Irritable Bowel Syndrome: A Diagnostic Approach

Irritable bowel syndrome (IBS) has long been misunderstood and misdiagnosed. It is one of a group of functional bowel diseases-physiologic disorders of the enteric nervous system (ENS) caused by a malfunction of chemical messengers such as serotonin. IBS may coexist or overlap with other GI tract or non–GI tract disorders.

The cost of IBS is high both economically and in its effect on quality of life.¹ To avoid unnecessary testing and treatment, the appropriate diagnostic approach is essential.

There is no diagnostic test, structural marker, or serologic finding for IBS; the diagnosis is based on clinical symptoms and the results of focused, limited testing.^2,3 In this article, I describe a symptom-based approach that ensures diagnostic accuracy. I will address treatment options in a subsequent article.

EPIDEMIOLOGY

One of the most common GI disorders seen in the primary care setting, IBS is responsible for about 30% to 50% of referrals to gastroenterologists.⁴ However, up to 70% of Americans who meet the diagnostic criteria for IBS do not seek medical care.⁵ This may be because of fear or embarrassment, because symptoms are mild, or because of a misperception that there is no effective treatment.

IBS affects both sexes and all races; however, women are affected 2 to 3 times more frequently than men in western countries.^3,6-8 About 14% to 24% of women and 5% to 19% of men in the United States and Great Britain have IBS.⁹ Symptoms usually begin in adolescence; however, most sufferers do not consult a physician until they are aged 30 to 50 years.⁸ Onset after age 40 years is unusual, except in patients in whom IBS is triggered by infection, medication, trauma, or a cholecystectomy.

Because of confusion about the cause of IBS symptoms, patients with this condition undergo more surgi- cal procedures-including hysterectomy, appendectomy, and cholecystectomy-than those who do not have this disorder.¹⁰ Organ removal rarely helps the patient and sometimes exacerbates symptoms. This is especially true for patients who have undergone cholecystectomy; several weeks or months later, they commonly experience bloating, indigestion, gas, and bile-salt diarrhea (which responds well to resins such as cholestyramine).

Patients with IBS have a higher rate of absenteeism and an increased number of physician visits per year compared with the general population.^11-15 They sometimes feel compelled to reduce their hours at work or turn down promotions. They may refuse to travel or participate in social activities because of concerns about symptoms.

PATHOPHYSIOLOGY

Overview of the ENS. IBS may be described as a "neuroenteric disorder," which suggests a malfunction of the neurons between the intestine, the ENS, and the brain.¹⁶ There are more neurons in the ENS-which controls the activity of the gut semi-independently from the CNS-than in the CNS.¹⁷ The neurons in the intestine use many of the same molecules as the neurons in the CNS-including serotonin and nitric oxide-to communicate with each other and with the CNS. Disorders of GI function involve altered intrinsic function within the ENS and altered communication between the ENS and the CNS.¹⁸

Key pathophysiologic features of IBS. Patients with IBS have altered gut motility and visceral hypersensitivity. Although the precise mechanisms of these phenomena remain elusive, certain features help elucidate the condition. Studies have demonstrated that the ileum, colon, and rectum of patients with IBS show an exaggerated response to different stimuli, such as distention, cholecystokinin, injections of corticotropin-releasing hormone, and emotional stress.^19-23

Studies have also documented that these patients have an enhanced perception of visceral events throughout the esophagus, stomach, and duodenum.^21,24,25 Moreover, up to 75% of patients report pain at a threshold that is below the normal range.^20-22

The sensory neurons in the ENS are responsible for pain perception. 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 patients to have multiple symptoms. The underlying molecular mechanisms of IBS, however, may not be the same in all patients. A clear understanding of each patient's symptom complex is the key to effective therapy.

ETIOLOGY

Precipitating factors. It is critical to identify the event that may have precipitated IBS. Postinfectious IBS develops in up to 30% of patients following Campylobacter and Salmonella gastroenteritis. Ask patients about antecedent events, such as antibiotic use, traveler's diarrhea, viral gastroenteritis, or food-borne illness. After an episode of gastroenteritis, the brush border of the small intestine is destroyed and lactase is therefore not secreted from the intestinal epithelium. Many physicians tell their patients to avoid lactose and other complex carbohydrates for a few weeks after severe gastroenteritis to prevent malabsorption, gas, and diarrhea. GI infections may result in the proliferation of potentially pathogenic bacteria and produce symptoms of IBS. Injury to the ENS may cause a postviral motility or sensitivity disorder. In other patients, a traumatic event-such as rape or assault-can trigger IBS.

Hormonal influences. Investigate hormonal causes in women with IBS symptoms who are using oral contraceptives or estrogen replacement therapy and those going through menopause. Because more women than men have IBS, some researchers have hypothesized that sex hormones play a role in the pathogenesis of this syndrome.^26,27 More generally, it has been postulated that cycling female sex hormones may be related to changes in bowel habits and/or exacerbation of IBS symptoms.^27-35 Premenopausal women report exacerbation of IBS symptoms with the onset of menses. Prostaglandin production has been thought to influence diarrhea associated with menstruation by inhibiting transepithelial ion transport in the small intestine. Postmenopausal women with IBS who use hormone replacement therapy report less bloating than patients who do not take hormones.

Estrogen receptors are found throughout the GI tract, in components of the pelvic floor, and in sensory neurons of the dorsal root ganglia, which suggests that female sex hormones may affect IBS symptoms. Estrogen induces nitric oxide synthase. Nitric oxide, which plays a role in peristalsis and sphincter function,³⁶ relaxes and dilates smooth muscle in the bowel in a similar fashion to its effect on the cardiac vessel endothelium. Pregnancy itself is associated with nausea and constipation.

Although hormones affect neuronal function in the ENS, the relationships are still unclear. Men may have their own triggers for IBS; for example, postinfectious IBS is 3 times more common in men than in women.³⁷ Evidence suggests that men may actually be "protected" from IBS by their sex hormones.²⁷ In one study, men with IBS exhibited fewer male characteristics than healthy controls.³⁸

In patients in whom the onset of symptoms is associated with a new formulation of hormone replacement therapy or oral contraceptive, consultation with a gynecologist about changing the agent is warranted. A formulation that contains more progesterone and less estrogen may help patients in whom functional nausea, weight loss, and IBS overlap.

Patients with a comorbid psychiatric illness or somatization disorder benefit from psychiatric treatment, group therapy, and stress management support groups.

EVALUATION

The symptoms of IBS are broad and sometimes vague, but the cardinal feature is abdominal pain or discomfort associated with changes in bowel habits.⁹ Other symptoms include bloating, straining, and feelings of incomplete evacuation (constipation), urgency (diarrhea), nausea, gas, and dyspepsia. IBS is most commonly seen in young women,^1,6 which is the same group in which Crohn disease, endometriosis, and celiac disease commonly occur.^39,40

IBS may be associated with constipation, diarrhea, or alternating constipation and diarrhea. Almost all patients have alternating patterns; the goal is to treat the dominant symptom. Some patients report that they alternate, when in fact they may have 3 days of no bowel movement followed by 1 loose stool on day 4 that they call "diarrhea." They may refer to the day of loose stool as their day of relief. In this case, the 1 loose bowel movement is probably the normal response to constipation (or perhaps a result of ingestion of over-the-counter [OTC] agents). Patients in this group are considered to have constipation, and that symptom should be treated first.

The first step in the evaluation of a patient with suspected IBS is a comprehensive history taking and physical examination, including a digital rectal examination and a pelvic examination in women (Table 1). During this assessment, determine whether the patient meets the Rome II criteria-guidelines that are used to streamline the diagnosis (Table 2).⁹ Assess for warning signs of cancer, infection, or inflammatory bowel disease (IBD) (Table 3). Nocturnal awakening with symptoms is more common in IBD or infection, but it can occur in severe IBS. A family history of celiac disease, GI cancer, or IBD may prompt a workup for those diseases.

History. An accurate history provides crucial clues in most cases. Allow the patient to tell his or her own story. If his narrative is completely unfocused, you may need to ask direct questions, such as "Can you describe what happened around the time these symptoms began?" or "What do you think may have triggered this?" Let the patient know how important it is that you work together toward the goal of improved function.

Inquire about the patient's intake of carbonated beverages and fructose-containing foods and beverages, as well as smoking, gum chewing, and alcohol habits. Sorbitol in sugar-free candies and gum and the ingestion of fatty foods or large amounts of cruciferous vegetables and bran can lead to discomfort and bloating that closely mimic symptoms of IBS. Sorbitol ingestion appears to cause fermentation of residual carbohydrate in the colon. Alcohol may be associated with bloating or diarrhea. Smoking may cause abdominal pain, cramping, and diarrhea. Lack of sleep and lack of exercise affect GI motility.

Many commonly used medications can mimic or exacerbate IBS-like symptoms, including constipation, diarrhea, bloating, and flatulence.⁴¹ Certain drugs-including alendronate, atorvastatin, aspirin, and NSAIDs-can cause GI distress. Iron and calcium supplements, among others, can cause constipation; magnesium may cause diarrhea. Oral contraceptives may cause nausea, bloating, and weight gain. Record when each medication was started in relation to the patient's symptoms. Postinfectious³⁸ and antibiotic-associated⁴² bowel dysfunction may sometimes trigger IBS. Anorexia nervosa and bulimia can lead to neuroendocrine and intestinal dysfunction⁴³; advise patients with these disorders to consult a psychotherapist and a nutritionist early in the course of treatment.

DIAGNOSTIC TESTING

If a patient meets the Rome II criteria and has no red flags, only minimal testing is necessary to diagnose IBS. If these tests have not been performed recently, the initial workup should include a complete blood cell count; chemistry panel; liver function tests; erythrocyte sedimentation rate; and, when warranted, thyroid-stimulating hormone measurement and tests for fecal occult blood, ova and parasites in the stool, and Clostridium difficile and Giardia antigen. In patients with IBS, these test results should be normal. Using this symptom-based diagnostic approach, virtually all patients will have a correct diagnosis at the 5-year follow-up.⁴⁴

Flexible sigmoidoscopy or colonoscopy is sometimes indicated. For example, colonoscopy is warranted in a 50-year-old person who has abdominal symptoms. If the patient is a young man with fever and nocturnal bloody diarrhea, a flexible sigmoidoscopy with biopsy and culture is appropriate to rule out ulcerative colitis. If a young woman presents with constipation, right abdominal pain, and weight loss, and you suspect right-sided Crohn disease, a colonoscopy is warranted because sigmoidoscopy visualizes only the distal colon.

It is appropriate to diagnose IBS, initiate treatment, and then reevaluate the patient in 3 to 6 weeks. It is also important not to "overtest." Further evaluation may be indicated if the patient does not respond to treatment, if he loses weight, or if the dominant IBS symptoms change or other red flags are identified.

RULING OUT OTHER ENTITIES

A diverse group of disorders present with symptoms similar to those of IBS. These disorders include IBD, lactase deficiency, celiac disease, bacterial overgrowth, diverticular disease, postinfectious IBS, C difficile infection, connective tissue disorders, and hormonal abnormalities.

IBD. IBS and IBD are easily confused. Some symptoms-such as diarrhea, constipation, and abdominal pain-are common to both conditions, although warning signs such as fever or weight loss are usually associated with IBD.

Patients with IBD have either Crohn disease or ulcerative colitis.⁴⁵ Crohn disease is characterized by transmural inflammation from the GI tract to surrounding organs and skin and occurs anywhere in the GI tract. Ulcerative colitis involves mucosal inflammation of the large intestine only and typically presents with bloody diarrhea and fever. Both IBS and IBD are characterized by altered motility and increased pain perception, but in IBD there is a major inflammatory component. IBS is a disorder of the ENS, and inflammation does not play a major role. IBS can follow an exacerbation of IBD and must be differentiated from IBD because different treatment is required.

Lactase deficiency. This common condition causes bloating, discomfort, and diarrhea. A lactose breath test is useful to make the diagnosis before the patient's diet is unnecessarily restricted. If the test is not readily available, a dairy-free trial may be used if intolerance of milk and milk products is a prominent feature. Replace dietary calcium with a bioavailable supplement, such as chewable calcium with vitamin D (1 tablet twice a day with a light snack); calcium carbonate tablets are also acceptable. Many OTC vitamins are hard to digest and have poor bioavailability; for menstruating women, prescription prenatal vitamins, which are bioavailable and contain iron, are helpful. Otherwise, chewable vitamins are preferable, because they are designed for children and rarely cause dyspepsia. Vitamins should be taken about 2 hours after a meal and not on an empty stomach in the morning with a cup of coffee.

Celiac disease. Because IBS is a chronic illness, evaluation of a patient who presents with abdominal pain and diarrhea or constipation of acute onset is best directed toward alarm symptoms. Bloating, constipation, anemia, iron deficiency, malabsorption, stress fractures, infertility, or unexplained osteoporosis may be signs of celiac disease (formerly called sprue), which was estimated in one study to occur in 0.05% of patients who meet the Rome II criteria for IBS.⁴⁶

Celiac disease is a lifelong sensitivity to gluten, which is found in rye, barley, and wheat.⁸ It is more common in patients with autoimmune disorders, and can present in a mild form that is easily confused with IBS. Patients with celiac disease report symptoms that include rancid gas, oily or floating stools, bloating, and constipation or diarrhea. Celiac disease is thought to affect about 1 in 5000 persons in North America, and becomes symptomatic in childhood or in the third decade of life. However, it is not diagnosed in many patients until they are in their 60s, when they present with osteoporosis.

The definitive diagnostic procedure for celiac disease is to obtain more than 6 duodenal specimens for biopsy; this can easily be done during upper endoscopy. A biopsy is essential because sometimes the changes are patchy and can be seen only microscopically. Pathology findings include flattening of villi and increased intraepithelial lymphocytes. Serologic studies of gliadin IgA and IgG, tissue transglutaminase, and anti-endomysial antibodies are about 90% accurate, depending on the laboratory. However, false-positive and false-negative results are common with serologic studies alone, which is why duodenal biopsies are so important. Patients with celiac disease are sometimes IgA-deficient, so levels of IgG and IgA antibody must be checked.

Bacterial overgrowth. This condition, which can develop in patients with diverticulosis or poor small-bowel motility or after a GI infection, is characterized by abdominal discomfort, bloating, gas, distention, or diarrhea.⁴⁷ Bacterial overgrowth may also be associated with features of malabsorption such as anemia, osteoporosis, and coagulopathy. Bacterial overgrowth results in bile salt conjugation and fat malabsorption, which contribute to diarrhea. Patients with bacterial overgrowth cannot absorb vitamin K, which results in prolonged prothrombin time. In severe cases, vitamin D is not absorbed, which leads to osteomalacia.

Breath tests can be used to measure the amount of hydrogen released after oral ingestion of glucose, which is metabolized by enteric bacteria. If the breath test is not readily available, a therapeutic trial of antibiotics is appropriate if bacterial overgrowth is suspected. Low-dose oral metronidazole (250 mg 2 or 3 times a day for 7 to 10 days with food) is usually well tolerated.

In patients with postinfectious IBS or antibiotic-associated diarrhea, a probiotic such as Saccharomyces boulardii, 50 mg twice a day, with or following the antibiotic to maintain the enteric flora, is helpful, especially when the principal symptoms are frequent loose stools and urgency.⁴⁸ n

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