore, the overt manifestations of deficiency of degraded by pancreatic proteases in the duodenum. In
members of this group, such as muscle weakness, fatigue pancreatic insufficiency when proteolytic enzymes are
and growth retardation, dermatitis and neuropathy, over- deficient, the complexes with R proteins are not degraded
lap. Water-soluble vitamins are required as cofactors in and the vitamin is not absorbed. The free Vitamin B12
many metabolic reactions. (cobalamin) then combines with another glycoprotein,
Most water-soluble vitamins are absorbed to an appre- intrinsic factor, which is secreted by the stomach (see
ciable extent by simple passive diffusion, but for many, Ch. 3). This complex is resistant to proteolytic degrada-
specific mechanisms are also available, although these tion. The formation of the vitamin B12–intrinsic factor
are not all clearly understood. complex is necessary for the vitamin to be absorbed via
Pyridoxine (vitamin B6) appears to be transported active transport in the terminal ileum. The complex is a
solely via passive diffusion and then metabolized within dimer of intrinsic factor that binds two vitamin B12 mol-
the epithelial cell. Biotin, inositol, choline and ribofla- ecules. The brush border membrane of the ileal epithelial
vin are absorbed by facilitated diffusion in the proximal cells contains receptors for the vitamin B12-intrinsic fac-
small intestine, whilst pantothenic acid, thiamin, inositol tor dimer complex. Binding of the complex to the recep-
and nicotinic acid are absorbed by active Na-dependent tor is Ca2-dependent. It seems likely that the complex is
mechanisms in the proximal small intestine. internalized by an active transport process. It dissociates
Ascorbate is absorbed mainly in the proximal ileum within the cell, and the free vitamin B12 binds to another
using a secondary active transport mechanism involving protein, transcobalamin II. This complex is then trans-
co-port with Na ions, in the brush border. The operation ported out of the cell, by an unknown mechanism, and

THE digestive SYSTEM 145

8
IF-B12 These include the fat-soluble vitamins A, D, E and K, and
Digestion and absorption

Receptor
Lumen the essential fatty acids.
Deficiency of vitamin A results in hyperkeratosis of
the skin, and xerophthalmia, a disturbance of epithelial
tissues. In the human an early symptom of this condition
is night blindness due to abnormal responses of the reti-
IF-B12 nal rods.
IF Vitamin D is required for Ca2 absorption (see below)
and for normal calcium and phosphate metabolism.
Deficiency of vitamin D and the resultant Ca2 deficiency
B12 + transcobalamin II B12-transcobalamin II lead to abnormalities in bones and teeth, paraesthesia
(due to impaired nerve conduction), skeletal pain and
tetany (due to impaired muscle function).
Vitamin E is an important antioxidant. Deficiency in
B12-transcobalamin II rodents causes sterility and muscle weakness, but its role
in the human is not entirely clear.
Vitamin K deficiency causes bleeding diathesis, due to
Blood B12-transcobalamin II defective blood coagulation as a result of failure to syn-
thesize prothrombin that is required for blood clotting.
Fig. 8.16  Possible scheme for vitamin B12 (cobalamin) absorption. IF, Part of the vitamin K requirement of an organism is sup-
intrinsic factor; B12, cobalamin. plied by bacteria that colonize the intestines.
The essential polyunsaturated fatty acids linoleic acid
(C18:2) and -linoleic acid (present in evening primrose
taken up into the portal blood. A scheme for its absorp- oil), linolenic acid (C18:3) and arachidonic acid (C20:4)
tion is shown in Figure 8.16. The vitamin does not appear are required for the proper functioning of the nervous
in the blood until 4 hours after it has been ingested. The system.
vitamin B12–transcobalamin II complex is taken up by Under normal circumstances, less than 6 g of fat is
receptor-­mediated endocytosis in the liver for storage. In eliminated in the faeces per day and most of this arises
Crohn’s ileitis the absorption of vitamin B12 is impaired from bacterial cells and cell debris. If larger amounts of
because the mucosa of the ileum is damaged and the fat are eliminated the condition is known as steatorrhoea,
transporters are lost from the epithelial cells (Case 8.2: 3). and indicates a deficiency in fat absorption (see Case 8.1: 3
Vitamin B12 is also absorbed passively to some extent and Case 8.2: 3).
throughout the small intestine. Probably only 1–2% of
the ingested vitamin is absorbed in this way, but if mas-
sive doses are eaten, enough can be absorbed to prevent Lipid solubility
pernicious anaemia. There is a shorter lag time involved in
absorption by the passive mechanism than via the receptor- Some lipids, for example short-chain fatty acids (with
mediated mechanism. The causes and consequences of a carbon chain 10), and some polyunsaturated com-
vitamin B12 deficiency are described in Box 8.6. plex lipids containing short-chain fatty acids or poly-
unsaturated fatty acids, are soluble in water. These are
absorbed by passive diffusion. They dissolve in the
Lipids membrane and are transported down their concentra-
tion gradients into the cell, and then into the portal
Dietary lipids blood. The transport of water-soluble lipids into the
blood is a rapid process.
The range of fat ingested by an individual varies enor- The digestion and absorption of most lipids are
mously. In Western countries, it is probably between 25 achieved by a variety of highly complex processes which
and 160 g/day. Most ingested fat is neutral lipid (triacyl­ enable the body to overcome the problem that although
glycerol) present in butter, margarine, cooking oil, meat, most lipid is insoluble in water, it has to be transferred
etc. In addition, some phospholipid and some cholesterol from the gut lumen to the lymph, and eventually the
ester, components of plant and animal cell membranes blood, via aqueous media:
are present in food, together with small amounts of other l The chyme in the lumen
lipids. l The cell’s interior
l The interstitial fluid
l The lymph
Fat-soluble vitamins and essential fatty acids l The blood.
Certain lipid molecules are ‘essential’ in the diet, as they A further problem is that the enzymes that cata-
are required in the body, but cannot be synthesized. lyse the breakdown of the complex lipids, i.e. lipases,

146 SYSTEMS OF THE BODY

 8

Digestion and absorption

Case
8.2 Crohn’s disease: 3

Malabsorption in Crohn’s Ileitis

If the terminal ileum is the main site involved, the absorption Anaemia and vitamin B12
of bile acids and vitamin B12, which are absorbed in the ter- Anaemia is common in individuals with Crohn’s disease, and
minal ileum, will be the primary processes affected. If other contributes to the patient’s lassitude, and feelings of tired-
regions are also severely affected, the absorption of many ness. There are a number of reasons for the development of
other nutrients can be impaired. anaemia in Crohn’s disease:

Bile acids l Pernicious anaemia due to vitamin B12 deficiency (see

Bile acids are absorbed in the ileum and recycled via the entero­ Box 8.1). If a large part of the ileum is diseased or resected,
hepatic circulation (see Ch. 6). In Crohn’s ileitis, reduced bile vitamin B12 deficiency will eventually develop, unless
acid absorption results in a reduced bile acid pool. This is due measures are taken to prevent it. Note: Folate deficiency,
to the reduced surface area available for absorption and loss which also leads to macrocytic anaemia, can also occur if
of bile acid transporters. If excessive bile acids are lost in the the jejunum is affected
faeces, the liver cannot replace them rapidly enough (by de l Iron-deficiency anaemia. Small but prolonged blood loss

novo synthesis) to maintain the bile acid pool. Furthermore, if often leads to iron-deficiency anaemia in Crohn’s disease
bacterial overgrowth is present, enzymes in the bacteria can l Poor nutrition. The abdominal pain and gastrointestinal

deconjugate the bile acids, and unconjugated bile acids are colic experienced in Crohn’s disease can inhibit food
not as rapidly absorbed as the conjugated derivatives. intake. The resultant dietary deficiencies can also
contribute to the development of anaemia (especially
Fats iron-deficiency anaemia).
In Crohn’s disease of the ileum, fat absorption is usually
impaired, leading to steatorrhoea. This is largely a conse- Other deficiencies
quence of defective bile acid absorption as these are impor- l Lactase deficiency may be present due to loss of mature
tant for emulsification and micelle formation. The intestinal enterocytes (if the proximal small intestine is involved)
and mesenteric lymphatics may also be extensively involved l Deficiencies of B complex vitamins may be present, leading
in the disease, and this can also contribute to impaired to a red tongue, cracked lips, dermatitis and peripheral
fat absorption. Malabsorption of complex lipids leads to a neuropathy. Vitamin supplements can be given when
reduced calorie intake, but this may not be important if car- there is evidence of deficiencies.
bohydrate absorption is unaffected. Medium-chain triacylglyc-
erols that contain fatty acids, which can be absorbed directly
into the blood, can be substituted for long-chain triacylglycer-
Protein loss
ols in the diet. This reduces the steatorrhoea. In Crohn’s disease, severe loss of protein, including albumen,
may occur across the region of ulcerated mucosa in the intes-
Fat-soluble vitamins tine. This can result in hypoalbuminaemia and ascites (a fluid
transudation into the peritoneum).
In Crohn’s disease, severe malabsorption of fat-soluble vita-
mins can occur. The problems associated with such deficiencies
are outlined above. Diarrhoea
The diarrhoea present in Crohn’s disease is partly ‘osmotic’
Gall stone disease (see Ch. 7), due to quantities of unabsorbed nutrients and bile
A reduced bile acid pool can result in cholesterol not being acids creating an osmotic gradient for water transport into
held in micellar suspension and it precipitates out to form gall the lumen. However, the diarrhoea is also due to the stimu-
stones (cholelithiasis, see Ch. 6). Disruption of the enterohe- lation of propulsive motility by bile salts entering the colon.
patic circulation of bile acids is probably the reason why there In addition, unabsorbed fats can be hydroxylated by bacteria
is an increased incidence of gall stone disease in individuals in the colon, and the hydroxylated fats can stimulate colonic
with Crohn’s disease. motility.

phospholipases and cholesterol esterases, are all water- Digestion

soluble and insoluble in lipid, but obviously have to gain
access to the lipid molecules before they can hydrolyse The digestion of triacylglycerol is catalysed by lipases
them. The mechanisms that enable these problems to be (glycerol ester hydrolases). The major lipase in the diges-
overcome will be described after the reactions involved tive tract is secreted by the pancreas. Minor lipases
in the digestion of lipids have been outlined. are present in saliva (lingual lipase) and gastric juice,

THE digestive SYSTEM 147

8
Box 8.6  Pernicious anaemia
Digestion and absorption

1. Triacylglycerol
CH2OCOR
Deficiency of intrinsic factor, due to atrophy of the gastric CHOCOR
mucosa, is the most common cause of pernicious anaemia.
Atrophy of the gastric mucosa also leads to the inability of CH2OCOR
the stomach to secrete HCl (achlorhydria) and pepsinogen.
However, it is only the lack of intrinsic factor that is serious, Lipase
because pepsinogen and acid are not essential to life (see
Ch. 3). Historically, intrinsic factor extracted from hog stom- CH2OH
ach was administered in this condition, and the vitamin
could then be absorbed normally. Many patients developed CHOCOR + 2RCOOH
antibodies to the intrinsic factor in their blood and it was CH2OH
once believed that these could be due to the presence of
the foreign intrinsic factor protein in the blood. This led to
the belief that the vitamin B12–intrinsic factor complex was
absorbed intact. However, it is now known that pernicious
anaemia can be an autoimmune disease and so patients can 2. Cholesterol ester
have high antibody titres in their blood even when foreign Cholesterol ester
intrinsic factor has not been ingested. Today, the vitamin is
injected intramuscularly, but this is usually only necessary Cholesterol esterase
once every 3 months, as it is stored in the liver.
The absorption of vitamin B12 is impaired in pancreatic
disease where proteases are deficient because it is not Cholesterol + fatty acid
released from haptocorrin to which it binds in the stomach,
and so cannot bind to intrinsic factor.
The complexity of vitamin B12 absorption is illustrated by
the existence of three types of pernicious anaemia seen in 3. Phospholipid
childhood: Phosphatidylcholine

1. An autoimmune condition resulting in gastric atrophy,

similar to that described above Lysophospholipase A2
2. A congenital deficiency of intrinsic factor with normal
secretion of pepsinogen and acid Lysophosphatidylcholine + fatty acid
3. Congenital vitamin B12 malabsorption syndrome. In this
condition, gastric function and release of intrinsic
Fig. 8.17  Digestion of complex lipids in the small intestine.
factor are normal but the absorption of vitamin B12 (in
the ileum) is impaired, due to a defect in the receptors
that bind the vitamin B12–intrinsic factor complex. Cholesterol esterase is secreted in pancreatic juice. In
intestinal chyme, it forms dimers that are resistant to pro-
Vitamin B12 is important for maturation of the red blood teolytic digestion. It cleaves the ester bond in cholesterol
cells. Pernicious anaemia is characterized by a low red cell ester with the formation of free cholesterol and fatty acid
count, and high mean red cell volume (as the immature red (Fig. 8.17). It also acts more slowly to hydrolyse triacyl­
cells present are larger than normal mature cells, i.e. they glycerol, lysophospholipids, monoacylglycerols and
are ‘macrocytic’). The symptoms that develop, if the condi- esters of fat-soluble vitamins.
tion is left untreated, include polyneuropathy, paraesthesia Phospholipase A2 is secreted in pancreatic juice as an
of fingers and toes, progressive weakness and ataxia, and inactive precursor. It is activated in the small intestine (see
dementia and other psychiatric problems. Ch. 5). It cleaves the ester bond at the 2 position in many
phospholipids, including phosphatidylcholine (lecithin),
phosphatidylserine and phosphatidylethanolamine, to
give fatty acid and lysophospholipid. The hydrolysis of
but these are probably only important when the pan- phosphatidylcholine is shown in Figure 8.17.
creatic enzyme is absent or inactive. The pancreatic
enzyme cleaves the ester bonds at positions 1 and 3
in the triacylglycerol molecule, in a stepwise man- Emulsification
ner, with the formation of 1,2 diacylglycerol and 2,3
diacyl­glycerol intermediates. The ultimate products are The process of emulsification is essential for the effi-
2-­monoacylglycerol, which is absorbed without further cient digestion of lipids. It enables the enzymes involved
degradation, and fatty acids. The overall reaction is given to gain access to their lipid substrates. If oil is added to
in Figure 8.17. water it forms a layer on top of the water because it is

148 SYSTEMS OF THE BODY

 8
insoluble, and is less dense than water. If some lipase is and fat-soluble vitamins, which are highly insoluble in

Digestion and absorption

added it dissolves in the water layer and will only attack water, are maintained in the core region of the micelle.
the lipid at the lipid–water interface. Therefore the rate Monoacylglycerol and lysophospholipids orientate them-
of lipid hydrolysis is proportional to the surface area of selves so that their acyl chains are in the core region,
the lipid–water interface. In the small intestine, the sur- and their more polar regions project towards the aque-
face area of the lipid–water interface is increased by the ous phase (i.e. in the shell region). Bile salts are present
process of emulsification, whereby the large droplets of in the shell region. The polar groups on the bile salt
lipid are broken down into tiny droplets that can be held impart a negative charge to the surface of the micelles.
in a stable suspension. The lipid–water interface is con- This causes mutual repulsion between different micelles,
sequently increased enormously, enabling lipid digestion keeping them in stable suspension in the chyme. The
to proceed at a rapid rate. negatively charged shell collects cations such as Na
The process of emulsification requires conjugated bile that form an outer shell around the micelle. When the
acids, which coat the lipid droplets and prevent them bile acid concentration is at or above, its critical micellar
coalescing together. These substances are secreted in bile. concentration, the bile acid and insoluble lipids such as
Within 20 min of the beginning of a meal the gall bladder monoacylglycerol aggregate as micelles. With increasing
contracts and empties concentrated bile into the duode- bile acid concentration more monoacylglycerol molecules
num. The structure and release of the bile acids is discussed are carried as micelles. In the normal human the critical
in Chapter 6. The emulsified droplets are 0.5–1.0 mm in micellar concentration is usually well below the concen-
diameter. A neutral or slightly alkaline environment is tration actually present, and micelles easily form. There
required for emulsification. This is normally provided by are certain disease states however, such as obstructive
the intestinal chyme in which the alkaline secretions mix jaundice (see Ch. 6), where the concentration is too low.
with the acid from the stomach and neutralize it. The critical micellar concentration (see Ch. 6) is higher
Lipase is essentially inactive in the presence of bile for unconjugated bile acids than for conjugated bile
acids, but colipase, a small protein (MW 10 000) present acids. Consequently, if a considerable fraction of the bile
in pancreatic juice, forms a complex with lipase and acids is deconjugated in the intestinal lumen by bacterial
bile acid, and this enables the colipase–lipase complex action, micelle formation may be impaired.
to spread over the surface of the minute droplets, and Most fatty acids and monoacylglycerol are absorbed in
hydrolyse the triacylglycerol present. Triacylglycerol is the duodenum and upper jejunum, while the bile acids
hydrolysed on the surface of the emulsion droplets and are absorbed more distally in the ileum. Cholesterol can
the products of digestion, monoacylglycerol and fatty be absorbed throughout the length of the small intestine,
acids, are liberated from the droplets into the aque- although a considerable proportion of it escapes into the
ous medium. The hydrolysis of triacylglycerol under colon. Thus, the composition of the micelles changes as
these circumstances is more rapid than the absorption they move down the small intestine; their content of fatty
of its products. A small proportion of the fatty acids acids and monoacylglycerol diminishes while their pro-
released from the droplets is water-soluble, and this can portional content of bile acids increases.
be absorbed directly into the blood. However, most free The constituent lipid molecules of micelles move back
fatty acids and monoacylglycerols are insoluble in water. and forth between the micelles and the aqueous solution
They would soon saturate the chyme and separate out with great rapidity. The aqueous chyme is kept saturated
into large droplets again, if it were not for the process of with lipid molecules by the movement of fatty acids and
micelle formation. monoacylglycerol from the micelles into the solution. Thus
the micelles serve as a reservoir of these products so that
the aqueous phase in contact with the enterocyte brush
Micelle formation border is always saturated with lipid molecules, and a
dynamic equilibrium between the micelle and the solution
A micelle is a lipid particle of 4–6 nm diameter, which is established. The dissolved fatty acids can be absorbed.
consists of an aggregate of approximately 20 lipid mol- However, the micelles first have to diffuse across the
ecules. Bile acids are required for micelle formation. Bile ‘unstirred layer’ to the enterocyte cell membrane.
itself contains micelles composed of bile salts, choles-
terol and phosphatidylcholine (see Ch. 6) but in the small
intestine the micelles have a more heterogeneous com- The unstirred layer
position. The process of micelle formation is discussed
in Chapter 6. In the small intestine, the initial constitu- The unstirred layer is a layer of fluid in contact with the
ents of the micelles in the duodenum are bile salts and epithelial surface, which does not readily mix with the
2-monoacylglycerols. These micelles then sequester other bulk of the chyme. It is 200–500 mm thick. Micelles and
fat-­soluble substances, such as long-chain fatty acids, nutrients have to diffuse through this layer to the surface
cholesterol, fat-soluble vitamins, and phospho­lipids. membrane of the enterocyte. Thus, there is a concentra-
An individual micelle may contain several or all of tion gradient of nutrients across the unstirred layer with
these molecules, although fatty acids are quantitatively the lowest concentration at the epithelial surface. A pH
the most important. Cholesterol, long-chain fatty acids gradient also exists across the unstirred layer, with the

THE digestive SYSTEM 149

8
fluid in contact with the brush border being slightly
Digestion and absorption

more acid than the bulk of the chyme. This promotes the Fatty acid + CoASH + ATP
absorption of fatty acids as they tend to be less ionized,
and therefore more easily absorbed across the lipid mem- Acyl CoA synthetase
brane (see Ch. 7).
Fatty acyl-S-CoA + H2O + AMP + P-P
A
Fate of lipid in the epithelial cell

Lipids can dissolve in the lipid of the brush border mem-

α-Glycerolphosphate
brane and easily diffuse across it. The transported lipids
are metabolized within the cell and used in the resyn-
2 fatty acyl-S-CoA
thesis of complex lipids (Fig. 8.18). The free fatty acids
Glycerolphosphate acyltransferase
react with coenzyme A to form acetyl-CoA (Fig. 8.19A). 2 CoASH
Triacylglycerol is synthesized via both the -glycerol-
phosphate pathway (that also operates in liver and other
Phosphatidic acid
tissues) and via the monoacylglycerol pathway, which
involves direct esterification of monoacylglycerol by fatty
acyl-S-CoA, a pathway which is restricted to the mucosal
Phosphatidate phosphohydrolase Pi
cell (Fig. 8.19B,C). Phospholipid is synthesized by ester-
ification of lysophospholipid with fatty acyl-S-CoA
(Fig. 8.19D) and cholesterol ester by esterification of free
cholesterol with fatty acyl-S-CoA (Fig. 8.19E). Diacylglycerol
The complex lipids are formed in the smooth endo-
Acyl-S-CoA
plasmic reticulum of the enterocyte. The complex lipid
molecules aggregate together to form droplets within the Diacylglycerol acyltransferase
CoASH

Triacylglycerol
B
FA, MG, LPL,
Chol, Vits A, D, E, K Micelle

2-Monoacylglycerol + 2 acyl-S-CoA

FA, MG, LPL, Monoacylglycerol acyltransferase

Unstirred layer
Chol, Vits A, D, E, K
Triacylglycerol + CoASH
C
FA, MG, LPL,
Chol, Vits A, D, E, K

Lysophospholipid + acyl-S-CoA

TG, PL, CE, Lysophospholipid acyltransferase

Lipid droplet
Vits A, D, E, K
Phospholipid + CoASH
D
Rough EPR

Cholesterol + acyl-S-CoA
Protein
Cholesterol acyltransferase
Chylomicron

Cholesterol ester + CoASH

E

Fig. 8.19  Synthesis of complex lipids in the small intestine.

Lymphatics
(A) Formation of acetyl-S-CoA. (B) Synthesis of triacylglycerol via the
Fig. 8.18  Transport of lipids in the enterocyte. MG, monoacylglycerol; -glycerol phosphate pathway. (C) Synthesis of triacylglycerol via
LPL, lysophospholipid; TG, triacylglycerol; PL, phospholipid; FA, fatty the monoacylglycerol pathway. (D) Synthesis of phospholipid from
acids; Chol, cholesterol; Vits, vitamins. lysophospholipid. (E) Synthesis of cholesterol ester from cholesterol.

150 SYSTEMS OF THE BODY

 8
cell. The phospholipids form at the surface of the drop- Box 8.7  Defects in fat digestion and absorption

Digestion and absorption

lets, with their polar heads oriented towards the exterior
of the droplets. The droplets become surrounded with Disease of various organs can lead to fat malabsorption and
rough endoplasmic reticulum and the ribosomes synthe- steatorrhoea. This a reflection of the complexity of fat diges-
size a -lipoprotein, which, together with the phospho­ tion and absorption. Some of these diseases are described
lipid, forms a coat around the droplets (see Fig. 8.18). The below:
droplet with its protein and phospholipid coat is known
as a chylomicron. Chylomicrons vary in size from a • Liver or biliary tract disease (such as gallstone disease,
fewnm to 750 nm in diameter. The different lipids, includ- cirrhosis, see Ch. 6) can result in a deficiency of
ing the fat-soluble vitamins, are sequestered together in conjugated bile acids and HCO3 resulting in impaired
the same chylomicrons. emulsification of lipids and impaired micelle formation.
The chylomicrons are extruded from the lateral sur- Note: Some drugs, for example cholestyramine, a resin
face of the cell and taken up into the lymph in the lac­teals. used to treat diarrhoea caused by bile acids, bind bile
After a meal, the intestinal lymph becomes milky due to salts thereby preventing them from forming micelles
the presence of chylomicrons. The uptake of chylomicrons • Pancreatic disease (such as chronic pancreatitis, see Ch. 5)
into the lymph is stimulated by adrenocorticoid hormones. can result in deficiency of enzymes such as lipase, which
Defects in the process of fat digestion and absorption digest fats, and reduced HCO3, leading to malabsorption
are described in Box 8.7. Furthermore, fat malabsorption of lipids. Other pancreatic enzymes are also deficient so
and steatorrhoea are features of both coeliac disease and malabsorption of other nutrients also occurs
Crohn’s disease (see Case 8.1: 3 and Case 8.2: 3). • Intestinal disease. In coeliac disease (see Case 8.1: 1
and 2), where the villi are flattened, there is a reduced
surface area available for absorption of nutrients such
Bile acids as fats in the affected regions. In Crohn’s disease that
commonly affects the ileum, the absorption of bile
Modification of bile acids in the small intestine acids is defective and the bile acid pool is reduced. This
leads to reduced emulsification and micelle formation
Bile acids are modified by intestinal bacteria. Primary bile
and therefore reduced fat digestion and absorption
acids are converted to secondary bile acids by dehydrox-
(see Case 8.2: 3)
ylation (see Ch. 6). Therefore excessive bacterial action
• -Lipoproteinaemia is an inherited disorder where
can lead to a greater proportion of secondary bile acids
-lipoprotein synthesis in the enterocytes, and
in the bile acid pool. In addition, a portion of the bile
elsewhere, is defective. Thus, in this condition the
acids can be deconjugated by bacterial enzymes with the
synthesis of the protein coat of chylomicrons is
release of the amino acid moieties. Conjugated bile acids
inadequate and only large chylomicrons, if any, are
have lower pKa values than the unconjugated acids, and
formed, and so fat absorption is impaired
are therefore more ionized and more water soluble at the
• Lymphatic disease (obstruction by, e.g. a tumour) can
slightly alkaline pH of the intestinal chyme. As they are
lead to impaired transport of lipids from the lymph to
ionized they exist as salts with Na and other cations.
the blood
• Adrenal disease, where there is a deficiency of
adrenocorticoid hormones, can lead to impaired transport
Absorption
of lipids to the lymph as these hormones stimulate the
Bile acids are absorbed from the ileum into the por- uptake of chylomicrons into the lymph. (Fat absorption is
tal blood and transported to the liver (see Ch. 6). The depressed in adrenalectomized animals.)
absorption in the small intestine is by both active and
passive mechanisms. The active transport occurs only
in the terminal ileum, and only ionized conjugated bile
acids are absorbed by this active process. It is very effi-
cient so that normally only approximately 5% of conju- Unionized conjugated bile acids are more fat-soluble
gated bile acids reach the colon. The active transport is than the ionized (conjugated) molecules. Glycine is a weak
via a co-port carrier molecule in the brush border mem- acid and a fraction of the glycoconjugates is un­ionized
brane, which also transports Na, in a manner similar and therefore fat-soluble. A small amount of it is absorbed
to that in the hepatocyte (see Ch. 6). The driving force passively through the lipid membrane. Taurine conjugates
for the transport across the brush border is the electro- are almost completely ionized at the pH of the small intes-
chemical gradient created by the pumping of Na out of tine and are therefore not absorbed in this way. Excessive
the cell. The process whereby bile acids are transported deconjugation of conjugated bile acids by intestinal bac-
out of the enterocyte has not yet been characterized. In teria leads to decreased absorption and a greater loss to
Crohn’s disease, bile acid absorption via the active trans- the colon with a resulting decrease in the size of the bile
port mechanism is usually impaired because the terminal acid pool. However, unconjugated bile acids are more
ileum is damaged. This leads to fat malabsorption and fat-soluble than conjugated bile acids and a proportion is
steatorrhoea (see Case 8.2: 3). absorbed by passive transport in the intestines.

THE digestive SYSTEM 151

8
Bile pigments Fat malabsorption
Digestion and absorption

Bile pigments are lipid substances with limited solu-

bility in aqueous solution. Unconjugated bilirubin is Fat digestion and absorption is a very complicated pro­
more lipid soluble than conjugated bilirubin, and it can cess necessitating the proper functioning of many organs
be absorbed by diffusion across the lipid membrane of including the liver, the pancreas and the small intestine.
the enterocyte. Bacterial action in the intestines decon- For this reason many different defects of digestion and
jugates some of the conjugated bile pigments, with the absorption can result in malabsorption of fats and steator-
result that some bile pigment is reabsorbed into the por- rhoea. Some of these defects and the diseases responsible
tal blood. The metabolism of bile pigments by bacteria are described in Box 8.7. Diseases where fat malabsorp-
and their absorption via the enterohepatic circulation is tion is a prominent feature include coeliac disease (see
described in Chapter 6. Case 8.1: 3) and Crohn’s disease (see Case 8.2: 3).

152 SYSTEMS OF THE BODY

 9
The absorptive and
post-absorptive
states

Chapter objectives
After studying this chapter you should be able to:

1. Understand how nutrients are utilized during the absorptive state to

provide energy, and how energy is provided when nutrients are not
being absorbed.

2. Consider how the absorptive and post-absorptive patterns of

metabolism are controlled by hormones, and how this control is
impaired in diabetes mellitus.
9
energy between meals or during fasting: a pattern of
The absorptive and post-absorptive states

Introduction energy metabolism known as the post-absorptive state.

The change from the absorptive state pattern to the post-
The nutrient state of the blood depends on whether or absorptive state pattern is brought about by changes in
not a meal is being processed in the gastrointestinal the blood concentrations of insulin and other hormones.
tract. When nutrients such as glucose and lipid are being The importance of maintaining the appropriate patterns
absorbed, and their concentrations in the blood are high, of metabolism can be illustrated by considering the meta-
the pattern of energy metabolism is known as the absorp- bolic defects present in insulin-dependent diabetes melli-
tive state. In this state, a fraction of the blood glucose is tus (IDDM, or type I diabetes), in which the secretion of
used by various tissues to meet their immediate energy insulin is severely impaired. In this chapter we shall con-
needs. The excess glucose and the absorbed lipid are sider the metabolic abnormalities present in this condition,
stored as glycogen and lipid that can be used to ­ provide and the consequences of these defects (Case 9.1: 1 and 2).

Case
9.1 Insulin-dependent diabetes mellitus: 1

A 12-year-old girl was taken to see her doctor. Her parents After considering the details of this case we can address the
were worried because she seemed listless and was losing following questions:
weight. They said she also seemed to be drinking a lot and
l Why is this patient likely to be suffering from
was frequently having to pass urine. The doctor noticed that
insulin-dependent diabetes mellitus (IDDM) rather than
her breathing was rapid and shallow (Kussmaul breathing),
non-insulin-dependent diabetes mellitus (NIDDM)?
and that it smelled of acetone. The patient provided a sam-
What are the basic defects in each condition? Would the
ple of urine. Clinistix tests on the urine sample indicated the
concentration of plasma insulin be low in both conditions?
presence of glucose and ketones. An appointment was made What is the explanation for the listlessness in this patient?
for her to attend a diabetes clinic. She was told to fast from l How is the control of blood glucose changed in diabetes
the evening before the appointment. A blood sample was mellitus?
taken and the blood glucose concentration was found to be l Why did the patient’s breath smell of acetone? Why was

(11.1 mmol/L). This is above the normal range (3.5–7.0 mmol/L), her acid–base status changed? Why was her breathing
indicating the presence of hyperglycaemia (high blood glu- abnormal (rapid and shallow)? How would the body
cose). Hypoinsulinaemia (low plasma insulin) and ketoacidosis normally compensate for the acidosis?
(high levels of ketone bodies in the blood) were also noted. l What are the mechanisms responsible for the high urine

The results confirmed that the patient was diabetic. She was output (polyuria), glucosuria and ketonuria, in this patient?
later taught how to inject herself with insulin, which had to l Are hormones other than insulin also affected in diabetes

be done three times a day, before meals. mellitus?

Case
9.1 Insulin-dependent diabetes mellitus: 2

Defect and cause

The patient was likely to be suffering from IDDM. This con- usually a feature of NIDDM. The presence of ketones on the
dition affects mostly young people, the commonest age of breath would therefore also support a diagnosis of IDDM.
onset being between 10 and 14 years, whereas NIDDM usu- IDDM affects both sexes equally, but there is a slightly
ally affects people in middle or later life. Hyperglycaemia earlier peak in age of onset in girls than boys. It is more preva-
is a characteristic of both conditions. In IDDM, it is due to lent in Caucasians than non-Caucasians, and more prevalent in
reduced secretion of insulin as a result of necrosis of the pan- people living in the Northern hemisphere than the Southern
creatic -cells. In NIDDM, destruction of many -cells eventu- hemisphere. There is a higher incidence of first diagnoses
ally occurs, but plasma insulin concentrations are not usually in winter than summer. The frequency of the disease has been
low until later in the disease (see Box 9.2). It is sometimes increasing during the last 60 years. This is probably in part
referred to as ‘insulin-resistant diabetes’ for this reason. In the due to dietary factors and increased obesity. Only approxi-
patient described above, the insulin concentration was low. mately 15% of diabetic patients suffer from IDDM (0.3 % of
The extent of the metabolic disturbance is usually less severe the population). The majority of diabetics suffer from NIDDM,
in NIDDM than in IDDM, and ketoacidosis (see below) is not although other rare forms of diabetes exist.

154 SYSTEMS OF THE BODY

 9

The absorptive and post-absorptive states

Case
9.1 Insulin-dependent diabetes mellitus: 2 (continued)

There is evidence for a genetic predisposition, particularly The aetiology of IDDM is largely unknown, although in some
to IDDM. In identical twins, there is a 30–50% concordance cases it may be due to a viral infection. Viruses that have been
for IDDM. The HLA genes on chromosome 6 are associated implicated are Coxsackie B virus, mumps and rubella. Evidence
with the condition, and a number of rare predisposing has also been reported, which implicates environmental toxins.
genetic mutations have recently been identified. However, (It has been known for many years that alloxan and strepto-
other factors are important (see below). zotocin can cause -cell necrosis and diabetes in rodents.) One
IDDM is an immune-mediated disease. Circulating anti- candidate is nitrosamines, found in some smoked foods, which
have been shown to be toxic to pancreatic -cells in animals.
bodies to cytoplasmic proteins of the -cell are present in
Bovine serum albumin present in cow’s milk has also been
most patients, although these particular antibodies may
implicated; antibodies to this protein are more common in the
be a secondary phenomenon as they disappear early in
blood of diabetic than non-diabetic patients, and they cross-
the disease. Evidence for a more direct involvement of
react with a peptide known as p69, which is often present on
­antigens that react with intracellular enzyme proteins, such
the surface of -cells during infectious episodes.
as glutamic acid decarboxylase and tyrosine phosphatase is Apart from the symptoms mentioned in the patient above
emerging. There is also strong evidence for defects in cell- (listlessness, weight loss, polyuria, polydipsia, Kussmaul
­mediated immunity in IDDM. Studies in first-degree relatives breathing), vomiting and abdominal discomfort, mental con-
of children with IDDM, who have a higher than normal risk fusion and coma, and tachycardia and hypertension can also
of developing the disease, have demonstrated islet antibod- be present. Secondary complications in IDDM are neuropathy
ies in the circulation in the first few years of life, i.e. years (sensory and motor), retinopathy, nephropathy, and cardio-
before diagnosis, and this could also prove to be a useful vascular defects such as ischaemic heart disease, cerebrovas-
tool in predicting the disease. cular disease, peripheral vascular disease and renal failure.

Liver Adipose tissue

The absorptive state
Energy Glycogen TAG TAG
In the absorptive state, the nutrients entering the blood
from the gastrointestinal tract are hexose sugars and amino
acids. The liver is the first port of call for these absorbed Keto acids Glycerol FFA
nutrients. It takes up a large fraction of the nutrients,
thereby altering the composition of the blood before it cir-
culates to the rest of the body. The nutrients remaining in Amino acids Glucose Glucose
the blood are taken up by adipose tissue, muscle and other
tissues. Lipids are absorbed from the small intestines into
the lymph as components of chylomicrons (ch. 8). They
enter the venous blood at the thoracic duct, and are then
metabolized and stored in adipose tissue.
AMINO ACIDS GLUCOSE TAG Blood

Fate of absorbed carbohydrate

Absorbed carbohydrate consists of glucose, galactose and

Amino acids Glucose Glucose
fructose. However, the liver converts fructose and galac-
tose to glucose and then releases glucose into the blood.
It is expedient therefore, to consider absorbed carbohy-
drate as glucose. Figure 9.1 illustrates the various fates of Protein Glycogen Energy
glucose during the absorptive state.
Muscle Other tissues
A large fraction of the absorbed glucose enters the
various cells of the body, where it is used for the produc- Fig. 9.1  Energy metabolism in the absorptive state. TAG, triacylglycerol;
tion of energy. During the absorptive state, glucose is the FFA, free fatty acids.
main fuel for most tissues of the body, which utilize it by
glycolysis, the citric acid cycle and other pathways. The
rest of the absorbed glucose is used to provide stores of Some of the glucose taken up by the liver is converted
energy for later use during the post-absorptive (fasting) to glycogen that is then stored in the liver, and some is
state (see below). The tissues that store most of the body’s converted to triacylglycerol. The glucose provides both
energy are liver, adipose tissue and muscle. Glucose is the glycerol and the fatty acid moieties of triacylgly­
taken up by all of these tissues in the absorptive state. cerol. Some of the triacylglycerol synthesized in the liver

THE digestive SYSTEM 155

9
is stored there, but most is released into the blood as a Box 9.1  Glycogen storage disorders
The absorptive and post-absorptive states

component of very low density lipoproteins. Very little

glucose and fat is utilized for energy in the liver itself. Most glycogen storage diseases are autosomal recessive dis-
(The liver’s main source of energy in the absorptive state orders. They are caused by enzyme defects that lead either to
is amino acids, see below.) accumulation of glycogen, or to an abnormality in the struc-
Another fraction of the blood glucose enters skeletal ture of glycogen. Glycogen is synthesized in liver or muscle.
muscle where it is converted to glycogen for storage in Some defects are restricted to liver and some to muscle.
the muscle. A further fraction enters adipose tissue, where
it is converted to fatty acids and -glycerol-phosphate, Defects in liver enzymes
which are used in the synthesis of triacylglycerol. The - • Phosphorylase or phosphorylase kinase (see fig. 9.9). A
glycerol-phosphate pathway for triacylglycerol synthesis defect in either of these enzymes leads to hepatomegaly
is outlined in Chapter 8. and hypoglycaemia; the prognosis is good
In summary, during the absorptive phase, glucose is • Phosphorylase 6 kinase. The defect leads to
used for energy production by most tissues of the body, hepatomegaly, hypoglycaemia and fatiguability
and the excess is stored in muscle and liver as glycogen, • Debranching enzyme. The defect leads to an abnormal
and in adipose tissue as fat. These relationships are out- structure of liver and muscle glycogen. The clinical
lined in Figure 9.1. features are similar to those for glucose-6-phosphatase
Various inherited disorders of carbohydrate metabo- deficiency (see below)
lism have been characterized, where either glycogen stor- • Branching enzyme. A defect in this enzyme results
age is excessive, or abnormal glycogen is produced (see in abnormal structure in liver glycogen. The clinical
Box 9.1). These conditions are due to defects in enzymes features are hepatomegaly and cirrhosis, and death in
involved in glycogen metabolism. the first 5 years of life
• Glucose 6-phosphatase (Von Gierke’s disease, see fig.
9.8). In this disease, the defect leads to hepatomegaly
(enlarged liver), ketototic hypoglycaemia, stunted
Fate of blood triacylglycerol growth, obesity and hypotonia. Liver, intestine and
kidney are affected. There is a high mortality rate.
Absorbed triacylglycerol is carried in the lymph as drop- Defects in muscle enzymes
lets partially coated with protein, known as chylomicrons
• Phosphorylase (McArdle’s disease). The symptoms are
(see Ch. 8). The triacylglycerol synthesized from glucose
muscle cramps and myoglobinuria after exercise. The
in the liver is released to circulate in the blood, but as com-
life-span is normal
ponents of very low density lipoproteins. The blood enters
• Phosphofructokinase (see fig. 9.8). The clinical features
the adipose tissue where the lipids present in both very
are similar to those seen in phosphorylase deficiency
low density lipoproteins and chylomicrons, are hydro-
(see above)
lysed to fatty acids and glycerol by a lipoprotein lipase
• Lysosomal acid -glucosidase. A defect in this enzyme
present in the endothelial surfaces of the capillaries. Most
leads to cardiomyopathy and heart failure, and
of the fatty acids produced are taken up into the adipose
death in infancy. Liver, muscle and heart tissues are
cells (adipocytes) by passive diffusion, although a small
affected.
fraction circulates to other tissues. The glycerol produced
is either taken up by the adipose tissue cells or transported
to other tissues. In adipocytes, the fatty acids and glycerol
are reconstituted to triacylglycerol via the -glycerol phos- Fate of absorbed amino acids
phate pathway (see Ch. 8), and stored in the cells. Thus,
during the absorptive state, triacylglycerol in adipose tis- In the absorptive state, a fraction of the absorbed amino
sue arises from three sources; absorbed glucose, very low acids is taken up by the liver (Fig. 9.1) and converted to
density lipoproteins released from the liver, and dietary ketoacids that are oxidized via the citric acid cycle and
triacylglycerol present in chylomicrons. These relation- other pathways. Ketoacids are the liver’s main source of
ships are summarized in Figure 9.1. energy in the absorptive state. Excess ketoacids can be
Adipose tissue is abundant in the body, and widely converted to triacylglycerol in the liver. The conversion
distributed in subcutaneous, perirenal, mesenteric and of amino acids to ketoacids involves deamination, with
other regions. An adipocyte contains a small amount of the formation of ammonia that is converted to urea in the
cytoplasm, which surrounds a large lipid droplet. There liver. The urea is released from the liver into the blood,
is very little water present in adipose cells. Lipid has a and subsequently secreted by the kidneys.
very low density. It provides a very efficient storage form Amino acids that are not taken up by the liver enter
of energy; 1 g of triacylglycerol contains more than twice other tissues, such as muscle, where they are utilized
as many calories as 1 g of glycogen or protein. Moreover, for protein synthesis. Muscle is quantitatively the most
a 70 kg man has approximately 15 kg triacylglycerol that important tissue in this respect. Protein is not a particu-
provides 135 000 kcal of energy, but only approximately larly labile source of energy, but it is broken down and
0.2 kg of glycogen, providing only 800 kcal of energy. used for energy during prolonged fasting.

156 SYSTEMS OF THE BODY

 9
C-peptide C-peptide

The absorptive and post-absorptive states

Insulin

Insulin has a central role in the control of metabolism. If Proteolysis

S S α-chain S S α-chain
it is injected, the absorptive state is duplicated, and if its
plasma concentration is very low, as in untreated IDDM, S S S S
the pattern of metabolism that predominates is an exag- S S S S
gerated version of that seen in the post-­absorptive state.
Insulin is a polypeptide (MW 6000), consisting of two β-chain β-chain
peptide chains that are connected together by two disul- Insulin Insulin
phide bridges (Fig. 9.2). The prohormone precursor of
insulin is a single peptide chain (MW 9000) known as Insulin prohormone
proinsulin, which is converted to insulin by proteolytic Fig. 9.2  Proteolytic processing of the insulin prohormone to insulin
cleavage. This results in the removal of a peptide, known and C-peptide.
as C peptide. In the prohormone, C-peptide connects the
two peptide chains of insulin (Fig. 9.2). Both insulin and
the C peptide are stored in granules in the -cells of the
pancreas. C peptide is secreted with insulin in a ratio of Plasma Insulin Glucose
1:1, but C peptide, unlike insulin that is removed from glucose secretion uptake into
the blood by the liver, is excreted in the urine. Its concen- increases stimulated cells
tration in the urine can be used to assess an individual’s
ability to secrete insulin. It has no established biological
function.
The release of insulin into the blood is stimulated by Stimulus
Plasma Plasma
eating and inhibited by fasting, and insulin is largely for insulin
insulin glucose
responsible for promoting the pattern of metabolism seen secretion
decreases falls
in the absorptive state. High levels of glucose and amino removed
acids in the blood (as when a meal is being processed) are Fig. 9.3  Feedback control of insulin release.
the primary stimuli for insulin secretion. The hormone
acts on most tissues of the body, but muscle, adipose
tissue and liver are quantitatively the most important. uptake and intracellular metabolism of glucose in the
However, some tissues, such as brain and erythrocytes, -cells. Glucose is transported into these cells via the
which are obligatory utilizers of glucose for fuel, are not GLUT2 transporter. The enzyme glucokinase which
sensitive to insulin. catalyses glucose 6 phosphate formation from glucose,
the rate-limiting step in glycolysis (see Fig. 9.8), is a key
Control of insulin secretion mediator in the -cells. However 3-carbon compounds
such as glyceraldehyde, which are intermediates formed
Insulin is a protein hormone secreted by the islets of downstream from glucose-6-phosphate in the glycolytic
Langerhans in the pancreas. It is released by exocytosis pathway, are potent stimulators of insulin release. The
in response to raised intracellular Ca2 concentrations. secretory mechanism depends on the generation of ATP
The second messengers involved include cAMP, but intra­ via glucose metabolism. ATP closes an ATP-sensitive K
cellular inositol trisphosphate, and diacylglycerol, which channel, and this results in depolarization of the cell,
activates protein kinase C, are also increased. The release causing a voltage-dependent Ca2 influx. Elevated intra-
of insulin from the pancreas is controlled to a large extent cellular Ca2 then causes insulin exocytosis.
by the concentration of glucose and amino acids in the Insulin lowers blood glucose by promoting its uptake
blood perfusing the pancreas. Other factors, such as hor- into cells (see below). Thus as the concentration of insulin
mones and neurotransmitters, potentiate or inhibit the in the blood rises, the concentration of glucose falls and
effects of the blood nutrients on insulin secretion. the stimulus for insulin secretion is removed. As a con-
sequence, the concentration of insulin falls. The feedback
control of insulin secretion by plasma glucose is summa-
Control by glucose rized in Figure 9.3.
The secretion of insulin in response to an increase in The concentration of plasma insulin normally paral-
blood glucose is under feedback control (Fig. 9.3). After lels the rise and fall in the levels of plasma glucose. This
a meal the blood glucose increases as it is absorbed is illustrated in Figure 9.4A that shows the results of a
from the gastrointestinal tract. This results in stimula- glucose drink in a fasting individual. Concentrations of
tion of insulin secretion from the -cells of the islets glucose above 5 mmol/L are effective in increasing insu-
of Langerhans. These cells respond to both the actual lin release. The response to an oral glucose load (glucose
glucose concentration, and the rate of change of glu- tolerance test) is used to diagnose diabetic states, where
cose concentration in the blood. The effect is due to the the fasting glucose concentration is not sufficiently raised

THE digestive SYSTEM 157

9
100
The absorptive and post-absorptive states

12.5 A Case
9.1 Insulin-dependent diabetes
80 mellitus: 3
10.0
60
7.5 Diagnosis and treatment
40 Tests that may be performed to assess the diabetic status
5.0 of an individual include plasma and urine glucose, plasma
20 insulin, and plasma and urine ketone bodies. Glucose and
ketone bodies in blood and urine can be measured by
2.5 automated colorimetric procedures and insulin by radio-
12.5 B 100 immunoassay. In untreated IDDM blood and urine glucose
concentrations are high and plasma insulin concentration is
Plasma glucose (mmol/L)

80

Plasma insulin (µU/mL)

10.0 very low, or undetectable. In severe cases, plasma and urine
ketone concentrations are high.
60
7.5
Glucose tolerance test in IDDM and NIDDM
40
The diabetic status of an individual can be assessed by an
5.0
20 oral glucose tolerance test, although this is rarely neces-
sary in IDDM because of the presence of a markedly raised
2.5 blood glucose concentration and glucosuria. For the glucose
tolerance test the patient fasts overnight and then drinks a
C 100
12.5 solution containing 75 g of glucose in 250–300 mL of water.
A ‘fasting’ sample of blood is obtained immediately prior
80
10.0 to the glucose load and then further blood samples are
obtained at 30-min intervals thereafter, for 3 h. Figure 9.5
60
shows the results of such a test in a normal individual, a
7.5
40 patient with IDDM, and a patient with NIDDM. In a normal
individual the fasting plasma glucose concentration is usually
5.0
20 within the range 3.5–7.0 mmol/L. After an oral glucose load it
increases to reach a peak between 30 and 60 min and returns
2.5
to normal by 2 h. In both of the diabetic patients, the fast-
0 1 2 3 ing concentration of glucose was abnormally high, but it was
Time (h) highest in the patient with IDDM. After the glucose load, the
Fig. 9.4  Glucose (solid line) and insulin (dotted line) responses to a
carbohydrate meal in (A) a normal individual, (B) an obese individual
and (C) an individual with reactive hypoglycaemia. The shaded areas 28
show the normal range for fasting plasma glucose concentration.
24 IDDM

to give a clear diagnosis on its own (Case 9.1: 3). In obese

20
individuals there is a slower uptake of glucose into cells
Plasma glucose (mmol/L)

after a meal, and an exaggerated insulin response to the

increase in plasma glucose (Fig. 9.4B). The plasma insu- 16
lin concentration rises to a higher level than in people of
normal weight. 12
Renal threshold
The glucose tolerance test may also be used to diag-
nose hypoglycaemic states. After a high carbohydrate 8 NIDDM
meal, the concentration of plasma glucose may rise rap- Normal
idly. This causes a rapid secretion of insulin from the - 4
cells, with an earlier and higher peak than after a more
balanced meal. This results in a rapid fall in plasma glu-
0
cose to levels that may be lower than normal (hypogly- 0 1 2 3
caemia). This effect is exaggerated in some individuals, Time (h)
whose -cells produce an excessive insulin response to
Fig. 9.5  Glucose tolerance curves in a normal subject, a subject
the rise in plasma glucose. They are said to have ‘­reactive
with IDDM, and a subject with NIDDM. The renal threshold for
hypoglycaemia’ (Fig. 9.4C). Various symptoms result from glucose reabsorption in the kidney tubules and glucose excretion
hypoglycaemia, including tremor, hunger, weakness, in the urine is indicated.
uncoordinated movements, blurred vision and impaired

158 SYSTEMS OF THE BODY

 9
Liver Adipose tissue

The absorptive and post-absorptive states

Case
9.1 Insulin-dependent diabetes Energy Glycogen TAG TAG
mellitus: 3 (continued)

plasma glucose concentration increased to a very high level Keto acids Glycerol FFA
in both patients but it was highest in the patient with IDDM,
and remained higher for longer than in the patient with
NIDDM. Amino acids Glucose Glucose

Treatment of IDDM
IDDM is treated by subcutaneous injections of insulin. If
inadequate insulin is administered, the patient may become
comatose as a result of ketoacidosis, electrolyte imbalance AMINO ACIDS GLUCOSE TAG Blood
and dehydration (see Case 9.1: 5). However, an overdose
of insulin can also lead to coma due to hypoglycaemia.
Therefore the amount of insulin administered must be care-
fully adjusted to bring the blood glucose concentration back
to normal. Figure 9.4C shows the changes in plasma glucose Amino acids Glucose Glucose
following an oral glucose load in a person with reactive
hypoglycaemia, a condition in which there is hypersecretion
of insulin. The response resembles that seen in an individual Protein Glycogen Energy
who has been injected with too much insulin.
Muscle Other tissues

mental ability. Such people need to control their blood Fig. 9.6  Control of energy metabolism by insulin in the absorptive
glucose levels by limiting their intake of carbohydrates, state. The bold arrows indicate the pathways and uptake mechanisms
and eating small meals at frequent intervals. Patients who stimulated by insulin, and the arrows crossed out indicate the
pathways inhibited by insulin. TAG, triacylglycerol; FFA, free
have undergone gastrectomy can have similar symptoms
fatty acids.
due to rapid entry of food into the small intestine. (This
situation is discussed in Ch. 3.)
cholecystokinin (CCK), gastric inhibitory peptide (GIP), and
glucagon-like peptide 1 (GLP-1) may be responsible. These
Control by amino acids hormones are all secreted when a meal is being processed in
Insulin secretion is also controlled by the levels of amino the gastrointestinal tract (see Chs 4 and 5).
acids in the blood. Thus, after a high protein meal, which
results in a high level of amino acids, insulin secretion is Control by nerves
increased. The most potent amino acids in this respect are
arginine, leucine and alanine. The mechanism whereby The islets of Langerhans are innervated by both parasym-
these amino acids exert this effect first involves their trans- pathetic and sympathetic nerves. Stimulation of the vagus
port into the -cells. The anionic amino acids depolarize (parasympathetic) nerve fibres that innervate the -cells
the membrane and open voltage-gated Ca2 channels. The potentiates insulin release via acetylcholine acting on
resulting Ca2 influx then stimulates insulin secretion. muscarinic receptors. It is phospholipase C-mediated and
involves Ca2 uptake into the -cells. Stimulation of the
sympathetic nerves inhibits insulin release via noradrena-
Control by other hormones line acting on 2-adrenergic receptors on the islet -cells.
Glucagon stimulates insulin release and somatosta-
tin inhibits it. Glucagon is produced by the -cells and Actions of insulin in the absorptive state
somatostatin by the D cells in the pancreas (see Ch. 5).
The actions of these hormones on insulin release from the The actions of insulin during the absorptive state are
pancreatic -cells may be local paracrine effects, or they indicated in Figure 9.6. It acts on membrane receptors in
may act locally via the blood in the islet capillaries. many cells to promote the uptake of glucose, amino acids,
Oral administration of glucose causes a greater increase K, Mg2 and PO43. In addition it stimulates or inhibits
in blood insulin levels than the same glucose load injected rate-limiting steps in many pathways involved in energy
into the blood. The mere presence of food in the gastroin- metabolism. It directly stimulates the entry of glucose into
testinal tract elicits an increase in insulin secretion (known muscle and adipose tissue, but not liver. This is a primary
as the ‘incretin effect’). This indicates that insulin secretion action of insulin. However, an increase in intracellular
is controlled by factors originating in the gastrointesti- glucose speeds up the reactions in which it is utilized, via
nal tract (the enteroinsular axis). The duodenal hormones the mass action effect due to the increased supply of the

THE digestive SYSTEM 159

9
reactant. These are secondary effects of insulin. Thus glu- - and two -subunits. The -subunit is situated on the
The absorptive and post-absorptive states

cose oxidation, and lipid and glycogen synthesis are all extracellular face of the membrane. Insulin binds to a site
stimulated in insulin-sensitive tissues when blood insulin on the -subunit. The -subunit spans the membrane,
concentration increases because more glucose enters the but most of it comprises a tail on the intracellular face.
cells. Each -subunit is bound to a -subunit by a disulphide
In addition to the secondary effects of insulin on bridge, and the two -dimers are joined extracellularly
metabolism, it also exerts primary effects on metabolism through the -subunit by another disulphide bridge.
by directly stimulating rate-limiting reactions in a vari- The receptor is a tyrosine kinase enzyme. When it is not
ety of pathways. It stimulates key reactions involved in bound to insulin, it is enzymatically inactive, but when it
the utilization of glucose for energy production via the combines with insulin, a conformational change occurs,
citric acid cycle, and in its utilization for the synthesis of which results in the exposure of three intracellular phos-
glycogen and triacylglycerol. At the same time it inhibits phorylation sites on the -subunit tail. These sites can
glycogenolysis, gluconeogenesis and lipolysis. be autophosphorylated, using ATP as the substrate, and
Insulin also directly stimulates the uptake of amino this results in activation of the enzyme. The phosphory­
acids into muscle and other tissues. This results in lated receptor kinase can then activate tyrosine resi-
increased synthesis of protein by a mass action effect. In dues on various intracellular proteins, known as insulin
addition it directly inhibits the breakdown of protein. receptor substrate (IRS) proteins. When these proteins
The overall effect of insulin in the absorptive state is to become phosphorylated they in turn phosphorylate a
provide glucose for utilization as energy, to promote the number of intracellular kinases and phosphatases. These
storage of excess carbohydrate and fat in forms (which activated enzymes then stimulate glucose and amino
can be used later to provide calories in the post-­absorptive acid uptake, and a number of rate-limiting reactions in
state and to increase protein synthesis (Fig. 9.6). various metabolic pathways. These actions determine
the net direction of those pathways. However, activation
of the receptor also suppresses the levels of intracellu-
The insulin receptor lar cAMP, which results in suppression of various cata-
Insulin binds to a receptor in the cell membrane of bolic processes as well as gluconeogenesis (see below).
­insulin-responsive tissues. The receptor is a transmem- The nature of all the post-receptor events stimulated by
brane glycoprotein with both extracellular and cytoplas- insulin has not been fully elucidated. After activation of
mic faces. Figure 9.7 shows the effects of activation of the receptor, it is endocytosed, and either degraded, or
the receptor by insulin. It is a tetramer composed of two recycled.

S S

S S
Insulin
S S

Receptor PO43-
K+
Cell α S S α
Glucose Amino acids Mg2+
membrane
S S S S

GLUT Transporter β β Tr A Transporter Channels

4

Tyrosine kinases

GLUT
Glucose Phosphorylation Amino acids PO43-
4
K+
Mg2+
Insulin receptor
substrates Membrane signals

Phosphorylation Dephosphorylation (↓ cAMP)

Metabolism Metabolic Metabolic enzymes

Phosphorylation enzymes (catabolic)

Fig. 9.7  The effects of activation of its receptor by insulin. GLUT4, hormone-sensitive GLUT4 glucose transporter; Tr A, amino acid transporter A.

160 SYSTEMS OF THE BODY

 9
Glucose entry into cells Inhibition of glycogenolysis, lipolysis and

The absorptive and post-absorptive states

Basal glucose uptake in muscle and adipose tissue is via gluconeogenesis
the GLUT1 transporter. However, facilitated glucose Insulin suppresses the mobilization of body energy stores.
transport involves GLUT4, which is an insulin-sensitive It inhibits glycogen and triacylglycerol breakdown and
transporter. This transporter is bound to endosomes gluconeogenesis by decreasing the level of intracellular
in the cytosol, and it cycles between the cytosol and the cAMP. cAMP is a second messenger which activates an
cell membrane (Fig. 9.7). When insulin concentration in intracellular cascade, which leads to phosphorylation of
the blood is low, most of the transporters reside in the enzymes involved in key steps in the catabolic pathways.
cytosol, bound to the endosomes. Activation by insulin of Figures 9.9 and 9.10 outline the intracellular cascades
its receptor stimulates the translocation of the transport- involved in glycogenolysis and lipolysis. cAMP phos­
ers from the cytosol into the membrane. This event may phorylates a protein kinase which then phosphorylates
involve the formation of phosphatidylinositol phosphates critical enzymes involved in these pathways. Thus, lower-
produced by the action of phosphatidylinositol-3-kinase, ing the levels of cAMP by insulin, causes a reduction in the
one of the enzymes that are activated by the receptor
tyrosine kinase. In addition insulin increases the synthesis
of the GLUT4 transporter, and possibly also its activity. At
low insulin concentrations, glucose transport is the rate-
limiting step in the utilization of glucose. After a meal, Glucose
when high concentrations of insulin are present, glu-
cose transport into cells can be stimulated up to 20-fold. Glucokinase Glucose-6-phosphatase
Reactions in the intracellular metabolic pathways then
become rate-limiting for the utilization of glucose.
Glucose-6-P

Glycolysis
Insulin increases the utilization of glucose via glycolysis
by increasing the synthesis of a number of the enzymes
involved (Fig. 9.8). It increases the synthesis of liver glu- Fructose-6-P
cokinase, phosphofructokinase and pyruvate kinase,
enzymes which catalyse key steps in the pathway. In addi- Phosphofructokinase Fructose-1, 6-biphosphatase
tion it inhibits the synthesis of glucose-6-phosphatase
and fructose-1,6-bisphosphatase which catalyse reactions
which oppose the utilization of glucose via glycolysis. Fructose-1, 6-diP

Glycogen synthesis
An increase in glucose in cells stimulates glycogen syn-
thesis by a mass action effect, but insulin also stimulates Phosphoenolpyruvate
glycogen synthesis directly, by stimulating the activity of
glycogen synthase, the rate-determining enzyme of the
Pyruvate kinase
pathway. In addition, insulin promotes the synthesis of
glucokinase in liver (but not muscle), which catalyses
the formation of glucose-6, phosphate (see above). These Pyruvate
actions enable more glucose to enter the glycogenic path-
way in liver. In addition insulin inhibits hepatic glu- Pyruvate dehydrogenase
cose-6-phosphatase thereby inhibiting the release of free
glucose into the blood.
AcetylCoA

Triacylglycerol synthesis
Figure 9.6 indicates the effect of insulin on the synthesis CAC
of triacylglycerol from glucose in adipose tissue. It stimu-
lates fatty acid synthesis from glucose by activating sev-
eral of the enzymes involved in the pathway, including
pyruvate dehydrogenase which catalyses the conversion CO2 + H2O
of pyruvate to acetyl CoA in the mitochondrion. Acetyl
CoA is then directed to fatty acid synthesis, because Fig. 9.8  Control of glycolysis by insulin. The bold arrows indicate the
insulin activates acetyl CoA carboxylase that diverts the enzymes whose synthesis is stimulated by insulin, and the crossed
acetyl CoA to the synthesis of fatty acid in the cytosol. arrows indicate those whose synthesis is inhibited by insulin.

THE digestive SYSTEM 161

9
A Glycogenolysis A Lipolysis
The absorptive and post-absorptive states

Triacylglycerol
Glycogen (n) + Pi

Lipase (hormone-sensitive)
Glycogen phosphorylase a
Diacylglycerol + FFA

Glycogen (n-1) + glucose-1-P

Lipase

B Activation of glycogen phosphorylase Monoacylglycerol + FFA

Lipase
ATP
Glycerol + FFA
Adenylcyclase HORMONES
B Activation of hormone-sensitive lipase

cAMP + PPi
ATP

Adenyl cyclase HORMONES

Inactive cAMP-dependent kinase

cyclic-AMP + P-P

cAMP

Active cAMP-dependent kinase Inactive cAMP-dependent kinase

cAMP

Active cAMP-dependent kinase

Inactive phosphorylase kinase

cAMP-dependent kinase, ATP

Inactive lipase kinase

Active phosphorylase kinase cAMP-dependent kinase

Active lipase kinase

Glycogen phosphorylase b
(inactive)
Inactive triacylglycerol lipase
Phosphorylase kinase

Lipase kinase
Glycogen phosphorylase a
(active)
Active triacylglycerol kinase
Fig. 9.9  Control of glycogenolysis by hormones. The number of
glucose residues in glycogen is denoted by ‘n’. In the absorptive state Fig. 9.10  Control of lipolysis by hormones. In the absorptive state
the formation of cAMP (bold arrows) is inhibited by insulin. In the the formation of cAMP (bold arrows) is inhibited by insulin. In the
post-absorptive state it is stimulated by adrenaline, glucagon, growth post-absorptive state it is stimulated by adrenaline, glucagon, growth
hormone, and cortisol. hormone, and cortisol.

162 SYSTEMS OF THE BODY

 9
activity of the protein kinase, and this leads to decreased starvation, when the blood glucose falls slowly, the nerv-

The absorptive and post-absorptive states

activity of these key enzymes and suppression of the met- ous system is able to adapt after a few days to use ketones
abolic pathway. Insulin decreases cAMP via activation of as a source of energy (see Case 9.2: 1 and 2). In IDDM
a membrane-associated phosphodiesterase that hydro- where insulin is deficient (see Case 9.1: 4) and in NIDDM
lyses it to 5AMP. where the tissues are insensitive to insulin (see Box 9.2),
the metabolic state resembles the post-absorptive state.
Amino acid transport and protein synthesis
Insulin facilitates the uptake of amino acids into cells via Glucose-supplying reactions
the amino acid transporter A, a sodium-dependent car-
rier that transports neutral amino acids and imino acids. The reactions that supply glucose to the blood during
Insulin controls the synthesis of mRNA for many spe- the post-absorptive state are outlined in Figure 9.12.
cific proteins, increasing some and suppressing others. During the post-absorptive state, glycogen stored in the
It stimulates the synthesis of mRNA for certain enzymes liver is broken down to glucose, which is liberated into
involved in glycolysis and represses the synthesis of the blood. Muscle glycogen is also broken down in the
mRNA for others that are involved in gluconeogenesis. It absorptive state, but muscle lacks glucose-6-phosphatase
also stimulates DNA synthesis, cell division and cell dif- (the enzyme which converts glucose 6 phosphate to free
ferentiation. The mechanisms involved in these actions of glucose), and so in muscle glucose-6-phosphate is broken
insulin are not fully understood. down to lactate and pyruvate, which are released into
the blood. These metabolites are taken up by the liver
and then converted to glucose (via gluconeogenesis, see
Insulin sensitivity below), which is liberated into the blood. The stores of
glycogen in liver and muscle can amount to 600–800 g in
The magnitude of the effects produced by insulin depends the post-absorptive state. This source of glucose is suffi-
not only on its concentration in the plasma, but also on the cient to meet the energy needs of the body for approxi-
sensitivity of the tissues to it. The responsiveness of tis- mately only 4 h.
sues to insulin varies even in normal individuals. Thus, In any prolonged period of fasting, the stored glycogen
for example, habitual exercise increases tissue sensitivity is used up and gluconeogenesis becomes the more impor-
to insulin. It is pertinent to note here, however, that glu- tant process for generating glucose and maintaining the
cose is taken up into muscle during acute exercise by an plasma glucose concentration. Lactate provides one sub-
insulin-independent mechanism, which has not yet been strate for gluconeogenesis, but in prolonged fasting, amino
elucidated, although it may partly depend on the increase acids derived from protein in muscle, and taken up by the
in plasma -endorphin that occurs during exercise as this
peptide stimulates glucose uptake in muscle.
Insulin sensitivity is decreased in obese individuals, Case
leading to abnormally slow uptake of glucose into tis- 9.2 Starvation: 1
sues after a meal (Fig. 9.4B). Relatively high amounts of
insulin are secreted in response to the resulting elevated
A round-the-world yachtsman was blown off course and
plasma glucose. The elevated insulin tends to maintain
his boat sank. He managed to get into the yacht’s dinghy
the fasting concentration of plasma glucose within the
and to retrieve a large container of drinking water from
normal range. The mechanisms underlying changes in
the boat. After 7 weeks without food, he was rescued by
insulin sensitivity in obesity are not clear.
a passing liner. His water supply had lasted out, but he was
weak and emaciated.
Consideration of this case history provokes the following
Post-absorptive state questions:

Some tissues, such as brain and erythrocytes, can only sur- l Which metabolic processes would have been occurring
vive if glucose is delivered to them for fuel. They cannot to enable this man to maintain his plasma glucose
initially utilize other nutrients to any significant extent. levels? Would his plasma insulin levels be normal?
Lack of glucose causes brain damage, coma and death l Would the man’s acid–base status be disturbed? Would
within minutes. During the post-absorptive state when he be excreting glucose and ketone bodies in his urine?
glucose is not being absorbed from the gastrointestinal Is it likely that acetone would be detectable on his
tract, the plasma levels of glucose are maintained within breath?
a physiological range. This is brought about in two ways. l Would the man’s plasma glucagon levels to be high or
First, glucose is generated by glycogen breakdown, glycog- low?
enolysis and gluconeogenesis. Second, many tissues can l What treatment would be recommended for the
utilize substrates other than glucose, such as fatty acids, starving yachtsman? Would it be advisable for him to
for energy provision. This spares the available glucose for drink a concentrated solution of glucose?
the tissues that are obligatory utilizers of it. However, in

THE digestive SYSTEM 163

9
The absorptive and post-absorptive states

Case
9.2 Starvation: 2

Metabolism in starvation
Plasma glucose most other tissues. Ketone bodies derived from fatty acids,
It is important that the yachtsman’s plasma glucose concen- would be utilized for energy in liver. He would be unlikely to
tration does not fall too far because the nervous system is an be excreting glucose and ketone bodies in his urine, but ace-
obligatory utilizer of glucose during the initial phase of fast- tone could probably be detected on his breath.
ing. Later, it can adapt to utilize keto acids. The man’s plasma glucagon concentration would be high
The metabolic processes that would have been occurring to initially, as low glucose stimulates glucagon secretion from
enable this man to maintain his plasma glucose concentration the pancreatic -cells. However, after a few days of fasting
are: it returns to normal. Thus in this man, the levels of glucagon
would not be elevated.
l Glycogenolysis in liver
l Glycogenolysis in muscle, which would provide glucose Acid–base status
indirectly via lactate production
The starving man would probably have a metabolic acidosis
l Gluconeogenesis in liver, which would provide glucose
due to the production of ketone bodies and fatty acids, but
from amino acids lactate and glycerol.
respiratory and renal compensation would be occurring.

The rescued man’s plasma insulin concentration would be at

the basal level, as it is largely controlled by plasma glucose con- Treatment
centration, which would have been maintained within physi- It would not be advisable for this man to drink a concentrated
ological limits. solution of glucose because it would pass too quickly into the
small intestine and cause osmotic diarrhoea, and he could
Energy provision become dehydrated. The rapid absorption of glucose could
The man’s energy provision for tissues that are not obliga- cause him to suffer from a rebound hypoglycaemia, and pos-
tory users of glucose would be mostly from stores of body sibly fainting. However, isotonic or hypotonic solutions would
fat. Fatty acids derived from triacylglycerol in adipose tissue help. He should probably drink isotonic fluid containing some
would provide a large part of the energy requirements of glucose for a while.

Case
9.1 Insulin-dependent diabetes mellitus: 4

Metabolic state
In untreated IDDM, when insulin concentrations are very low, acetyl CoA production in the liver exceeds the capacity of the
plasma glucose concentration is high because the uptake citric acid cycle to oxidize it and the excess is converted to
of glucose into muscle, adipose tissue and other tissues is ketone bodies (Fig. 9.11). These are released into the blood,
impaired, and the utilization of glucose for energy provision resulting in high concentrations of plasma ketone bodies and
and glycogen and fat synthesis, is reduced. Insulin also inhibits ketosis. Metabolic acidosis results from the high concentra-
glycogenolysis and lipolysis, so these catabolic processes occur tions of (acidic) ketone bodies and fatty acids in the blood
at an increased rate in its absence. Increased glycogenolysis plasma (see Case 9.1: 5).
in liver results in glucose release into the blood. Increased Amino acid uptake into tissues is also reduced in IDDM, due
glycogenolysis in muscles results in lactate release, which is to very low insulin levels, and protein breakdown is increased.
used by the liver for glucose production by gluconeogenesis. This results in an excessive conversion of amino acids to glu-
Increased lipolysis results in fatty acids and glycerol being cose via gluconeogenesis in the liver. Thus, the overall effect
released into the blood. The glycerol is taken up and used to of these metabolic disturbances is elevated levels of glucose,
produce glucose via gluconeogenesis. Thus these processes all ketone bodies and fatty acids in the plasma.
result in further increases in blood glucose, and exacerbate
the hyperglycaemia. Comparison with post-absorptive state
Fatty acids formed in the adipose tissue are released into The pattern of metabolism in untreated IDDM is an exaggera-
the blood and taken up by various tissues and oxidized to tion of that seen in the post-absorptive state. Insulin levels are
acetyl CoA. In IDDM, if the levels of fatty acids are excessive, low, glucose and amino acid uptake into tissues is reduced,

164 SYSTEMS OF THE BODY

 9

The absorptive and post-absorptive states

Case
9.1 Insulin-dependent diabetes mellitus: 4 (continued)

and glycogenolysis, lipolysis, gluconeogenesis and protein

breakdown increase. These events result in increases in plasma
glucose, plasma fatty acids and ketone bodies. Furthermore, in
FFA diabetes mellitus, in spite of the presence of hyperglycaemia,
there are increases in many of the hormones associated with
the post-absorptive state, including plasma catechol­amines,
glucagon, cortisol and ACTH, and sometimes growth hormone.
FFACoA Increases in secretion of these hormones accompany various
types of stress, and they are probably partly due to activation
of the sympathetic nervous system. Thus, for example, stimu-
lation of the preganglionic sympathetic nerves to the adrenal
CAC AcetylCoA Acetoacetate medulla causes the release of adrenaline into the blood, and
stimulation of the sympathetic nerves to the -cells of the pan-
creas causes release of glucagon. However, in IDDM, the pre-
dominating mechanism causing the release of these hormones
CO2 + H2O 3-hydroxybutyrate (which are normally suppressed by hyper­glycaemia) is largely
unknown.
In non-diabetic subjects, in the post-absorptive state, the
plasma glucose and ketone bodies do not normally exceed the
Ketone bodies threshold for reabsorption in the kidney, so metabolites do not
appear in the urine.

Fig. 9.11  Ketone body formation in the post-absorptive state.

The dashed arrow indicates where the build up of acetyl CoA
diverts it away from the citric acid cycle in the mitochondrion,
towards ketone body formation in the cytosol.

Box 9.2  Non-insulin-dependent diabetes mellitus

In the UK, non-insulin-dependent diabetes mellitus (NIDDM) A further serious defect in NIDDM is that tissues such as
is known to affect approximately 2% of the population, and liver, muscle and adipose develop insulin resistance. The
surveys of adults show that in at least another 2% the con- resistance involves not only glucose uptake into muscle and
dition is present, but undiagnosed. It affects more men than adipose tissue, but also the metabolic actions of insulin, such
women (ratio 3:2), and is much more prevalent in ethnic as its effects to stimulate glycogen synthesis in muscle and
minority groups, especially those originating from the Indian liver and to inhibit lipolysis in adipose tissue. In consequence,
subcontinent (typically 7%). Obesity and lack of physical exer- circulating glucose and plasma free fatty acids are increased.
cise are predisposing factors for NIDDM. Thus the incidence In most cases, insulin binds normally to its receptor but insulin
of NIDDM is increasing in the Western world, as more people signalling in the cell is attenuated. The mechanism is unknown.
are becoming obese and more are following sedentary life- In a few cases of NIDDM there is a structural abnormality of
styles. In both NIDDM and IDDM there is a predisposition to the receptor or a known intracellular protein. The metabolic
vascular disease and hypertension, high cholesterol, high very defects are similar to those seen in IDDM (see Case 9.1: 4)
low density lipoproteins (VLDL), neuropathy, retinopathy and but they are usually less severe. Thus, ketosis is not usually
nephropathy. It may be pertinent that some of these prob- present.
lems, for example hypertension, are associated with obesity
Treatment
even in non-diabetic individuals. (The differential diagnosis of
NIDDM can often be controlled if the patient follows a
NIDDM is discussed in Case 9.1: 3.)
healthy, calorie-restricted diet and a more active lifestyle.
Defects These measures increase tissue sensitivity to insulin. If they are
In NIDDM, insulin secretion is eventually impaired, although the insufficient, oral drugs are used. These include:
plasma concentration may be initially normal or even increased
in response to the hyperglycaemia. As the disease progresses, • Sulphonylureas. These drugs stimulate insulin secretion
the -cells become less responsive to increases in plasma glu- by binding to a component of the ATP-sensitive K
cose, and the -cell mass may eventually be diminished by up to channel in the -cell membrane, and directly closing
40% (whereas in IDDM these cells are completely destroyed). it. They are therefore only effective in patients with

THE digestive SYSTEM 165

9
Box 9.2  Non-insulin-dependent diabetes mellitus (continued)
The absorptive and post-absorptive states

a functioning -cell mass. A potentially serious side- output by suppressing gluconeogenesis. It does not
effect is hypoglycaemia because the action of many induce hypoglycaemia or cause weight gain
sulphonylureas can persist for over 24 h. They may also • Thiazolidinediones. These drugs promote insulin resistance
promote weight gain. Tolbutamide is a relatively short- by an unknown mechanism. They reduce hepatic glucose
acting sulphonylurea output and enhance glucose uptake into tissues
• Meglitinides. These drugs also stimulate insulin secretion • Intestinal enzyme inhibitors. Inhibitors of -glucosidase,
by closing the ATP-sensitive K channel in the -cells. such as acarbose, suppress carbohydrate absorption,
They are short-acting, and promote insulin secretion in thereby reducing the rise in blood glucose that
response to meals accompanies meal consumption. Side-effects are osmotic
• Biguanides. Metformin is a useful biguanide drug that diarrhoea and flatulence due to undigested carbohydrate
increases insulin sensitivity, and reduces hepatic glucose passing into the colon (see Ch. 7).

Liver Adipose tissue many other tissues and oxidized to CO2 and water via
the fatty acid oxidation pathway and the citric acid cycle.
Glycogen TAG In the post-absorptive state the liver takes up a por-
tion of the fatty acids from the blood. In the liver fatty
Amino acids Glycerol acids can be converted to acetyl CoA which is degraded
to CO2 and water by fatty acid oxidation and the citric
acid cycle, with the production of energy. However when
large quantities of fatty acids are being produced, as in
Lactate Glucose Glycerol FFA the post-absorptive state (or diabetes mellitus) the rate of
acetyl CoA formation can exceed the capacity of the liver
to utilize it via the citric acid cycle. The acetyl CoA is then
converted to ketone bodies (Fig. 9.13). Some of the ketone
bodies are used for energy purposes in the liver, and the
rest are liberated into the blood, taken up by other tissues
AMINO ACIDS LACTATE GLUCOSE GLYCEROL Blood
and utilized via the citric acid cycle (after conversion to
acetyl CoA). The ketone bodies are acetone, acetoacetate
and -hydroxybutyrate. The production of acetone dur-
ing the fasting state accounts for the distinctive breath
odour of fasting people and patients with IDDM (see
Amino acids Lactate Glucose
Case 9.1: 5). Thus, the liver uses ketone bodies for energy
production and ceases to use amino acids during the
post-absorptive state, thereby sparing them for gluconeo-
Protein Glycogen Energy genesis. Thus ketone body production is also a means of
supplying extrahepatic tissues with fuel during fasting.
Muscle Other tissues
Some ketone bodies are weak acids, i.e. acetoacetic acid
Fig. 9.12  Glucose-supplying reactions in the post-absorptive state. and -hydroxybutyric acid, and in pathological condi-
TAG, triacylglycerol; FFA, free fatty acids. tions such as diabetes mellitus, where there is excessive
fat utilization, excessive ketone body production can
liver, are quantitatively the most important substrate for the result in severe acidosis (see Case 9.1: 5).
generation of glucose via gluconeogenesis. Glycerol derived Thus in the post-absorptive state, fatty acids and
from triacylglycerol in adipose tissue, and taken up by the ketone bodies are provided to tissues which can utilize
liver is also converted to glucose via gluconeogenesis. them for energy during fasting, sparing the glucose for
tissues such as the nervous system, which is dependent
on it. The energy provided during the post-absorptive
Glucose-sparing reactions state by glycogenolysis and gluconeogenesis provides
about 800 kcal/day, which is the equivalent of approxi-
Most of the energy requirement of the body during the mately 180 g glucose/day. However, the average adult
post-absorptive state is derived via glucose-sparing reac- needs between 2000 and 3000 kcal/day. Thus, most
tions that utilize the energy stored as triacylglycerol dur- energy is provided by substrates other than glucose (i.e.
ing the absorptive state. Fat is broken down in adipose largely free fatty acids and ketone bodies). Most adults
tissue to glycerol and free fatty acids, which are released have enough energy stored in triacylglycerol in adipose
into the blood. The glycerol is used for gluconeogenesis tissue to supply sufficient fuel to enable them to survive
in liver (see above), but the fatty acids are taken up by without food for several weeks.

166 SYSTEMS OF THE BODY

 9

The absorptive and post-absorptive states

Case
9.1 Insulin-dependent diabetes mellitus: 5

Diabetic ketosis and fluid and electrolyte

disturbances
Diabetic ketoacidosis is the first presentation of IDDM in 20–30% Furthermore, the increased level of glucose and ketone bod-
of patients. In these individuals, insulin levels are usually below ies in the plasma causes water to pass out of the cells of the
the levels of detection. Mortality from ketoacidosis is 2–5% in body, down the osmotic gradient, into the plasma. This helps
developed countries. Ketoacidosis can be precipitated in patients to maintain the plasma volume. However, as the polyuria
with IDDM by a number of factors, including infections, neglect causes the plasma volume to become more severely decreased,
of insulin medication, and myocardial infarction, but in many renal perfusion declines. This results in further elevation of
cases the precipitating factor is unknown. plasma glucose.
Lipolysis increases in untreated IDDM. This is due to the In ketoacidosis the plasma Na concentration is usually
absence of insulin, and the presence of elevated plasma gluca- normal or low. This is partly because of the osmotic effect
gon, catecholamines, cortisol and growth hormone (see Case 9.1: of plasma glucose drawing water out of the cells, but also
4). Increased lipolysis leads to increased production of ketone because the hormone aldosterone is released from the adre-
bodies (hyperketonaemia). The consequent high plasma concen- nal cortex into the blood, in response to the reduced extracel-
trations of the keto acids, -hydroxybutyrate and acetoacetate, lular fluid volume. This hormone decreases Na excretion by
cause metabolic acidosis. The increase in plasma H ions results increasing its reabsorption in the kidney tubules, and opposes
in stimulation of the rate of breathing which partially read- the effect of decreased insulin and elevated glucagon.
justs the blood pH (see the companion volume The Respiratory Total body K also falls in diabetic ketoacidosis. Insulin nor-
System). The kidneys are also involved in compensatory adjust- mally increases K uptake into cells (see above), and when the
ments for acidosis by excreting H ions (see the companion vol- plasma concentration of insulin is low, the plasma concentra-
ume The Renal System). In untreated clinical ketoacidosis, these tion of K increases. A net loss of K from cells of the body
compensatory mechanisms are not sufficient to maintain the pH occurs in ketoacidosis as intracellular K is exchanged for
within the normal physiological range (i.e., 7.25–7.45). H from the blood, and K is consequently lost in the urine.
In ketoacidosis, ketones as well as glucose are lost in the urine Treatment of ketoacidosis involves administration of insulin,
as the threshold for reabsorption in the kidney proximal tubules fluid and electrolytes.
is exceeded. The presence of these solutes in the urine causes an The causes of some of the symptoms in individuals with
osmotic diuresis (polyuria). The increased flow of urine causes ketoacidosis are not entirely clear. The weight loss is partly due
dehydration and thirst (polydipsia), which are exacerbated by to loss of fluid in the urine, and partly to loss of muscle and adi-
increased water loss via the lungs (as a consequence of hyperven- pose tissue mass, as a consequence of increased proteolysis and
tilation). Although vasopressin (ADH), the hormone which stimu- lipolysis, respectively. The mental confusion and coma are partly
lates water reabsorption, is released from the posterior pituitary attributable to the acidosis and dehydration, but other factors
in response to the increased osmolarity of the blood and the such as cerebral hypoxia, are probably also involved. The cause
reduced blood volume, the osmotic diuretic effect prevails. of the abdominal discomfort and vomiting is unclear.

The overall effect of the hormones that control metab-

Control of the post-absorptive state
olism in the post-absorptive state is to increase plasma
levels of glucose, by inhibiting glucose uptake in tissues,
The onset of the pattern of metabolism in the post- and by stimulating glycogenolysis and gluconeogenesis.
absorptive state is due to both the decline in insulin They also stimulate processes that lead to the provision
concentration in the plasma and the increase in the con- of alternative energy substrates. Thus, they promote both
centrations of a number of other hormones. These hor- glucose-supplying reactions and glucose-sparing reac-
mones include adrenaline, glucagon, cortisol, growth tions. These effects are summarized in Figures 9.14 and
hormone, TSH and ACTH. They are all released either 9.15. Thus, the effects of this group of hormones oppose
directly or indirectly, in response to low blood glucose. the actions of insulin and facilitate the post-absorptive
When the blood glucose concentration falls, the main state. The plasma concentrations of many of these hor-
stimulus for insulin release is removed and the insulin mones are also increased in IDDM (see Case 9.1: 4).
concentration falls. Thus, the major stimulus for glucose
uptake into tissues and for synthesis of energy stores is
abolished. The inhibitory effect of insulin on glycogeno­ Release of hormones in the post-absorptive state
lysis and lipolysis is also abolished. Thus, the pattern of
metabolism occurring in the absorptive state is effectively Adrenaline is released from the adrenal medulla by activ-
suppressed. The pattern of metabolism in untreated IDDM ity in the preganglionic sympathetic nerves that inner-
resembles the post-absorptive state (see Case 9.1: 4). vate it. Sympathetic nerves are stimulated by low blood

THE digestive SYSTEM 167

9
Liver Adipose tissue Liver Adipose tissue
The absorptive and post-absorptive states

TAG TAG
Ketone bodies Ketone bodies

FFA FFA Glycerol FFA FFA Glycerol

Ketone bodies FFA Blood Ketone bodies FFA Blood

FFA Ketone bodies FFA FFA Ketone bodies FFA

Energy Energy Energy Energy

Muscle Other tissues Muscle Other tissues

Fig. 9.13  Glucose-sparing reactions in the post-absorptive state. TAG, Fig. 9.15  Effect of hormones on glucose-sparing reactions in the post-
triacylglycerol; FFA, free fatty acids absorptive state. The bold arrow indicates the stimulation of lipolysis
by adrenaline, glucagon and growth hormone in the post-absorptive
state. The effect of cortisol on lipolysis is permissive.

Liver Adipose tissue

glucose. For this reason, low blood glucose precipitates
Glycogen TAG the symptoms associated with activation of the sympa-
Amino acids Glycerol
thetic nervous system, such as an increase in anxiety lev-
els and palpitations. Many individuals experience these
symptoms in the late afternoon when the blood sugar
concentration tends to be low.
Glucagon is produced by the -cells of the islets of
Lactate Glucose Glycerol FFA Langerhans. Its release is regulated by the concentration of
plasma glucose. Low plasma glucose stimulates glucagon
release and high blood glucose inhibits it. Thus, blood glu-
cagon concentrations are high during the post-absorptive
period. The release of growth hormone from the pituitary
AMINO ACIDS LACTATE GLUCOSE GLYCEROL Blood is also stimulated by low blood glucose. This is possibly
due to activation of glucoreceptors in the hypothalamus,
which results in the release of growth hormone releasing
factor (GHRF) that, in turn, acts on the pituitary to stimu-
late the release of growth hormone. An increase in plasma
Amino acids Lactate Glucose glucose inhibits growth hormone release. Other pituitary
hormones are also secreted in response to low blood glu-
cose via an effect on the hypothalamus to cause secre-
Protein Glycogen Energy tion of releasing factors which act on the pituitary cells to
stimulate the secretion of the hormones. Thus, low blood
Muscle Other tissues glucose causes the release of corticotrophin releasing fac-
tor (CRF) from the hypothalamus. This in turn stimulates
Fig. 9.14  Effect of hormones on glucose-supplying reactions in the
the release of ACTH from the pituitary. Thus ACTH is
post-absorptive state. The bold arrows indicate the pathways that
are stimulated, and the crossed arrow indicates inhibition of glucose
increased in the blood during the post-absorptive state.
uptake by cortisol and growth hormone. In liver, glycogenolysis ACTH in turn causes the release of hormones such as cor-
is stimulated by adrenaline and glucagon and gluconeogenesis tisol from the adrenal cortex. Table 9.1 lists some of the
from amino acids is stimulated by glucagon and cortisol. In muscle hormones that are released in the post-absorptive state, in
glycogenolysis is stimulated by adrenaline. response to low blood glucose.

168 SYSTEMS OF THE BODY

 9

The absorptive and post-absorptive states

Table 9.1  Hormones secreted in the post-absorptive state Table 9.2  Control of the post-absorptive state

Hormone Origin Effect Adrenaline Glucagon Growth Cortisol

hormone
Glucagon -cells of the pancreas
Adrenaline Adrenal medulla Plasma ↑ ↑ ↑ ↑
glucose
Cortisol Adrenal cortex
Glucose ↓ ↓
Growth hormone Anterior pituitary uptake
Adrenocorticotropin (ACTH) Anterior pituitary Glyco- ↑ ↑
Thyroid stimulating hormone (TSH) Anterior pituitary genolysis
Gluco- ↑ ↑
The hormones listed are collectively responsible for the pattern
neogenesis
of energy metabolism that pertains in the post-absorptive state.
They are all secreted either directly, or indirectly, in response to Plasma FFA ↑ ↑ ↑ ↑
low blood glucose. (Lipolysis)

Effects of some of the hormones, released in the post-absorptive

state on aspects of energy metabolism, which result in either
Actions of hormones in the post-absorptive state increases in blood glucose, or the provision of energy substrates
(FFA, free fatty acids) that spare glucose for the tissues dependent
on it for their energy requirements.
Effects on glucose-supplying reactions
The effects of hormones on glucose-supplying meta-
bolic pathways in the post-absorptive state are shown
Effects on glucose-sparing reactions
in Figure 9.14. Growth hormone and cortisol inhibit the
uptake of glucose by reducing the number of GLUT4 Figure 9.15 shows the effects of hormones on glucose-
transporters in the cell membrane. For this reason, sparing metabolic pathways in the post-absorptive state.
patients with growth hormone producing tumours can Adrenaline, glucagon and growth hormone stimulate
develop diabetes. Moreover, in diabetic animals, removal lipolysis in adipose tissue, thereby increasing the free fatty
of the pituitary, which secretes growth hormone, reduces acid concentration in the plasma. Cortisol has a permis-
the severity of diabetes. sive effect on lipolysis, i.e. it has no effect by itself but it
Adrenaline and glucagon stimulate glycogen break- potentiates the effects of adrenaline, glucagon and growth
down to glucose in liver, with the liberation of glucose hormone. The sympathetic nerves to adipose tissue are
into the blood. In addition, adrenaline, but not glucagon, also stimulated by low blood glucose. These nerves release
stimulates glycogen breakdown to lactate and pyruvate, in mainly noradrenaline that, like adrenaline, increases
muscle. These products are released into the blood, taken lipolysis in adipose tissue. The effects of adrenaline and
up by the liver, and converted to glucose via gluconeogen- noradrenaline are exerted on the rate-limiting step in the
esis, and the glucose is then released into the blood. The lipolysis pathway, i.e. the hydrolysis of triacylglycerol to
action of these hormones on glycogen breakdown is via diacylglycerol and free fatty acid, which is catalysed by
stimulation of the rate-limiting step that is catalysed by the ‘hormone-sensitive’ lipase. The effect of these hor-
phosphorylase. This increases the concentration of cAMP mones involves an increase in the intracellular concen-
that activates a kinase, which in turn activates phospho- tration of cAMP that triggers an intracellular cascade of
rylase kinase, leading to activation of phosphorylase itself reactions (Fig. 9.15) similar to that seen for the activation
(Fig. 9.9). In addition, cortisol also stimulates glucose-6- of phosphorylase (see above). The subsequent hydrolysis
phosphatase resulting in increased release of glucose into of diacylglycerol to monoacylglycerol and free fatty acid,
the blood. Furthermore, glucagon and cortisol stimu- and of monoacylglycerol to glycerol and free fatty acid,
late gluconeogenesis from amino acids in liver. Cortisol by other lipases, is extremely rapid. Table 9.2 summarizes
also stimulates the breakdown of protein to amino acids the effects of hormones to control glucose-supplying and
in liver. ­glucose-sparing reactions in the post-absorptive state.

THE digestive SYSTEM 169

The colon 10
Chapter objectives
After studying this chapter you should be able to:

1. Understand the functioning of the large intestine.

2. Understand the consequences of disease of the large intestine.

10
colon and the rectum. The rectum is the portion beyond
THE COLON

Introduction
the sigmoid colon. The lumen of the colon becomes nar-
rower towards the rectum. The lumen of the rectum,
The colon is the last 150 cm or so of the gastrointestinal which is wider, provides a reservoir for faecal material,
tract. It is a tube of approximately 6 cm in diameter that prior to defecation.
extends from the ileum to the anus. Its main function is to The caecum forms a blind-ended pouch below the
store faecal material, and regulate its release into the exter- junctions of the small intestine and the large intestine.
nal environment. It also absorbs water and electrolytes from The appendix is a small finger-like projection from
the chyme, with the result that the faecal material becomes the end of the caecum. It has no known function in the
more solid as it passes through the colon. In addition it human. It has a thick wall, and a very narrow lumen that
produces a thick mucinous secretion, which lubricates the often collects debris.
passage of the faecal material through it. It also provides In the large intestine, the outer longitudinal smooth
an environment for bacteria, some of which synthesize an muscle layer is arranged in three prominent bands,
important part of the vitamin requirement of the body. known as taeniae coli. These bands are shorter than the
Disease of the colon can result in diarrhoea, or consti- other coats of the colon. There is also a segmental thicken-
pation, or both. In this chapter, Hirschsprung’s disease ing of the circular smooth muscle. Together these features
will be used to illustrate the importance of the motor impart a sacculated appearance to the organ. It has no
function of the colon. It is a condition in which there is villi (only projections). Its coat is therefore smoother than
an absence of intramural ganglion cells from the wall of that of the small intestine, and the consequence of this
the colon, usually in a distal region (Case 10.1: 1). is that the surface area of the colon is only one-thirtieth
that of the small intestine.
The anal canal is the terminal portion of the rectum. It
Anatomy begins at a region where the rectum suddenly becomes
narrower. The surface of the upper portion of the anal
The arrangement of the large intestine and its associ- canal exhibits a number of vertical folds, known as
ated structures is shown in Figure 10.1. It can be divided anal (or rectal) columns (Fig. 10.2). These folds are rela-
into various regions: the caecum, the ascending colon, tively more pronounced in children than in adults. The
the transverse colon, the descending colon, the sigmoid depressions between the anal columns are known as
anal sinuses. The sinuses end abruptly at the lower ends
of the columns (the dentate line) where there are small
Case crescent-shaped folds of mucosa oriented around the
10.1 Hirschsprung’s disease: 1

A newborn infant was observed to have a distended abdo- Left colic

Transverse
men. He had passed very little meconium in the 2 days since flexure
Taeniae colon Descending
he had been born. The doctor examined the infant’s rectum Right colic coli colon
by inserting a finger. The examination revealed that the flexure
rectum was empty. However, when the doctor withdrew
her finger, there was a gush of meconium, and decompres-
sion of the abdomen. The obstruction reoccurred within a
day or so. By this time, the child had started to vomit exces-
sively. The symptoms were relieved by an enema. A biopsy
of the rectum was performed and Hirschsprung’s disease Ascending colon
was diagnosed. An abdominal operation was arranged. Haustre
The surgeon removed the distal large bowel and sutured
Ileocaecal valve
the remaining colon to the lower rectum. The child made a
good recovery, and his symptoms disappeared.
After examining the details of this case, the following
questions arise:
Ileum
Epiploic
l Why was the infant’s abdomen distended, and why had Vermiform appendage
Caecum
he passed no meconium since he was born? appendix
l What is the defect in this condition, and what causes it?
Sigmoid colon
What did the biopsy reveal? Internal Rectum
l Why was it necessary to resect a segment of the infant’s
anal sphincter
intestine?
External
l How does this abnormality affect motility in the colon?
anal sphincter
l How does the abnormality affect defecation?
Fig. 10.1  Anatomical features of the large intestine.

172 SYSTEMS OF THE BODY

 10
wall. These folds are termed anal valves. The anal canal muscle that is attached to the external side of the wall of

The colon
is surrounded by sphincter muscle that controls the the anal canal, pulls the upper canal forward. This pro-
release of faecal material. The internal sphincter is a duces a sharp angle between the rectum and the anal
thickening of the circular layer of the muscularis externa. canal, and prevents faeces from entering the anal canal,
The external sphincter, which consists of several parts, until defecation is initiated. The levator ani and the pubo­
is composed of striated muscle. The arrangement of the rectal muscles are innervated by somatic motor fibres in
sphincters is shown in Figure 10.2. the pudendal nerve.
Terminals of afferent sensory nerve fibres are present
in the mucosa, submucosa and muscle layers of the
Innervation colon. The colon is fairly insensitive to painful stimuli
but it is very sensitive to changes in pressure. Stretching
The ascending colon and most of the transverse colon are of the colon as a consequence of overdistension results in
innervated by the parasympathetic vagus nerve. Beyond abdominal pain, but removal of lesions, such as polyps,
that the pelvic nerves innervate the colon. These are the from the lining of the colon can be achieved painlessly
sacral outflow of the parasympathetic nervous system. without anaesthetic. There is a profusion of sensory
Figure 10.3 illustrates the extrinsic innervation of the nerve fibres in the wall of the anal canal. Some of these
large intestine. The cholinergic parasympathetic nerves are sensitive to touch, some to cold, some to pressure,
synapse with neurones in the intramural plexi. They and some to friction.
also synapse directly on the smooth muscle of the colon
and the internal anal sphincter. Excitatory cholinergic
neurones are also present in the ganglia of the submu- Histology
cosal and myenteric intramural plexi. In Hirschsprung’s
disease intramural ganglion cells are absent from the As in other regions of the gastrointestinal tract, the wall
myenteric and submucosal plexi (Case 10.1: 2). of the large intestine is composed of four layers: the
The colon is also innervated by adrenergic sympa- mucosa, the muscularis externa, the submucosa and the
thetic nerves from the lower thoracic and upper lumbar serosa (Fig. 10.5A).
segments of the spinal cord. These nerves synapse with The mucosa contains numerous straight tubular glands
inhibitory nerves in the intramural plexi. They also syn- that extend through the full thickness of the mucosa
apse directly with the smooth muscle of the colon and (Fig. 10.5B). The surface epithelium of the mucosa and
internal anal sphincter. The external anal sphincter is glands consists of simple columnar epithelial cells. The
innervated by somatic motor fibres in the pudendal predominant cell type is the columnar absorptive cell.
nerves. It is controlled both reflexly and voluntarily. This cell has a thin striated border on its apical surface. In
Contraction of the levator ani, an external skeletal many respects, it resembles the enterocytes of the small
muscle, constricts the lower end of the rectum. Contrac­ intestine. Its main function is to absorb ions and water.
tion of another external skeletal muscle, the puborectal However, some nutrients are also absorbed, especially in

Vagus nerve

Rectum

SMG
Internal
anal sphincter
T10
T11 IMG
T12
L1
L2 PG

Anal column

Anal sinus S1
Dentate line
S2
S3 Pudendal nerve

Fig. 10.3  Autonomic innervation of the colon. Grey-filled lines

indicate parasympathetic nerves, and solid black lines indicate
Skin sympathetic nerves. T10, T11, T12, thoracic segments; L1, L2, lumbar
External
Anal canal anal sphincter segments; S1, S2, S3, sacral segments, of the spinal cord.
SMG, superior mesenteric ganglion; IMG, inferior mesenteric
Fig. 10.2  Structure of the anal canal. ganglion; PG, pelvic ganglion.

THE digestive SYSTEM 173

10
THE COLON

Case
10.2 Hirschsprung’s disease: 2
10.1

Defect, diagnosis and treatment

Defect
Hirschsprung’s disease, also known as congenital megacolon In Hirschsprung’s disease, intramural ganglion cells are
(enlarged abdomen), is a familial disease that affects one in absent from the myenteric and submucosal plexi, usually in a
5000 live births. It is more common in males. There is an asso- segment of the distal colon. This is due to a defect in embry-
ciation with Down’s syndrome. The genetic mechanism is not onic development, involving the arrest of the caudal migra-
fully understood, but it involves multiple chromosomal dele- tion from the neural crest, of the cells that are destined to
tions. A similar condition (acquired megacolon) can arise later become ganglion cells of the intramural plexi. Examination
in life, from a variety of causes (Fig. 10.4). of biopsy specimens reveals an absence of ganglion cells from
the affected segment. Excitatory and inhibitory neurones are
missing. The segment involved is of variable length, in a region
extending from the anal canal proximally up the colon. The
lumen becomes narrowed in the aganglionic segment, due to
tonic contraction of the smooth muscle. The passage of faecal
material is obstructed at this narrowed segment and it accu-
mulates in the region proximal to the aganglionic segment.
Usually the normal reflex relaxation of the internal anal sphinc-
ter in response to distension of the rectum cannot be elicited
in this condition. Because the aganglionic segment creates an
obstruction to faecal flow, the proximal large bowel becomes
chronically distended, giving rise to the name ‘megacolon’.

Diagnosis
The normal reflex relaxation of the internal anal sphincter in
response to distension of the rectum usually cannot be elic-
ited in this condition.
A well-known finding in Hirschsprung’s disease is an ele-
vated level of acetylcholinesterase in the narrowed segment.
This is indicative of an abnormality of the cholinergic innerva-
tion. Diagnosis of Hirschsprung’s disease is by barium enema
and biopsy showing an absence of ganglion cells. In cases
where the diagnosis is unclear, a histological frozen section of
the region can be stained for the enzyme to see if the levels
are elevated, to aid the diagnosis.

Treatment
Surgery is effective in correcting the disturbance of motil-
ity. Various procedures can be performed, depending on the
Fig. 10.4  An abdominal X-ray showing a grossly dilated colon filled extent of involvement of the colon. They all involve removal
with gas (megacolon). The mucosa has been coated with barium. of the aganglionic segment.

the proximal colon. There are also goblet cells. These are usually extend into the submucosa. In the region of the
more numerous in the colon than in the small intestine. junction between the rectum and the anal canal, the mus-
They produce mucus, which lubricates the intestine and cularis mucosa breaks up into bundles, and further down
coats the faecal material, which becomes increasingly the anal canal it disappears.
more solid as it passes through the colon. This enables it The muscularis externa consists of circular and longi-
to move along easily. There are also undifferentiated cells, tudinal layers of smooth muscle, as elsewhere in the gas-
and sparsely distributed APUD cells of various types that trointestinal tract. However, in the large intestine (except
secrete hormones into the blood (see Ch. 1). The lamina for the rectum) the outer longitudinal layer appears to be
propria, muscularis mucosa of the colon, and submucosa incomplete. It is arranged in three bands, known as tae-
are similar in the small and large intestines. Nodules of niae coli. However, between these bands there is actually
lymphatic tissue are present in the mucosa, and these a very thin sheet of longitudinal muscle. In the rectum,

174 SYSTEMS OF THE BODY

 10
Openings of crypts

The colon
Case
10.2 Ulcerative colitis: 1

A 22-year-old woman, who had, for the past 2 years, been

experiencing intermittent attacks of diarrhoea and rectal
Epithelium bleeding, visited her general practitioner. She said each
Submucosa attack lasted for several weeks, but there was complete
remission of the symptoms between attacks. During the
Circular
muscle layer attacks she experienced lower abdominal cramps and some-
times felt feverish. The general practitioner thought the
Longitudinal symptoms could be explained by the presence of a number
muscle layer
of different conditions, including infection, irritable bowel
A syndrome and ulcerative colitis, and she decided to send
Lymph node Serosa
the patient to see a specialist. The patient was referred to
an outpatient clinic, and subjected to sigmoidoscopy (direct
visual examination of the rectum and distal sigmoid colon)
and a radiographic examination of her abdomen. The pro-
visional diagnosis of ulcerative colitis was made on the basis
Absorptive cell of the finding of inflamed and bleeding mucosa. A rec-
tal biopsy specimen was taken during the procedure, and
sent to the pathology laboratory to confirm the diagnosis.
Goblet cells A blood sample was taken for determination of plasma
electrolytes, blood haemoglobin and plasma albumen. The
APUD cell patient was prescribed aminosalicylate and corticosteroids,
and these drugs ameliorated the symptoms of the disease
B within a week or so.
After studying this case history, we should consider the
Fig. 10.5  Structure of the wall of the colon. (A) Layers present. following questions:
(B) Cell types in the epithelium.
l What would the sigmoidoscopy and radiography
the outer longitudinal muscle is a uniformly thick layer probably have shown?
l Why were the patient’s plasma electrolytes determined?
(as in the small intestine) and this presumably aids defe-
l Why was the patient’s haemoglobin determined?
cation. The inner layer of the muscularis externa consists
l Why was the patient’s plasma albumen concentration
of circular rings of smooth muscle, which allow effective
peristalsis as is the case in the small intestine. determined?
l What could be the cause of the diarrhoea, and frequent
The submucosa is similar to that present elsewhere
in the gastrointestinal tract. The outer layer is a typical bowel movements?
l What is the rationale for treating this patient with
serosa, except where it is in direct contact with other
structures (as on much of its posterior surface), when its corticosteroids?
outer layer is an adventitia.
Ulcerative colitis is a fairly common disease of the large
intestine which usually starts in the rectum, and may becomes obstructed. An abscess forms within it, resulting
extend proximally. It is an inflammatory condition where in a secondary inflammatory process within the wall. This
the mucosa becomes ulcerated (Case 10.2: 1 and 2). inflammation can result in thrombosis of the blood ves-
sels (appendicular artery and vein) supplying it. The loss
of blood supply leads to gangrene and perforation of the
Appendix appendix. It is the absence of any secondary blood supply
to the appendix (that could prevent gangrene) that makes
The appendix is a narrow, tube-like structure. Its wall appendicitis such a dangerous condition.
resembles that of the colon, except that it has a complete
layer of outer longitudinal muscle, and numerous lymph
nodules, in the mucosa and submucosa, which disrupt the Anal canal
muscularis mucosa, giving it the appearance of isolated
lengths of smooth muscle. The appendix is the common- In the submucosa of the anal columns are the termi-
est source of intra-abdominal sepsis (appendicitis). This nal ramifications of the superior rectal artery and veins.
condition can be life-threatening if the appendix ruptures, The numerous veins in this region are longitudinal, and
thereby allowing the sepsis to spread within the perito- thin-walled. They can become dilated and convoluted,
neal cavity (peritonitis). This occurs when the appendix to produce a condition known as haemorrhoids or piles.

THE digestive SYSTEM 175

10
THE COLON

Case
10.2 Ulcerative colitis: 2

Defect, diagnosis and treatment

Defect Histological findings show that the inflammation is restricted
Ulcerative colitis is a fairly common condition in which the to the mucosa and (to a lesser extent) the submucosa.
mucosa of the colon is ulcerated and diffusely inflamed Near the tips of the crypts are accumulations of polymorpho-
(Fig. 10.6). It is the most common cause of bloody diarrhoea nuclear cells (crypt abscesses). The epithelial cells in the crypts
in the Western world. It affects both men and women and is show evidence of degeneration (mucosal atrophy). Ulceration
most common in people aged 20–40 years. In many ways, the of the mucosa may also be evident. The aetiology of this dis-
condition resembles Crohn’s disease, although the latter more ease is unknown, although it has been variously ascribed to
commonly affects the small intestine, while in ulcerative coli- infection, and to an abnormality of the immune system.
tis, the distal colon and rectum are always affected. The damaged mucosa cannot absorb water and ions ade-
quately, and this results in diarrhoea. Frequent bowel move-
ments can result from large volumes of diarrhoea, but may
also be due to colonic or rectal irritability in this condition.
T
Diagnosis
The patient’s abdomen may be distended, but the anus is usu-
ally normal. At sigmoidoscopy, the mucosa of the colon would
probably be seen to have a smooth, glistening pink surface.
S
Radiography would show dilation of the colon, and may
reveal an irregular mucosa, indicative of mucosal atrophy. It
may also show foreshortening of the colon and loss of haus-
tration. A barium enema may reveal fine ulceration.
The patient’s plasma electrolytes were determined because
loss of Na and K from the colon could lead to dehydration
(reduced ECF), hyponatraemia and hypokalaemia. Loss of
HCO3 could lead to metabolic acidosis. Her haemoglobin was
determined because mucosal ulceration results in chronic loss of
blood from the colon which can lead to iron-deficiency anaemia.
Her plasma albumen concentration was determined because
chronic protein losses from the colon can occur in this condition.

Treatment
This patient was treated with oral aminosalicylate. This is bro-
ken down to 5-aminosalicylate by bacteria in the colon. Its
mode of action is presumed to be anti-inflammatory and it is
usually effective in inducing remission. Corticosteroids (usually
rectal prednisolone) also have a powerful anti-inflammatory
action and are used in all types of inflammatory disease. They
reduce the redness and swelling and also the degree of dilata-
tion of blood vessels, thereby reducing fluid exudation. Their
predominant effect is to reduce the inflammatory response to
R mucosal ulceration.
Fig. 10.6  Ulcerative colitis. An X-ray of the large bowel in which In severe cases, surgery is required to prevent perforation
the mucosa has been coated with barium (a double contrast and secondary peritonitis. This usually involves an ileostomy,
barium enema). The normal mucosal folds are seen in the and removal of the colon and the rectum. Surgery for ulcera-
transverse colon (T). The ulcerated mucosa extends from the splenic tive colitis is curative because, unlike in Crohn’s disease, the
flexure (S), to the rectum (R). disease is limited to the large bowel.

176 SYSTEMS OF THE BODY

 10
The mucosa of the upper part of the anal canal is simi-

The colon
+
H HCO3- K
+

lar to that of the large intestine, with straight, tubular Lumen

glands. Numerous goblet cells are found throughout
the epithelium. In the region of the anal sinuses, are + +
anal glands. Most of these extend into the submucosa, Na Na Cl-
but some extend into the muscularis externa. They are
branched, straight, tubular glands containing mucous
cells. The duct of each gland consists of stratified colum-
nar epithelium. It opens into the anal crypt, which is Na+
a small depression in the mucosa. If a duct becomes
occluded, the glands can become infected, creating peri- ATP
anal abscesses. The epithelium of the lower portion of Lateral K+
Cl-
the anal canal is stratified squamous epithelium. In the space
intermediate zone between the simple columnar epithe-
lium of the upper canal, and the stratified squamous epi- Fig. 10.7  Absorption and secretion of ions in the epithelial cell of the
thelium of the lower region, there is a variable amount of colon.
stratified columnar epithelium. The stratified squamous
epithelium of the lower area is continuous with that of
the skin. In the skin of the circumanal region are large Na and Cl occurs by mechanisms similar to those in
apocrine glands known as circumanal glands. the ileum. However, in the colon the transport of Na
The key function of the anal canal is that performed by across the luminal membrane occurs via an electrogenic
the sphincter, which comprises an internal (smooth mus- Na channel. This produces an electrical potential of
cle) ring and an outer (striated muscle) ring. This sphinc- about 30 mV (lumen negative) across the mucosa.
ter, which is under both autonomic and somatic nerve The electrical potential caused by Na absorption, pro-
control, enables defecation to occur (see below). motes the secretion of K into the lumen (see above), but
K is also absorbed in the distal colon, where the trans-
port is via exchange with H ions. The latter is an active
process, involving an anionic exchange mechanism simi-
Functions lar to that for H/K exchange in the stomach.
The absorption of water and ions is under both neu-
Secretion ral control via the enteric nerve plexi, and hormonal con-
trol. Aldosterone increases net water absorption in the
The large intestine secretes a thick mucinous secretion, colon by stimulating the synthesis of the electrogenic
with a high content of K and HCO3 ions. The electrical Na channel in the luminal membrane of the epithelial
potential across the mucosa, set-up by the entry of Na cell, and increasing the number of Na,K-ATPase mol-
into the cell (see below) is partly responsible for driving ecules in the basolateral membrane. Glucocorticoids also
the transport of K ions into the lumen, through the tight stimulate the transport of Na ions by increasing the
junctions. Other, as yet unclear, mechanisms may also be number of ATPase pumps (hence the fluid retention seen
involved in the secretion of K ions in the colon. HCO3 in patients taking prednisolone and other steroid medica-
ions are secreted in exchange for Cl ions (Fig. 10.7). tion), and angiotensin stimulates the absorption of water
Secretion of the colon is stimulated by distension, and and Na in the colon. Vasopressin (antidiuretic hormone,
by mechanical irritation of the walls. Secretomotor neu- ADH) decreases water absorption.
rones from the submucosal and myenteric nerve plexi In ulcerative colitis, the damaged mucosa cannot
stimulate secretion, probably via the release of acetylcho- absorb ions and water adequately and this results in diar-
line and vasoactive intestinal peptide (VIP). Stimulation rhoea (Case 10.2: 2).
of the parasympathetic pelvic nerves also elicits secretion.
This is directly via synapses on the epithelial cells, and
indirectly via synapses with neurones in the intramural Products of bacterial action
plexi. Stimulation of the sympathetic nerves suppresses
The human body is composed of approximately 1014 cells,
secretion in the colon via adrenaline and somatostatin
but only 10% of these are human cells. The rest are micro-
release. For this reason, somatostatin analogues can be
bial cells that colonize the body surfaces and the gastroin-
administered to treat secretory diarrhoea (see Ch. 7).
testinal tract. The gastric acid of the stomach destroys
most microflora, and the stomach and small intestines
Absorption and digestion are only sparsely colonized by them. Most of the flora
that colonize the gastrointestinal tract, reside in the
large intestine. A large number of bacteria are lost in the
Ions and water faeces, and human faeces contain approximately 1011
The absorption of ions and water occurs mainly in the bacteria/g. More than 99% of the bacteria in faeces are
proximal region of the colon. The net absorption of rod-shaped, non-sporing, anaerobes. Apart from anaerobic

THE digestive SYSTEM 177

10
bacteria, lactobacilli and coliforms also colonize the large known as haustration. The rectum is more active in seg-
THE COLON

intestine. The colonic microflora population is so com- mental contractions than the colon.
plex, that most of the bacteria are yet to be typed.
The bacteria in the large intestine synthesize cer-
tain vitamins that are required by the body. These are Propulsion
­vitamins of the B complex, including thiamin, riboflavin,
vitamin B12 and vitamin K. The synthesis of vitamin K is Propulsion of material in the large intestine is affected
especially important because the average diet does not by segmental propulsion, peristalsis and peristaltic mass
contain enough for normal blood clotting. In fact animals movements.
bred in germ-free conditions develop clotting defects. Segmental propulsion involves sequential haustration.
The vitamins are probably absorbed by passive diffusion Several segments may contract simultaneously, propel-
in the large intestine. Vitamin K is fat-soluble, and there- ling the contents along. Although this can result in the
fore may be absorbed fairly readily. A small proportion of material being propelled in both directions, it is usually
the synthesized vitamins may be refluxed into the small pushed in the caudad direction. Material is displaced
intestine, and absorbed in that region. through several haustrae, approximately every 30 min.
Intestinal bacteria also have digestive actions. Thus Peristalsis involves waves of contraction which travel
they convert primary bile acids to secondary bile acids, towards the anus, pushing the contents slowly along. At
and deconjugate conjugated bile acids. The lipid solu- rest, these waves travel at approximately 5 cm/h, but the
bility of these substances is greater than that of the pri- speed increases to approximately 10 cm/h after a meal.
mary bile acids, and a proportion of them are absorbed Peristaltic mass movements involve the simultaneous
passively in the colon. Colonic bacteria also convert contraction of large segments of the ascending and trans-
bilirubins to urobilinogens. The reactions involved are verse colon, which can propel the contents one-third to
described in Chapter 6. three-quarters of the length of the colon in a few seconds.
There are also additional peristaltic movements in the
descending colon that deliver the faecal material into the
Absorption of drugs rectum.
Some drugs can be administered via the rectum. Thus
anti-inflammatory drugs can be used in this way to
treat the rectal mucosa in ulcerative colitis. However, Effect of food
this route can also be used for drugs that produce sys- Ingested material can affect motility in the large intes-
temic effects. It is used following abdominal surgery, in tine in two ways. First, food that contains large amounts
patients suffering from vomiting, or who require analge- of indigestible material causes stimulation of mechano­
sia. In such patients absorption from the small intestine receptors in the walls of the colon, resulting in its rapid
can be unreliable. transit through the large intestine. This is how ‘fibre’ in
the diet prevents constipation. Second, some substances
(e.g. laxatives) stimulate chemoreceptors in the walls of
Motility
the colon to stimulate motility.
The motor function of the large intestine serves both
to mix the contents of the lumen, and to propel them Distension
towards the anus. The chyme entering the large intes-
tine is semi-liquid, but water is absorbed from it, and The volume of faeces entering the colon can be increased
the residual matter gradually becomes solid, as it passes if fibre is ingested. Fibre consists of polymeric substances
along the colon. A major function of the distal large such as cellulose, hemicelluloses, pectins, gums, muci-
bowel (particularly the rectum) is to store faecal material. lages, and lignins. Most of these are polysaccharides,
The passage of the luminal contents through the stomach although lignin is a phenyl propane polymer. These sub-
and small intestine usually takes less than 12 h, but the stances are found in bran, fruit and vegetables. Western
residue from a meal can remain in the large intestine for diets are low in fibre compared with diets in many other
over a week. However, normally 80% has been extruded parts of the world such as rural Africa, and the relative
by the end of the 4th day. The expulsion of material from lack of fibre in the diet may account for the higher preva-
the colon is highly variable, being under both autonomic lence of many diseases of the large intestine in Western
and somatic control. populations than in other populations.
These diseases include:
l Constipation
Mixing l Diverticular disease
Mixing or kneading of the contents of the large intestine l Haemorrhoids
is due to contractions of the circular muscle. These con- l Polyps (adenomatous)
tractions result in the formation and reformation of sacs, l Cancer of the colon
known as haustrae, and this type of segmental motility is l Irritable colon.

178 SYSTEMS OF THE BODY

 10
Adding fibre to the diet prevents or remedies consti-

The colon
pation, eases haemorrhoids, and relieves the symptoms
of diverticular disease. It is interesting in this respect, 15 mV
that Seventh Day Adventists, living in the USA, who are
predominantly vegetarian, have a very low incidence of
cancer of the colon. 5g
Adding fibre to the diet prevents constipation partly
because it increases the bulk of the material entering A
the colon. This increases the stimulation of the smooth
muscle, and decreases the transit time for the passage of
material through the colon. Moreover, polysaccharides,
such as cellulose, take up water and swell to form gels. 15 mV
This makes the faeces softer, and more easily moved
through the colon and anus. Haemorrhoids are caused
in constipated individuals who strain to defecate. Thus, 5g
dietary fibre relieves this condition, by reducing the
need for straining during defecation. The reasons for the 5 10-7 M ACh
other beneficial effects of fibre are not clear. However, it
is possible that constipation leads to the accumulation of B
carcinogens and other toxins that may cause cancer and
inflammatory disease respectively. Thus adding fibre to
the diet could (in theory) help to prevent these condi- Fig. 10.8  Oscillating membrane potential (upper traces) and
contractile activity (lower traces) in the circular smooth muscle of the
tions developing, by preventing constipation, and dilut-
colon. (A) Unstimulated muscle. (B) The effect of acetylcholine (ACh)
ing any toxins. Intestinal gas can also stimulate motility (added at the arrow).
in the colon, mainly via causing distension. The gases
that can be present include carbon dioxide, hydrogen,
oxygen, methane and nitrogen. These gases do not smell. membrane potentials. In the longitudinal layer the ampli-
The odour associated with expelled gas is due to traces tude of the oscillations sometimes reaches the threshold
of other substances, such as ammonia, hydrogen sul- level for action potential generation, resulting in spon-
phide, indole, skatole, short chain fatty acids and vola- taneous contractions of the muscle. In the circular layer,
tile amines. A normal individual releases approximately however, contractions do not usually occur unless the
500 mL of gas per day. The gases are partly swallowed muscle is stimulated by nerves, which release transmit-
air, but they can also be derived from substances in the ters such as acetylcholine, in the vicinity of the pace-
food, or be produced in the lumen by neutralisation of maker cells. Acetylcholine increases the time course of
gastric acid, or by bacterial fermentation processes. They the slow wave oscillations, and these longer waves elicit
can also arise via diffusion from the blood. contractions (Fig. 10.8).
Haustration and segmentation are occurring most
Laxatives of the time, although they are not perceived. However
the frequency of these movements diminishes during
Some ingested substances stimulate motility in the colon sleep. They are spontaneous contractions that are modi-
via activation of chemoreceptors. An example of such a fied by various factors, such as stretch that increases the
compound is senna bisacodyl. The increase in motility strength of the contractions (see Ch. 1). Other factors
is mediated via the myenteric plexus. This plexus can that control colonic motility include extrinsic autonomic
be damaged by prolonged high doses of laxatives. Thus nerves, intrinsic nerves in the intramural nerve plexi and
long-term use of these agents will reduce their efficacy. hormones.

Emotions Nervous control

The effect of emotions on colonic motility has been stud- Motility in the colon is controlled by intrinsic nerves of
ied in patients who have been provided with a colostomy. the intramural plexi and by extrinsic autonomic nerves.
It has been shown that anger and resentment increase Figure 10.9 illustrates these pathways. Intrinsic nerves
motility, whilst depression decreases it. The mechanisms that release acetylcholine or substance P stimulate motil-
involved are not clear, but they presumably involve auto- ity, and intrinsic nerves that release purines, VIP and
nomic nerves. nitric oxide (NO) inhibit it. The importance of the intrinsic
nerve plexi to the normal functioning of the colon is illus-
trated by the problems that occur in Hirschsprung’s dis-
Control of motility in the colon ease (Case 10.1: 3) and Chagas disease (trypanosomiasis).
The smooth muscle cells of both the longitudinal layer Both conditions are characterized by an absence of intra-
and the circular layer exhibit spontaneously oscillating mural ganglion cells in a narrowed region of the colon.

THE digestive SYSTEM 179

10
plexi to modulate the effects of the intrinsic innerva-
THE COLON

Thoracic and
lumbar spinal cord tion, and they innervate the smooth muscle directly.
Stimulation of the parasympathetic nerves increases
motility, both via the interneurones and via their direct
action on the muscle. Stimulation of the sympathetic
Sacral spinal cord nerves inhibits motility via the interneurones in the plexi,
but their direct action on the muscle causes increased
contraction (Fig. 10.9). -Adrenergic receptors are present
at the synapses of sympathetic nerves, both in the plexi
and on the muscle. The inhibitory interneurones in the
+ + plexi, which the sympathetic nerves synapse, are not
- Intramural plexi
adrenergic (see above).

+ + + Muscularis mucosa Reflex control

Distension of some regions of the colon causes relaxation
Fig. 10.9  A simplified scheme for the control of motility in the colon. in other parts. This is the colono-colic reflex. In addition
other regions of the gastrointestinal tract can reflexly
influence colonic motility. Thus a marked increase in
Case motility in the large intestine occurs three to four times
10.1 Hirschsprung’s disease: 3 a day due to the gastro-colic reflex. This reflex is a
response to food in the stomach, and it usually coincides
with the ileo-gastric reflex (see Ch. 7). The gastro-colic
Motility
reflex depends on the parasympathetic innervation of
The importance of the intramural nerves in the control of the colon, but the hormones gastrin and cholecystokinin
motility in the colon becomes clear from the symptoms of (CCK) may also be involved.
Hirschsprung’s disease. Loss of the ganglionic cells from a
segment of the large bowel disrupts the coordinated pro-
pulsive activity of the organ, leading to severe constipation.
Defecation
Both excitatory and inhibitory neurones are affected.
An absence of excitatory cholinergic ganglion cells pre-
Defecation (see fig. 10.10) is a reflex response to the sud-
vents segmental contractions and coordinated propulsion
den distension of the walls of the rectum resulting from
from taking place. However, the parasympathetic choliner-
mass movements in the colon moving the faecal material
gic fibres from the sacral spinal cord innervate the muscle
into it. The reflex response has four components:
directly and their activity results in sustained contraction,
because modification of the contractile activity by inhibi- l Increased activity in the sigmoid colon
tory interneurones in the plexi can no longer take place. l Distension of the rectum
(Furthermore, the adrenergic sympathetic nerve fibres can no l Reflex contraction of the rectum
longer act via inhibitory interneurones to augment the inhi- l Relaxation of the internal and external anal sphincters
bition of the cholinergic nerves in the plexi.) Thus, effective (which are normally closed).
relaxation of the circular muscle is lost. Moreover extrinsic
Figure 10.10 illustrates the process of defecation.
sympathetic nerves also synapse directly on smooth muscle,
and activation of the -receptors on the smooth muscle cells
by these nerves produces excitation and increased muscle
tone. Thus both parasympathetic and sympathetic extrinsic Control of defecation
influences lead to sustained tonic contraction of the smooth The caudal extremity is under nervous control.
muscle in the aganglionic segment. The presence of the con- Defecation is basically an intrinsic reflex mediated by
tracted segment results in blockage of the colon. impulses in the internal nerve plexi, which is reinforced
by an autonomic reflex that is transmitted in the spinal
cord. The reflex is integrated via the defecation centre in
the sacral spinal cord. However, defecation is also influ-
Hirschsprung’s disease is a congenital abnormality, enced by signals from higher centres. Figure 10.11 illus-
while the defect in Chagas disease is due to trypanosome trates the pathways involved in the neural control of
parasites (Trypanosoma cruzi) which infest the wall of the defecation. When faeces enter the rectum, distension of
intestines. The parasites produce a toxin that destroys the the wall activates pressure receptors. These send affer-
intramural ganglion cells, leading to symptoms similar to ent signals that spread through the myenteric plexus to
those seen in Hirschsprung’s disease. initiate peristaltic waves in the descending and sigmoid
Extrinsic autonomic nerves are also involved in the regions of the colon, and the rectum. These waves of con-
control of the colon. They synapse with neurones in the traction force the faeces towards the anus. As the wave

180 SYSTEMS OF THE BODY

 10

The colon
A B

Fig. 10.10  An X-ray showing a rectum filled with contrast (barium) (A) before and (B) during contraction/defecation.

Cortex

Case
10.1 Hirschsprung’s disease: 4
Spinal cord
The defecation reflex
The loss of reflex inhibition of the internal anal ­ sphincter
Parasympathetic in Hirschsprung’s disease illustrates the importance of
nerves 2 Sensory the intramural nerves in the reflex control of defecation.
afferent
2 The innervation of the internal sphincter is defective in this
nerves
condition and there is a fluctuating but continuous con-
traction of the sphincter (this process is sometimes referred
2 Intramural plexi to as ‘sampling’). The normal relaxation response of the
sphincter muscle to distension of the rectum does not occur.
1, 2 1 This is because its relaxation normally depends on the pres-
Somatic
motor ence of inhibitory fibres in the intramural plexi. Hence sec-
Colon
nerves ondary relaxation of the external sphincter does not occur
and defecation does not occur.
The basic defecation reflex in response to distension
of the rectum depends on the transmission of affer-
External ent impulses to the intramural nerve plexi, and efferent
anal sphincter Pressure receptor
impulses from these plexi to the muscle of the rectum and
in rectum
(distension) internal anal sphincter, to cause reflex contraction of the
Internal rectum and relaxation of the internal anal sphincter. This
anal sphincter
basic reflex cannot be operational if the ganglion cells are
Fig. 10.11  A simplified scheme illustrating the neural control of absent. Moreover the anal sphincter is innervated directly
defecation. The basic reflex operates via the intramural plexi, and the by parasympathetic cholinergic and sympathetic -adrener-
spinal parasympathetic reflex reinforces the basic reflex. Control is also gic nerve fibres. The activity in the extrinsic nerves normally
exerted by the conscious brain. 1, components of the basic reflex; reinforces the basic reflex via synapses with neurones in the
2, components of the spinal sympathetic reflex.

THE digestive SYSTEM 181

10
The sacral control centre also coordinates the other
THE COLON

Cases
10.1 Hirschsprung’s disease: 4 (continued)
effects which accompany defecation, including a deep
inspiration, closure of the glottis, and contraction of the
abdominal muscles, which forces the faeces downwards
plexi. However in Hirschsprung’s disease these influences and extends the pelvic floor, so that it pulls outward on
cannot occur, and both the direct parasympathetic and the anus to expel the faeces. The reflex normally initiates
the direct sympathetic innervation of the sphincter muscle contraction of the external anal sphincter, which tem-
cause contraction of the sphincter. In Hirschsprung’s disease porarily prevents defecation. The conscious mind then
the sphincter remains contracted. takes over, and either it inhibits the external sphincter to
The response of the external anal sphincter is normal in cause relaxation and allow defecation to occur, or it keeps
Hirschsprung’s disease as the somatic motor innervation is it contracted it so that defecation is resisted. Pain inhibits
not affected. relaxation, and this results in straining. If this becomes
chronic it leads to dilation of the haemorrhoidal veins
(‘piles’), and may even prolapse the rectum through the
anal canal. Interestingly rectal prolapse is also seen in
approaches the anus, the sphincters are inhibited, and weightlifters, in whom the process of repeated lifting
they relax. The external sphincter that is innervated by requires straining against a contracted external sphincter.
somatic motor nerves is under voluntary control. If the The sensation of fullness of the rectum and the desire
external sphincter is relaxed voluntarily when the faeces to defecate often follows the ingestion of a meal. If the
are pushed towards it, defecation will occur. urge to defecate is resisted, the sensation subsides, and
This intrinsic reflex is augmented by an autonomic the sphincters regain their normal tone. Therefore the
reflex. This involves parasympathetic nerve fibres in the reflex reactions to distension of the colon are transient.
pelvic nerves arising from the sacral spinal cord, which The frequency of defecation, and the time of day
innervate the terminal colon. Thus activation of pres- when it is performed is a matter of habit. In two-thirds
sure receptors by distension of the rectum sends affer- of healthy individuals it is between five and seven times
ent impulses to the spinal cord (as well as to nerves in a week.
the intramural plexi). This results in impulses being In the human adult, approximately 150 g of material
transmitted in the parasympathetic nerve fibres to the are eliminated per day. Of this 150 g, two-thirds are water
descending colon, the sigmoid colon and the rectum. The and one-third is solids. The solids are normally mostly
parasympathetic signals intensify the peristaltic waves, undigested cellulose, bacteria, cell debris, bile pigments
and augment the effect of the intrinsic neurones to cause and some salts. There is a high content of K ions in the
increased motility, contraction of the rectum, and relaxa- faeces, relative to the concentration in the fluid enter-
tion of the internal and external anal sphincters. Thus the ing the colon, because K is secreted by the walls of the
parasympathetic reflex converts the weak intrinsic reflex colon. The brown colour of faeces is due to the pres-
to a powerful reflex. In Hirschsprung’s disease the inner- ence of stercobilin and urobilin (see Ch. 6). The odour is
vation of the internal anal sphincter is defective, resulting caused mainly by traces of other substances, including
in loss of reflex inhibition of the sphincter (Case 10.1: 4). products of bacterial fermentation (see above).

182 SYSTEMS OF THE BODY

Gastrointestinal
pathology 11
Chapter objectives
After studying this chapter you should be able to:

1. Provide an overview of gastrointestinal disease.

2. Give an insight into the relative clinical importance, in terms of

incidence and clinical import, of the different disorders.

3. Explain the features of the more common disorders in terms of

disruption of the normal function.
11
Gastrointestinal pathology

Introduction Table 11.1  Common gastrointestinal cancers

Understanding normal body function is the foundation of Site Cases per Presenting symptoms
clinical practice. In this book the normal anatomy, physi- annum (England
ology and histopathology of the gastrointestinal tract has and Wales)
been applied to explain why different clinical conditions
manifest their specific signs and symptoms. In the first 10 Large bowel 35 000 Alteration in bowel action
chapters, clinical examples of diseases have been selected Stomach 10 000 Indigestion, epigastric pain
to highlight specific aspects of physiological gastrointes- Pancreas 10 000 Jaundice, back pain,
tinal function. The final chapter provides an overview of steatorrhoea
gastrointestinal pathology and its manifestations. Oesophagus 8000 Regurgitation, difficulty in
The diseases described in this chapter are addressed swallowing (dysphagia)
anatomically under the headings: the oral cavity, the
Liver 500 Features of chronic liver
oesophagus, the stomach, the duodenum, the pancreas,
(hepatoma) disease. A history of
the liver and biliary tract, the small bowel and the large alcohol abuse or hepatitis
bowel. In addition to these sections, three other clinical
areas are addressed separately. These are: Some 40% of all deaths from cancer in the Western world are
attributable to gastrointestinal malignancy. Most early symptoms
1. Cancer of the gastrointestinal tract, which is the are due to the abnormal function of the organ.
commonest cause of death from digestive tract
disorders.
2. Abdominal pain, which is one of the most frequent
causes of acute presentation to the health service. Environmental factors may also alert the clinician to the
3. Gastrointestinal surgery, which provides further underlying diagnosis. Thus, a history of prolonged alcohol
insight into the functional importance of the intake and chronic liver disease can alert the clinician to
components of the digestive tract. the possibility of a primary liver tumour (hepatoma).
The importance of dietary intake in causing gastroin-
testinal malignancies has long been recognized. In the
Indian subcontinent chewing beetle nut is known to pre-
Gastrointestinal malignancy dispose to oral cancer, ingestion of pickles and salted fish
in Japan is associated with an increased incidence of gas-
In the Western world, malignancy of the gastrointesti- tric cancer, and the high animal fat, low roughage diet of
nal tract accounts for approximately 10% of all deaths the Western world predisposes to colorectal cancer. More
and 40% of deaths from cancer. Effective and even cura- recently it has been recognized that many gastrointestinal
tive treatment is available for these tumours if they are malignancies develop because of an underlying inherited
diagnosed at an early stage. For these reasons, malignan- genetic predisposition.
cies of the gastrointestinal tract must be considered at an Genetic predisposition may influence up to one-third
early stage in the diagnostic process for any patient pre- of all colorectal cancer. In patients who are already pre-
senting with gastrointestinal symptoms (Table 11.1). disposed to an inherited colorectal tumour, the tumours
A number of general factors will influence the clini- will tend to occur at an earlier age than in the general
cian as to the likelihood of any symptom being due to an population. In addition, the tumours may be multiple
underlying malignancy: because the predisposition affects all the cells in the large
bowel mucosa. A clinical history from the patient may
l The age of the patient
reveal first-degree relatives affected by the same tumour,
l The duration of symptoms
l
because they are usually inherited in an autosomal domi-
The progression of symptoms
l
nant fashion. The genetic defects that have led to the pre-
Identifiable aetiological factors
l
disposition pertain to fundamental cellular functions.
A family history of malignancy.
It is usual for these patients to be at risk of developing
Solid tumours, including gastrointestinal cancers, occur in more then one type of tumour, and so a history of several
patients with increasing frequency with advancing years. different tumours in the same patient would also lead to
They are rarely diagnosed in patients under the age of 50 the suspicion of an underlying inherited predisposition.
years, but thereafter rapidly increase in frequency into the The most common tumours of the gastrointestinal
seventh decade of life. Symptoms may start in an insidi- tract affect its mucosal lining. These cells are presumed
ous fashion, but often progress over a period of weeks to be most at risk because of their high rate of prolifera-
or months. This is in contrast to acute infection, which tion. Moreover, these cells are constantly subjected to
often has a sudden onset of symptoms, or chronic inflam- injury by ingested carcinogens. By comparison, tumours
matory conditions, which commonly display periods of of the muscle wall, connective tissue, lymphatics or sero-
exacerbation and remission. sal surface of the bowel (peritoneum) are rare. The vast

184 SYSTEMS OF THE BODY

 11
majority of gastrointestinal tumours are tumours of the

Gastrointestinal pathology
glandular structures (adenocarcinomas), that develop
from the glandular cells of the mucosal lining of the gas-
trointestinal tract. In the clinical setting, if a metastatic
tumour deposit is identified, histological features of an
Foregut
adenocarcinoma would alert the clinician to look for a
Spleen/
primary tumour in the digestive tract. Gallbladder pancreas

Symptoms of gastrointestinal malignancy

Midgut
It is helpful to categorize symptoms of malignant disease Renal Renal
into three groups:
l Symptoms due to primary disease
l Symptoms due to secondary disease
l Symptoms due to non-metastatic manifestations of

malignancy.
Appendicitis
Primary disease Hindgut

The symptoms of malignant disease of the gastrointestinal

tract will depend upon the site and function of the part
of the gastrointestinal tract that is affected. Carcinoma
of the oesophagus will usually present with difficulty in
swallowing (dysphagia), whereas adenocarcinoma of the Fig. 11.1  Visceral pain is referred to its site of embryological origin.
colon will usually manifest with symptoms of a change Parietal pain is more localized and is derived from inflammation of the
of bowel habit. In addition to symptoms of disordered overlying parietal peritoneum. The pointing pain in the right iliac fossa
function, the site of the pain may also help to localize the in appendicitis is typical of parietal pain.
tumour. Pancreatic adenocarcinoma often presents with
back pain because of the retroperineal position of the pan-
creas, where a tumour of the liver may be associated with
in the liver. Abdominal examination may reveal enlarge-
pain in the right side of the upper abdomen because of a
ment of the liver in the right sub-costal region and affected
localized inflammatory response in the overlying perito-
individuals may occasionally present with symptoms of
neum (Fig. 11.1).
pain or jaundice.

Secondary disease
Non-metastatic manifestations of malignancy
One of the features of malignancy is the ability of the
tumour to spread from the site of primary disease. This Malignancy, particularly in its advanced stages, is asso-
spread may occur via the lymphatics, the bloodstream ciated with an increased metabolic rate. This is due in
or through the peritoneal cavity (transcoelomic spread). part to the rapid cell division and tumour growth, and
The lymphatic drainage follows its arterial blood sup- also due to secreted proteins released from the tumour.
ply. Consequently, tumours of the stomach, small bowel This catabolic state results in loss of body weight and, in
or large bowel can spread via the lymphatics to the root its advanced stages, visible loss of muscle mass. This can
of the coeliac artery, superior mesenteric artery, and infe- occur in the presence of a normal dietary intake, and is
rior mesenteric artery respectively. As these lymph nodes one of the most common non-metastatic manifestations
are deep inside the abdominal cavity such spread is often of malignancy. A further common finding is anaemia,
initially undetected. The tumour may spread further up due to bone marrow suppression. Because gastrointes-
the thoracic chain and manifest as a swelling in the supra­ tinal malignancies usually disrupt the epithelial lining,
clavicular lymph nodes in the neck. Because the thoracic which protects the gastrointestinal tract from injury,
duct drains into the veins on the left side of the neck, an blood loss from the gastrointestinal tract is also common.
enlarged lymph node in the left supraclavicular region is The blood loss may be chronic and is often not clinically
always suspicious of lymphatic spread from an underly- apparent. As the iron stores are depleted, red blood cor-
ing gastrointestinal malignancy. puscle maturation becomes impaired. An iron-­deficient
The venous drainage from the gastrointestinal tract is via anaemia develops, in which the red blood cells are
the portal vein to the liver. For this reason gastrointestinal smaller (microcytic) and contain a reduced haem compo-
malignancies commonly develop blood-borne metastases nent (hypochromic).

THE digestive SYSTEM 185

11
Gastrointestinal pathology

Case
11.1 Colorectal cancer: 1
Table 11.2  Oesophageal cancer

Symptom Mechanism
Colon cancer
Difficulty in The tumour may encase the oesophagus
A 60-year-old woman presented to her general practitioner
swallowing leading to narrowing or infiltration of
(GP) because of gastrointestinal symptoms. On direct ques- (dysphagia) the mucosal coat resulting in impaired
tioning she said that the frequency of her bowel action had motility
increased over the preceding weeks. In addition she had
A history for many It can develop following longstanding
noticed some traces of blood in her stool on two occasions. She
years of painful oesophagitis in the lower oesophagus
also complained that the consistency of her stool had changed swallowing
and that she had not passed a formed stool in the preceding
Weight loss This may be due to alteration in diet
6 weeks. No other person in the family had suffered any recent
secondary to difficulty in swallowing
gastrointestinal upset and she had not suffered similar symp-
toms in the past. On specific questioning, she informed her GP Respiratory Problems with swallowing will usually
symptoms predate the development of metastatic
that her father had died from colorectal cancer.
disease. The patient may have symptoms
On examination, the GP found the patient to be anaemic,
from local infiltration of the organ such as
and her clothes were loose, indicating she had recently lost the bronchi or trachea
weight. Examination of her abdomen revealed an enlarged
liver.
The GP was concerned that she may have an underlying
colonic cancer and referred her to the hospital for further
investigation. The consultant arranged a barium enema Carcinoma of the oesophagus
and a CT (computerized tomography) scan of her liver.
The barium enema revealed a narrowing in the colon con- Carcinoma of the oesophagus affects approximately
sistent with a carcinoma. The CT scan of the liver revealed 5/100 000 of the population per annum. Two-thirds of
a single metastasis in the right lobe. The diagnosis was the tumours are squamous carcinomas and the rest are
explained to the patient and arrangements were made for adenocarcinomas. This reflects the epithelial lining of the
surgery. At operation a left hemicolectomy was performed. oesophagus, which is of squamous type. Adenocarcinomas
This involved removal of the sigmoid and descending colon are usually localized to the distal third of the oesophagus
with its blood supply, and subsequent anastomosis of the and probably develop from ectopic gastric mucosa.
splenic flexure to the recto-sigmoid junction. In addition, The classical symptom is of difficulty in swallowing
the right lobe of the liver, containing the metastasis, was (dysphagia). The symptoms are slowly progressive, with
removed. patients describing difficulty in swallowing ­ solids and
Following operation, the patient made a slow but steady often having altered their diet to compensate. Oesophageal
recovery. She returned to a normal diet on the 6th postop- tumours may enlarge into the lumen, but more often, will
erative day. She did not become jaundiced following her infiltrate diffusely along and around the oesophageal wall
operation. (Table 11.2). The tendency for these tumours to grow along
the wall of the oesophagus makes complete surgical resec-
tion difficult. Furthermore, the lack of a serosal covering
to the oesophagus enables direct extension of the tumour
into the mediastinum. Involvement of the adjacent tra-
chea and bronchi will result in respiratory problems. The
Common gastrointestinal malignancies oesophagus and rectum are the only two parts of the gas-
trointestinal tract that are not covered by a peritoneal coat,
In the Western world over half of deaths are accounted and tumours in these two locations commonly invade sur-
for by diseases of the cardiovascular system. The next rounding local structures. Spread into the lymphatic sys-
most frequent cause of death is that of malignancy, tem may manifest with a palpable supraclavicular lymph
which accounts for approximately 40% of all deaths. node, and spread into the portal venous system results in
Gastrointestinal malignancies account for over 30% of the development of liver metastases. Because tumours of
all deaths from cancer, some 60 000 deaths per annum in the oesophagus do not usually invade the lumen of the
England and Wales alone. Unfortunately, although early oesophagus, dysphagia is a late feature and as a conse-
tumours can often be cured by surgery, most patients quence the tumour is rarely curable. Only 6% of patients
present after the disease has spread and as a conse- survive for 5 years.
quence, treatment is less likely to be curable. The reserves A number of aetiological factors are known to be asso-
of function in the gastrointestinal tract are such that radi- ciated with this tumour. The most frequent of these are
cal resection of large sections is still compatible with a heavy alcohol intake and smoking. These factors probably
full and active life. account for much of the variation in instance seen across

186 SYSTEMS OF THE BODY

 11

Gastrointestinal pathology
Case
11.1 Colorectal cancer: 2

Treatment
Alteration in bowel habit is a common symptom of colonic creates a rigid narrowing that is easily visualized (Fig. 11.2).
cancer. It can be due to partial obstruction of the lumen of the Computerized tomography is a useful way of defining abnor-
large bowel or be the result of ulceration of the mucosal sur- mal areas of tissue in solid organs like the liver. The increased
face. Ulceration can also give rise to the symptoms of intermit- vascularity of metastatic tumours makes these easy to visual-
tent bleeding. ize on a CT scan (Fig. 11.3).
Colorectal cancer clusters in families in up to 20% of cases Surgical treatment required removal of the primary tumour,
and so a family history of this disease is not uncommon in the draining lymph nodes, and the single metastasis in the
affected individuals. This is believed to be genetically deter- liver. Because blood-borne metastases from colonic cancer
mined, although the molecular basis in most families is not preferentially spread to the liver, resection of these advanced
understood. Non-metastatic manifestations of gastrointesti- tumours can still be curative for selected cases. It is important
nal malignancies are more common in advanced disease and to exclude other sites of metastatic disease before undertak-
include weight loss and anaemia. The patient may have also ing such a procedure. The second most common site of spread
been anaemic because of chronic gastrointestinal bleeding. from colonic tumours is the lung, which is why the chest X-ray
The GP was suspicious that the enlarged liver was due to was reviewed prior to surgery.
metastatic disease, and in the light of the patient’s large Normal bowel function following segmental resection of
bowel symptoms the GP felt that a colorectal cancer was the the colon would be expected. No impairment of liver function
most likely diagnosis. A double-contrast barium enema out- would be anticipated following a limited resection so jaun-
lines the lining of the bowel, and infiltration by neoplasm dice or fat malabsorption would not be anticipated.
Sp
len
ic f
lex
ure

M Liver

M
M Stomach
Tra

Aorta
n
sve
rse

Spleen
co
lon

Tumour

Fig. 11.2  An X-ray of the large bowel showing the large bowel
lined with a coating of barium. A large tumour is visible at the Fig. 11.3  A CT scan showing a cross-section of the upper
splenic flexure. This encircles and narrows the lumen, creating abdomen. Multiple opacities are seen in the liver due to
the typical ‘apple core’ appearance. blood-borne metastases (M) from a primary colonic cancer.

different populations. A further interesting aetiological Gastric carcinoma

factor is that of acid reflux. Chronic oesophagitis associ-
ated with an incompetent gastro-oesophageal sphincter Gastric carcinoma (Table 11.3) is exceptional, in that its
causes damage to the mucosa in the lower third of the incidence has been in steady decline for the last 30 years,
oesophagus. This chronic injury appears to predispose while other gastrointestinal tumours have increased
to the development of adenocarcinoma in the lower third in frequency with increased longevity. Despite this, it
of the oesophagus. These different aetiological factors remains the third most common cause of death from gas-
all result in a chronic injury to the oesophageal mucosa trointestinal tumours in Western countries, and is a major
which over a period of time can lead to neoplastic change. health issue in Japan and Chile. Variation in populations

THE digestive SYSTEM 187

11
may present with pain from the injury to the mucosa,
Gastrointestinal pathology

Table 11.3  Gastric cancer bleeding from erosion into underlying blood vessels, or
peritonitis from perforation of the ulcer allowing gastric
Aetiology The storage function of the stomach makes it contents to leak into the peritoneal cavity. In contrast, dif-
particularly susceptible to ingested toxins and fuse gastric cancer often presents with a more insidious
dietary factors that can contribute to malignant
onset. The infiltrating nature of this tumour leads to a
change
constricted stomach with a grossly thickened wall (lieni-
Symptoms tis plastica). The nature of diffuse-type cancer mitigates
Bleeding Ulceration of the tumour results in exposure of against successful surgical resection. Unfortunately many
the submucosal vessels gastric cancers present at an advanced stage. Patients
Abdominal Gastric tumours often spread from the serosal may have an enlarged liver and associated jaundice
distension surface of the stomach creating peritoneal due to blood-borne metastases. The disease may spread
metastases. Leakage of extracellular fluid occurs through the stomach wall onto the peritoneum causing
in association with these lesions and gives rise to ascites. In these situations the tumour is incurable.
ascites
Weight This is more a feature of advanced disease in
loss gastric cancer because the tumours do not
usually prevent the passage of ingested food
Tumours of the pancreas
(unlike oesophageal cancer)
In common with other gastrointestinal tumours, the
majority of tumours of the pancreas are adenocarcinomas
developing from the exocrine component of the organ.
is believed to be due to local environmental, mainly die- Because of the high concentration of endocrine cells in the
tary, factors. Recognized dietary factors include spiced pancreas, they are also the commonest site for endocrine
foods, dietary nitrates, as well as smoking and alcohol. tumours and account for 15% of pancreatic neoplasms.
Helicobacter pylori infection, which is known to predis- The site of the tumour in the pancreas and the nature of
pose to peptic ulcer disease, has also been implicated in the cell type involved in the tumour will determine its pre-
gastric carcinomas. Conditions injurious to the gastric senting symptoms.
mucosa, such as pernicious anaemia and atrophic gas- Adenocarcinomas often present with insidious symp-
tritis, are also associated with an increased incidence of toms of unexplained back pain and weight loss. Weight
subsequent neoplastic change. Symptoms due to the loss is particularly marked in pancreatic cancer, per-
primary gastric tumour either arise as a consequence of haps because of malabsorption compounding the cata-
ulceration of the mucosa, or from diffuse infiltration of bolic effects of the tumour. The non-specific nature of
the muscular wall. The ulcerating lesion has been classi- these symptoms can delay diagnosis and as a conse-
fied as ‘intestinal’, whereas widespread infiltration of the quence, these tumours are often unresectable. Tumours
muscle is classified as ‘diffuse’ type. Ulcerating tumours that involve the head of the pancreas may present earlier

Case
11.2 Adenocarcinoma of the pancreas: 1

Adenocarcinoma of the pancreas

A 70-year-old man presented to his GP with symptoms of vague including the pancreas, and endoscopic retrograde pancreat­
upper abdominal pain, which he had noticed over the preced- ography (ERCP). His serum glucose was found to be mildly
ing weeks. From the clinical history, the doctor noted that the elevated, and the CT scan demonstrated a lesion in the head
patient was a smoker. He suspected the symptoms may be due of the pancreas which was compressing the common bile
to peptic ulcer disease and prescribed a course of H2 antagonists. duct. At ERCP, cytology brushings were taken from the pan-
The patient returned after 2 weeks without resolution of his creatic duct, which subsequently supported the diagnosis
symptoms. On this occasion, the patient declared that the pain of adenocarcinoma at the head of the pancreas. During the
had spread to his back. The doctor considered the symptoms may same procedure, a short plastic tube (stent) was placed into
be due to gallstones and arranged an ultrasound scan of the gall the common bile duct to allow free drainage of bile from the
bladder. The ultrasound scan confirmed stones in the gall blad- liver.
der, but also suggested that there was a degree of dilatation of Unfortunately, the tumour was found to be encasing the supe-
the common bile duct. The serum bilirubin level was checked rior mesenteric artery and curative resection was not possible, as
and was found to be elevated. These findings suggested that it would require division of the blood supply to the small bowel.
there was an obstruction at the lower end of the common bile Nonetheless, the patient’s symptoms from obstructive jaundice
duct and the GP referred the patient to a gastroenterologist. were relieved with the stent and pain control was achieved by
At the hospital, the patient underwent further investiga- injection of the nerves in the coeliac plexus.
tions including blood glucose, CT scan of the upper abdomen

188 SYSTEMS OF THE BODY

 11
because of obstruction to the common bile duct. The com- of the tumour can be associated with restoration of normal

Gastrointestinal pathology
monest symptoms are progressive jaundice due to obstruc- glucose control. This could provide a future mechanism for
tion of the bile duct, and steatorrhoea due to obstruction earlier diagnosis of this increasingly common condition.
of the pancreatic duct and malabsorption of fat. Some
early tumours of the head of the pancreas may be curable
with radical surgery. The rarer endocrine tumours of the Acute abdominal pain
pancreas will often present with symptoms due to hyper-
secretion of hormones. An insuloma or glucagonoma may Diagnosis of the cause of acute abdominal pain is one of
present with hypoglycaemia or diabetes, respectively, the more challenging aspects of clinical medicine. Because
whereas a gastrinoma will present with intractable peptic of the lack of a somatic sensory nerve supply, identify-
ulceration and diarrhoea (Zollinger–Ellison syndrome). ing the diseased organ and the nature of the pathology
It has long been recognized that pancreatic cancer is asso- requires a clear understanding of the anatomy, innervation
ciated with maturity-onset diabetes. It was believed that the and physiological function of the different gastrointestinal
injurious process that caused diabetes resulted in subse- structures. There are two sources of intra-abdominal pain.
quent tumour development. However, more recent studies Pain may arise from stimulation of the autonomic affer-
have shown that pancreatic adenocarcinomas may secrete ent nerves innervating the abdominal organs. This results
an anti-insulin factor that can cause diabetes, and removal in poorly localized abdominal discomfort that manifests

Case
11.2 Adenocarcinoma of the pancreas: 2

Treatment
Abdominal pain that is localized to the upper abdomen can
be caused by any structure derived from the foregut. This
would include conditions affecting the stomach, gall bladder,
or pancreas. Pancreatic diseases may involve the coeliac plexus
which lies in close proximity and results in pain that also radi-
ates through to the back.
Investigation of the upper abdomen frequently identifies
gallstones, but these are often asymptomatic and may not
be the cause of the pain. The bile duct passes through the
head of the pancreas before entering the duodenum, and
as a consequence tumours in this area can compress the duct
and obstruct the flow of bile from the liver. This results in
(obstructive) jaundice. The bile duct and pancreatic duct can
be visualized by endoscopy. The tissue of the pancreas is best
demonstrated by a CT scan of the upper abdomen (see Fig.
4.6). At ERCP, cells that have been shed into the ducts can be
Bile

sampled for microscopic evidence of neoplastic change (cytol-

duct

ogy). Because tumour tissue is generally friable this provides a

useful method of diagnosis in less accessible tumours. A rigid
e
op

plastic tube can be placed into the bile duct at endoscopy to

sc
do

relieve the obstruction (Fig. 11.4).

En

The superior mesenteric artery passes just posterior to the

neck of the pancreas. This vessel supplies the whole of the
midgut. It has to be preserved or the small bowel will be
devascularized. If a tumour is involving this artery, surgical
excision is impossible. Pain from advanced disease of the pan-
creas is often due to involvement of the nearby coeliac plexus
nt
Ste

of autonomic nerves. Injection of this region can safely oblit-

erate the nerves and so help to reduce the pain.

Fig. 11.4  A radio-opaque stent has been placed in the common

bile duct using an endoscope, which has been passed via the
stomach into the duodenum. The grossly dilated bile ducts have
been made visible by the injection of contrast via the stent.

THE digestive SYSTEM 189

11
in the region of the corresponding somatic afferent nerve rise to a pain of more insidious onset (gall bladder). Pain
Gastrointestinal pathology

root. This is known as referred pain. Because the gastroin- due to distension is initially due to stimulation of stretch
testinal tract is derived embryologically from a mid-line receptors. As a consequence, the pain is often cyclical in
structure, pain is referred to the mid-line, usually ante- nature (colic). This contrasts with pain from inflamma-
riorly. This is typified by inflammation of the appendix, tion of tissue, which gives rise to a persistent pain (such
which derives its autonomic nerve supply from the level as pancreatitis).
of T10 (along with the rest of the midgut). Pain is there-
fore referred to the peri-umbilical region, which is inner-
vated by somatic sensory nerves that enter the spinal cord Surgical resections
at the same level (T10). Pain from the large bowel also
refers to the mid-line, but to the infra-umbilical region. Most major surgical resections performed on the gas-
Pain from foregut structures (stomach and duodenum) trointestinal tract are for the treatment of cancer. The fact
is referred to the central upper abdominal region (epigas- that, following most procedures, patients are able to con-
trium, see Fig. 11.1). tinue a normal and active life without nutritional support
The second type of abdominal pain is due to inflam- demonstrates the considerable amount of redundancy in
mation of the overlying parietal peritoneum. This has the digestive system, and also its ability to adapt even
its own somatic innervation and, therefore, results in after radical resections.
well-localized pain over the area of inflammation. This is Major surgical resection of the oesophagus is under-
referred to as peritonism. In the case of appendicitis, pain taken for oesophageal carcinoma, when the disease is local-
moves from the peri-umbilical region to the right lower ized. Although this operation is rarely curative it provides
abdomen region (right iliac fossa) once the inflammatory remarkably good symptomatic relief from pain and obstruc-
process in the appendix penetrates through the serosal tion, allowing the patient to return to a largely normal
surface resulting in secondary inflammation of the over-
lying parietal peritoneum (Fig. 11.1).
The speed of onset of the pain can also help determine
the nature of the organ involved. Very muscular struc- Case
tures with a narrow lumen will quickly cause severe pain 11.3 Acute appendicitis: 2
if they become acutely distended (such as the ureter).
Thin-walled distensible structures will, however, give Pathophysiology
The pain from the appendicitis often starts in the peri-
umbilical region. As a midgut structure it derives an auto-
nomic nerve supply from the level of T10, which is referred
Case
11.3 Acute appendicitis: 1 to the umbilicus. Once the inflammatory process in the
wall of the appendix reaches the serosal surface, it causes
secondary inflammation of the overlying peritoneum. This
Case history results in somatic pain, which becomes localized to the
A 20-year-old man called out his GP complaining of severe right iliac fossa. Any stretching of the peritoneum, which
lower abdominal pain. On enquiry, the patient described a may be caused by movement or by palpation, will result in
pain that had started insidiously and was initially centred pain localizing to the right lower quadrant. This inflamma-
around his umbilicus. He had first noticed it when he got tory process also produces reactive changes in the overly-
out of bed, but had thought nothing of it. When he arrived ing structures such as the small bowel and omentum, which
at work, the pain started to become more severe. He could become adherent. The inflammatory exudate, which is seen
not get comfortable and was unable to eat lunch. The pain at operation as a purulent fluid in the peritoneal cavity,
shifted to the right lower abdomen and started to prevent contains large numbers of white blood cells. Patients com-
him from walking. He returned home early and despite monly describe a loss of appetite. This is believed to be due
going to bed the pain persisted. to the triggering of the ileo-gastric reflex, which impairs
On examination, the GP found the patient to have pyrexia gastric emptying. In addition there is a protective ‘ileus’,
and a tachycardia. Palpation of his abdomen revealed ten- which reduces the peristaltic activity of the small bowel.
derness localized to the right lower quadrant. The pain was The appendix has an end artery supply, and inflammation
made worse on releasing pressure (rebound tenderness). through the wall of the appendix can easily result in throm-
The GP also tested the patient’s urine but found no evidence bosis of the blood supply. This can cause gangrene in the
of protein or blood. He contacted the local hospital which wall and result in perforation of the appendix. Delaying the
admitted the patient and as his symptoms and signs had diagnosis and treatment of appendicitis is a common cause
not improved, proceeded to arrange for him to undergo an of peritonitis, because of perforation of the appendix wall.
appendectomy. At operation the small bowel and omentum The doctor checked the patient’s urine for evidence of a uri-
were adherent to an inflamed, swollen, necrotic appendix. nary tract infection which may have mimicked the symptoms
Postoperatively, the patient made a rapid recovery and was of appendicitis. As there were no red blood cells or protein in
able to return home on the third postoperative day. the urine, a urinary tract infection was regarded as unlikely.

190 SYSTEMS OF THE BODY

 11
diet. Most tumours of the oesophagus involve the lower Oesophagus

Gastrointestinal pathology
two-thirds. Removal of this portion of the oesophagus is
possible. Restoration of continuity can be achieved by mobi-
lization of the stomach, which is brought into the chest and
connected to the remaining oesophagus in the upper thorax.
This is possible because the blood supply of the stomach is
so plentiful that the right gastric vessels can be divided and
the blood supply sustained on the left gastric artery. If a A
more radical resection of the oesophagus is required then a
length of small bowel can be placed in the chest to be joined
from the throat to the stomach. This requires re-anastomosis
of the arterial supply and venous drainage as the superior
mesenteric vessels (supplying the small bowel) are insuffi-
ciently long to reach into the upper thorax. Jejunum
Replacement of the oesophagus will result in loss
of normal peristalsis and so the patient will need to sit
upright when eating. In addition there will be impair- Common
ment of the motility and storage capacity of the stomach bile duct
because of division of the vagal nerves. This requires the
patients to eat smaller and more frequent meals to sus-
tain their nutrition. This minor lifestyle adaptation is
usually all that is required.
Removal of the antrum and pylorus of the stomach can
be undertaken for the complications of peptic ulcer dis-
ease and occasionally for carcinoma of the stomach. This
portion of the stomach mucosa contains the majority of Duodenum
the gastrin-secreting G cells, and as a result, resection dra-
matically reduces acid secretion in the stomach. In addi-
tion, there is loss of the pyloric control of gastric emptying B
and reduced storage capacity. The stomach remnant can
be reconnected to the proximal duodenum or the upper Fig. 11.5  The anatomical arrangement following a total gastrectomy
jejunum. This results in premature release of chyme from usually performed for a carcinoma of the stomach. The proximal
the stomach, in advance of the release of digestive juices jejunum (A) is joined to the oesophagus. The bile and pancreatic juice
from the gall bladder and pancreatic duct. The main con- is directed away from the oesophagus by rejoining the fourth part of
sequence of this is impaired fat absorption and sometimes the duodenum to the mid-jejunum (B).
osmotic diarrhoea from incomplete digestion. Patients can
usually control these symptoms by simple modification of
their diet. The functional consequences of the loss of gas- on gastrointestinal function. However, loss of intrinsic
trin are not usually clinically apparent. An interesting, but factor does require replacement therapy by subcutaneous
relatively rare, complication of this operation is paradoxical injection of vitamin B12.
hypoglycaemia following meals. The patient complains of Removal of the gall bladder (cholecystectomy) is one
symptoms of sweating and feeling faint soon after meals. of the most common abdominal procedures performed in
This is due to inappropriate release of insulin from the the Western world. The gall bladder is removed by divi-
pancreas in response to ingestion of food, but in advance sion of the cystic artery and cystic duct, but the common
of sufficient absorption of glucose from the gastrointestinal bile duct is left intact to enable free drainage of bile from
tract to counterbalance the insulin release. the liver into the duodenum. Loss of the storage reservoir
Gastric carcinoma may require total gastrectomy in an for bile salts results in adaptation of bile salt present in
attempt to cure the disease. In this case, the jejunum is the liver. Following surgery, the bile is present in higher
brought up to connect with the oesophagus, and the distal volumes from the liver and is released continuously into
(the fourth part of) duodenum is re-joined to the jejunum the duodenum at a slow rate. On ingestion of a fatty
more distally (Fig. 11.5). This anatomical rearrangement meal, liver bile release increases rapidly which compen-
is necessary because the alkaline secretions from the gall sates for the lack of a gall bladder, and patients are able
bladder and pancreas would cause severe ulceration of the to tolerate meals with even a high fat content. There is an
unprotected oesophageal mucosa if allowed to come into interesting secondary effect from this operation and that
direct contact with it. Loss of the whole stomach does sig- is the increased rate of bile uptake from the ileum into
nificantly impair the storage capacity of the digestive tract. the enterohepatic circulation. This results in a higher pro-
As a consequence, the patients must eat more frequent and portion of secondary bile acids because of the increased
smaller meals to maintain nutrition. Loss of acid secretion, circulation of the bile. There is some evidence to suggest
pepsinogen and gastrin, all have surprisingly little effect that this may have a potentially carcinogenic effect on the

THE digestive SYSTEM 191

11
large bowel and there is an association with an increased
Gastrointestinal pathology

incidence of colorectal cancer.

Resection of the pancreas is a technically challenging
procedure carried out both for inflammatory diseases of
the pancreas (pancreatitis) and also for pancreatic cancer.
Most pancreatic tumours arise in the head of the pancreas.
1
When they are diagnosed at an early stage they can be
treated successfully by removal of the head and neck of 3
the pancreas. Because the pancreas receives a joint blood 2
supply with the duodenum, it is safer to remove the duo-
denum together with the head of the organ. This requires
the common bile duct, tail of the pancreas, and stomach, to
be re-joined with a loop of jejunum (Fig. 11.6). Safely join-
ing the bowel to the pancreas is a hazardous procedure.
This is partly because the tissue of the pancreas is soft
and friable but also because activated digestive enzymes
released from the pancreas interfere with the healing pro­
cess at the anastomosis. Following this major procedure,
patients will have impaired fat and protein metabolism.
This is not usually due to insufficient pancreatic secretion,
but rather to premature stomach emptying without coor- 4
dinated secretion from the pancreas and liver. It can be
partially overcome by preservation of the pyloric sphinc-
A
ter (pylorus-preserving Whipple’s procedure).
Total pancreatectomy is in one respect a safer opera-
tion, because anastomosis to the remaining pancreas is
not required. It does, however, involve loss of all endo-
crine and exocrine secretions from the pancreas. For
satisfactory digestion of food, it is necessary to add pan-
creatic enzyme supplements to the diet. In addition, these
patients are diabetic, and because there is loss of both
insulin and glucagon, control of their diabetes is espe-
cially difficult, sometimes referred to as brittle diabetes.
Liver resection is being undertaken with increasing
frequency, particularly for the treatment of metastases
from colorectal cancer. Gastrointestinal tumours most
commonly metastasize via the portal venous system to
the liver, making this a common site for metastatic dis-
ease. The ability of the liver to cope with even major
resections is remarkable. It is perfectly feasible to remove
75% of the liver and still retain normal function of the
organ. This is in part due to its regenerative properties.
These were recognized even by the Ancient Greeks. The
God Prometheus was punished by Zeus, who ordered
him to be tied to a rock and have an eagle eat his liver.
Prometheus was said to have survived this repeated B
insult because of the regenerative capacity of the liver.
The redundant capacity of the small bowel and its abil- Fig. 11.6  The foregut anatomy (A) before and (B) after a partial
ity to adapt, even after major resection, is similarly note- pancreaticoduodenectomy (Whipple’s resection). The stomach antrum
is divided (1) along with the head of the pancreas (2) common bile
worthy. As a consequence, satisfactory digestive and
duct (3) and the fourth part of the duodenum (4). The specimen is
absorptive capacity is present, even if 60% of the ileum and removed and the proximal jejunum joined to the stomach, bile duct
jejunum are removed. Nutritional support via intravenous and body of pancreas as shown. The operation is usually done for
feeding (parenteral nutrition) may be required if more then a carcinoma of the head of the pancreas.
75% of the ileum and jejunum are removed. This is an un-
usual situation and is usually only required after a vascu-
lar catastrophe when the blood supply from the superior there is insufficient residual digestive and absorptive
mesenteric artery is lost, and the embryological midgut function to sustain life. In addition, the patient will lose
cannot survive on the collateral circulation from the coeliac considerable quantities of fluid (up to 7 L/day), which
and inferior mesenteric arteries. Following such a ­resection, also need to be replaced. It is possible to markedly reduce

192 SYSTEMS OF THE BODY

 11
the secretion by the use of omeprazole (a proton pump

Gastrointestinal pathology
inhibitor), which reduces gastric juice secretion, and as a Table 11.4  Parotid disease
consequence of the higher pH of the chyme, also reduces
secretions in the duodenum. Long-acting somatostatin Presentation Cause Mechanism
analogues, such as octreotide, inhibit pancreatic secretion
Parotid swelling
and can also help to control the fluid and salt loss. Despite
these measures intravenous fluid and nutritional support Painful Infection Ascending bacterial infection
are required. Segmental resections of the small bowel are from the mouth, via the parotid
duct
frequently and safely performed for conditions such as
Crohn’s disease. These segmental resections rarely result in Calculus Parotid duct obstruction results
any significant loss of physiological function. in secondary inflammation in
The large bowel is a common area of surgical pathology the obstructed gland. The pain
is exacerbated by eating which
in the gastrointestinal tract. The most common conditions
stimulates secretion from the
are inflammatory disorders, such as ulcerative colitis and gland
neoplasia, both of which involve the lining of the large
Painless Tumour Usually involves the superficial
bowel. Colorectal carcinoma is usually treated by surgery.
portion of the gland, but
This is both to prevent the life-threatening complications
malignant tumours can invade
of obstruction and perforation and to attempt to cure the the facial nerve which passes
disease. Treatment involves a segmental resection of the through the gland. This will
large bowel along with its arterial blood supply. The arte- result in weakness of the facial
rial blood supply is taken in order to remove the draining muscles on that side
lymph nodes into which tumours commonly spread. As
long as the anal canal is left intact it is possible to reconnect
the two bowel segments, reconstituting intestinal continu-
ity. This results in little change in gastrointestinal function of oral contents into the respiratory tract. The digestive
unless the rectum is removed, in which case there is loss function of this part of the gastrointestinal tract is not
of the storage capacity, and a more frequent bowel action. essential and its impairment has few nutritional conse-
The major function of the large bowel is water absorption quences. Functional impairment in safely transporting
and any remaining colon quickly adapts to overcome the food into the oesophagus can, however, have serious con-
loss of function of the resected segment. sequences in terms of both nutrition and acute respiratory
Ulcerative colitis, when it requires surgical interven- complications.
tion, usually affects the lining of the whole of the large A wide range of benign and malignant conditions can
bowel. As a consequence, surgical treatment involves affect the mouth and oropharynx. Any painful condition
removal of the colon and rectum from the caecum to the can inhibit the patient from eating, including problems
anal canal. Despite the radical nature of this resection, it is with dentition or other infections of the oral mucosa.
still possible to restore continuity by joining the terminal Painless causes include weakness of the facial muscles,
ileum to the anus. The terminal ileum is reconstructed to impairing chewing and swallowing. The commonest
form a new reservoir to replace the rectum. Most patients cause of this is a vascular injury to the contralateral cer-
can maintain continence following this procedure. There ebral hemisphere.
is considerable adaptation of the small bowel, which An acute cerebral vascular injury commonly damages
reduces its secretions and increases the fluid absorption. the motor area, resulting in contralateral facial weakness,
As a consequence, although patients will not pass formed impaired mastication, and dribbling. Injury to the cranial
stools, they will usually only open their bowels three to nerves, particularly the glossopharyngeal nerve, will impair
four times a day. Remarkably, the adaptation of the small swallowing and can result in aspiration of food into the tra-
bowel is such that even in this extreme situation salt and chea, because of loss in sensation to the posterior third of
water loss is controlled and dietary supplements are rarely the tongue and oropharynx. Damage to the hypoglossal
required. There may be an increased loss of bile acids nerve will impair tongue movement but actually has lit-
because of loss of absorption in the terminal ileum and tle effect on the ability to swallow. A viral infection of the
large bowel. This can lead to persistent diarrhoea, but is facial nerve can cause ipsilateral paralysis of the facial mus-
controllable by oral chelating agents which bind the bile cles (Ramsay Hunt syndrome), as can idiopathic paralysis
salts and so reduce their osmotic potential. (Bell’s palsy). The process of mastication is not impaired as
these muscles are innervated by the mandibular nerve.
The salivary glands are another common site of dis-
Mouth and oropharynx ease. Examples of parotid disease are shown in Table
11.4. A painful swelling of the cheek may be due to an
The primary function of the mouth and oropharynx is to acute bacterial infection of the parotid gland. These infec-
initiate the digestive process by chewing and producing tions usually ascend from the mouth via the parotid
salivary secretions, to convey food from the mouth into duct. Drainage from the duct may be impaired by the
the oesophagus, and simultaneously to prevent ­aspiration formation of stones (calculi). Obstruction of the parotid

THE digestive SYSTEM 193

11
Gastrointestinal pathology

Table 11.5  Oesophageal disease

Condition Clinical features Mechanism

Varices Massive gastrointestinal Portal hypertension results in dilation and engorgement of the veins
haemorrhage, and haematemesis communicating between the portal and systemic circulation. Spontaneous
haemorrhage occurs because of the raised venous pressure
Features of cirrhosis Chronic liver disease is associated with morphological changes in the
hepatic architecture. This occludes venous drainage into the inferior vena
cava and results in portal hypertension
Infection Associated with impaired The squamous epithelium of the oesophagus provides effective protection
immunity against infection. This can be impaired by immunosuppression
Infection is often by organisms Impaired immunity results in overgrowth of organisms that are commonly
that are not normally pathogenic present in the oropharynx such as Candida (a yeast) or herpes simplex
viruses
Oesophageal pouch The patient is usually elderly and Weakness in the wall of the upper oesophagus allows the mucosa to bulge
(diverticulum) complains of regurgitation of through the muscle coat. Because this sac is not enclosed by muscle it
‘old’ food cannot contract, so food can collect in it

duct can result in secondary inflammation and swelling

of the gland. The symptoms are exacerbated by eating, Table 11.6  Oesophagitis
because this stimulates the secretion of the obstructed
gland. A painless swelling of the cheek may be due to Aetiology Reflux of gastric content into lower oesophagus
an underlying parotid tumour. Because the facial nerve Failure to clear luminal contents into the stomach
passes through the parotid gland, malignant tumours Symptoms Mechanism
often involve the branches of the facial nerve, and this is Pain Inflammatory changes in the lower oesophageal
a further cause of unilateral facial weakness. mucosa
Dysphagia Secondary fibrosis and narrowing of the lower
oesophagus
Oesophagus
Impaired motility due to damage to underlying
smooth muscle
Disorders of the oesophagus can be divided into motor dis-
Regurgitation Blockage of the lumen. This may result from
orders and mucosal disease (Table 11.5), though the two secondary neoplastic change
can co-exist. In the majority of cases motor disorders are
incompletely understood. Failure to relax the lower end of Weight loss More common in the presence of neoplastic
change
the oesophagus and the lower oesophageal sphincter (LOS)
results in a functional obstruction. This is known as achalasia. Investigation
This unusual condition usually manifests in adult life. Oral Endoscopy Allows direct visualization of the mucosa and
contrast can be swallowed and X-ray imaging will demon- biopsy for histological assessment
strate a grossly dilated proximal oesophagus. A second dis- Barium Allows visualization of the level of an obstruction,
order of peristalsis is known as diffuse oesophageal spasm. swallow and also shows function of peristalsis
In this condition, peristalsis is dysfunctional throughout the
length of the oesophagus. Failure of peristalsis in both of
these conditions results in regurgitation of food. Most condi-
tions can be helped by smooth muscle relaxants. An oesopha- Mucosal disorders of the oesophagus are widespread
geal pouch is also thought to be a motor disorder of the in the population; the most common of these is reflux
oesophagus. The diverticulum occurs between the cricopha- oesophagitis (Table 11.6). Reflux of gastric contents and
ryngeus muscle and the pharyngeal constrictor muscles. A failure to promptly clear the lumen results in chronic
congenital weakness in the wall of the oesophagus allows irritation to the lower oesophageal mucosa. The squa-
the mucosa to bulge through the muscle coat creating a sac in mous epithelium is not designed to be an effective bar-
which food can collect. The condition is thought to develop rier to extreme shifts in the pH. Reflux oesophagitis is a
because of failure of the cricopharyngeus muscle to relax on chronic inflammatory process mediated by acid and pep-
swallowing. Food that collects in the pouch can regurgitate sin from the stomach as well as bile from the duodenum,
into the mouth and pass into the airway (aspiration). A large and can result in ulceration of the mucosa and secondary
pouch may be visible in the neck, and itself can impair swal- fibrosis in the muscle wall. The latter leads to narrowing
lowing because of pressure on the oesophagus. of the lower oesophagus. It is believed that secondary

194 SYSTEMS OF THE BODY

 11
changes in the mucosa may occur, with metaplasia of the

Gastrointestinal pathology
­squamous epithelium into columnar epithelium (Barrett’s Table 11.7  Peptic ulcer disease
oesophagus). This is considered a premalignant condi-
tion and regular endoscopic surveillance is undertaken Aetiology Helicobacter infection of the mucosa impairs the
in these patients. Ulceration of the lower oesophagus protective mechanisms and allows secondary
damage from the acid environment
associated with oesophagitis may also lead to haemor-
rhage. This is unusual and major haemorrhage is more Symptoms Mechanism
commonly associated with peptic ulcer disease or varices Epigastric Inflammatory reaction to chemical injury to the
of the lower oesophagus. pain mucosa, notably hydrochloric acid and pepsin
Oesophageal varices are due to portal hypertension. This Bleeding Erosion of the submucosa exposes the underlying
is a common complication of cirrhosis of the liver which blood vessels which are then vulnerable to damage
causes obstruction to the portal blood flow. The porto- and secondary haemorrhage
systemic anastomoses at the lower end of the oesophagus Sudden Further damage to the deeper muscle layers of the
become massively dilated in response to the raised venous severe wall leads to fibrosis and ischaemia. If this is allowed
pressure. These veins are thin-walled and bleed easily. epigastric to progress the ulcer can erode through the serosal
Bleeding can be massive and life-threatening. The associated pain surface leading to life-threatening peritonitis
liver disease can complicate the situation because of impair- Profuse This is occasionally seen in chronic ulcers in the
ment of coagulation. Optimal management requires occlu- vomiting pyloric region and the duodenum because of the
sion of the veins by endoscopic ligation or sclerotherapy. narrow lumen. Large ulcers in this region can
Infections of the oesophagus are surprisingly rare; cause obstruction to the outlet of the stomach
the squamous epithelium is a highly effective barrier.
Nonetheless, in the presence of impaired immunity, or
obstruction and secondary stasis, infection can occur.
Candidal fungal infection, seen as white plaques in the
oesophagus, is a common infecting organism, particu- caused by a lack of vitamin B12. Approximately 1 in 12
larly if patients have been on long-term antibiotics. Viral affected patients will develop a carcinoma of the stom-
infections are also seen in the immunocompromised ach, and for this reason, regular surveillance endoscopy
patient, notably herpes simplex and cytomegalovirus. of the stomach is performed.
The reason some patients with acute mucosal ulcera-
tion may progress to chronic peptic ulcer disease has
been a field of extensive investigation because of the high
Stomach and duodenum prevalence of this condition (Table 11.7). Environmental
and genetic factors have been implicated. It has been
The most common clinical conditions in the stomach and shown that patients with duodenal ulcers tend to have
duodenum involve the mucosa. The common benign a high basal level of acid secretion in the stomach.
conditions include acute and chronic gastritis, and pep- However, the overlap between the normal range and
tic ulcer disease. Malignant disease in the stomach is an that seen in patients with peptic ulcer disease is consid-
important site for gastrointestinal malignancy, but inter- erable. A major development in understanding this con-
estingly is relatively rare in the duodenum, as is the case dition followed the discovery of H. pylori. This organism
for the rest of the small bowel. This observation indicates is resistant to acid secretion and so can proliferate in the
that the common aetiological factors involved in the mucosa of the stomach and the duodenum. A strong
development of peptic ulcers may differ from those that association between this infection and chronic ulceration
predispose to gastric cancer. has now been established. Historically, the treatment of
Acute gastritis is an inflammatory injury to the peptic ulcer disease has centred on reducing acid secre-
mucosa of the stomach, which is usually due to the tion either by surgical or medical means in order to mini-
ingestion of toxic substances such as drugs or bacteria mize the mucosal damage. Modern therapy, however,
in food. It is probably most commonly seen following focuses on clearing Helicobacter infection by the use of
alcohol ingestion. The condition is self-limiting and does antibiotics. This treatment has been shown to result in a
not usually progress to chronic ulceration. Chronic gastri- high percentage of ulcer healing and, importantly, a low
tis, like other conditions that result in longstanding injury incidence of recurrence of the disease. Historically, pep-
to the bowel mucosa, predisposes to malignant change. tic ulcer disease was one of the most common reasons
The aetiology of chronic gastritis is multifactorial but is for intestinal surgery. The advent of medical therapy
best documented in pernicious anaemia. This is a famil- has revolutionized the management of this condition
ial disorder with a history of an affected relative in 30% and surgery is now largely restricted to the treatment of
of patients. Serum antibodies against gastric parietal cells complications from peptic ulcer disease. Because of the
and intrinsic factor are commonly found. Intrinsic factor erosive nature of these ulcers, they can result in cata-
antibody causes B12 deficiency. The condition is increas- strophic gastrointestinal haemorrhage, or perforation of
ingly common in older patients who may present with the ulcer into the peritoneal cavity. These complications
(megaloblastic) anaemia or even neurological ­ disorders still require surgical intervention.

THE digestive SYSTEM 195

11
they can be asymptomatic. Obstruction of flow of bile from
Gastrointestinal pathology

Hepatobiliary disease
the gall bladder into the common bile duct will, however,
result in biliary colic when the gall bladder attempts to
Disorders of the hepatobiliary system include both dis- contract, and secondary infection in the gall bladder due
eases of the biliary tree and diseases affecting hepato- to stasis (cholecystitis). If the stones pass into the common
cytes (Table 11.8). Diseases that primarily involve the bile duct they often lodge at the narrowing created by the
hepatocytes impair liver function. This causes reduced ampulla of Vater, where the duct enters the duodenum.
production of serum proteins including albumin, and In this position they also obstruct the flow of bile from
as a consequence leakage of fluid into the extracellular the liver and result in obstructive jaundice. This results
space by osmosis (oedema). The patient also develops in dark-coloured urine because of reflux of conjugated
an impaired immune status, resulting in a susceptibil- bile into the systemic circulation, and pale stools because
ity to a range of infections. Derangement of the hepato- of the absence of bile pigment in the faeces, as well as the
cyte organization can obstruct the drainage of the portal classic yellow pigmentation of the skin, most easily seen
vein into the inferior vena cava and so produce a rise in in the sclera of the eyes. Common bile duct stones may,
pressure in the portal venous system. The combination in addition, interfere with the flow of secretions from the
of reduced protein production and raised portal pres- pancreas, and cause acute pancreatitis. An interesting
sure causes fluid to collect inside the abdominal cavity aspect of pain from the gall bladder is discomfort in the
(ascites). right shoulder. This is because it is partly derived embryo-
Disorders of the biliary tree can result in blockage of logically from the diaphragm and shares its autonomic
drainage of the bile into the duodenum. This manifests innervation via the phrenic nerve. These nerves enter the
as jaundice. Chronic obstruction of bile flow can also spine at the level of C4, along with sensory fibres from the
produce (secondary) damage to the hepatocytes because shoulder tip.
of back pressure in the biliary system. It will primarily The management of complications from gallstone dis-
cause obstructive jaundice, which manifests with skin ease is largely surgical. It involves the removal of any
pigmentation, pale stools (due to the lack of bilirubin), stones from the biliary tree in addition to removal of the
and dark urine (due to the excretion of excess bilirubin gall bladder. In the Western world, the vast majority of
by the kidneys). gallstones form primarily in the gall bladder. In the Far
East, where infections of the biliary tract are more com-
Disorders of the biliary tree mon, the formation of stones primarily in the hepatic
duct around the porta hepatis creates considerable man-
The commonest disorder to affect the biliary tree is gall- agement problems because of their inaccessible position.
stone disease. This affects over 5% of the adult population Obstruction to the flow of bile may result from fibrosis
in Britain. While these stones remain in the gall bladder, in the wall of the biliary tree. This is a rare disorder known

Table 11.8  Hepatobiliary disease

Condition Features Mechanism

Gallstones Right-sided abdominal pain Gallstones may obstruct the flow of bile from the gall bladder. Pain is referred to
and shoulder tip pain the shoulder tip because of the level of autonomic innervation (C4). Abdominal
tenderness is due to inflammation of the overlying parietal peritoneum
Fever The stagnant bile becomes infected (cholecystitis)
Jaundice Gallstones may pass from the gall bladder and lodge at the ampulla of Vater. This
will obstruct the flow of bile from the liver
Acute hepatitis Right upper quadrant pain Swelling of the liver stimulates nerves in the liver capsule and overlying peritoneum
Bleeding and bruising Impaired coagulation results from failure to manufacture proteins required for the
clotting cascade
Reduced level of Toxins build up in the systemic circulation because of failure of detoxification and
consciousness excretion in the liver
Chronic hepatitis History of previous liver Most patients have suffered a clinical attack of acute hepatitis. Occasionally this is
damage subclinical and passes unnoticed. This has been seen in hepatitis C infection from
infected blood transfusions
Chronic liver Jaundice Failure to excrete bilirubin
disease (cirrhosis) Oedema (fluid collecting Failure of protein production reduces intravascular osmotic pressure and allows fluid
in the extracellular space), to leak into the extracellular space
swollen ankles, ascites

196 SYSTEMS OF THE BODY

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as primary sclerosing cholangitis. It is occasionally seen in poor prognosis as the reserves of liver function are often

Gastrointestinal pathology
association with inflammatory bowel disease, especially not sufficient to allow safe resection of the primary tumour.
ulcerative colitis, and for this reason is believed to be of Transplantation of the liver, in the presence of a hepatoma
immunological aetiology. The chronic and progressive and cirrhosis, is hazardous. This is because immunosup-
obstruction of the flow of bile results in secondary damage pression, required to prevent rejection of the transplant,
to the hepatocytes. There are currently no effective treat- will result in rapid tumour progression, if there is any
ments for this chronic inflammatory disorder and, if pro- residual disease.
gressive, liver transplantation can be required.

Hepatocellular disease Pancreas

Conditions that result in primary damage to hepatocytes Disorders of exocrine function of the pancreas are an
result in acute hepatitis. This can be due to infections, important cause of malabsorption because of the cen-
usually viral (hepatitis A and B for example), or damage tral role of this organ in the digestion of fat and pro-
by drugs such as paracetamol, or by toxins such as alco- tein. Inappropriate activation of digestive enzymes in
hol. This can result in a range of presentations from mild the pancreas can result in destruction of the organ with
sub-clinical liver injury to massive liver necrosis and potentially catastrophic consequences. This secondary
hepatic failure. Any acute hepatitis can result in long- destructive process results in severe unrelenting epigas-
standing liver cell damage (chronic hepatitis). Progressive tric pain, which usually radiates through to the back.
chronic liver cell injury results in disordered liver archi- The most important endocrine functions of the pancreas
tecture associated with fibrosis and regenerative nod- are the production of insulin and glucagon. Destruction
ules. This is known as cirrhosis. This is an irreversible of these islet cells results in diabetes. The pancreas has
state resulting in impaired hepatic function encompass- considerable reserves of function and destruction of over
ing bilirubin excretion, protein manufacture including 70% of the organ is required before clinical manifestation
immune function, and detoxification of drugs. This gives of diabetes or malabsorption becomes apparent.
rise to the classic stigmata of chronic liver disease. Two Acute pancreatitis is a medical emergency, resulting
important sequelae of cirrhosis are portal hypertension in autodestruction of the organ (Table 11.9). This process
and liver cell tumours (hepatoma). The only therapeutic can be precipitated by bile duct stones, which disrupt
option for advanced cirrhosis is liver transplantation. free drainage of the pancreatic duct, or by acute alcohol
Nutrients from the gastrointestinal tract are transported ingestion, which is toxic to the organ.
via the venous system into the portal vein, which drains The clinical presentation is often seen in middle-aged
directly into the liver. Derangement in the liver architec- women (due to gallstone disease) and young men (fol-
ture, commonly caused by cirrhosis, results in obstruction lowing excessive alcohol ingestion). The destructive
to the blood flow and a rise in portal venous pressure. This process results in severe upper abdominal pain, and is
results in opening up of the collateral venous pathways and commonly associated with vomiting as a consequence of
enlargement of the spleen (splenomegaly). The enlarged irritation of the overlying stomach. The autolysis causes
spleen traps circulating platelets leading to thrombocyto- a massive fluid and protein shift into the extracellular
penia (low blood platelet levels). Collateral veins open up space, depleting the intravascular volume. This can lead
around the falciform ligament, leading to the appearance to poor perfusion of the kidneys (renal failure), leakage
of dilated veins around the umbilicus (caput medusae). The of fluid into the lungs (pulmonary oedema), and general-
clinically important collateral pathway is the communication ized hypotensive shock. The key to treatment is prompt
between the left gastric vein and azygous vein in the lower and rapid intravenous fluid replacement.
oesophagus. These dilated veins in the lower oesophagus Chronic pancreatitis is a related disorder, usually caused
(varices) are fragile and can burst spontaneously, leading by excessive longstanding alcohol ingestion. In this disease,
to life-threatening haemorrhage. As the bleeding is often the destruction of the pancreas is a slow and progressive
accompanied by thrombocytopenia and deranged clotting disorder. Patients gradually develop steatorrhoea because
(because of the underlying cirrhosis), this can exacerbate the of fat malabsorption, and diabetes because of injury to the
bleeding problem. Treatment requires ligation or sclerosis of islet cells. The destruction of the pancreatic tissue results
the dilated veins, which can often be achieved endoscopi- in secondary calcification in the organ and cystic changes
cally via the oesophagus. In the acute setting, direct bal- that are presumed to be due to obstruction of drainage of
loon compression of the veins may be required. This is done the small ductules in the gland. Successful management is
using a specially designed tube (Minnesota tube), which can largely reliant upon the patient ceasing to take alcohol.
be passed from the mouth into the stomach. Cystic fibrosis is a condition that is inherited in an
The commonest malignant tumours of the liver in the autosomal recessive fashion, where both parents are
West are metastatic cancer, often from primary cancers carrying one defective gene. It is due to failure of the chlo-
elsewhere in the gastrointestinal tract. Primary malignant ride pump at the duct cell surface. Before the genetics of
tumours of the liver (hepatoma) are usually seen on a the disease were fully understood, the diagnosis relied
background of cirrhosis. These patients have a particularly upon excessive sodium and chloride being found in the

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small intestine are surprisingly rare given the size of the
Gastrointestinal pathology

Table 11.9  Acute pancreatitis organ, and as a consequence, the most common condi-
tions affecting the small bowel are concerned with altera-
Aetiology Autodigestion of the pancreas by secreted tions of function. The key functional unit in the small
enzymes. Caused by toxic damage (e.g. bowel is the mucosa, and malabsorption is invariably
alcohol) or by obstruction of secretions
due to conditions that are injurious to the mucosal lin-
(e.g. gallstones)
ing. These can be broadly divided into infective and non-
Symptoms infective causes (Table 11.11).
Epigastric pain Local inflammation process damages Improvements in living standards and hygiene in the
autonomic nerves from the coeliac plexus Western world have reduced the frequency and clinical
Vomiting Local irritation of the stomach, which importance of gastrointestinal infections. An acute his-
overlies the pancreas tory of nausea, vomiting and diarrhoea of sudden onset,
Systemic damage often affecting a number of family members, implicates
Shortness of There are massive fluid shifts into the
an infective cause. A range of viruses, bacteria, protozoa
breath extracellular space due to inflammatory or toxins can be implicated. Diagnosis can often be made
injury and local release of digestive by culture of the liquid diarrhoea. Key to the successful
enzymes. Fluid leaks into the lung management of acute infections is the replacement of
extracellular space and into alveoli salts and fluid by the oral route, or, if necessary, the intra-
(pulmonary oedema) venous route. Blood-stained diarrhoea is most likely to be
Hypotension Loss of fluid from the vascular space. This due to a bacterial organism, such as Salmonella, and will
results in underperfusion of many organs benefit from appropriate antibiotic therapy. Most infec-
including the kidneys tions in Britain today are due to viruses or toxins, and are
Investigations self-limiting. Cholera remains a major killer worldwide,
although improvements in water supply and sewerage
Serum amylase Inappropriately released into the system
from the damaged pancreatic cells
have helped to control this infection. Salmonella remains
an important bacterial infection even in the West, and
CT scan This will demonstrate swelling and
in the 1990s, reports of infection by poultry products
destruction of the pancreatic gland and
surrounding tissue
received considerable media attention. Chronic sub-
clinical infections can occur, usually in the biliary tree. As
ERCP This enables the pancreatic and bile ducts a consequence, members of the public who handle food
to be visualized and can demonstrate
and food products continue to be a source of outbreaks
gallstones stuck at the ampulla of Vater
(see Fig. 11.4). Stones can also be removed
of this infection.
at this procedure

Crohn’s disease
patients’ sweat. Because this is such an important cellular The cause of chronic symptoms of diarrhoea can be more
mechanism, the consequences are widespread (Table 11.10). difficult to ascertain. Crohn’s disease provides a good
Newborn babies may be born with acute constipation due example of chronic small bowel disease (Table 11.12).
to meconium obstruction in the large bowel; this is known Although it is relatively rare, with an incidence in the UK
as meconium ileus. They may also have a failure in lung of approximately 1 in 10 000, Crohn’s disease is a chronic
expansion because of difficulty in clearing secretions. This condition with periods of remission and exacerbation, and
problem continues throughout life. Secretory problems in patients are frequent presenters to the health services. They
the pancreas result in obstruction of the duct and late pan- develop classical symptoms of diarrhoea and abdomi-
creatic failure as well as the development of adult onset nal pain, associated with weight loss. It can be genetically
cirrhosis of the liver. The management of this condition determined, and mutations in the CARD15 gene (encod-
has progressed rapidly over the last decade. Identification ing for the NOD2 receptor) have been shown to cause the
of the cystic fibrosis gene enables detection of carriers of disease in some families. This protein is involved in the
the affected gene. Life expectancy has been prolonged by inflammatory response and is believed to alter the response
aggressive chest physiotherapy to help with secretory to some infective/inflammatory stimuli in the gut.
problems in the lungs, and respiratory failure can now be This chronic granulomatous disease can affect any part
treated by lung transplantation. Gene therapy trials are of the gastrointestinal tract, but most commonly involves
now underway for this condition. the terminal ileum. Genetically determined predisposi-
tion is known to play a part in this condition, but a wide
range of aetiological factors have been implicated. These
Small bowel conditions include viral infection, microbial infection, dietary and
vascular factors. None of these have been established as
The primary function of the small intestine is to absorb causative in the condition and the aetiology is likely to
fluid and nutrients that are ingested. Tumours of the be multifactorial.

198 SYSTEMS OF THE BODY

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Gastrointestinal pathology
Table 11.10  Pancreatic diseases

Condition Features Mechanism

Diabetes mellitus Polyuria and polydipsia Failure of insulin secretion results in a high blood sugar. This increases the
osmotic potential of the filtrate and causes high urine volumes (polyuria). The
hypovolaemia and raised serum osmolality stimulate thirst receptors (polydipsia)
Coma Deranged glucose and fatty acid metabolism results in a metabolic acidosis.
Combined with hypovolaemia this causes a reduced level of consciousness, and
death, if not treated promptly
Chronic pancreatitis Longstanding alcohol abuse Alcohol is toxic to the pancreatic gland
Epigastric pain Inflammation around the autonomic nerves in the coeliac plexus
Weight loss and diarrhoea Failure of exocrine function results in incomplete digestion
Diabetes mellitus Failure of islet cell function
Cystic fibrosis Constipation Failure in the Na/Cl exchange pump results in pancreatic failure and deranged
fluid secretion/absorption in the gut. This manifests as mechanical obstruction in
the neonate (meconium ileus) and constipation in later life
Respiratory failure Abnormal secretions in the alveoli and bronchioli result in airway obstruction and
alveolar collapse. Neonates may suffer from impaired lung expansion and adults
suffer recurrent respiratory infections

Table 11.11  Small bowel conditions

Condition Clinical features Mechanisms

Malabsorption
Coeliac disease Chronic diarrhoea, weight loss, Autoimmune disease of the small bowel. Malabsorption of fat results
anaemia. Most commonly in adults in bulky, pale, offensive-smelling stools that often float in the toilet.
Failure to absorb protein results in a net loss of protein from the body
and loss of muscle bulk. Anaemia may result from failure to absorb
folate and iron
Infection
Salmonella typhus Sudden profuse watery diarrhoea, The bacillus infection causes acute ulceration of the mucosa
which may be blood-stained. throughout the small and large bowel with associated loss of water
Associated with a high fever and protein, resulting in watery diarrhoea. The ulcerated mucosa
tends to bleed. The bacillus spreads through the bloodstream via the
portal vein, infesting the liver and creating a marked inflammatory
response with a high temperature
Cholera Severe watery diarrhoea with loss of The Vibrus cholera bacterium does not cause ulceration of the
many litres of fluid each day mucosa, but causes failure of the salt/water exchange pump allowing
profuse amounts of water to pass into the bowel lumen. This
results in watery diarrhoea because the colonic mucosa is unable to
reabsorb the high volume. Protein loss is not seen
Ischaemia Abdominal distension, bleeding from Impaired blood supply damages the mucosa first because of its large
the bowel and abdominal pain oxygen requirement and high cell turnover. This results in mucosal
ulceration and venous bleeding. The ischaemic bowel loses its normal
contractility, resulting in bowel dilatation and abdominal distension

The inflammatory process in Crohn’s disease affects formation and perforation into other loops of bowel or
the full thickness of the bowel wall. As a consequence, other organs, such as the bladder, can occur (fistula). A
ulceration and secondary fibrosis can result in blockage combination of medical treatment to control the disease,
of the lumen. As the inflammatory process penetrates to and surgical treatment to deal with its complications, is
the external surface of the bowel (serosa), local abscess required. At present there is no curative therapy.

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Gastrointestinal pathology

Table 11.12  Crohn’s disease

Aetiology Multifactorial: genetic predisposition has been established through family studies, but
only one specific genetic defect has yet been identified (NOD2). Microbiological flora,
superimposed infection, and dietary factors have all been implicated. These factors may exert
their effect on a genetically predisposed population
Symptoms Mechanism
Abdominal pain/weight loss Usually from (incomplete) blockage to the passage of food through the small bowel due to
narrowing of the lumen. Malnutrition results from reduced nutritional intake, in addition to
impaired absorption and protein loss from the diseased mucosa
Diarrhoea Fluid and protein loss from the ulcerated mucosa is the primary cause. Secondary bacterial
overgrowth proximal to the obstruction compounds the symptoms
Fatigue Anaemia is a common feature of this condition. Poor nutrition combined with chronic
bleeding from the ulcerated mucosa results in an iron deficiency. The terminal ileum is
commonly involved in this disease and impaired resorption of intrinsic factor may result in B12
deficiency
Localized abdominal swelling Intra-abdominal abscesses are a common feature of this condition. Because the whole
thickness of the bowel wall is involved in the inflammatory process deep ulcers or fissures can
perforate through to the serosal surface
Painful mouth ulcers and anal canal ulcers The condition can affect any part of the digestive tract. As the mouth and anal canal are the
only regions with a somatic innervation, these lesions are locally painful

Coeliac disease disruption of the mucosal barrier. Persistence of the ischae-

mic episode will result in secondary damage to the bowel
Coeliac disease is a rare condition that affects the mucosa wall by digestive enzymes. Resolution of the ischaemia at
of the small bowel and, like Crohn’s disease, also results this stage can result in secondary fibrosis and stricturing.
in malabsorption. It does not, however, cause ulceration Ischaemia that persists beyond a few hours results in loss
or stricture formation. It is caused by a sensitivity to glu- of integrity of the bowel wall (perforation) and ultimately
ten in the diet. Symptoms are usually completely relieved leakage of intestinal contents into the peritoneal cavity
by adoption of a gluten-free diet. (peritonitis), which can be fatal. Acute ischaemia of the
Like Crohn’s disease, there is known to be an inher- gastrointestinal tract is a relatively rare event because of
ited predisposition to coeliac disease, with up to 20% the extensive collateral circulation between the mesenteric
of siblings being affected. The genetic determinants of arteries. Complete occlusion of the superior mesenteric
this condition are as yet undefined. The classical his- artery, either by thrombosis or an embolic event, may still
tological features are of villous atrophy, which is most not lead to infarction because of the collateral blood supply
marked in the proximal small bowel, associated with a of the coeliac axis and the inferior mesenteric artery.
chronic inflammatory infiltrate. Although the disease Ischaemia of the small bowel is more frequently a result
may present at any age, it is most commonly seen in the of localized venous occlusion. This is most commonly seen
third and fourth decades, suggesting that the sensitivity when the bowel is twisted or trapped in a hernia sac. This
to gluten is in part acquired. In addition to chronic diar- is made possible because of the mobile nature of the small
rhoea, the most prominent symptoms are weight loss and bowel, the blood supply of which is provided through the
fatigue, due to malabsorption. mesentry. Here, the arterial pressure is usually sufficient
to continue to perfuse the loop of bowel, but the venous
drainage which is at a lower pressure is occluded. In this
Acute ischaemia situation, back pressure into the capillary beds results in
ischaemia by secondary obstruction to arterial flow.
Acute ischaemia of the gastrointestinal tract is a medical
emergency. Some 10% of the cardiac output flows to the
gastrointestinal tract. Interruption of this blood flow first Infective diarrhoea
affects the mucosal layer of the bowel. Fluid collects in
the submucosa resulting in oedema and the mucosal cells Intestinal infections (Table 11.11) have historically been
quickly start to slough into the lumen. This results in blood- a major cause of morbidity and mortality, and continue
stained diarrhoea. These changes are reversible because the to be so in underdeveloped countries. The main causes
mucosa has regenerative properties. It can be associated of death are dehydration and electrolyte loss, making
with a fever, due to an associated bacteraemia, because of infants and the elderly particularly susceptible.

200 SYSTEMS OF THE BODY

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Cholera is due to infection of the gastrointestinal tract

Gastrointestinal pathology
by Vibrio cholera and continues to be an important infec- Table 11.13  Large bowel disease
tion in developing countries because of contaminated
drinking water. The symptoms of profuse watery diar- Condition Features Mechanism
rhoea are as a consequence of the blockade of the sodium
Diverticular Central, lower, Referred pain from the
exchange pump by the enterotoxin. Fluid loss can be as
disease abdominal pain embryonic hind gut. Muscle
high as 1 L/h and rapidly results in hypovolaemic shock, hypertrophy in the wall of
acute renal failure and metabolic acidosis. the bowel results in spasms
In contrast, Salmonella typhi and Shigella infections of pain (colic)
directly damage the mucosa of the gastrointestinal tract.
Fever The diverticulum can become
Shigella infections result in moderate amounts of diar- obstructed and infected. This
rhoea associated with a high fever. Damage to the bowel results in a small abscess in
mucosa also results in protein and microscopic blood the wall of the colon
loss. Shigella dysenteriae has more effect on the large Generalized Rupture of the diverticulum
bowel mucosa, and is associated with frank blood loss in abdominal into the peritoneal cavity
the stool, because the blood is not degraded by protein- pain and can cause generalized
ases as when it occurs in the small bowel. Salmonella typhi tenderness intraperitoneal infection
infections can be transmitted from contaminated water or (peritonitis)
food and, like Shigella, directly invade the small intesti- Ulcerative Diarrhoea and Ulceration of the large bowel
nal mucosa. This initial infection is not, however, directly colitis bleeding mucosa results in failure
toxic to the mucosal cells and the organisms spread to the to absorb water from the
liver via the mesenteric blood supply. Here, a secondary lumen, and bleeding from
incubation period is followed by a clinical bacteraemia. the submucosal vessels
The accompanying inflammatory reaction to this infec- Abdominal Mucosal failure results in loss
tion results in ulceration of the bowel mucosa, producing distension of peristalsis and a functional
diarrhoea, bleeding and fever. As a consequence of the obstruction. The proximal
direct damage to the mucosa, the diarrhoea results in bowel can dilate and even
protein loss in addition to salt and water loss. Because perforate causing peritonitis
these infecting organisms have a different mechanism (toxic megacolon)
of action, the incubation period for each infection varies. Dysentery May follow Infection from ingestion of
A cholera infection will manifest symptoms within 12 h, foreign travel contaminated food or water
but a Shigella infection will usually take several days. Entamoeba Blood-stained Ulceration of the mucosa
Because of the secondary incubation period, a Salmonella histolytica diarrhoea results in water/protein
infection has an incubation period of about 10 days. loss and bleeding from the
Amoebic dysentery remains an important cause of infec- submucosal vessels
tive diarrhoea in the tropics. It is caused by the ingestion
of food and water contaminated by the cysts of Entamoeba
­histolytica. The cysts develop into trophozoites, which invade in bowel habit, which may be either diarrhoea or constipa-
the mucosa of the colon and can penetrate all the layers of tion, together with rectal bleeding and lower abdominal
the intestinal wall. This results in ulcer formation and sec- pain. Inflammation of the mucosa of the large bowel usu-
ondary blood-stained diarrhoea. As is the case with many ally results in diarrhoea. The important causes are diver-
intestinal infestations, some individuals fail to develop inva- ticulitis, ulcerative colitis and infection.
sive disease and remain asymptomatic carriers. The con- Diverticular disease has a high prevalence in the
dition can mimic ulcerative colitis because of the mucosa Western world. This is believed to be due to a low-fibre
ulceration, but the diagnosis is readily established from diet, which results in raised intraluminal pressure in
biopsy of the ulcer or from examination of fresh stools for the large bowel. This in time leads to muscle hypertro-
the presence of cysts. The condition is readily treated by anti- phy in the wall of the colon and pulsion diverticula in
biotics. Because the ulcers penetrate the full thickness of the the wall of the bowel (Fig. 11.7). The diverticula are out-
bowel wall, secondary stricture formation in the large bowel pouchings of the mucosa through the muscle coat of the
can be seen following treatment. colon. Without a muscle coat these little mucosal sacs
are unable to empty, and faecal residues become lodged
in the sac, predisposing the individual to secondary
Large intestine infection. Colonic diverticulae are present in 30% of the
population aged 55 years and over, but the majority are
The most important disease of the large bowel is that of asymptomatic. Complications occur because ulceration
colorectal cancer. Nonetheless, benign disorders of the large of the mucosa in the wall of the diverticulum results in
bowel also form an important group of clinical ­ disorders ­bleeding, or obstruction to the neck of the diverticulum
(Table 11.13). All large bowel disease results in alteration results in abscess formation with or without perforation
of bowel habit. The key symptoms are those of a change into the peritoneal cavity. These complications are only

THE digestive SYSTEM 201

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Gastrointestinal pathology

Ulcerative colitis

This is an inflammatory condition that is limited to the

mucosa of the large bowel. Its incidence has been esti-
mated at approximately 2% per annum in the West, but
the vast majority of these patients have disease that is
mild and limited only to the rectal mucosa. In a small
proportion of cases, the inflammation extends throughout
the large bowel mucosa and can result in a more florid
illness. The aetiology of this condition is not known, but
like Crohn’s disease, it is believed to be due to a sensitiv-
ity to environmental factors that have yet to be identified.
There is an underlying genetic predisposition in at least a
proportion of cases. It is interesting to note that ulcera-
tive colitis and Crohn’s disease may be seen in the same
family, suggesting common aetiological factors.
Extensive mucosal damage results in watery, blood-
stained diarrhoea. Infective causes of diarrhoea should
always be excluded. Diagnosis is by histological exami-
nation of mucosal biopsies. As is the case elsewhere in
the digestive tract, extensive ulceration of the mucosa
can result in bacteria migrating from the lumen into the
Fig. 11.7  An X-ray of the large bowel, which has been coated with
barium. Moderate diverticular disease is apparent in the sigmoid
portal system. Although the condition is limited to the
colon. This shows up as small out-pouches filled with barium (circled). mucosal lining of the bowel, acute florid attacks will
result in transmural inflammation and can lead to sec-
ondary perforation and peritonitis. Treatment requires
seen in about 1 in 50 patients with diverticular disease, fluid and salt replacement and antibiotics to control any
but when they do occur they can be life-threatening. secondary infection.
Obstruction to the flow of faecal contents in the large Immune suppressive therapy is used to dampen down
bowel is life-threatening, because the ileocaecal valve, lying the inflammatory destruction. In a small percentage of
at the proximal end of the colon, creates a closed loop that patients, medical treatment is unsuccessful and emer-
can only decompress by perforation of the colon. Perforation gency surgery with removal of the large bowel (colec-
usually occurs at the caecum where the wall is thin and dis- tomy) is required. Longstanding disease also increases
tends easily. Colorectal cancer is the commonest cause of the risk of secondary colorectal cancer in these patients
large bowel obstruction, but obstruction of a diverticular and occasionally a prophylactic colectomy is necessary to
abscess or scarring in the wall of the colon following acute prevent malignant disease developing. Advances in sur-
diverticulitis can also cause this problem. The treatment is gical techniques have enabled the development of ileo-
surgical, and requires resection of the obstructing segment, anal anastomosis, which reconstitutes bowel continuity
and where possible, reconstitution of the bowel continuity and avoids the formation of a permanent stoma in many
by anastomosis to the rectum. of these patients.

202 SYSTEMS OF THE BODY

GLOSSARY

abetalipoproteinaemia – a rare autosomal recessive the wall of the abdomen.

disorder characterized by a low plasma level of betalipo- computed tomography (CT) scanning – a radiographic
protein. scanning procedure where the detailed structure of a
aborally – in a direction away from the mouth. tissue is revealed by densitometry. The body is imaged
achalasia – a motor disorder in which a muscle is unable in cross-sectional slices and the computer quantifies the
to relax, particularly the lower oesophagus and the lower X-ray absorption by the tissues.
oesophageal sphincter (cardiospasm). congestive heart failure – a pathological condition that
achlorhydria – lack of hydrochloric acid secretion in reflects impaired cardiac pumping of the left and right
gastric juice. ventricles.
acholic – absence of bile secretion. constipation – difficulty in passage of stools or infre-
adenocarcinoma – a malignant tumour of the glandular quent passage of stools.
epithelium (e.g. colonic mucosa). cytopemsis – vesicular transport.
aetiology – the study of the causes of a disease. deglutition – swallowing.
aganglionic – displaying an absence of ganglionic cells. diarrhoea – an abnormal increase in stool liquidity and
amorphous – without visible structure. in daily stool volume.
anaemia – a reduction in total blood haemoglobin. diuresis – increased production of urine.
anastomosis – a connection between two vessels or a diverticulitis – infection in one or more diverticula, usu-
surgical joining of two bowel segments to allow flux of ally of the sigmoid colon.
the contents from one to the other. diverticulosis – the presence of pouch-like herniations
aneurysm – a localized dilatation of the wall of a blood (diverticula) in the muscular layer of the colon, especially
vessel. the sigmoid colon.
anorexia nervosa – a condition in which the desire for dysaesthesia – altered perception of oral sensation.
food is lost. dysphagia – difficulty in swallowing.
antidiuretic – a substance which diminishes urine ectasia – dilatation of a duct, vessel or hollow viscus,
production. usually resulting from obstruction to flow or degenera-
aphagia – a condition in which there is an inability to tive changes of the wall.
swallow. ectopic – present in an abnormal location (e.g. in preg-
ascites – a fluid collection in the peritoneal cavity. nancy).
atony – a lack of contractile function. embolus – a substance (usually dislodged atheroma or
atrophy – wasting or shrinking (of an organ or tissue). blood clot) lodged in a blood vessel, which blocks the
autoimmune – pertaining to the development of an flow of blood.
immune response (antibody production) to the body’s emetic – a substance which causes vomiting.
own tissues. emollients – substances which alter the consistency (of
bacteriostatic – tending to restrain the reproduction of the faeces).
bacteria. encephalopathy – any disease or degenerative condition
benign – non-malignant (pertaining to tumours). of the brain.
bilirubinuria – the presence of bilirubin in the urine. endocytosis – process whereby a molecule or particle
calculus – an abnormal stone formed in tissues by an becomes surrounded by the cell membrane and engulfed
accumulation of mineral salts. into the cell in a vesicle.
cathartic – a (purgative) medicine which increases endogenous – originating within the tissues.
evacuation of the bowels. endoscopic retrograde pancreatography (ERCP) –
caveolae – invaginations of the cell membrane extending a procedure employing a combination of fibre optic
into its cytoplasm. endoscopy and radiography to investigate the presence
chloridorrhoea – excessive loss of chloride ions in the of biliary and pancreatic disease.
faeces. endoscopy – visual examination of a hollow organ (e.g.
cholangitis – a bacterial infection of bile in the bile duct. the gastrointestinal tract) by insertion of an endoscope
cholecystectomy – removal of the gall bladder. (an illuminated optical instrument).
cholecystitis – infection (of bile) in the gall bladder. enteritis – inflammation of the intestines.
cholelithiasis – the presence of gall stones. epigastric – in the upper central abdominal region.
cholephilic – attracted to bile; easily dissolved in bile. excoriation – an injury to the surface of the body, e.g. a
cholestasis – interruption of bile flow. scratch.
cirrhosis – a progressive inflammatory disease in the exocytosis – the process by which vesicles release their
liver where there is an increase in non-functioning tissue contents by fusing with the cell’s plasma membrane.
and disruption of the architecture. exogenous – originating from outside the tissues.
colectomy – removal of part of the large bowel (colon). extrinsic – originating (usually situated) outside
colic – cyclical intra-abdominal pain owing to the tissue.
dysfunctional peristalsis of the intestine. exudate – a fluid that has oozed out of a tissue and so
colitis – inflammatory disease of the colon. has a high protein content.
colostomy – a surgically created opening of the colon in fenestrae – pores.
 fibrosis – proliferation of fibrous connective tissue. ileitis – inflammatory disease of the ileum.
Glossary

fistula – an abnormal passage from an internal organ to ileus – loss of peristalsis in the small bowel, usually fol-
the body surface or between two organs. lowing surgery, that results in a functional obstruction.
gastrectomy – surgical removal of the stomach. inanition – loss of weight.
glucagonoma – a glucagon-secreting tumour of the inspissated – thickened.
pancreatic islet cells. insulinoma – a tumour of the insulin-secreting cells of
glucostatic theory – control of feeding via blood glucose the pancreas.
levels. intrinsic – originating within the tissue.
glycosuria – glucose in the urine. ischaemia – decreased supply of oxygenated blood to an
granuloma – a chronic inflammatory lesion character- organ or structure.
ized by accumulation of macrophages. isosmotic – having the same total solute concentration as
gustation – taste. extracellular fluid.
haemodynamics – the study of the physical aspects of isotonic – containing the same number of effectively
the blood circulation. non-penetrating solute particles as extracellular fluid.
haemolytic – causing the red blood cells to break down jaundice – yellowish discolouration of the skin, mucous
and release haemoglobin. membranes and sclerae owing to deposition of bilirubin.
haemorrhoid – a submucosal swelling in the anal canal ketoacidosis – acidosis accompanied by an accumula-
caused by congestion of the veins of the haemorrhoidal tion of ketones in the body.
plexus. leukocytosis – an increase in the number of white blood
hemicolectomy – surgical removal of part of the large cells, usually in response to infection.
bowel with restoration of continuity. lipolysis – breakdown of lipids.
hepatitis – an inflammation of the liver. lipostatic theory – control of feeding by lipid metabo-
hepatoma – a primary tumour of the liver. lites.
homeostasis – constancy of the internal environment of lithotripsy – shattering of (gall or kidney) stones by
the body. ultrasound waves.
hydrophilic – attracted to, and easily dissolved in, water. macrocytic – high mean cell volume (usually pertaining
hydrophobic – not attracted to, and insoluble in, water. to red blood cells).
hyperaemia – increased (regional) blood flow. malignancy – a tumour with the ability to invade and
hyperbilirubinaemia – an abnormally high concentra- spread to other tissues and organs.
tion of bilirubin in the plasma. mastication – chewing.
hyperglycaemia – increased plasma glucose. meconium – greenish material which fills the intestines
hyperinsulinaemia – increased plasma insulin. of the fetus and forms the first bowel movement in the
hyperkeratosis – overgrowth of the cornified epithelium newborn.
layer of the skin, e.g. a wart. meconium ileus – obstruction of the small intestine
hyperketonaemia – an abnormally high level of ketone in the newborn by impaction of meconium (usually in
bodies in the plasma. cystic fibrosis).
hyperplasia – abnormal growth of a tissue owing to an megacolon – a massively enlarged colon.
increased rate of cell division. megaloblast – an abnormally large, nucleated, immature
hypertension – chronically increased arterial blood pres- erythrocyte present in large numbers in pernicious anae-
sure. mia or folate-deficiency anaemia.
hypertonic – containing a higher concentration of ef- metastasis – the process by which tumour cells spread to
fectively membrane-impermeable solute particles than distant parts of the body.
normal (isotonic) extracellular fluid. microcytic – characterized by the presence of cells with
hypertrophy – enlargement of a tissue or organ because low mean cell volume (usually pertaining to red blood
of increased cell size rather than increased cell number. cells).
hypoalbuminaemia – decreased plasma albumin. myogenic – pertaining to (cardiac and smooth) muscle
hypocalcaemia – decreased plasma calcium. that does require nerve impulses to initiate and maintain
hypochromia – a low haemoglobin concentration in the a contraction.
erythrocytes. necrosis – localized tissue death in response to disease or
hypoglycaemia – low plasma glucose. injury.
hypoinsulinaemia – low plasma insulin. neoplasm – an abnormal new development of cells (a
hypokalaemia – decreased plasma K concentration. tumour).
hypotension – low blood pressure. nexus – gap junction; a zone of apposition between two
hypotonic – containing a lower concentration of ef- cells where action potentials can be conducted between
fectively non-penetrating solute particles than normal the cells.
(isotonic) extracellular fluid. oedema – accumulation of excess fluid in interstitial
hypovolaemia – low blood volume. spaces.
hypoxia – deficiency of oxygen (in a tissue). olfaction – smell.
idiopathic – of unknown cause. orad – in a direction towards the mouth.

204 SYSTEMS OF THE BODY

osmolality – total solute concentration per unit weight of sclerotherapy – a technique using sclerosing solutions to

Glossary
solvent (water). cause obliteration of pathological blood vessels (as in the
osmolarity – total solute concentration of a solution. treatment of haemorrhoids).
osteopaenia – a reduction in bone mass. secretagogue – a substance that regulates the release of
pancreatitis – inflammatory disease of the pancreas. a secretion.
paracrine – relates to an agent that exerts its effects on sigmoidoscope – a rigid tubular instrument used for direct
cells near its site of secretion (by convention, excludes visualization of the rectal and sigmoid colonic mucosa.
neurotransmitters). somatic – pertaining to one of two major divisions of the
parenteral – relating to treatment other than through peripheral nervous system, consisting of sensory neu-
the digestive system (e.g. by intravenous administra- rones concerned with sensation from the skin and body
tion). surface and motor neurones to the skeletal muscles, the
parietal cells – oxyntic cells; acid-secreting cells of the other division being the autonomic nervous system.
stomach. splenomegaly – enlargement of the spleen.
periodontal – pertaining to the area around the teeth. steatorrhoea – a condition where the faeces have a high
peritonism – exquisite abdominal tenderness which fat content.
encourages the patient to lie still. It is indicative of acute stenosis – a narrowing or constriction of a tube (e.g.
inflammation of the parietal peritoneum, usually due to bowel) or aperture (e.g. ampulla of Vater).
infection and classically associated with appendicitis. stent – a short plastic tube.
peritonitis – inflammatory disease of the peritoneum, submodality – subclass of a stimulus which evokes a
often secondary to perforation of the bowel. sensory response.
pinocytosis – endocytosis when the vesicle encloses submucosal – beneath the mucosa.
extracellular fluid or specific molecules in the extracellu- tetany – a maintained contraction.
lar fluid that have bound to proteins on the extracellular thrombocytopaenia – deficiency of thrombocytes (blood
surface of the plasma membrane. platelets).
polydipsia – excessive drinking (usually seen in hyper­ thrombocytosis – an abnormal increase in the number of
glycaemia). thrombocytes (blood platelets).
polyuria – high urine output. thrombus – a clot which attaches to the wall of a vessel.
prophylactic – an agent used to prevent the develop- tonic – undergoing continuous muscular activity.
ment of a disease. toxaemia – presence of bacterial toxins in the blood plasma.
purgative – a strong medication used to promote evacu- transcoelomic – spreading through the peritoneal cavity.
ation of the bowels. transudate – fluid that has leaked out of a tissue, usually
pyroplasty – division of the pyloric muscle to allow because of increased osmotic/hydrostatic pressure and
easier emptying of the stomach. therefore having a low protein content.
roughage – non-digestible dietary fibre, important to vagotomy – division of the vagus nerves.
promote gut motility. varices – dilated veins, usually of the oesophagus, owing
ruga – a fold of mucosa in the stomach. to raised portal vein pressure.
satiety – cessation of the feeling of hunger. vasoconstriction – constriction of blood vessels.
scintigraphy – a clinical procedure consisting of the vasodilator – a substance which causes dilatation of
administration of a radiolabelled agent with a specific arterioles.
affinity for an organ or tissue of interest, followed by viscera – body organs (e.g. liver, pancreas).
determination, with a detector, of the distribution of the xenobiotic – an organic substance which is foreign to the
radiolabelled compound. body (e.g. a drug or an organic poison).
sclerosis – hardening of a tissue, especially by the over- xerophthalmia – a disturbance of epithelial tissues.
growth of fibrous tissue. xerostomia – dry mouth.

THE digestive SYSTEM 205

index
A trace elements, 141–144 bile acid absorption, 151
vitamin B12, 146f, 148, 145–146 calcium absorption, 142
Abdominal pain, 184, 189–190 water, 118 small peptide absorption, 140–141, 141f
Absorbents, diarrhoea treatment, 123 water-soluble vitamins, 144–146 Acute gastritis, 195
Absorption, 2–3, 114–117, 130 Absorptive cells, small intestine wall, 111 Acute hepatitis, 196t
barriers to, 114–115 Absorptive state, 155–156 Acute ischaemia, 200
bile acids, 151 amino acids, 156 Acute pancreatitis, 83, 197, 198t
into blood, 117, 117–118 carbohydrates, 155–156 enzyme defects, 79
carbohydrates, 130–132 energy metabolism, 155, 155f Adenocarcinoma, pancreas see Pancreas
disaccharides, 135f insulin see Insulin Adrenal disease, lipid digestion/absorption
glucose, 155 triacylglycerols, 156 defects, 151
monosaccharides see below Acetylcholine Adrenaline, post-absorptive state regulation,
control, 120 colon motility, 179–180 167–168, 169
drugs, 116–117 colon secretion control, 177 Adrenergic sympathetic nerves, stomach
affecting factors, 117 gastric secretion regulation, 55 motility control, 64
lipid soluble drugs, 116, 116t pepsinogen secretion, 58 Adrenocorticotropic hormone (ACTH), post-
strong electrolyte drugs, 117 saliva regulation, 33 absorptive state regulation, 168
weak electrolyte drugs, 116–117, 117f Acetylcysteine, paracetamol overdose Alcohol
folic acid, 145 treatment, 98 cirrhosis, 88
ions, 118–120 Achalasia (cardiospasm), 38, 194 oesophageal cancer, 186–187
calcium, 142f, 142–143 Achlorhydria, 43 stomach absorption, 46
see also specific ions Acid–base balance stomach cancer, 187–188
iron see Iron absorption cholera, 115 Alcohol dehydrogenase, 95
lipids, defects, 151, 152 disturbances, 45, 45f Alimentary regulation, feeding, 5
into lymph, 117, 118 excessive vomiting, 49 Alkalosis, metabolic, 122
minerals, 141–144 gastrinomas, 68 Allergies, protein absorption, 141
monosaccharides, 135–138, 137f peptic ulcer disease, 68 American trypanosomiasis see Chaga’s disease
physiological regulation, 138 starvation, 164 Amino acids
potential difference effects, 116, 116t Acid reduction therapy, 59–63, 63f absorption, 140, 140f, 140t
proteins, 130 antacids, 59 insulin, 160, 163
amino acids see Amino acids antibiotics, 62–63 malabsorption diseases, 141
products, 140 histamine H2 receptor antagonists, 59 see also specific diseases/disorders
see also specific products muscarinic receptor antagonists, 62 5-Aminosalicylate, ulcerative colitis
small peptides, 140–141, 141f proton pump inhibitors, 59–62 treatment, 176
routes, 116 Acinus, pancreas, 74f, 75f, 74–75 Amoebic dysentery, 201, 201t
saliva functions, 31 Action potentials, smooth muscle Amphetamines, obesity treatment, 6
sites of, 131f contraction, 11–12 Ampulla of Vater, 109
small intestine adaptations, 114f Active transport, 9 pancreas, 72
 -Amylases chloride ion absorption, 119–120, 120f absorption, 142f, 142–143
index

carbohydrate digestion, 134, 134f pancreatic secretion, 76, 76f requirements, 141–142
saliva, 30, 30–31, 134 saliva, 32 smooth muscle contraction, 11, 11f, 12
Amylopectin, 132 Biguanides, non-insulin-dependent diabetes Calculi, salivary glands, 193–194
degradation, 134f mellitus treatment, 166 Canalicular multiorganic anion transporter
structure, 134f Bile, 3, 86, 89–90 (cMOAT), 96–97, 98f
Amylose, 132 anion preferential secretion, 96 Canaliculi, 89
degradation, 134f biliary lipids, 90–91 anion transporters, 95–96
Anaemia, 46 composition, 89, 90t liver, 87
Crohn’s disease, 147 functions, 89 Cancer see Malignancies
iron-deficiency, 46 gallbladder, 100–101 Capsule of Glisson, 87
malignancy effects, 185 organic ion transport, 96–97 Carbohydrates
pernicious, 46 proteins, 99–100 absorption, 130–132
Anal canal, 172–173, 173f, 175–177 secretion sites, 89f absorption diseases, 136
Anatomy (of digestive system), 2, 4f duct cell secretion, 90 see also specific diseases/disorders
see also specific components hepatocyte secretion, 90 digestion, 134–135
Anions Bile acids, 90, 151–152 structures, 130–131
bile preferential secretion, 96 absorption, 151 see also specific carbohydrates
biotransformation, UDP-glucuronyl composition, 91f Carboxypeptidase A, 139
transferase, 95, 95f conjugated, 149 Carboxypeptidases, 77
conjugation Crohn’s disease, 147 Cardiospasm (achalasia), 38, 194
hepatocyte biotransformation, 95f electrical polarity, 92f Cardiovascular effects, cholera, 121
hepatocytes, 95f enterohepatic circulation, 103–104, 104f Cations
see also specific anions formation, 90–91 active transport, 9
Anion transporters, canaliculi, 95–96 gallstone treatment, 103 see also specific cations
Antacids, acid reduction therapy, 59 micelles, 91 Caveolated cells, crypt epithelium, 112
Antibiotics small intestine, modification in, 151 CCK see Cholecystokinin (CCK)
acid reduction therapy, 62–63 uptake/secretion, 91, 91f Cellulose, structure, 131–132
diarrhoea treatment, 123 Bile pigments, 152 Cementin, teeth, 27
Antidiuretic hormone (ADH), thirst, 6 in gastrointestinal tract, 99 Cephalic phase
Antiemetic drugs, 50, 50t, 127 metabolism, 99f eating regulation, 17
Antimotility drugs, diarrhoea treatment, 123 Bile salts hepatobiliary system regulation, 104
Antrectomy, peptic ulcer disease treatment, calcium absorption, 142–143 pancreatic secretion regulation, 82
62 micelle formation, 149 stomach regulation, 65, 67f
Antrum, 40 Biliary tree diseases/disorders, 196–197 CFTR see Cystic fibrosis transmembrane
motility control, 63, 64f Bilirubin conductance regulator (CFTR)
surgery, 191 bile, 90 Chaga’s disease
Appendicitis, 175, 189–190 hepatocyte conjugation, 95f motility, 179–180
case history, 190 metabolism, 98f, 97–99 swallowing problems, 38
pathophysiology, 190 structure, 98f Cheeks, 20
Appendix, 172f, 175 Biliverdin, structure, 98f Chemoreceptor trigger zone (CTZ), 48, 49
APUD (endocrine) cells, 16, 16f, 113f Biting forces, 27 Chenodeoxycholic acid
colon, 173–174, 175f Bitter, 24 bile acids, 90–91
crypt epithelium, 112 Blood, absorption into, 117, 117–118 gallstone treatment, 103
small intestine wall, 112 Blood flow, saliva regulation, 34 structure, 91f
Arachidonic acid, 146 Blood glucose, ingestion regulation, 5 Chewing see Mastication (chewing)
Arterial blood pressure, thirst, 6 Blood supply, 6–7 Chief (peptic) cells, 41, 42, 42f
Ascending colon, 172 liver, 87 secretions, 44–46
Ascorbate (vitamin C), absorption, 144–145, regulation, 16–17 Chloride ions (Cl)
145 Blood volume, thirst, 6 absorption, 118–120
ATP-dependent active transport, organic ion Body temperature, feeding regulation, 6 colon, 177
transport, 96–97 Bradykinin, saliva regulation, 34 HCO3 exchange, 119–120, 120f
Auerbach’s plexus (myenteric plexus), 14 Branching enzyme, defects, 156 cystic fibrosis transmembrane
Autoimmune disease, cirrhosis, 88 Brunner, glands of, 109 conductance regulator, 76f, 77
Autonomic nerves, 15f, 15–16 Brush border enzymes, carbohydrate intestinal secretions, 112, 114f
see also Parasympathetic nerves; digestion, 134–135 osmotic gradient effects, 118
Sympathetic nerves Bulk-forming agents, constipation oxyntic (parietal) cells, 43–44
treatment, 126 Chloridorrhoea, congenital see Congenital
chloridorrhoea
B Chlorpromazine, hepatocyte
C biotransformation, 95f, 96
Back pain, pancreatic adenocarcinoma, 185 Cholecystectomy, 191–192
Bacteriostatic effects, saliva, 31 Ca2-ATPase, calcium absorption, 142 Cholecystitis, 196
Bell’s palsy, 193 Caecum, 172, 172f Cholecystokinin (CCK), 13t
Bicarbonate (HCO3) Calcium (Ca2) blood flow control, 17

208
 colon motility, 180 ascending, 172 inflammation, 199

index
hepatobiliary system regulation, 105 bacterial digestion, 177–178 lactase deficiency, 147
hydrochloric acid secretion, 55–57, 58t cancer, 186 malabsorption, 147
ingestion regulation, 5 see also Colorectal cancer bile acids, 147
insulin secretion control, 159 descending, 172, 172f fats, 147
intestinal digestion, 108–109 digestion, 177 fat soluble vitamins, 147
pancreatic secretion regulation, 80, 83 distension, 178–179 protein loss, 147
pepsinogen secretion, 58 functions, 177–182 treatment, 133
receptors, 52 see also specific functions see also Ulcerative colitis
sphincter of Oddi, 103 histology, 173–175 Crypt epithelium, 112
Cholecystokinin-A (CCK-A) receptor, 52 innervation, 173, 173f Crypts of Lieberkühn see Intestinal glands
Cholera, 198, 201, 199t mixing, 178 (crypts of Lieberkühn)
acid–base balance, 115 motility, 178–180 Cyanocobalamins, 44
cardiovascular adjustments, 121 control, 179–180, 180f Cystic fibrosis, 74, 197–198, 199t
case history, 108 nervous control, 179–180 defects, 79
causes, 115 reflex control, 180 diagnosis, 79
electrolyte balance, 115 muscle layer, 172 functional impairment, 81
hypersecretion, 115 secretion, 177 secretion failure, 77
hypovolaemia, 121 sigmoid, 172, 172f treatment, 81
rehydration therapy, 120 submucosa, 175 Cystic fibrosis transmembrane conductance
renal adjustments, 121 surgery, 193 regulator (CFTR), 112, 114f
toxin mechanisms, 115 transverse, 172, 172f chloride ion secretion, 76f, 77
Cholesterol wall structure, 175f pancreatic secretion, 76
absorption, 149 Colonic bacteria, osmotic diarrhoea, 121–122 regulation, 77
hepatocytes, 91 Colorectal cancer, 201, 184t, 187f Cystinuria, 141
micelle formation, 149 CT, 187, 187f
structure, 91f genetic predisposition, 184
Cholesterol esterase, 148 surgery, 193 D
Cholesterol gallstones, 94 treatment, 187
Cholic acid surgery, 187 D cells, 41
bile acids, 90–91 Columnar epithelial cells, 113f Debranching enzyme, defects, 156
structure, 91f crypt epithelium, 112 Defaecation, 181f, 180–182
Cholinergic parasympathetic nerves, colon, Golgi saccules, 112 control of, 181f, 180–182
173 stomach, 40 Hirschsprung’s disease, 181–182
Chronic gastritis, 195 Computed tomography (CT) Defective ion transport, diarrhoea, 121
Chronic hepatitis, 196t acute pancreatitis, 83f Denervation, wisdom tooth extraction, 23,
Chronic pancreatitis, 72, 73, 197, 199t colorectal cancer, 187, 187f 25–26
causes, 78 Conditioned reflexes, 34–35 Dental health, saliva function, 25
functional impairment, 80 Congenital chloridorrhoea, 121 Dentine, teeth, 27
physiology, 81 defects, 122 Deoxycholic acid, structure, 91f
secretion failure, 77 diarrhoea, 122 Descending colon, 172, 172f
treatment, 81 metabolic alkalosis, 122 Detoxification, liver, 86
Chylomicrons, 150–151 treatment, 122 Diabetes mellitus type 1 see Insulin-
Chymotrypsin, 139 Conjugated bile acids, lipid emulsification, dependent diabetes mellitus (IDDM)
pancreatic secretion, 77 149 Diabetes mellitus type 2 see
Chymotrypsinogen, activation, 79 Constipation Non-insulin-dependent diabetes
Cirrhosis, 87, 88, 197, 196t dietary fibre, 179 mellitus (NIDDM)
cMOAT (canalicular multiorganic anion treatment, 126 Diarrhoea, 120–122
transporter), 96–97, 98f Corticotrophin releasing factor (CRF), coeliac disease, 138
Cobalamins, vitamin B12 absorption, post-absorptive state regulation, 168 congenital chloridorrhoea, 122
145–146 Cranial nerve V see Trigeminal nerve (cranial Crohn’s disease, 147
Coeliac artery, 7 nerve V) defective ion transport, 121
Coeliac disease, 130, 200, 199t Cranial nerve VII (facial nerve), saliva gastrinomas, 66
defect, 132 regulation, 33 infective, 200–201
diagnosis, 132 Cranial nerve XI (glossopharyngeal nerve), intestinal hypermobility, 122
diarrhoea, 138 saliva regulation, 33, 35 osmotic, 121–122
lipid digestion/absorption defects, 151 Cricopharyngeal spasm, 38 secretory, 120–121
malabsorption, 138 Crigler Najjar disease, 99 treatment, 123
treatment, 132 Crohn’s disease, 131, 198–199, 200t Diet
Colipase, 149 anaemia, 147 malignancies, 184
Colon, 171 defect, 133, 133f post-gastric surgery, 191
absorption, 177–178 diagnosis, 133 stomach cancer, 187–188
drugs, 178 diarrhoea, 147 Dietary fibre, 179
anatomy, 172f, 172–173 gallstones, 147 constipation, 179
see also specific components genetics, 198 haemorrhoids, 179

209
 Diffuse oesophageal spasm, 38 Enterocytes, GLUT1, 137–138 cholesterol, 94
index

Digestion, 2 Enteroglucagon, 13t common bile duct stones, 196

carbohydrates, 134–135 small intestine motility, 125 composition, 94
lipids, 147–148, 148f Epithelial cells, columnar see Columnar Crohn’s disease, 147
defects, 151 epithelial cells detection, 93, 93f
saliva functions, 25, 30–31 Excessive vomiting, 49 endoscopy, 102f
Dipeptides, absorption, 139f acid–base disturbances, 49 formation, 94
Disaccharides, 132 acid–base status, 49 gallbladder, 101
absorption, 135f electrolytes, 49 occurrence, 94
digestion, 134, 135f mechanism, 50 pain, 93
Diseases/disorders, 183 treatment, 50 pigment stones, 94
drug absorption effects, 117 Excitatory nerves, smooth muscle, 14 surgery, 196
see also specific diseases/disorders Excretion, liver, 86 treatment, 102–103
Diverticular disease, 201–202, 201t, 202f Exocrine glands/tissue, 3 bile acids, 103
Diverticulum (oesophageal pouch), 194t, 195 pancreas see Pancreas lithotripsy, 102–103
DMT1, iron absorption, 144 Exocrine pain, pancreatic disease, 197 surgery, 102, 102f
Domperidone, 127 Exopeptidases, 139 Ganglia, enteric nervous system, 14
Drugs Extracellular fluid volume, intestinal Gastrectomy, 40, 191, 191f
absorption see Absorption absorption, 47 digestive consequences, 46
conjugation, 94–96 Extrahepatic ducts, 89 Gastric glands, stomach, 40
oxidation, 95 Gastric inhibitory peptide (GIP), 13t
Duct cells, pancreas, 74–75, 76f hydrochloric acid secretion, 55–57, 58t
Duodenal ulcers, 60 F insulin secretion control, 159
Duodenum Gastric juice
anatomy, 109 Facial nerve (cranial nerve VII), saliva composition, 43
contractions, vomiting, 48–49 regulation, 33 ions, 43, 43f
diseases/disorders, 195 Facilitated diffusion, 9–10 secretion mechanisms, 41, 43–44
distension, ingestion regulation, 5 Familial iminoglycinuria, 141 food, regulation by, 65–66
glands of Brunner, 109 Fats see Lipids (fats) see also specific cell types
intestinal glands (crypts of Lieberkühn), 109 Fat-soluble vitamins, 146 Gastric phase
intestinal juice, 108 Crohn’s disease, 147 eating regulation, 17, 17–18
lipid absorption, 149 Fatty acids, post-absorptive state, 166 hepatobiliary system regulation, 104
plicae circularis, 109 Feeding (hunger) centre, 5 pancreatic secretion regulation, 82
Dysentery, 201t Feeding regulation stomach regulation, 65, 67, 67f
Dysphagia, oesophageal cancer, 185, 186 alimentary regulation, 5 Gastric pits, 40
body temperature, 6 structure, 42f
nutritional regulation, 4, 5–6 Gastric ulcers, 56, 60–61
E Fibre see Dietary fibre X-ray, 56f
Folic acid, absorption, 145 Gastrin, 13t, 52, 54
Elastase, 139 Food active forms, 52
pancreatic secretion, 77 saliva regulation, 34–35 blood flow control, 17
Electrolytes stomach secretion control, 65–66 ECL cell, 54
cholera, 115 Fructose G cells, 52, 54f
excessive vomiting, 49 absorption, 135 histamine secretion, 54
Emollients, constipation treatment, 126 GLUT5 transport, 137 hydrochloric acid secretion, 53–54, 54f
Emotions, colonic mobility, 179 Fundus, stomach, 40 oxyntic (parietal) cell effects, 53–54
Emulsification, lipids, 148–149 pancreatic secretion regulation, 80
Enamel, teeth, 27 small intestine motility, 125
Endocrine cells see APUD (endocrine) cells G Gastrin-CCK-B receptor, 52
Endocrine system Gastrinomas, 53
pancreas, 73–74 Galactose absorption effects, 66
regulatory function, 16 absorption, 135 acid–base balance, 68
see also APUD (endocrine) cells malabsorption, 136 acid secretion, 61
see also specific hormones Gallbladder, 86, 100–105 causes, 57
Endopeptidases, 139 anatomy, 86f, 100, 101f diagnosis, 57
Endoscopy, gallstones, 102f contraction, 101–103 digestion effects, 66
Energy provision, starvation, 164 functions, 100–103 treatment, 62
Entamoeba histolytica infection, 201, 201t gallstones, 101 see also Zollinger–Ellison syndrome
Enteric fistulae, Crohn’s disease, 133 histology, 100 Gastrin receptors, 52
Enteric nervous system, 14f, 13–15 ion transport, 101f Gastrin-releasing peptide (GRP), 13t
anatomy, 14–15 neck, 100 gastric secretion regulation, 55
intrinsic interneurones, 14 surgery, 191–192 Gastritis, 195
intrinsic motoneurones, 14 wall, 100 acute, 195
sensory neurones, 15 Gallstones, 86, 196t chronic, 195
Enterochromaffin (ECL)-like cells, 41 case history, 93 Gastroileal reflex, small intestine motility, 126

210
G cells, gastrin, 52, 54f -1,6 Glycosidase, carbohydrate digestion, 134 treatment, 174

index
Genetic predisposition, malignancies, 184 Goblet cells, 42, 113f Histamine
GH (growth hormone), post-absorptive state anal canal, 175–177 gastric juice, 43
regulation, 169 colon, 173–174, 175f secretion, gastrin, 54
GHRF (growth hormone releasing factor), secretions, 46 stomach, 41
post-absorptive state regulation, 168 small intestine wall, 111 Histamine H2 receptor antagonists, 59
Gilbert’s syndrome, jaundice, 99 stomach, 42f peptic ulcer disease treatment, 61
GIP see Gastric inhibitory peptide (GIP) Golgi saccules, columnar epithelial cells, 112 Hormones
Glands of Brunner, 109 Granular cells see Paneth cells pancreatic secretion regulation, 80–81
Glisson, capsule of, 87 Growth hormone (GH), post-absorptive post-absorptive state, 167–168, 168f, 169, 169t
Glossopharyngeal nerve (cranial nerve XI), state regulation, 169 small intestine motility, 125
saliva regulation, 33, 35 Growth hormone releasing factor (GHRF), stomach secretion control, 52
Glossopharyngeal phase, pharyngeal phase post-absorptive state regulation, 168 see also specific hormones
of swallowing, 36 GRP see Gastrin-releasing peptide (GRP) H secretion, oxyntic (parietal) cells, 43
GLP-1 (glucagon-like peptide 1), insulin Hunger contractions (pains), 4, 5
secretion control, 159 Hunger, lipostatic theory, 6
Glucagon H Hydrochloric acid secretion
insulin secretion control, 159 food, control by, 65
post-absorptive state regulation, 168, 169 Haem gastrin, 53–54, 54f
secretion, 73 iron absorption, 143, 143f inhibitory controls, 55–57, 58f
Glucagon-like peptide 1 (GLP-1), insulin structure, 98f feedback control, 55
secretion control, 159 Haemochromatosis, 145 neutralization by bile, 90
Glucocorticoids, absorption control, 120 Haemolytic jaundice, 99 oxyntic (parietal) cells, 43–44, 44f
Glucogenesis, inhibition by insulin, 161–163 Haemorrhoids, 175–177 peptic ulcer disease, 56t
Gluconeogenesis, post-absorptive state, 166 dietary fibre, 179 protective mechanisms, 59
Glucose Haem oxygenase (HO-1), 143, 143f Zollinger–Ellison syndrome, 56t
absorption, 135, 155 Hartnup’s disease, 141 see also Acid reduction therapy
glycogen, conversion to, 155–156 Haustration, colon, 178, 179 Hydrogen ion exchange, sodium ion
insulin effects, 161 Helicobacter pylori infection absorption, 119–120, 120f
malabsorption, 136 antibiotic therapy, 62 Hydrogen ion secretion, oxyntic (parietal)
plasma see Plasma glucose peptic ulcer disease, 61, 63, 195 cells, 43
skeletal muscle, 156 stomach cancer, 187–188 Hyperbilirubinaemia, 99
sparing reactions, post-absorptive state see Hepatic artery, 87 Hyperglycaemia, diabetes mellitus, 154
Post-absorptive state Hepatitis, 197 Hyperphagia, 5
structure, 134f acute, 196t Hypersecretion, cholera, 115
supplying reactions, post-absorptive state chronic, 88, 196t Hypoglossal nerve trauma, 193
see Post-absorptive state Hepatobiliary disease, 196–197, 196t Hypoglycaemia, 47
Glucose 6-phosphatase defects (von Gierke’s see also specific diseases/disorders Hypovolaemia, cholera, 121
disease), 156 Hepatobiliary system, 86 Hypovolaemic shock, 111
Glucose tolerance test, 158f, 158–159 anatomy, 86f
Glucuronide production, 95 regulation during a meal, 104–105
GLUT1, 136 see also Gallbladder; Liver I
insulin, effects of, 161 Hepatocellular disease, 197
structure, 137f Hepatocellular jaundice, 99 IDDM see Insulin-dependent diabetes
GLUT2, 136 Hepatocytes, 87, 87f, 88–89 mellitus (IDDM)
glucose transport, 157 anion conjugation, 95f Ileocaecal sphincter, 126
upregulation, 138 cholesterol, 91 Ileo-gastric reflex, colon motility, 180
GLUT3, 136 drug conjugation, 94–96 Ileum
GLUT4, 136 functions, 89f anatomy, 109, 109–110
insulin, effects of, 161 metabolite conjugation, 94–96 lipid absorption, 149
GLUT5, 136 organic ion transport, 96 segmentation, 123–124
fructose absorption, 137 phospholipids, 91 surgery, 192–193
Glyceryl trinitrate, oral absorption, 31 Hereditary haemochromatosis, 145 water absorption, 118
Glycogen H exchange, sodium ion absorption, Inanition, 6
biosynthesis 119–120, 120f Infections
glucose, 155–156 Hexose transporters, 137f oesophagus, 194t, 195
insulin, 161 monosaccharide absorption, 136 small intestine, 198, 199t
periportal cells, 88–89 specificity, 137t see also specific infections
skeletal muscle, 156 structure, 137f Infective diarrhoea, 200–201
structure, 132 see also specific transporters Inferior mesenteric artery, 7
Glycogenolysis Hirschsprung’s disease, 14, 172, 173 Inflammation, Crohn’s disease, 199
insulin effects, 162f, 161–163 defaecation, 181–182 Inflammatory bowel disease (IBD), 196–197
post-absorptive state, 166 defects, 174 see also Crohn’s disease; Ulcerative colitis
Glycogen storage disorders, 156 diagnosis, 174, 174f Ingestion regulation, 5f, 4–6
Glycolysis, insulin, 161, 161f motility, 179–180, 180 hunger, 4

211
 Inherited diseases, cirrhosis, 88 Ion transport Lieberkühn, crypts of see Intestinal glands
index

Inhibitory nerves, smooth muscle, 14 gallbladder, 101f (crypts of Lieberkühn)

Insulin, 157–163 organic ions see Organic ion transport Lingual nerve, 22
absorptive state, 159–163 Iron absorption, 143f, 143–144 bite regulation, 28
amino acids, 163 haem absorption, 143, 143f Linoleic acid, 146
glucogenesis inhibition, 161–163 non-haem absorption, 144 -Linoleic acid, 146
glucose entry to cells, 161 regulation, 144 Linolenic acid, 146
glycogenolysis inhibition, 162f, 161–163 Iron-deficiency anaemia, 46, 144 Lipases, lipid digestion, 147–148
glycogen synthesis, 161 Crohn’s disease, 147 Lipid route, absorption, 116
glycolysis, 161, 161f Ischaemia, acute, 200 Lipids (fats), 146–152
lipolysis inhibition, 162f, 161–163 Islets of Langerhans, 73 absorption
triacylglycerol synthesis, 161 pancreas, 72 cellular transport, 150, 150f
actions, 157 defects, 151, 152
blood glucose vs., 157–158, 158f epithelial cells, 150–151
energy metabolism control, 159f, 160 J pancreatic juice, 75
processing, 157f unstirred layer, 149–150
secretion control, 157–159 Jaundice, 99 Crohn’s disease, 147
amino acids, 159 Crigler Najjar disease, 99 dietary, 146
glucose, 157f, 157–159 Gilbert’s syndrome, 99 digestion, 147–148, 148f
hormones, 159 haemolytic, 99 defects, 151
nervous control, 159 hepatocellular, 99 emulsification, 148–149
secretion of, 73 intrahepatic, 99 malabsorption, 102
Insulin-dependent diabetes mellitus obstructive, 99, 100 diarrhoea, 122
(IDDM), 154, 199t pancreatic adenocarcinoma, 188–189 solubility, 146–147
cause, 154–155 post-hepatic, 99, 100 synthesis in small intestine, 150f
defects, 154–155 prehepatic, 99 Lipid soluble drugs, absorption, 116, 116t
diabetic ketoacidosis, 167 Jejunum Lipolysis, insulin effects, 162f, 161–163
diagnosis, 158–159 anatomy, 109, 109–110 -Lipoproteinaemia, lipid digestion/
metabolic state, 164 lipid absorption, 149 absorption defects, 151
post-absorptive state vs., 164–165 segmentation, 123–124 Lipostatic theory, hunger, 6
treatment, 159 surgery, 192–193 Lips, 20
see also Non-insulin-dependent diabetes water absorption, 118 Lithocholic acid, structure, 91f
mellitus (NIDDM) Lithotripsy, gallstone treatment, 102–103
Insulin receptor, 160, 160f Liver, 2
Insulin receptor substrate (IRS) proteins, 160 anatomy, 86f, 87f, 86–100
Insulin sensitivity, 163
K capsule of Glisson, 87
Interneurones, intrinsic, enteric nervous lobes, 86
system, 14 Kallikreins lobules, 86
Intestinal enzyme inhibitors, non-insulin- blood flow control, 17 blood supply, 87
dependent diabetes mellitus salivary gland regulation, 30 canaliculi, 87
treatment, 166 Ketoacids, 156 cancer, 184t, 197
Intestinal glands (crypts of Lieberkühn), 112 Ketone bodies functions, 86
duodenum, 109 insulin-dependent diabetes mellitus, 164, detoxification, 86
Intestinal phase 165f excretion, 86
eating regulation, 17, 18 post-absorptive state, 166 glycogen storage diseases, 156
hepatobiliary system regulation, 104–105 Kupffer cells, 87–88 histology, 87–89
pancreatic secretion regulation, 82–84 morphology, 86–100
stomach regulation, 65, 67–69, 68f secretory system, 3, 88f
Intestine-intestine reflex, small intestine L sinusoids, 87
motility, 125 surgery, 192
Intrahepatic jaundice, 99 Lactase, carbohydrate digestion, 134, 135f see also under hepatic
Intralobular ducts, pancreas, 74 Lactase deficiency, 136 Liver disease, lipid digestion/absorption
Intravenous rehydration, cholera, 120 Crohn’s disease, 147 defects, 151
Intrinsic factor osmotic diarrhoea, 121–122 Lobes, liver, 86
cyanocobalamin absorption, 44 Lactose, digestion, 134, 135f Lobules, liver, 86
oxyntic (parietal) cells, 44 Lamina propria, stomach, 40 Longitudinal muscles, small intestine
vitamin B12 absorption, 44, 145–146 Lansoprazole, 59 motility, 123
Intrinsic nerves Large intestine Lubrication, saliva, 25, 30
colon motility, 179–180 diseases/disorders, 201–202, 201t Lymphatic nodules, tongue, 23
enteric nervous system, 14 see also specific organs Lymphatic system
Ions Laxatives, 126 absorption into, 117, 118
absorption, colon, 177, 177f colonic mobility, 179 lipid digestion/absorption defects, 151
gastric juice, 43, 43f osmotic, 126 oesophageal cancer, 186
saliva, 30 secretory, 126 Lysophospholipids, micelle formation, 149
see also specific ions Lecithin see Phosphatidylcholine Lysosomal acid -glucosidase defects, 156

212
M MMC (migrating myoelectric complex), 123, Non-insulin-dependent diabetes mellitus

index
124f (NIDDM), 154, 165–166, 199t
Main body, stomach, 40 Moistness, saliva function, 25 defects, 165
Malabsorption, coeliac disease, 138 Monoacylglycerol, micelle formation, 149 treatment, 165–166
Malignancies, 184, 184–185 2-Monoacylglycerols, micelle formation, see also Insulin-dependent diabetes
diet, 184 149 mellitus (IDDM)
environmental factors, 184 Monosaccharides Non-occlusive ischaemic disease, 2
genetic predisposition, 184 absorption see Absorption diagnosis, 2b
non-metastatic manifestations, 185 see specific monosaccharides membrane transport, 9
primary disease, 185 Motilin, 13t treatment, 2b
secondary disease, 185 small intestine motility, 125 Non-steroidal anti-inflammatory drugs
small intestine, 198 Motility, 3, 10–13 (NSAIDs)
solid tumours, 184 Chaga’s disease, 179–180 chronic pancreatitis treatment, 81
symptoms, 185 colon see Colon diarrhoea treatment, 123
types, 184t control of, 13 ulceration, 59
see also specific cancers see also Autonomic nerves; Endocrine Noradrenaline, small intestine secretion
Maltase, 134, 135f system; Enteric nervous system control, 114
Maltose, digestion, 134, 135f Hirschsprung’s disease, 179–180, 180 Nuclei, hepatocytes, 88–89
Mastication (chewing), 27f, 27–29 stomach, 47–50 Nucleus tractus solitarius (NTS), vomiting,
bite regulation, 28 see also Smooth muscle 49
control, 27f, 27–28 Motoneurones, intrinsic, 14 Nutritional feeding regulation, 4
denervation problems, 25 Mouth, 20–22
movement generation, 28 anatomy, 20–22, 22f
tongue, 28–29 diseases/disorders, 193–194 O
McArdle’s disease, 156 innervation, 22
Mechanoreceptors, pancreatic secretion Mucins Obesity, 6
regulation, 82 mucous (goblet) cell secretion, 46 insulin sensitivity, 163
Meglitinides, non-insulin-dependent saliva, 30, 31 treatment, 6
diabetes mellitus treatment, 166 Mucosa Obstructive jaundice, 99, 100
Meissner’s plexus (submucous plexus), anal canal, 175–177 Oddi, sphincter of, 72, 86, 103, 109
enteric nervous system, 14 barrier to acid, 59 Oesophageal pouch (diverticulum), 194t, 195
Membrane transport, 7–10 stomach, 40 Oesophagitis, 194–195, 194t
active transport, 9 ulceration, peptic ulcer disease, 60–61 cancer, 186–187
passive transport vs., 9t Mucous cells see Goblet cells Oesophagus, 35–38
concentration gradients, 9, 10f Muscarinic receptor antagonists, 62 anatomy, 35
facilitated diffusion, 9–10 Muscle cancer, 186–187, 184t, 186t
mechanisms, 8–10 glycogen storage diseases, 156 motility, 185
non-occlusive ischaemic disease, 9 smooth see Smooth muscle surgery, 190–191
passive transport, 7 Muscularis externa diseases/disorders, 38, 194–195, 194t
active transport vs., 9t colon, 174–175 see also specific diseases/disorders
pinocytosis, 10 intestinal wall structure, 111 infections, 194t, 195
potential difference, 7–8 Muscularis mucosae innervation, 37f
Ménétrièr’s disease, 42 intestinal wall structure, 111 lower oesophageal sphincter, 38
Metabolic alkalosis, congenital small intestine motility, 125 motility control, 36–38
chloridorrhoea, 122 stomach, 40 skeletal muscle see Skeletal muscle
Metabolism Myenteric plexus (Auerbach’s plexus), 14 smooth muscle see Smooth muscle
malignancy effects, 185 Myogenic reflex, 13, 13f surgery, 190–191
starvation, 164 stomach motility control, 64 swallowing see Swallowing
Metabolite conjugation, hepatocytes, upper oesophageal sphincter, 36, 36–38
94–96 varices, 194t
Micelles N Olfactory mucosa structure, 26f
bile acids, 91 Omeprazole, 59
formation, 92–94, 149 Nerves, intrinsic see Intrinsic nerves side effects, 62
mixed, 92 Nervous system Opioids, absorption control, 120
phospholipid, 94 small intestine motility, 125 Oral health, saliva function, 25
primary, 92 see also specific nervous systems Oral rehydration therapy
structure, 92f Neuroepithelial cells, taste buds, 24 cholera, 120
Microvilli, 113f Neurological regulation, stomach secretion diarrhoea treatment, 123
canaliculi, 89 control, 54–55 Organic ion transport, 96–99
Migrating myoelectric complex (MMC), 123, Neurotransmitters bile, 96–97
124f small intestine motility, 125 hepatocytes, 96
Milk teeth, 26 vomiting, 49–50 Orlistat, 6
Minerals, absorption, 141–144 Neutral amino acids, sodium ion absorption, Oropharynx, diseases/disorders, 193–194
Misoprostol , acid reduction therapy, 63 119, 119f Osmotic diarrhoea, 121–122
Mixed micelles, 92 Non-haem absorption, iron absorption, 144 Osmotic gradients, water absorption, 118

213
 Osmotic laxatives, 126 Paracetamol overdose, 96, 197 Phosphofructokinase, defects, 156
index

Osteomalacia, 143 toxicity, 97 Phospholipase A2, 148

Oxyntic (parietal) cells, 41, 42f, 43–44 treatment, 98 Phospholipids
gastrin effects, 53–54 drugs, 98 hepatocytes, 91
hydrochloric acid secretion, 43–44, 44f transplantation, 98 micelles, 94
intrinsic factor, 44 Parasympathetic nerves, 15, 15f Phosphorylase defects, 156
blood flow control, 16–17 Phosphorylase, defects (McArdle’s disease),
cholinergic, colon, 173 156
P defaecation, 182 Phosphorylase kinase defects, 156
insulin secretion control, 159 Physiological processes, 2–6
Pacemaker cells saliva regulation, 33 see also specific processes
smooth muscle contraction, 12, 13 small intestine secretion control, 114 Pigment gallstones, 94
stomach motility control, 63 Parathyroid hormone (PTH), calcium Piles see Haemorrhoids
Pain loss, denervation problems, 26 absorption, 142 Pinocytosis, 10
Pancreas, 2, 71 Parietal cells see Oxyntic (parietal) cells bile in protein, 100
adenocarcinoma, 188–189, 188 Parietal juice, 43 Pirenzepine, 62
back pain, 185 Parotid salivary gland, 29 Plasma glucose
treatment, 189, 189f diseases/disorders, 193–194, 193t post-absorptive state, 163
alkaline secretion, 75–77 Passive diffusion, ion absorption, 142 starvation, 164
composition, 75 Passive flux, sodium ions, 118 Plasma membrane, hepatocytes, 93
functions, 75 Passive mechanisms, calcium absorption, 142 Plasma osmolality, thirst, 6
anatomy, 72, 72f, 72–75 Pentagastrin, gastric juice, 43 Plicae circularis, duodenum, 109
ampulla of Vater, 72 Pepsin, 139 Pore routes, absorption, 116
sphincter of Oddi, 72 chief (peptic) cell secretion, 44–45 Portal vein, 7
blood supply, 109 peptic ulcer disease, 61 Post-absorptive state, 163–166
cancer, 188–189, 192, 184t Pepsinogen, 65–66 control of, 167–169
diseases/disorders, 72, 197–198, 199t activation, 45 glucose sparing reactions, 166, 198f
lipid digestion/absorption defects, 151 chief (peptic) cell secretion, 44–45 hormones, 168f, 169, 169t
endocrine tissue, 73–74 secretion regulation, 57–58, 58f glucose supplying reactions, 163–166, 166f
see also specific hormones Peptic cells see Chief (peptic) cells hormones, 168f, 169, 169t
enzymes, 77–79 Peptic ulcer disease, 53, 195, 195t hormones, 167–168
precursor activation, 78–79, 82f, 82t acid–base balance, 68 insulin-dependent diabetes mellitus vs.,
secretion mechanisms, 77–78, 82f causes, 56 164–165
see also specific enzymes diagnosis, 56 plasma glucose, 163
exocrine tissue, 72 hydrochloric acid secretion, 56t Post-hepatic jaundice, 99, 100
histology, 74f, 74–75 mucosal ulceration, 60–61 Postoperative gastric stasis, 64
morphology, 72–75 pepsin, 61 Post-surgical pancreatic fistula, 76
pancreatic juice, 75 stomach function, 66 Potassium (K) ions
secretion mechanisms, 76–77 treatment, 61–62 absorption, 118–120
composition changes, 77, 79f drugs, 61 intestinal secretions, 112, 114f
secretion regulation, 79–84 surgery, 61–62 osmotic gradient effects, 118
cephalic phase, 81 triple therapy, 61 saliva, 32
gastric phase, 81–82 see also Helicobacter pylori infection Potential difference
hormonal, 79–81 Periportal cells, glycogen, 88–89 absorption, 116, 116t
see also specific hormones Perisinusoidal spaces, liver, 87–88 membrane transport, 7–8
intestinal phase, 82–84 Peristalsis PP see Pancreatic polypeptide (PP)
during meals, 81–84 colon, 178 PPIs see Proton pump inhibitors (PPIs)
nervous control, 81–84 small intestine motility, 124, 124f Preganglionic parasympathetic nerves, 15
surgery, 192, 192f stomach, 48 Prehepatic jaundice, 99
Pancreatectomy, 192 Peritonitis, 175 Primary micelles, 92
Pancreatic juice, 75 Permanent teeth, 26 Primary teeth, 26
Pancreatic lipase, gastrinomas, 66 Pernicious anaemia, 46, 148 Procarboxypeptidase, activation, 78
Pancreatico-duodenal artery, 73–74 Crohn’s disease, 147 Processed quantities, 3–4, 4f
Pancreatic polypeptide (PP) gastrinomas, 66 Proelastase, activation, 78
gallbladder control, 103 Peyer’s patches, 109–110 Proglumide, acid reduction therapy, 63
secretion, 73 pH Prophospholipase A, activation, 78
Pancreatitis saliva, 30, 31, 32 Prostaglandins, acid reduction therapy, 63
acute see Acute pancreatitis see also Acid–base balance Protection, saliva, 25, 31
chronic see Chronic pancreatitis Phenacetin, hepatocyte biotransformation, Proteins, 138–141
Pancreato-duodenal artery, 109 95f, 96 absorption, 130
Paneth cells, 113f Phosphate (PO43) ions, requirements, digestion, 139f, 139–140
crypt epithelium, 112 141–142 small intestine, 139–140
small intestine wall, 111 Phosphatidylcholine stomach, 139
Papillae, tongue, 23 in bile, 91 see also specific enzymes
Paracellular sieving, bile in protein, 100 structure, 91f structure, 139, 139f

214
 index
Proton exchange, sodium ion absorption, hydrochloric acid secretion, 55–57, 58t nervous control, 125
119–120, 120f intestinal digestion, 108–109 peristalsis, 124, 124f
Proton pump inhibitors (PPIs), 44 pancreatic secretion regulation, 81, 82–83 reflex control, 125–126
acid reduction therapy, 59–62 Secretion, 3 segmentation, 123–124, 124f
chronic pancreatitis treatment, 80 control of, 13, 13t smooth muscle, 122
peptic ulcer disease treatment, 61 Secretomotor neurones, small intestine spontaneous contractions, 123
Proton secretion, oxyntic (parietal) cells, 43 secretion control, 114 types, 123
Purinergic fibres, stomach motility control, Secretory diarrhoea, 120–121 Small peptides, absorption, 140–141
64 Secretory laxatives, 126 Smell, 24–26
Pyloric sphincter, 40, 48 Segmentation olfactory mucosa structure, 26f
control of, 65 colon motility, 179 Smoking
Pyloroplasty, peptic ulcer disease treatment, ileum, 123–124 oesophageal cancer, 186–187
62, 62f jejunum, 123–124 stomach cancer, 187–188
Pylorus, surgery, 191 small intestine motility, 123–124, 124f Smooth muscle, 10, 11f
Pyridoxine (vitamin B6), absorption, 145 Sensory neurones, enteric nervous system, cell types, 10
15 circular coat, 10
Serosa, stomach, 40 contraction initiation, 11, 12f
R SGLT1, 136, 136–137 longitudinal coat, 10
structure, 137f oesophagus, 35, 37f
Ramsay–Hunt syndrome, 193 SGLT2, 136 disorders, 38
‘Reactive hypoglycaemia’, 158f, 158–159 Shigella dysenteriae infections, 201 phasic, 10
Rectum, 172, 172f Sigmoid colon, 172, 172f regulation, 11–13
Reflex control, small intestine motility, Sinusoidal spaces, liver, 87–88 small intestine motility, 122
125–126 Sjögren’s syndrome tonic, 10
Reflux oesophagitis, 38, 194–195 submandibular glands, 21f Sodium (Na) ions
Regulation (of gastrointestinal system), xerostomia, 21 absorption, 118–120
during a meal, 17, 17–18 Skeletal muscle colon, 177
Rehydration therapy glucose, 156 H exchange, 119–120, 120f
cholera, 120 glycogen, 156 neutral amino acids, 119, 119f
intravenous, cholera, 120 oesophagus, 35, 37f passive flux, 118
oral therapy see Oral rehydration therapy disorders, 38 transcellular route, 118–119, 119f
Renal adjustments, cholera, 121 Small intestine, 107 intestinal secretions, 112, 114f
Resting membrane potential (RMP), smooth absorption, 47 osmotic gradient effects, 118
muscle contraction, 11–12, 12, 12f anatomy, 109–111 saliva, 32
Riboflavin, colonic bacterial synthesis, 178 blood supply, 110–111 Nadependent co-porters, amino acid
Rickets, 143 digestion, 108–109 absorption, 140
regulation, 109t Na dependent/glucose transporter
structures, 108f (SGLT1), 118–119
S diseases/disorders, 198–201, 199t Solid tumours, malignancies, 184
infections, 198, 199t Solution, saliva function, 25
Sacral control centre, defaecation, 182 obstruction, 119f Somatostatin, 13t
Saliva, 2, 29–30 tumours, 198 analogues, 84
composition, 29, 33t protein digestion, 139–140 hydrochloric acid secretion, 55
-amylases, 134 secretions, 112, 114f pancreatic secretion regulation, 81
changes over time, 32, 33f control of, 114 secretion, 73
functions, 25, 30–31 submucosa, 110f stomach, 41
mastication, 27 surface area, 114 Sour, 24
regulation, 33–35 surgery, 192–193 Spasm, cricopharyngeal, 38
blood flow, 34 wall structure, 111–122 Speech
cellular mechanisms, 33–34 cell types, 112, 113f denervation problems, 25
food, 34–35 see also specific cell types saliva functions, 31
secretion, 31–32 crypts of Lieberkühn, 112 Sphincter of Oddi, 72, 86, 103, 109
denervation problems, 26 histology, 111–112 Splanchnic circulation, 7f, 8f, 6–7
taste, 24, 24f muscularis externa, 111 regulation, 17
Salivary glands, 2, 29, 30–35 muscularis mucosae, 111 Splenomegaly, 197
calculi, 193–194 x-ray, 110f Spontaneous contractions, small intestine
diseases/disorders, 193–194 Small intestine motility, 122–123 motility, 123
histology, 30, 30f control, 125–126 Starch, structure, 132
salivon structure, 32, 32f drugs, 126–127 Starvation, 163
structure, 29f, 30 gastroileal reflex, 126 acid–base status, 164
see also specific glands hormonal control, 125 energy provision, 164
Salmonella typhi infections, 198, 201, 199t hypermobility, diarrhoea, 122 metabolism, 164
Salt, 24 migrating myoelectric complex, 123, 123, plasma glucose, 164
Satiety centre, 5 124f Steatorrhoea, pancreatic adenocarcinoma,
Secretin, 13t muscularis mucosae contraction, 125 188–189

215
 Stomach, 39, 51 peptic ulcer disease treatment, 61–62 Tubuloacinar lands, pancreas, 72
index

absorption, 46 pylorus, 191 Tumours see Malignancies

acid secretion see Hydrochloric acid small intestine, 192–193
secretion stomach, 191
anatomy, 40, 41f ulcerative colitis, 176, 193 U
cancer, 187–188, 184t, 188t Swallowing, 35f, 35–38
surgery, 191 control, 36 UDP-glucuronyl transferase, anion
control by food, 65–69 denervation problems, 25 biotransformation, 95, 95f
cephalic phase, 65, 65–66, 67f oesophageal phase, 36, 36f, 37f Ulceration, non-steroidal anti-inflammatory
gastric phase, 65, 67, 67f pharyngeal phase, 36 drugs, 59
intestinal phase, 65, 67–69, 68f voluntary phase, 35–36 Ulcerative colitis, 175, 196–197, 202, 201t
diseases/disorders, 195 Sweet, 24 defect, 176
distension, 5 Sympathetic nerves, 15f, 15–16 diagnosis, 176, 176f
histology, 41–42 post-absorptive state regulation, 167–168 surgery, 193
see also specific cell types saliva regulation, 33 treatment, 176
hydrochloric acid secretion see small intestine, 111, 125 see also Crohn’s disease
Hydrochloric acid secretion Ultrasound
iron absorption, 44–46 acute pancreatitis, 83f
mixing/emptying, 47–48 T gallstones, 93f
morphology, 40 Unconditioned reflexes, 35
motility, 47–50 Taeniae coli, 174–175 Ursodeoxycholic acid, gallstone treatment,
food, effects on, 66, 67, 68–69 Taste, 24 103
regulation, 63–64, 64f, 64t denervation problems, 25
peristalsis, 48 saliva secretion, 24, 24f
protein digestion, 139 stomach, effects on, 65 V
secretion control, 52–57 Taste buds, 24
food, by, 65–66 electrical potentials, 26f Vagal fibres, 15
food, effects on, 67, 68 structure, 23f Vagotomy, gastric juice secretion, 65–66
hormones, 52 Teeth, 26–27 Vagus nerve
see also specific hormones structure, 27f pancreas innervation, 74
neurological, 54–55 Tetrapeptide absorption, 139f, 139–140 small intestine, 111
see also specific secretions Thiamin, colonic bacterial synthesis, 178 Varices, oesophagus, 194t
secretory mucosa, 41, 42f Thiazolidediones, non-insulin-dependent Vasoactive intestinal peptide (VIP), 13t
see also under gastric diabetes mellitus treatment, 166 colon secretion control, 177
Straight tubular glands, colon, 173–174 Thirst, 6 gallbladder control, 103
Strong electrolyte drugs, absorption, 117 Thirst receptors, 6 hydrochloric acid secretion, 55–57, 58t
Sublingual salivary glands, 29 Tongue, 22–29 intestinal secretion control, 112
Submandibular salivary glands, 29 extrinsic muscles, 23f pancreatic secretion regulation, 79, 81
Sjögren’s syndrome, 21f glands, 22–23 saliva regulation, 33
Submucosa, stomach, 40 see also Taste buds Vasodilation, saliva regulation, 34, 34f
Submucous plexus (Meissner’s plexus), Total parenteral nutrition (TPN), Crohn’s Venous occlusion, ischaemia, 200
enteric nervous system, 14 disease, 133 Vibrio cholerae infection see Cholera
Substance P Trace elements, absorption, 141–144 Villi, 111
colon motility, 179–180 Transcellular route, sodium ion absorption, countercurrent exchange, 111
saliva regulation, 33 118–119 structure, 111f
Sucrase, 134, 135f Transcobalamin II, vitamin B12 absorption, Villous epithelium, 112
Sucrase-isomerase deficiency, 136 145–146 Visceral pain, 185f
Sucrose, digestion, 134, 135f Transverse colon, 172, 172f Vitamin(s)
Sulphonylureas, non-insulin-dependent Triacylglycerol synthesis, insulin, 161 fat soluble see Fat-soluble vitamins
diabetes mellitus treatment, 165–166 Trigeminal nerve (cranial nerve V), 22 water-soluble, absorption, 144–146
Superior mesenteric artery, 7, 110 mandibular division, 22f see also specific vitamins
Superior rectal artery, 175–177 pharyngeal phase of swallowing, 36 Vitamin A deficiency, 146
Surgery, 184, 190–193 Triggers, vomiting, 48 Vitamin B12
antrum, 191 Tripeptides, absorption, 139f, 139–140 absorption, 146f, 148, 145–146
colon, 193 Triple therapy, peptic ulcer disease intrinsic factor, 44
gallbladder, 191–192 treatment, 61 colonic bacterial synthesis, 178
gallstone treatment, 102, 102f Trypanosomiasis, American see Chaga’s deficiency, 44, 145
ileum, 192–193 disease Vitamin B complex
jejunum, 192–193 Trypsin, 139 absorption, 144–145
liver, 192 acute pancreatitis, 83 colonic bacterial synthesis, 178
obesity treatment, 6 enzyme activation, 78 Vitamin C (ascorbate), absorption, 144–145,
oesophagus, 190–191 pancreatic secretion, 77 145
pancreas, 192, 192f Trypsinogen, trypsin, conversion to, 78 Vitamin D, 146

216
 calcium absorption, 142 W diagnosis, 21–22

index
deficiency, 142 symptomatic, 21
Vitamin E, 146 Water absorption, 118 treatment, 34
Vitamin K colon, 177
colonic bacterial synthesis, 178 Water intake control, saliva functions, 31
deficiency, 146 Water-soluble vitamins, absorption, 144–146 Z
Voltage-determined Ca2 channels Weak electrolyte drugs, absorption, 116–117,
(VDCCs) 117f Zollinger–Ellison syndrome, 188–189
insulin secretion control, 159 Whipple’s procedure, 192, 192f hydrochloric acid secretion, 56t
smooth muscle contraction, 11 Wisdom tooth extraction, denervation, 23, see also Gastrinomas
Vomiting, 48–50 25–26
control, 49
excessive see Excessive vomiting
transmitters, 49–50 X
triggers, 48
Vomiting centre, 48 Xerostomia, 20, 20f
Von Gierke’s disease, 156 cases, 21

217