Clinical Biochemistry:

Liver Dysfunction

Rizky Abdulah
Division of Pharmacology and Clinical Pharmacy
Faculty of Pharmacy, Universitas Padjadjaran, INDONESIA.

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 The Liver
What is my liver?
Your liver is a large and
important organ in your body

Where is my liver?

Your liver is located behind the lower right

part of your ribs

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 The Liver
What does my liver do?
• Stores vitamins, sugars, fats and other nutrients
from the food that you eat
• Builds chemicals that your body needs to stay
healthy
• Breaks down harmful substances, like alcohol
and other toxic (poisonous) chemicals
• Removes waste products from your blood
• Makes sure that your body has just the right
amount of other chemicals that it needs
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LIVER
Liver is the largest gland and second largest organ in the body and
weighs about 1.5 kg in an adult.

Liver play role in synthesis, storage, secretion, excretion, and

specific modification of endogenously and exogenously derived
substances.

Liver represents 2-3% of body mass but it accounts for 25-30% of

oxygen consumption.

In the liver, 90% of the cell mass are hepatocytes, which about
3x1011 cells.

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Diagram of a Hepatocyte

Hepatocytes are particularly rich in endoplasmic reticulum, as

they carry out intensive protein and lipid synthesis.

The cytoplasm contains granules of insoluble glycogen.

Between the hepatocytes, there are bile capillaries through which

bile components are excreted.
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The Structure of The Liver
• Liver cells called hepatocyte,
derived from the primitive gut
epithelium.

• Hepatocytes are close contact

with the blood, which enters the
liver from the portal vein and the
hepatic arteries, flows through
capillary vessels known as
sinusoids, and is collected again in
the central veins of the hepatic
lobes.

• A scanning electron micrograph of

a portion of the liver. The larger
channels are vessels that
distribute and collect the blood
that flows through the sinusoids.

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• The blood is separated from the
surface of the hepatocytes by a
single layer of flattened
endothelial cells that covers the
exposed faces of the hepatocytes.

• This structure facilitates the chief

functions of the liver, which
depend on the exchange of
metabolites between hepatocytes
and the blood.

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• A single thin sheet of endothelial cells
with interspersed macrophagelike
Kupffer cells separates the hepatocytes
from the bloodstream.

• Small holes in the endothelial sheet,

called fenestrae (Latin for “windows”),
allow the exchange of molecules and
small particles between the hepatocytes
and the bloodstream.

• Besides exchanging materials with the

blood, the hepatocytes form a system of
tiny bile canaliculi into which they
secrete bile, which is ultimately
discharged into the gut via bile ducts.
The real structure is less regular than
this diagram suggests.

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Liver Functions
1. Uptake of nutrients supplied
by the intestines via the
portal vein.

2. Biosynthesis of endogenous
compounds and storage,
conversion, and degradation
of them into excretable
molecules (metabolism).
In particular, the liver is responsible for the biosynthesis and
degradation of almost all plasma proteins.

3. Supply of the body with metabolites and nutrients.

4. Detoxification of toxic compounds by biotransformation.

5. Excretion of substances with the bile.

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Hepatic Metabolism
The liver is involved in pratically of all groups of metabolites. Its
function primarily manage the balance of concentrations of these
substances in the blood, due to a constant supply to the peripheral
tissues (homeostasis).

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1. Carbohydrate metabolism.
After a meal containing carbohydrate, liver becomes a net consumer of
glucose and will elevetad levels of intracellular glucose in the
hepatocyte. These glucose will be conversed into glycogen and stored in
the liver, or converted into fatty acids. When there is a drop in the blood
glucose level, the liver releases glucose again by breaking down
glycogen. If the glycogen store is exhausted, glucose can also be
synthesized by gluconeogenesis from lactate, glycerol, or the carbon
skeleton of amino acids

2. Lipid metabolism.
Liver is the primary tissue for de novo synthesis of fatty acids. The fatty
acids formed are then used to synthesize fats and phospholipids, which
are released into the blood in the form of lipoproteins. The liver’s special
ability to convert fatty acids into ketone bodies and to release these
again is also important. Like other organs, the liver also synthesizes
cholesterol, which is transported to other tissues as a component of
lipoproteins. Excess cholesterol is converted into bile acids in the liver or
directly excreted with the bile.
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3. Amino Acid and Protein Metabolism
The liver controls the plasma levels of the amino acids. Excess amino
acids are broken down. With the help of the urea cycle, the nitrogen
from the amino acids is converted into urea and excreted via the
kidneys. The carbon skeleton of the amino acids enters the
intermediary metabolism and serves for glucose synthesis or energy
production. In addition, most of the plasma proteins are synthesized or
broken down in the liver

4. Biotransformation.
Steroid hormones and bilirubin, as well as drugs, ethanol, and other
xenobiotics (foreign chemicals including drugs, drug metabolites, etc)
are taken up by the liver and inactivated and converted into highly
polarmetabolites by conversion reactions.

5. Storage.
The liver not only stores energy reserves and nutrients for the body,
but also certain mineral substances, trace elements, and vitamins,
including iron, retinol, and vitamins A, D, K, folic acid, and B12.
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Liver Regeneration
The liver has a remarkable capacity to regenerate after injury
and to adjust its size to match its host. Within a week after
partial hepatectomy, which, in typical experimental settings
entails surgical removal of two-thirds of the liver, hepatic mass
is back essentially to what it was prior to surgery. Some
additional interesting observations include:

• In the few cases where baboon livers have been

transplanted into people, they quickly grow to the size of a
human liver.
• When the liver from a large dog is transplanted into a small
dog, it loses mass until it reaches the size appropriate for a
small dog.

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Attempts to transplant hepatocytes directly into the liver led to very limited success

Liver sinusoidal endothelial cells (LSECs), when activated, are critical to liver regeneration
and may enable proper engraftment (new blood-forming cells start to grow on
trasnplantation) when hepatocytes are implanted into the injured liver.

LSECs genes produce the angiocrine growth factors Id1 or Wnt2 and "hepatocyte
growth factor" (HGF) would initiate and sustain liver regeneration. It is thought that
Wnt2 and HGF work together in initiating regeneration, and that the LSECs and the
liver cells must be next to each other for successful regeneration. 14
Liver Diseases:

• Is it acute or chronic?
• Is the disease hepatocellular or
cholestatic?

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 Acute:
1. Viral (Hepatitis A, B, D, E, C (less likely))
2. Toxin (Alcohol, drug abuse)
3. Became chronic
hepatocellular

Chronic:
1. Viral (Hepatitis B, C.)
2. Toxin (Chronic Alcohol/drug abuse)
3. Inherited Diseases (i.e. Wilson disease)

Acute:
Drug
cholestatic Cirhosis
Bile can’t flow
from liver to
duodenum Chronic:
Primary biliary cirrhosis
(slow progressive destruction of the small
bile ducts within the liver)

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 What Is Cirrhosis?
Cirrhosis, (pronounced "sir-o-sis"), is a medical term
that means “scarring of the liver." When you have
cirrhosis, large parts of your liver are damaged. Because
it has been damaged, your liver may not work as well as
it should.

Cirrhosis
can be very
dangerous
if it is not
treated
properly. 17
Cirrhosis is a consequence of chronic liver disease characterized by replacement
of liver tissue by fibrosis, scar tissue and regenerative nodules leading to loss of
liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C,
and fatty liver disease, but has many other possible causes. Some cases are
idiophatic （unknown cause).

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Jaundice
Jaundice is not a disease but rather a sign that can occur in many different diseases.
Jaundice is the yellowish staining of the skin and sclerae (the whites of the eyes) that
is caused by high levels in blood of the chemical bilirubin. The color of the skin and
sclerae vary depending on the level of bilirubin. When the bilirubin level is mildly
elevated, they are yellowish. When the bilirubin level is high, they tend to be brown.

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Bilirubin comes from red blood cells. When red blood cells get old, they are
destroyed. Hemoglobin, the iron-containing chemical in red blood cells that carries
oxygen, is released from the destroyed red blood cells after the iron it contains is
removed. The chemical that remains in the blood after the iron is removed becomes
bilirubin

The liver removes bilirubin from the blood. After the bilirubin has entered the liver
cells, the cells conjugate (attaching other chemicals, primarily glucuronic acid) to the
bilirubin, and then secrete the bilirubin/glucuronic acid complex into bile. The
complex that is secreted in bile is called conjugated bilirubin. The conjugated
bilirubin is eliminated in the feces. (Bilirubin is what gives feces its brown color.)
Conjugated bilirubin is distinguished from the bilirubin that is released from the red
blood cells and not yet removed from the blood which is termed unconjugated
bilirubin.

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 RBC

RBC
RBC RBC

RBC
Bil

Hb

Bil BU

Bile
BC Intestine

BC: conjugated bilirubin (direct bilirubin), water soluble, bound to glucorinic acid
BU: uncinjugated bilirubin, (indirect bilirubin, water insoluble Feces 21
Tbil: BC+BU
Alcoholic Liver Disease

• Alcoholic liver disease is arises from the

excessive ingestion of alcohol.
• The major cause of liver disease in Western
countries.

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• How alcohol damages the liver is not
completely understood.
• It is known that
alcohol produces
toxic chemicals like
acetaldehyde which
can damage liver
cells, but why this
occurs in only a few
individuals is still in
debate.
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Alcohol metabolism in the liver

• Chronic alcohol consumption depresses

the activity of mitochondrial complexes
• The rate of ATP synthesis in liver cells
exposed to ethanol is typically reduced
• As a result, the energy metabolism of liver
cells can be severely impaired and this
would lead to tissue damage.

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Viral Hepatitis
What is hepatitis?

Hepatitis is an inflammation of the liver

characterized by the presence of inflammatory
cells in the tissue of the organ.
The condition can be self-limiting (healing on
its own) or can progress to fibrosis (scarring)
and cirrhosis.

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Hepatitis is acute when it lasts less than six
months and chronic when it persists longer.

A group of viruses known as the hepatitis

viruses cause most cases of hepatitis
worldwide, but it can also be due to toxins
(notably alcohol, certain medications and
plants), other infections and autoimmune
diseases.

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 Types of Viral Hepatitis
A B C D E

Source of Blood/blood- Blood/blood- Blood/blood-

Feces Feces
virus derived body derived body derived body
fluids fluids fluids
Route of Percutaneous Percutaneous Percutaneous
Fecal-oral Fecal-oral
transmission permucosal permucosal permucosal
Chronic
No Yes Yes Yes No
infection
Pre/post-
Blood donor
Pre/post- Pre/post- exposure
screening; Ensure safe
Prevention exposure exposure immunization;
risk behavior drinking water
immunization immunization risk behavior
modification
modification

Source: Center for Disease Control and Prevention (CDC)

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What Are the Symptoms of Hepatitis C?

Symptoms of hepatitis C are usually very mild. You

may not have any symptoms at all. Even though
hepatitis C might not make you feel sick, it is still a
serious illness. In most cases, hepatitis C never goes
away. Over time, it can cause other problems,
including cirrhosis and liver cancer.

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Can I Get a Vaccine Against Hepatitis C?
There is not a vaccine that will keep you from getting
hepatitis C. There are vaccines that can keep you from
getting other kinds of hepatitis, such as A and B.

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Liver function tests
LFT, which include liver enzymes, are groups of
clinical biochemistry laboratory blood assays
designed to give information about the state of
a patient's liver. Most liver diseases cause only
mild symptoms initially, but it is vital that these
diseases be detected early.

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LFT can be used to:

(1) detect the presence of liver disease

(2) distinguish among different types of liver
disorders
(3) gauge the extent of known liver damage,
and
(4) follow the response to treatment

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 Liver Function Test
Advantages Disadvantages
• sensitive, noninvasive • lack sensitivity
method of screening liver – normal results in serious liver
dysfunction disease
• pattern of laboratory test • not specific for liver
abnormalities to recognize
dysfunction
type of liver disorder
• assess severity of liver • seldom lead to specific
dysfunction diagnosis
• follow cause of liver disease

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 Liver Function Test
• interpretation must be performed within the
context of the patient’s risk factors,
symptoms, concomitant conditions,
medications, and physical findings
• rarely provide specific diagnosis, but rather
suggest a general category of liver disease
• differing laboratories  differing normal
values

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Parameters of LFT

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(International normalized ratio (INR) is blood-clotting test. It is a test used to measure how quickly
your blood forms a clot, compared with normal clotting time).

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 Liver Function Test
classified in 3 groups
•synthetic function : albumin, PT
•hepatocyte injury : AST, ALT
•cholestasis : bilirubin, ALP, GGT

PT, albumin, bilirubin-most common tests

used as prognostic factors

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 AST/ALT ratio
90

80

70

60

50

AST/ALT >1
40
AST/ALT >2
30

20

10

0
alcoholic post necrotic chronic obstructive viral hepatitis
cirrhosis hepatitis jaundice 38
 Albumin
• depend on nutrition, volume status, vascular
integrity, catabolism, hormone, loss in stool
and urine
• not specific for liver disease
• T1/2 19-21 D
– not reliable indicator of acute liver disease

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 Hypoalbuminemia
globulin chol/TG Hb
1.decrease synthesis
-protein malnutrition
-chronic liver disease
-chronic inflammation
2.increase loss
-PLE (Protein-losing enteropathy )
-NS (Nephrotic syndrome)
3.increase Vd -> volume of distribution (ascites, overhydration)
4.increase turnover (catabolic state, steroid)

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 Globulin
• produced by stimulated B lymphocyte
• elevation in
• chronic liver disease
• chronic inflammation and malignant
disease

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 Prothrombin time
• liver synthesize coagulation factor except
FVIII
• most present in excess, clotting abnormal
occur only when substantial impairment in
ability of liver to synthesis
• PT : FI, II, V, VII, IX and X
• T1/2 FVII 6 hrs. (shortest)
• prognosis : acute, chronic hepatocellular
disease
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 AST/ALT ratio
• < 1 : majority of liver disease
• >2
– extrahepatic source
– alcoholic hepatitis
– ischemic and toxin
– acute Wilson’s disease : hemolysis
– cirrhosis
• >4 : fulminant Wilson’s disease

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 Liver Function Test
• normal may have abnormal test
• normal value not ensure that patient is free
of liver disease
• level of abnormality does not reflect severity
but may help in diagnosis
• decrease in the value does not mean
improvement
• limitation in sensitivity and specificity
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References

1. Koolman J., Roehm KH., Colour Atlas of Biochemistry : Liver, p: 306-320,

2nd edition, Thieme, Stuttgart, 2005.
2. Champe PC., Harvey RA., Lippincott’s Illustrated Reviews Biochemistry:
The feed/fast cycle, p: 321-325, 3rd edition, Wolters Kluwer-Lipincott
Williams & Wilkins, Philadelphia, 2008.

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