APPROACH TO THE PATIENT: Irritable Bowel Syndrome
Because IBS is a disorder for which no pathognomonic abnormalities have been identified, its diagnosis relies on recognition of positive clinical features and elimination of other organic diseases. Symptom-based criteria have been developed for the purpose of differentiating patients with IBS from those with organic diseases. These include the Manning, Rome I, Rome II, and Rome III criteria (Table 352-1). The diagnostic values of these criteria are shown in Table 352-3. In a validation study, Rome III performed less well than either the Rome I and II criteria and all criteria studied to date showed positive predictive values of <50%, which underscores the need for developing diagnostic strategies for IBS that are more cost-effective than the current approaches. 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.
On the other hand, the appearance of the disorder for the first time in old age, progressive course from time of onset, persistent diarrhea after a 48-h fast, and presence of nocturnal diarrhea or steatorrheal stools argue against the diagnosis of IBS.
Because the major symptoms of IBS—abdominal pain, abdominal bloating, and alteration in bowel habits—are common complaints of many GI organic disorders, the list of differential diagnoses is a long one. 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. Postprandial pain accompanied by bloating, nausea, and vomiting suggests gastroparesis or partial intestinal obstruction. Intestinal infestation with Giardia lamblia or other parasites may cause similar symptoms. When diarrhea is the major complaint, the possibility of lactase deficiency, laxative abuse, malabsorption, celiac sprue, hyperthyroidism, inflammatory bowel disease, and infectious diarrhea must be ruled out. On the other hand, constipation may be a side effect of many different drugs, such as anticholinergic, antihypertensive, and antidepressant medications.
Endocrinopathies such as hypothyroidism and hypoparathyroidism must also be considered in the differential diagnosis of constipation, particularly if other systemic signs or symptoms of these endocrinopathies are present. In addition, acute intermittent porphyria and lead poisoning may present in a fashion similar to IBS, with painful constipation as the major complaint. These possibilities are suspected on the basis of their clinical presentations and are confirmed by appropriate serum and urine tests.
Few tests are required for patients who have typical IBS symptoms and no alarm features. Unnecessary investigations may be costly and even harmful. The American Gastroenterological Association has delineated factors to be considered when determining the aggressiveness of the diagnostic evaluation. These include the duration of symptoms, the change in symptoms over time, the age and sex of the patient, the referral status of the patient, prior diagnostic studies, a family history of colorectal malignancy, and the degree of psychosocial dysfunction. Thus, a younger individual with mild symptoms requires a minimal diagnostic evaluation, while an older person or an individual with rapidly progressive symptoms should undergo a more thorough exclusion of organic disease. Most patients should have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not responding to simple antidiarrheal agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis. In those age >40 years, an air-contrast barium enema or colonoscopy should also be performed. If the main symptoms are diarrhea and increased gas, the possibility of lactase deficiency should be ruled out with a hydrogen breath test or with evaluation after a 3-week lactose-free diet. Some patients with IBS-D may have undiagnosed celiac sprue. Because the symptoms of celiac sprue respond to a gluten-free diet, testing for celiac sprue in IBS may prevent years of morbidity and attendant expense. Decision-analysis studies show that serology testing for celiac sprue in patients with IBS-D has an acceptable cost when the prevalence of celiac sprue is >1% and is the dominant strategy when the prevalence is >8%. In patients with concurrent symptoms of dyspepsia, upper GI radiographs or esophagogastroduodenoscopy may be advisable. In patients with postprandial right upper quadrant pain, an ultrasonogram of the gallbladder should be obtained. Laboratory features that argue against IBS include evidence of anemia, elevated sedimentation rate, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d. These findings would necessitate other diagnostic considerations.
TREATMENT Irritable Bowel Syndrome PATIENT COUNSELING AND DIETARY ALTERATIONS
Reassurance and careful explanation of the functional nature of the disorder and of how to avoid obvious food precipitants are important first steps in patient counseling and dietary change. Occasionally, a meticulous dietary history may reveal substances (such as coffee, disaccharides, legumes, and cabbage) that aggravate symptoms. Excessive fructose and artificial sweeteners, such as sorbitol or mannitol, may cause diarrhea, bloating, cramping, or flatulence. As a therapeutic trial, patients should be encouraged to eliminate any foodstuffs that appear to produce symptoms. However patients should avoid nutritionally depleted diets. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) (Table 352-4) has been shown to be helpful in IBS patients. FODMAPs are poorly absorbed by the small intestine and fermented by bacteria in the colon to produce gas and osmotically active carbohydrates. Clinical studies demonstrate that in IBS patients, ingestion of FODMAPs such as lactose, fructose, or sorbitol, alone or in combination, produce gut symptoms such as gas and diarrhea. On the other hand, a randomized controlled study showed that a diet low in FODMAPs reduced symptoms in IBS patients. This approach may be used in diarrhea-predominant IBS patients with severe gas and bloating. Durable adherence can be expected in up to 75% of patients. Stool-Bulking Agents
High-fiber diets and bulking agents, such as bran or hydrophilic colloid, are frequently used in treating IBS. The water-holding action of fibers may contribute to increased stool bulk because of the ability of fiber to increase fecal output of bacteria. Fiber also speeds up colonic transit in most persons. In diarrhea-prone patients, whole-colonic transit is faster than average; however, dietary fiber can delay transit. Furthermore, because of their hydrophilic properties, stool-bulking agents bind water and thus prevent both excessive hydration and dehydration of stool. The latter observation may explain the clinical experience that a high-fiber diet relieves diarrhea in some IBS patients. Fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive effect on visceral afferent function.
The beneficial effects of dietary fiber on colonic physiology suggest that dietary fiber should be an effective treatment for IBS patients, but controlled trials of dietary fiber have produced variable results. This is not surprising since IBS is a heterogeneous disorder, with some patients being constipated and other having predominant diarrhea. Most investigations report increases in stool weight, decreases in colonic transit times, and improvement in constipation. Others have noted benefits in patients with alternating diarrhea and constipation, pain, and bloating. However, most studies observe no responses in patients with diarrhea- or pain-predominant IBS. It is possible that different fiber preparations may have dissimilar effects on selected symptoms in IBS. A cross-over comparison of different fiber preparations found that psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and distention. Despite the equivocal data regarding efficacy, most gastroenterologists consider stool-bulking agents worth trying in patients with IBS-C. Fiber should be started at a nominal dose and slowly titrated up as tolerated over the course of several weeks to a targeted dose of 20–30 g of total dietary and supplementary fiber per day. Even when used judiciously, fiber can exacerbate bloating, flatulence, constipation, and diarrhea. Antispasmodics
Clinicians have observed that anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. Although controlled clinical trials have produced mixed results, evidence generally supports beneficial effects of anticholinergic drugs for pain. A meta-analysis of 26 double-blind clinical trials of antispasmodic agents in IBS reported better global improvement (62%) and abdominal pain reductions (64%) compared to placebo (35% and 45%, respectively), suggesting efficacy in some patients. The drugs are most effective when prescribed in anticipation of predictable pain. Physiologic studies demonstrate that anticholinergic drugs inhibit the gastrocolic reflex; hence, postprandial pain is best managed by giving antispasmodics 30 min before meals so that effective blood levels are achieved shortly before the anticipated onset of pain. Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary hesitancy and retention, blurred vision, and drowsiness. They should be used in the elderly with caution. Some physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and produce fewer undesirable side effects. Antidiarrheal Agents
Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D. Physiologic studies demonstrate increases in segmenting colonic contractions, delays in fecal transit, increases in anal pressures, and reductions in rectal perception with these drugs. When diarrhea is severe, especially in the painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed. These agents are less addictive than paregoric, codeine, or tincture of opium. In general, the intestines do not become tolerant of the antidiarrheal effect of opiates, and increasing doses are not required to maintain antidiarrheal potency. These agents are most useful if taken before anticipated stressful events that are known to cause diarrhea. However, not infrequently, a high dose of loperamide may cause cramping because of increases in segmenting colonic contractions. Another antidiarrheal agent that may be used in IBS patients is the bile acid binder cholestyramine resin. Antidepressant Drugs
In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation and delays orocecal and whole-gut transit, indicative of a motor inhibitory effect. Some studies also suggest that tricyclic agents may alter visceral afferent neural function.
A number of studies indicate that tricyclic antidepressants may be effective in some IBS patients. In a 2-month study of desipramine, abdominal pain improved in 86% of patients compared to 59% given placebo. Another study of desipramine in 28 IBS patients showed improvement in stool frequency, diarrhea, pain, and depression. When stratified according to the predominant symptoms, improvements were observed in IBS-D patients, with no improvement being noted in IBS-C patients. The beneficial effects of the tricyclic compounds in the treatment of IBS appear to be independent of their effects on depression. The therapeutic benefits for the bowel symptoms occur faster and at a lower dosage. The efficacy of antidepressant agents in other chemical classes in the management of IBS is less well evaluated. In contrast to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI) paroxetine accelerates orocecal transit, raising the possibility that this drug class may be useful in IBS-C patients. The SSRI citalopram blunts perception of rectal distention and reduces the magnitude of the gastrocolonic response in healthy volunteers. A small placebo-controlled study of citalopram in IBS patients reported reductions in pain. However, these findings could not be confirmed in another randomized controlled trial that showed that citalopram at 20 mg/d for 4 weeks was not superior to placebo in treating nondepressed IBS patients. Hence, the efficacy of SSRIs in the treatment of IBS needs further confirmation. Antiflatulence Therapy
The management of excessive gas is seldom satisfactory, except when there is obvious aerophagia or disaccharidase deficiency. Patients should be advised to eat slowly and not chew gum or drink carbonated beverages. Bloating may decrease if an associated gut syndrome such as IBS or constipation is improved. If bloating is accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a dietary exclusion trial may be worthwhile. Avoiding flatogenic foods, exercising, losing excess weight, and taking activated charcoal are safe but unproven remedies. Data regarding the use of surfactants such as simethicone are conflicting. Antibiotics may help in a subgroup of IBS patients with predominant symptoms of bloating. Beano, an over-the-counter 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
Antibiotic treatment benefits a subset of IBS patients. In a double-blind, randomized, placebo-controlled study, neomycin dosed at 500 mg twice daily for 10 days was more effective than placebo at improving symptom scores among IBS patients. The nonabsorbed oral antibiotic rifaximin is the most thoroughly studied antibiotic for the treatment of IBS.
In a double-blind, placebo-controlled study, patients receiving rifaximin at a dose of 550 mg two times daily for 2 weeks experienced substantial improvement of global IBS symptoms over placebo. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients. The drug has a favorable safety and tolerability profile compared with systemic antibiotics. A systematic review and meta-analysis of five studies of IBS patients found that rifaximin is more effective than placebo for global symptoms and bloating (odds ratio 1.57) with a number needed to treat (NNT) of 10.2. The modest therapeutic gain was similar to that yielded by other current available therapies for IBS. However, currently there are still insufficient data to recommend routine use of this antibiotic in the treatment of IBS.
Because altered colonic flora may contribute to the pathogenesis of IBS, this has led to great interest in using probiotics to naturally alter the flora. A meta-analysis of 10 probiotic studies in IBS patients found significant relief of pain and bloating with the use of Bifidobacterium breve, B. longum, and Lactobacillus acidophilus species compared to placebo. However, there was no change in stool frequency or consistency. Large-scale studies of well-phenotyped IBS patients are needed to establish the efficacy of these probiotics. Serotonin Receptor Agonist and Antagonists
Serotonin receptor antagonists have been evaluated as therapies for IBS-D. Serotonin acting on 5-HT3 receptors enhances the sensitivity of afferent neurons projecting from the gut. In humans, a 5-HT3 receptor antagonist such as alosetron reduces perception of painful visceral stimulation in IBS. It also induces rectal relaxation, increases rectal compliance, and delays colonic transit. Meta-analysis of 14 randomized controlled trials of alosetron or cilansetron showed that these antagonists are more effective than placebo in achieving global improvement in IBS symptoms and relief of abdominal pain and discomfort. These agents are more likely to cause constipation in IBS patients with diarrhea alternating with constipation. Also, 0.2% of patients using 5-HT3 antagonists developed ischemic colitis versus none in the control group. In postrelease surveillance, 84 cases of ischemic colitis were observed, including 44 cases that required surgery and 4 deaths. As a consequence, the medication was voluntarily withdrawn by the manufacturer in 2000. Alosetron has been reintroduced under a new risk-management program where patients have to sign a patient-physician agreement. This has significantly limited its usage.
Novel 5-HT4 receptor agonists such as tegaserod exhibit prokinetic activity by stimulating peristalsis. In IBS patients with constipation, tegaserod accelerated intestinal and ascending colon transit. Clinical trials involving >4000 IBS-C patients reported reductions in discomfort and improvements in constipation and bloating, compared to placebo. Diarrhea is the major side effect. However, tegaserod has been withdrawn from the market; a meta-analysis revealed an increase in serious cardiovascular events. Chloride Channel Activators
Lubiprostone is a bicyclic fatty acid that stimulates chloride channels in the apical membrane of intestinal epithelial cells. Chloride secretion induces passive movement of sodium and water into the bowel lumen and improves bowel function. Oral lubiprostone was effective in the treatment of patients with constipation-predominant IBS in large phase II and phase III randomized, double-blinded, placebo-controlled multicenter trials. Responses were significantly greater in patients receiving lubiprostone 8 μg twice daily for 3 months than in those receiving placebo. In general, the drug was quite well tolerated. The major side effects are nausea and diarrhea. Lubiprostone is a new class of compounds for treatment of chronic constipation with or without IBS. 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. A phase III, double-blind, controlled trial showed that linaclotide, 290 μg given once daily, significantly improved abdominal pain, bloating, and spontaneous bowel movement. The only significant side effect was diarrhea, which occurred in 4.5% of the patients. The drug has been approved for treatment of constipation in IBS-C patients. SUMMARY
The treatment strategy of IBS depends on the severity of the disorder (Table 352-5). 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. A smaller portion have moderate symptoms that are usually intermittent and correlate with altered gut physiology, e.g., worsened with eating or stress and relieved by defecation. For IBS-D patients, treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, bile acid binders, and the newer gut serotonin modulators (Table 352-6). In IBS-C patients, increased fiber intake and the use of osmotic agents such as polyethylene glycol may achieve satisfactory results. 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. A small proportion of IBS patients have severe and refractory symptoms, are usually seen in referral centers, and frequently have constant pain and psychosocial difficulties (Fig. 352-1). This group of patients is best managed with antidepressants and other psychological treatments (Table 352-6).