Harrison’s 20th ed.

IRRITABLE BOWEL SYNDROME Pp.2276

IRRITABLE BOWEL SYNDROME -at first, constipation may be episodic, but eventually it
becomes continuous and increasingly intractable to
-is a functional bowel disorder characterized by treatment with laxatives.
abdominal pain or discomfort and altered bowel habits -stools are usually hard with narrowed caliber, possibly
in the absence of detectable structural abnormalities. reflecting excessive dehydration caused by prolonged
-NO clear diagnostic markers exist for this colonic retention and spasm.
-female predominance - sense of incomplete evacuation leading to repeated
-IBS symptoms tend to come and go over time and often attempts at defecation in a short time span.
overlap with other functional disorders such as - diarrhea resulting from IBS usually consists of small
fibromyalgia, headache, backache, and genitourinary volumes of loose stools of <200 may be accompanied
symptoms. by passage of large amounts of mucus.
-involved are altered gastrointestinal (GI) motility, visceral -may be aggravated by emotional stress or eating.
hyperalgesia, disturbance of brain–gut interaction, - bleeding is not a feature of IBS unless hemorrhoids are
abnormal central processing, autonomic and hormonal present, and malabsorption or weight loss does not
events, genetic and environmental factors, and occur.
psychosocial disturbances. (depends individually)
Bowel pattern subtypes:
CLINICAL FEATURES IBS-diarrhea predominant (IBS-D), IBS-constipation
- affects all ages but most have 1st symptoms before age predominant (IBS-C), and IBS-mixed (IBS-M) forms
45.
- more in women, 2 to 3x GAS AND FLATULENCE
- PAIN is a key symptom for the diagnosis and is - abdominal distention and increased leching or
associated with defecation and/or have their onset flatulence
associated with a change in frequency or form of stool. - IBS patients tend to reflux gas from the distal to the
- supportive symptoms that are not part of the diagnostic more proximal intestine, which may explain the belching
criteria include defecation straining, urgency or a feeling
of incomplete bowel movement, passing mucus, and UPPER GI SYMPTOMS
bloating. - dyspepsia, heartburn, nausea, and vomiting
- Rome IV criteria: abdominal pain to occur at a minimum
of once a week and eliminates “discomfort” as one of PATHOPHYSIOLOGY
the criteria -Pathogenesis of IBS is poorly understood, although roles
of abnormal gut motor and sensory activity, central
ABDOMINAL PAIN neural dysfunction, psychological disturbances, mucosal
- prerequisite clinical feature inflammation, stress, and luminal factors such as bile
- frequently episodic and crampy, but it may be acid malabsorption and gut dysbiosis have beenproposed.
superimposed on a background of constant ache during
waking hours.
- exacerbated by eating or emotional stress
- improved by passage of flatus or stools

ALTERED BOWEL HABITS

- most consistent clinical feature in IBS
- most common pattern is constipation alternating with
diarrhea, usually with one of these symptoms
predominating.
GI Motor Abnormalities Postinfectious IBS
-patients may exhibit increased rectosigmoid motor - may be induced by GI infection
activity for up to 3 h after eating. -Risk factors for developing postinfectious IBS include, in
- inflation of rectal balloons both in IBS-D and IBS-C order of importance, antibiotic treatment, prolonged
patients leads to marked and prolonged distention- duration of initial illness, toxicity of infecting bacterial
evoked contractile activity. strain, smoking, mucosal markers of inflammation, female
- GREATLY INCREASED motility index and peak amplitude sex, depression, hypochondriasis, and adverse life events
of high-amplitude propagating contractions (HAPCs) in in the preceding 3 months.
diarrhea-prone IBS patients -microbes involved in the initial infection are
Campylobacter, Salmonella, and Shigella.
Visceral Hypersensitivity
- exhibit exaggerated sensory responses to visceral Immune Activation and Mucosal Inflammation
stimulation. -signs of low-grade mucosal inflammation with activated
-may be due to (1) increased end-organ sensitivity with lymphocytes, mast cells, and enhanced expression of
recruitment of “silent” nociceptors; (2) spinal proinflammatory cytokines.
hyperexcitability with activation of nitric oxide and -Other studies also indicate that peripheral blood
possibly other neurotransmitters; (3) endogenous (cortical mononuclear cells (PBMCs) from IBS patients show
and brainstem) modulation of caudad nociceptive abnormal release of proinflammatory cytokines such as
transmission; and (4) over time, the possible development IL6, IL1β, and TNF.
of long term hyperalgesia due to development of -these abnormalities may contribute to abnormal
neuroplasticity, resulting in permanent or semipermanent epithelial secretion and visceral hypersensitivity.
changes in neural responses to chronic or recurrent -transient receptor potential (TRP) cation channels such
visceral stimulation. as TRPV1 (vanilloid) channels are central to the initiation
- frequency of perceptions of food intolerance is at least and persistence of visceral hypersensitivity.
twofold more common than in the general population - Mucosal inflammation can lead to increased expression
*prolonged fasting in IBS patients is often associated with of TRPV1 in the enteric nervous system.
significant improvement in symptoms - Enhanced expression of TRPV1 channels in the sensory
- Lipids lower the thresholds for the first sensation of neurons of the gut has been observed in IBS, and such
gas, discomfort, and pain in IBS patients. expression appears to correlate with visceral
hypersensitivity and abdominal pain
Central Neural Dysregulation - increased intestinal permeability in patients with IBS-D
-functional brain imaging studies such as magnetic - psychological stress and anxiety can increase the
resonance imaging (MRI) have shown that in response to release of proinflammatory cytokine which can alter
distal colonic stimulation, the mid-cingulate cortex—a intestinal permeability.
brain region concerned with attention processes and -IBS-D patients have an increase intestinal permeability
response selection—shows greater activation in IBS as measured by the lactulose/mannitol ratio and also
patients. have higher Functional Bowel Disorder Severity Index
-IBS patients also show preferential activation of the (FBDSI) score and increased hypersensitivity to visceral
prefrontal lobe, which contains a vigilance network within nociceptive pain stimuli.
the brain that increases alertness. These may represent
a form of cerebral dysfunction leading to the increased Altered Gut Flora
perception of -general IBS patients had decreased proportions of the
visceral pain. genera Bifidobacterium and Lactobacillus and increased
ratios of Firmicutes:Bacteroidetes.which may be related
Abnormal Psychological Features to stress and diet.
-patients with IBS frequently demonstrate increased motor -Firmicutes is the dominant phylum in adults consuming
reactivity of the colon and small bowel to a variety of a diet high in animal fat and protein.
stimuli and altered visceral sensation associated with - Gut dysbiosis may alter mucosal permeability and
lowered sensation thresholds which may result from CNS– increase antigen presentation to the immune cells in the
enteric nervous system dysregulation. lamina propria which may result in mast cell activation
-Brain functional MRI studies show greater activation of and altered enteric neuronal and smooth muscle function
the posterior and middle dorsal cingulate cortex, which causing IBS symptoms.
is implicated in affect processing in IBS patients with a
past history of sexual abuse.
-In addition, release of cytokines and chemokines from APPROACH TO THE PATIENT
mucosal inflammation may generate extra GI symptoms
such as chronic fatigue, muscle pain, and anxiety. -diagnosis relies on recognition of positive clinical
features and elimination of other organic diseases.
-refer to the Manning, Rome I, Rome II, Rome III, and
Rome IV criteria (defined IBS on the basis of abdominal
pain and altered bowel habits that occur with sufficient
frequency in affected patients)

✓ A careful history and physical examination are

frequently helpful in establishing the diagnosis.
(Clinical features suggestive of IBS include the following:
recurrence of lower abdominal pain with altered bowel
habits over a period of time without progressive
deterioration, onset of symptoms during periods of stress
or emotional upset, absence of other systemic symptoms
such as fever and weight loss, and small-volume stool
without any evidence of blood.
✓ The quality, location, and timing of pain may be
helpful to suggest specific disorders.

(Pain due to IBS that occurs in the epigastric or

periumbilical area must be differentiated from
biliary tract disease, peptic ulcer disorders,
intestinal ischemia, and carcinoma of the stomach
and pancreas.)

If pain occurs mainly in the lower abdomen, the

possibility of diverticular disease of the colon,
inflammatory bowel disease (including ulcerative
colitis and Crohn’s disease), and carcinoma of the
colon must be considered
.
✓ Factors to be considered when determining the
aggressiveness of the diagnostic evaluation:
1. the duration of symptoms
Abnormal Serotonin Pathways 2. the change in symptoms over time
-the serotonin (5-HT)-containing enterochromaffin cells in 3. the age and sex of the patient
the colon are increased in a subset of IBS-D patients 4. the referral status of the patient, prior diagnostic
compared to healthy individuals or patients with studies,
ulcerative colitis. 5. family history of colorectal malignancy
-Furthermore, postprandial plasma 5-HT levels were 6. the degree of psychosocial dysfunction.
significantly higher in this group of patients compared to
healthy controls. ✓ CBC, sigmoidoscopic examination and stool
-Tryptophan hydroxylase 1 (TPH1) is the rate-limiting specimens
enzyme in enterochromaffin cell 5-HT ✓ In patients with persistent diarrhea not responding
biosynthesis, functional TPH1 polymorphism has been to simple antidiarrheal agents, a sigmoid colon biopsy
shown to be associated with IBS habit subtypes. should be performed to rule out microscopic colitis.
-increased release of serotonin may contribute to the ✓ In those age >40 years, an air-contrast barium
postprandial symptoms of these patients and provides a enema or colonoscopy should also be performed.
rationale for the use of serotonin antagonists in the ✓ Hydrogen breath test or with evaluation after a 3-
treatment of this disorder. week lactose-free diet for possibility of lactase
✓ In patients with concurrent symptoms of blood levels are achieved shortly before the anticipated
dyspepsia, upper GI radiographs or onset of pain.
esophagogastroduodenoscopy may be advisable. -The drugs are most effective when prescribed in
✓ ultrasonogram of the gallbladder for patients anticipation of predictable pain.
with postprandial right upper quadrant pain. -dicyclomine that have less effect on mucous membrane
✓ Laboratory features that argue against IBS secretions and produce fewer undesirable side effects.
include evidence of anemia, elevated sedimentation rate, Side effects: most anticholinergics contain natural
presence of leukocytes or blood in stool, and stool belladonna alkaloids, which may cause xerostomia,
volume >200–300 mL/d. *These findings would urinary hesitancy and retention, blurred vision, and
necessitate other diagnostic considerations. drowsiness. They should be used in the elderly with
caution.

Antidiarrheal Agents
TREATMENT -Peripherally acting opiate-based agents are the initial
therapy of choice for IBS-D.
Patient Counseling and Dietary Alterations -Physiologic studies demonstrate increases in segmenting
➢ Food precipitants are important first steps in patient colonic contractions, delays in fecal transit, increases in
counseling and dietary change. anal pressures, and reductions in rectal perception with
➢ Excessive fructose and artificial sweeteners, such as these drugs.
sorbitol or mannitol, may cause diarrhea, bloating, -small doses of loperamide, 2–4 mg every 4–6 h up to a
cramping, or flatulence. maximum of 12 g/d, for severe diarrhea especially in the
➢ patients should avoid nutritionally depleted diets. painless diarrhea variant of IBS.
➢ A diet low in fermentable oligosaccharides, -most useful if taken before anticipated stressful events
disaccharides, monosaccharides, and polyols (FODMAPs) that are known to cause diarrhea.
has been shown to be helpful in IBS patients (see Low -However, not infrequently, a high dose of loperamide
FODMAP Diet at the last page). may cause cramping because of increases in segmenting
colonic contractions.
Stool-Bulking Agents -other is bile acid binder cholestyramine resin as up to
➢ High-fiber diets and bulking agents, such as bran or 30% of IBS-D patients may have bile acid malabsorption.
hydrophilic colloid, are frequently used in treating IBS.
(Fiber can increase fecal output of bacteria and speed Antidepressant Drugs
up colonic transit and stool-bulking agents bind water -In IBS-D patients, the tricyclic antidepressant imipramine
and thus prevent both excessive hydration and slows jejunal migrating motor complex transit propagation
dehydration of stool.) and delays orocecal and whole-gut transit, indicative of
➢ Fiber supplementation with psyllium has been shown a motor inhibitory effect.
to reduce perception of rectal distention with some .-the selective serotonin reuptake inhibitor (SSRI)
patients being constipated and other having predominant paroxetine accelerates orocecal transit, raising the
diarrhea. possibility that this drug class may be useful in IBS-C
(It is possible that different fiber preparations may patients.
have dissimilar effects on selected symptoms in IBS.) (The SSRI citalopram blunts perception of rectal
➢ Psyllium preparations tend to produce less bloating distention and reduces the magnitude of the
and distention. gastrocolonic response in healthy volunteers.)
Fiber should be started at a nominal dose and slowly
titrated up as tolerated over the course of several weeks Antiflatulence Therapy
to a targeted dose of 20–30 g of total dietary and -The management of excessive gas is seldom satisfactory,
supplementary fiber per day. except when there is obvious aerophagia or
disaccharidase deficiency.
Antispasmodics ✓ Patients should be advised to eat slowly and not
-Anticholinergic drugs may provide temporary relief for chew gum or drink carbonated beverages.
symptoms such as painful cramps related to intestinal ✓ Avoiding flatogenic foods, exercising, losing
spasm. excess weight, and taking activated charcoal are safe but
*Anticholinergic inhibits the gastrocolic reflex; hence, unproven remedies.
postprandial pain is best managed by giving
antispasmodics 30 min before meals so that effective
 ✓ A low FODMAP diet has been shown to be quite
effective to reduce gas and bloating (see Low FODMAP
Diet)
✓ Beano, an OTC oral β-glycosidase solution, may reduce
rectal passage of gas without decreasing bloating and
pain.
✓ Pancreatic enzymes reduce bloating, gas, and fullness
during and after high-calorie, high-fat meal ingestion.

Modulation of Gut Flora

-altered colonic flora (gut dysbiosis)

Antibiotics
✓ Neomycin dosed at 500 mg twice daily for 10 days
✓ patients receiving rifaximin at a dose of 550 mg two
times daily for 2 weeks experienced substantial
improvement of global IBS symptoms being the only
antibiotic with demonstrated sustained benefit beyond
therapy cessation in IBS patients.
Serotonin Receptor Agonist and Antagonists
Prebiotics -Serotonin acting on 5-HT3receptors enhances the
-are nondigestible food ingredients that stimulate growth sensitivity of afferent neurons projecting from the gut.
and/or activity of bacteria in the GI tract and defined as ✓ In humans, a 5-HT3 receptor antagonist such as
live microorganisms that when administered in adequate alosetron reduces perception of painful visceral
amounts confer a health benefit on the host. stimulation in IBS. It also induces rectal relaxation,
-significant relief of pain and bloating with the use of increases rectal compliance, and delays colonic transit.
Bifidobacterium breve, B longum, and Lactobacillus -Novel 5-HT4 receptor agonists such as tegaserod exhibit
acidophilus species compared to placebo but no change prokinetic activity by stimulating peristalsis.
in stool frequency or consistency. Being diarrhea its major side effect.
*** Low FODMAP Diet A diet rich in FODMAP (fermentable
oligo saccharides, disaccharides, monosaccharides, and Chloride Channel Activators
polyols) often triggers symptoms in IBS patients. ✓ Lubiprostone is a bicyclic fatty acid that stimulates
*** FODMAPs are poorly absorbed by the small intestine chloride channels in the apical membrane of intestinal
and fermented by bacteria in the colon to produce gas epithelial cells.
and osmotically active carbohydrates. Them entering the ✓ Chloride secretion induces passive movement of
colon, FODMAPs may serve as nutrient for the colonic sodium and water into the bowel lumen and improves
bacteria and promote the growth of gram negative bowel function.
commensal bacteria which may induce epithelial damage ✓ Oral lubiprostone was effective in the treatment of
and subclinical mucosa inflammation. Fructose and patients with constipation-predominant IBS in large phase
fructans induce IBS symptoms in a dose-dependent II and phase III significantly greater in patients receiving
manner. lubipros tone 8 μg twice daily for 3 months.
✓ Low FODMAP diet reduces IBS symptoms ✓ Drug was quite well tolerated. The major side effects
are nausea and diarrhea.
Guanylate Cyclase-C Agonist
✓ Linaclotide is a minimally absorbed 14-amino-acid
peptide guanylate cyclase-C (GC-C) agonist that binds to
and activates GC-C on the luminal surface of intestinal
epithelium. Activation of GC-C results in generation of
cyclic guanosine monophosphate (cGMP), which triggers
secretion of fluid, sodium, and bicarbonate. In animal
models, linaclotide accelerates GI transit and reduces
visceral nociception. The analgesic action of linaclotide
appears to be mediated by cGMP acting on afferent pain
fibers innervating the GI tract.
 ✓ For patients with more severe constipation, a chloride
channel opener (lubiprostone) or GC-C agonist
(linaclotide) may be considered.
✓ For IBS patients with predominant gas and bloating, a
low-FODMAP diet may provide
significant relief.
✓ Some patients may benefit from probiotics and
rifaximin treatment.
✓ Those have severe and refractory symptoms, are
usually seen in referral centers, and frequently have
constant pain and psychosocial difficulties.
Best managed with antidepressants and other
psychological treatments (Table 320-4).

Summary
The treatment strategy of IBS depends on the severity of
the disorder

✓ Most IBS patients have mild symptoms.

They are usually cared for in primary care practices, have
little or no psychosocial difficulties, and do not seek
health care often.
Treatment usually involves education, reassurance,
and dietary/ lifestyle changes.
✓ IBS-D patients, treatments include gut-acting
pharmacologic agents such as antispasmodics,
antidiarrheals, bile acid binders, and the newer gut
serotonin modulators (Table 320-4).
✓ In IBS-C patients, increased fiber intake and the use
of osmotic agents such as polyeth ylene glycol may
achieve satisfactory results.

JMD 2023