Irritable Bowel Syndrome

Emerg Med 36(6):9-15, 2004

The authors provide an update on avoiding pitfalls along the way to this still-difficult diagnosis, giving patients dietary advice, and choosing among controversial therapies.

By Christine L. Frissora, MD, Sarmela Thevarajah, MD, and Kenneth L. Koch, MD

What is irritable bowel syndrome (IBS)?

Irritable bowel syndrome is altered pain perception and motility in the intestine. Abdominal pain or discomfort associated with a change in the form or frequency of defecation is the primary symptom. Abnormal stool frequency is defined as greater than three bowel movements per day or fewer than three bowel movements per week. Irritable bowel syndrome is the most common disorder of gastrointestinal function, meaning there is no structural abnormality—no ulcer, cancer, inflammation, or infection—and therefore the patient's symptoms are presumed to stem from a physiologic or "functional" problem. Although the syndrome does not cause cancer or death, its troublesome and embarrassing symptoms often prevent the patient from living a normal life. Unfortunately, it is a common syndrome affecting 1 in 5 Americans; two thirds of those affected are women.

The enteric nervous system (ENS) contains more neurons than the central nervous system (CNS) and in a very real sense has "a mind of its own." The same molecules that are involved in neuronal function in the CNS affect the ENS. We think of IBS as a chemical imbalance of the ENS. When there is a problem in the function of the ENS, altered pain perception and altered motility (too fast or too slow) occur.

Irritable bowel syndrome typically begins in adolescence or early adulthood, is chronic, and waxes and wanes without obvious cause. Approximately one third of patients with IBS report diarrhea as the predominant symptom, one third report constipation as the principal symptom, and the final third report alternating diarrhea and constipation. These patterns may be referred to as IBS-D, IBS-C, and IBS-A, respectively. However, over time almost all patients alternate; even patients with IBS-C will have a day or two of diarrhea now and then. There are also variants of IBS, such as functional abdominal pain and bloat-predominant IBS.

Patients with IBS may have hard or loose watery stool, feelings of incomplete evacuation or retained stool, bloating or abdominal distension, and the passage of mucus. Many patients also have nausea, reflux, gastroparesis, and upper gastrointestinal motility disturbances as well. There is an overlap particularly between IBS-C and functional dyspepsia.

Each IBS patient has his or her own unique constellation of symptoms. The therapeutic goal is to improve the symptoms that are interfering with the patient's life.
 

What is the pathophysiology of IBS?

While the pathophysiology of IBS remains elusive, certain features specific to IBS help to elucidate the condition. Studies have demonstrated that the ileum, colon, and rectum of IBS patients display an exaggerated response to different stimuli, such as distension, stress, cholecystokinin, and injections of corticotropin-releasing hormone. Several studies have also documented that IBS patients have an enhanced perception of visceral events throughout the esophagus, stomach, duodenum, and ileum. Along these lines, 50% to 70% of IBS patients report pain at a threshold that is below the normal range.

The sensory neurons in the enteric nervous system are responsible for the perception of pain. When the enteric nerves do not function properly, peristalsis, gastric emptying, small bowel transit, and colonic motility can all be affected, so it is common for IBS patients to have multiple symptoms.
 

Do hormones play a role in IBS?

Researchers have cited the observation that more women than men suffer from IBS to hypothesize that sex hormones play a role in the pathogenesis of IBS. More generally, it has been postulated that cycling female sex hormones may be related to changes in bowel habits. Premenopausal women report exacerbation of IBS symptoms with onset of menses. Postmenopausal women taking hormone replacement therapy report less bloating than patients not taking hormones. Prostaglandin production has been thought to influence diarrhea associated with menses by inhibiting transepithelial ion transport in the small intestine.

Expression of estrogen receptors is found throughout the gastrointestinal tract, in components of the pelvic floor, and in sensory neurons of the dorsal root ganglia, suggesting that female sex hormones may play a role in IBS symptoms. Estrogen induces nitric oxide synthetase. Nitric oxide is a "bloat molecule," relaxing and dilating smooth muscle in the bowel in similar fashion to its effect on the cardiac vessel endothelium.

Pregnancy itself (high estrogen and progesterone) is associated with nausea and constipation. Although hormones play a role in neuronal function in the ENS, the relationships are still unclear.

Men may have their own gender-specific triggers for IBS; postinfectious IBS-D is one example.
 

Since there is no specific biologic test or marker, what are the criteria used to diagnose IBS?

The patient with IBS presents initially with unexplained abdominal pain or discomfort. Therefore, one must consider the differential diagnosis of abdominal pain and run through a mental checklist to assess the likelihood of a functional disorder. For instance, the presence of red flags such as fever, weight loss, and bleeding would prompt investigation for inflammatory bowel disease, infection, or cancer. Also, pregnancy must be excluded in any menstruating woman with unexplained abdominal pain, whether or not she is taking an oral contraceptive.

The Rome II criteria (see box, below) were developed for research purposes by a group of gastroenterologists during a consensus meeting in Rome. Evaluating the patient against these simple criteria is the first step in the diagnostic process, as shown.

What are the steps to diagnosing IBS?

The most important part of diagnosing IBS is obtaining the history. Does the patient have abdominal discomfort that coincides with a change in the form or frequency of the stool and is relieved by defecation? If so, that is consistent with IBS. Further supporting symptoms are gas pain, cramping, nausea, mucus, incomplete evacuation, and straining. Many times patients will not volunteer these symptoms and it is necessary to ask pointedly, "When you defecate do you feel it empties completely?" It is also imperative during the history to exclude red flags. Usually we give patients three or four minutes to vent with no interruption and then ask them about "red flag" symptoms that would raise concern about other disorders.

Diagnosis of a patient with altered bowel function begins with a detailed diet and medication history. Common triggers of osmotic diarrhea are sorbitol (contained in diet soda, sugarless drinks, and gum), high fructose corn syrup (a common additive to food and drinks), and antacids that contain magnesium. Ask about fecal incontinence; sometimes patients with incontinence complain of diarrhea even if the stool is formed. One clinical definition of diarrhea is more than three bowel movements a day. Often, a patient will complain of "diarrhea" based on a pattern of one loose stool each morning, which might actually represent normal function.
 

What are the "red flag" symptoms or signs?

"Red flags" are features of the patient's history that indicate there may be infection, inflammation, or cancer. These are alarm symptoms that would promote further evaluation. Red flags from the history are:

• unintentional or unexpected weight loss;

• nocturnal symptoms (more common in inflammatory bowel disease, celiac sprue, infection, or cancer);

• fever, weight loss, and bleeding, which suggest ulcerative colitis or cancer;

• abdominal pain with bloat, anorexia, rectal abscess, and constipation, which could signal Crohn's disease;

• abdominal pain with iron deficiency and stress fractures, which could be celiac disease or another small bowel disorder causing malabsorption;

• gastrointestinal blood loss (gross or occult), which could be due to cancer.

Fever is present in infection, inflammatory bowel disease, and cancer. The patient should be asked pointedly about all of these symptoms.
 

What kinds of tests are needed to diagnose IBS?

Initial routine bloodwork is needed on all patients: complete blood count (CBC); chemistry panel with liver function tests and calcium, and erythrocyte sedimentation rate. If appropriate, obtain stool for occult blood, ova and parasite, culture, and Clostridium difficile antigen. In young patients with weight changes and bowel dysfunction, it may be helpful to check thyroid-stimulating hormone (TSH) and thyroxine (T4). Hypercalcemia can be caused by hyperparathyroidism or malignancy and result in constipation. If the patient is English, Irish, German, or Italian and complains of gas and bloating, think of celiac disease (sprue) and order the gliadin IgG and anti-endomysial Ab tests.

The presence of anemia, macrocytosis, hypoalbuminemia, osteoporosis, or excess stool fat suggests intestinal malabsorption. Specific tests are indicated to diagnose small intestinal bacterial overgrowth, celiac disease, or pancreatic exocrine insufficiency (which may occur occasionally in advanced chronic cases of type I diabetes). Quantitation of stool fat over 72 hours may be helpful in rare cases but should not be ordered unless malabsorption is present. Fecal fat excretion greater than 15 gm/d would be indicative of nutrient malabsorption, whereas lower levels of fecal fat (7 to 14 gm/d) do not distinguish between motor and secretory disorders.
 

What are other disorders that present with symptoms like IBS or can be confused with IBS?

At least three specific disorders can easily be mistaken for IBS.

Bacterial overgrowth. Symptoms of periumbilical abdominal discomfort, bloating, gas, distension, or diarrhea may represent bacterial overgrowth, which can be associated with features of malabsorption such as anemia, osteoporosis, and coagulopathy. The diagnosis of bacterial overgrowth is by quantitative culture of jejunal aspirates; a count exceeding 105 aerobes or 103 anaerobes/mL is diagnostic. Alternatively, breath tests can be used measuring the amount of H₂ or ¹⁴CO₂ released after oral ingestion of a simple substrate such as glucose that is metabolized by enteric bacteria (the ¹⁴C d-xylose test). If the breath test is not available, a therapeutic trial of antibiotics is appropriate if the clinical suspicion is high. The treatment for bacterial overgrowth is a low-dose antibiotic such as metronidazole 250 mg twice daily with food for 7 to 10 days. This can be repeated every six months to one year if needed.

Celiac disease or sprue. Patients allergic to gliadin (a constituent of rye, barley, and wheat) may present with symptoms indistinguishable from IBS. This condition known as celiac disease, or sprue, can cause a variety of symptoms including rancid gas, oily or floating stools, bloating, and constipation or diarrhea. The gold standard for diagnosis is a small bowel biopsy showing flattening of villi and increased intraepithelial lymphocytes. However, patients also will exhibit antibodies to gliadin and tissue transglutaminase. In individuals with sprue, IgA deficiency is common, so one must check IgG antibodies as well. Celiac patients have a congenital and lifelong intolerance of wheat, rye, and barley. The first diagnostic phase is serologic assays for gliadin IgG and anti-endomysial antibodies. Upper endoscopy with six duodenal biopsies for confirmation should be obtained before starting a gluten-free diet. If the diagnosis of celiac disease is missed, patients can develop infertility, iron deficiency, osteoporosis, and perhaps small bowel tumors and other malignancies. Celiac disease affects twice as many women as men, begins in infancy, and surfaces in the third decade of life—the same time that IBS and inflammatory bowel disease often appear. Though difficult, it is imperative to make the diagnosis.

Bile salt diarrhea. Commonly reported in the months following cholecystectomy, bile salt diarrhea may go on for more than ten years after the procedure before it is recognized as such. Bile salt malabsorption is treated with cholestyramine powder (beginning at 4 to 16 gm daily) and by retarding small intestine motility with loperamide.
 

What is the treatment approach for IBS patients?

Treatment begins by making a positive diagnosis and legitimizing the disorder for the patient. An appropriate statement would be: "IBS is an imbalance of the movement of the intestine that can be frustrating because we do not understand the triggers well. It is bothersome but will not cause cancer or death."

Dietary measures such as limiting crude fiber and residue (such as the skin of bell peppers or eggplant) and eliminating soda, fatty foods, artificial sweeteners, and alcohol are important. Soluble dietary fiber that is not wheat-based can be helpful: oatmeal, legumes, raspberries, strawberries, blackberries, peaches, papaya, and mango. There is little evidence that fiber supplements improve IBS symptoms, although calcium polycarbophil has been shown to be of some benefit. The single most crucial intervention you can make is to persuade and help the patient to stop smoking—especially for women taking oral contraceptives or hormones who are at risk of forming a blood clot. Bupropion is an effective aid. Introducing exercise and better sleep habits can enhance well-being.

Empiric trials of anticholinergic agents, such as dicyclomine, have traditionally been used to treat the "spasm-like" pain reported by many patients with IBS. Some patients may respond but controlled clinical trials have not been performed. Relief for patients with discomfort, cramping, and diarrhea may be achieved with hyoscyamine, an orally disintegrating tablet that the patient should take two to three times daily before meals, or scopolamine, 5 mg two or three times daily before meals. The side effects of the anticholinergic antispasmodics include constipation, blurred vision, and dry mouth. The next step would be to introduce medications targeted for the patient's symptom complex.
 

What targeted medications are currently available for IBS patients?

The approach to treating motility disorders has recently advanced to targeting specific peptide receptors. By modulating a specific receptor, motility and visceral sensitivity can be regulated. In order to maximize the safety and efficacy of each drug, the mechanism of action needs to be clearly understood.

Serotonin deserves special mention because there are several medications that are being developed to treat motility disorders by modulating serotonin. More than 95% of the serotonin in the body is actually located in the intestine and only 3% is located in the CNS. Serotonin has at least 20 receptors located throughout the body. In the intestine, the serotonin 3 and 4 receptors seem to be important. Stimulating the serotonin 3 and 4 receptors increases motility and blocking them inhibits motility. For example, tegaserod (see table below) is a partial serotonin 4 agonist that increases motility. These mechanisms are important to remember as new motility drugs become available.

Tegaserod is the only drug currently approved by the FDA for abdominal pain, constipation, and bloating in women. The drug is contraindicated in renal failure and severe liver disease. Tegaserod is a prokinetic agent for IBS, and there is evidence it may help patients with dyspepsia and chronic constipation as well. Currently tegaserod is indicated for women with IBS whose primary symptom is constipation, at 6 mg twice daily. The drug also is available in a 2-mg strength. Diarrhea is the number one side effect, which is transient and usually occurs in the first week of treatment. To avoid this side effect, we often initiate treatment with half a tablet twice a day. Tegaserod works best when taken 15 to 20 minutes before meals. Patients must have adequate water and soluble fiber intake.

Tegaserod is contraindicated in the presence of severe renal impairment, moderate or severe hepatic impairment, history of bowel obstruction, symptomatic abdominal adhesions, gallbladder disease, or suspected sphincter of Oddi dysfunction. There are no known drug interactions with tegaserod and it can be used with antidepressants, digoxin, coumadin, or oral contraceptives. Tegaserod is pregnancy category B. There is no human data to support its use in pregnancy. Currently, 12-month safety data is published for the treatment of IBS-C. Tegaserod does not cross the blood-brain barrier and does not cause weight gain, sexual dysfunction, or fatigue. Although there were no cases of ischemic colitis in the clinical trials, a recent package insert update warns about hypovolemia, diarrhea, and ischemic colitis.
 

Is alosetron still available? Is it safe?

Alosetron (see table) was the first drug to be approved for women with IBS-D. It was voluntarily withdrawn from the market in 2000 due to reported complications of constipation, ischemic colitis, and mesenteric ischemia. Not all of these cases were documented by biopsy. The withdrawal of alosetron was met with an outcry from patients who had suffered from IBS-D for many years and could only live a normal life with the drug. After a year of planning, the FDA and GlaxoSmithKline created a unique risk management plan for prescribing alosetron. The risks of alosetron (ischemia and constipation) are greater in the elderly, institutionalized population, and may be dose-related.

Colonic ischemia is common in people who have transient low-flow states. It is usually self-limiting and patients may have low-grade pain, diarrhea, and occult blood in the stool. The symptoms may be so transient that the patient does not report them to the physician. In more severe cases, the patient is hospitalized for hydration and antibiotics such as ciprofloxacin and metronidazole. Dehydration, antihypertensives, and diuretics can all predispose to low-flow states. Colonic ischemia has been reported in IBS patients, and it is not clear what the etiology is. It could be oral contraceptives or severe spasm with transient decreased blood flow. Mesenteric ischemia, which is a medical and surgical emergency, may occur in patients who are at risk for atherosclerosis. Small bowel ischemia is life-threatening and needs to be diagnosed quickly. In these cases, the pain is out of proportion to the findings on exam.
 

Who can prescribe alosetron?

Currently, any physician who feels confident about diagnosing IBS-D can enroll in the risk management plan through the Internet or by contacting GlaxoSmithKline. The patient and physician each sign a consent form outlining the risks and indications for alosetron. In practice we prescribe alosetron 1 mg daily, but carefully instruct patients to drink plenty of water and to hold alosetron if they do not defecate. We also instruct patients to take the alosetron after the first bowel movement of the day, so that constipation is avoided. (The drug is now available in a 0.5-mg tablet.)

Alosetron is indicated for the treatment of women with severe IBS-D. It is contraindicated in Crohn's disease, ulcerative colitis, diverticulitis, hypercoaguable states, ischemic colitis, thrombophlebitis, strictures, and bowel obstruction. In the long-term safety study of alosetron (Wolfe 2001), there were two deaths—a 50-year-old woman with a history of heart disease and a 54-year-old man with hypertension. Due to this, we do not recommend alosetron for patients with unstable angina or coronary artery disease, or for smokers taking oral contraceptives or hormonal therapy who are likely to develop blood clots or pulmonary emboli.

We often prescribe alosetron to patients with severe IBS-D who are otherwise healthy but cannot live normally or are suffering from severe symptoms (soiling, incontinence). Alosetron remains one of the best studied and most effective treatments for IBS-D, and if the dose and bowel function are carefully monitored, many complications can be avoided.
 

What are future treatment options for IBS?

There is an investigational compound called R-tofisopam, an atypical benzodiazepine that is not known to cause dependence, sedation, or addiction. Tofisopam represents a way to treat the "brain-gut connection" without causing addiction or sedation as classic benzodiazepines do. R-tofisopam has demonstrated safety and efficacy in various animal models and has been shown in phase 1 trials to be well tolerated in healthy volunteers. A clinical trial is ongoing in the United States for the investigation of R-tofisopam for IBS-D.

New anticholinergics, selective muscarinic type-3 receptor antagonists (zamifenacin, darifenacin), are being developed that have a better side-effect profile than traditional anticholinergics. Probiotics, thought to repopulate the intestine with healthy flora, are also under study. Saccharomyces boulardii has been shown to prevent antibiotic-associated diarrhea and may have a role in postinfectious IBS.

Neurokinin (NK) antagonists are thought to reduce pain and motility. These include the NK3 antagonist talnetant, which is currently under investigation in the United States.

Cilansetron, a type 3 serotonin receptor antagonist, has completed phase 3 trials for IBS-D in men and in women. The effective dose appears to be 2 mg three times daily. Whether there is an association between cilansetron and ischemic colitis is unclear. More published data about cilansetron are expected in the year ahead.

The future of safe and effective treatments for IBS is promising thanks to the commitment of physicians and scientists to this clinically underserved patient population.

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