IRRITABLE BOWEL SYNDROME

IRRITABLE BOWEL SYNDROME

  1. 1
    Current Diagnosis
    • Detailed history and physical examination to elicit red flags and exclude secondary causes
    • Appropriate laboratory and imaging studies based on symptoms
    • Identification of the subcategory of irritable bowel syndrome that best describes the patient’s symptoms
  2. 2
    Current Therapy
    • Establishment of a strong physician-patient relationship
    • Dietary and behavioral modifications
    • Pharmacotherapy based on the subcategory of irritable bowel syndrome
  3. 3
    Epidemiology

    Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, with a worldwide prevalence estimated to be between 10% and 20%. It is a syndrome characterized by chronic abdominal pain or discomfort and irregular bowel habits that has a significant impact on affected individuals and society. The diagnosis of IBS is based on the absence of detectable structural or biochemical causes and the presence of a constellation of symptoms as outlined by the so-called Rome III criteria (Box 1).

    Box 1
    Rome III Criteria for the Diagnosis of Irritable Bowel Syndrome
    Recurrent abdominal pain or discomfort (with onset at least 6 months before diagnosis) that

    •   Occurred on at least 3 days per month in the last 3 months, and

    •   Is associated with two or more of the following:

    •   Improvement with defecation

    •   Onset associated with a change in frequency of stool

    •   Onset associated with a change in form (appearance) of stool

    Adapted from Longstreth GF, Thompson WG, Chey WD, et al: Functional bowel disorders. In Drossman DA, Corazziari E, Delvaux M, et al. (eds): Rome III: The functional gastrointestinal disorders, 3rd ed. McLean, VA, Degnon, 2006, p  487–555.

    Bloating or visible abdominal distention often is present in patients with IBS but is not considered essential for diagnosis. The Rome III diagnostic criteria divide IBS into subgroups based on stool form and not frequency. Each of the top three IBS subgroups constitutes approximately one third of all IBS patients (Box 2).

    Box 2
    Subgroups of Irritable Bowel Syndrome (IBS)
    • IBS with diarrhea (more common in men)

    •   IBS with constipation (more common in women)

    • IBS with mixed bowel habits (previously known as IBS with alternating bowel habits based on Rome II criteria)

    • IBS unsubtyped (not enough stools are abnormal to meet criteria for any other subtype)

    Adapted from Longstreth GF, Thompson WG, Chey WD, et al: Functional bowel disorders. In Drossman DA, Corazziari E, Delvaux M, et al. (eds): Rome III: The functional gastrointestinal disorders, 3rd ed. McLean, VA, Degnon, 2006, p  487–555.

    Gender differences have been documented in terms of both prominent symptoms and response to treatment. In the community, the ratio of women to men with IBS is estimated to be between 2:1 and 4:1; this difference is greater in the population of IBS patients who seek health care. Women with IBS report greater overall IBS symptom severity, greater intensity of abdominal pain and bloating, greater impact of symptoms on daily life, and lower health-related quality of life, compared to men with IBS. The estimated prevalence of IBS in children is similar to that in adults, and newly diagnosed adults frequently report symptoms of IBS (or other related functional gastrointestinal symptoms) dating back to childhood. The most common age group seen by physicians for treatment of IBS is 20- to 50-year-olds. Patients with a diagnosis of IBS are at increased risk for other, nongastrointestinal functional disorders, such as fibromyalgia, chronic pelvic pain, interstitial cystitis, and migraine headaches.

    IBS is associated with substantial economic costs, including the direct costs of excess physician visits, diagnostic testing, medications, hospitalizations, and surgeries and indirect costs from absenteeism and decreased productivity at work (presenteeism). Patients with IBS have been reported to miss three times as many days of work compared to those without bowel symptoms. In 2006, there were at least 2.4 to 3.5 million U.S. physician visits for IBS. The annual direct and indirect costs of IBS were recently estimated to be at least $1.6 billion and $19 billion, respectively.

  4. 4
    Pathophysiology

    The pathophysiology of IBS is multifactorial and complex (Box 3). Altered bowel motility, visceral hypersensitivity, central nervous system effects, an imbalance in neurotransmitters, and alterations in epithelial barrier function with increased mucosal immune activation have all been considered. In addition, roles for infection, small-bowel bacterial overgrowth, abnormal colonic bacterial flora, genetics, and environmental and psychosocial factors have been proposed.

    Box 3
    Pathophysiologic Factors of Irritable Bowel Syndrome
    •   Altered bowel motility

    •   Visceral hypersensitivity

    •   Altered epithelial permeability

    •   Intramucosal immune activation

    •   Central nervous system effects

    •   Neurotransmitter imbalance (i.e., serotonin)

    •   Infection

    •   Psychosocial factors

    •   Genetics

    In about 10% of patients the onset of IBS-like symptoms can be attributed to a preceding episode of acute viral or bacterial gastroenteritis. Furthermore, a longer duration of the acute illness confers a higher risk of eventually developing IBS. Altered contractility of the colon and small bowel has been described in patients with IBS and may be related to ingestion of food and psychological or physical stress. For example, there have been reports of an exaggerated contractile response of the colon (gastrocolic reflex) and small intestine to a high-fat meal.

    Patients with IBS also perceive pain abnormally related to irregular small bowel motor activity. There are studies using balloon distention of the rectosigmoid and the ileum that suggest patients with IBS perceive pain and bloating at balloon volumes and pressures significantly lower than those required by normal subjects to elicit similar symptoms. Functional magnetic resonance imaging and positron emission tomography of the brain have revealed different levels of activity in the thalamus and the anterior cingulate cortex after balloon distention of the rectum in patients with IBS compared to normal subjects. This phenomenon is referred to as visceral hypersensitivity.

    Both altered motility and visceral hypersensitivity could be mediated by imbalances of neurotransmitters, including serotonin, which has a significant presence in the gastrointestinal tract and known associations with symptoms including nausea, vomiting, abdominal pain, and bloating. Increased concordance of IBS in monozygotic versus dizygotic twins and familial aggregation in IBS may support a genetic component to IBS. Additionally, there are reports that IBS is more frequent and more severe in women with a history of physical and/or sexual abuse.

    Finally, a growing body of evidence describes compromised epithelial barrier function in patients with IBS. This alteration in permeability may be related to altered expression of tight junction proteins. Expression of the epithelial tight-junction protein E-cadherin was significantly lower in cecal samples from patients with mixed- type or diarrhea-predominant IBS compared to controls, and levels of E-cadherin expression were also associated with symptom duration and severity of abdominal pain. IBS patients also have increased numbers of immune cells in the gut mucosa including mast cells, T lymphocytes, and enteroendocrine cells. The inflammatory mediators released by these cells and their presence in the mucosa could relate to the impaired epithelial barrier function in IBS and abnormal enteric nervous system signaling that leads to gut hypersensitivity.1

  5. 5
    Evaluation

    Current clinical guidelines recommend that IBS can generally be diagnosed without additional testing beyond careful history taking, a general physical examination, and routine laboratory studies to exclude other organic causes in patients who have symptoms that meet the Rome criteria and who do not have alarm warning signs (red flags).

    The red flags include, but are not limited to, blood in the stool (gross or occult), anemia, anorexia, weight loss, fever, family history of colon cancer, inflammatory bowel disease or celiac disease, onset of the first symptom after 50 years of age, nocturnal symptoms that awaken the patient from sleep, and a major change in symptoms.

    Routine laboratory tests have been suggested to include a complete blood count (CBC), thyroid function studies, stool studies for ova and parasites, and a comprehensive metabolic panel. In addition, it has recently been proposed that patients being evaluated for IBS-like symptoms who have a predominance of diarrhea be screened with serologic tests for celiac disease.

    If the patient meets the Rome III criteria and does not have any red flags, classification of the IBS into one of the subcategories is recommended to guide and facilitate empiric therapy. If a red flag is present, diagnostic tests should be performed as appropriate based on the presenting symptoms, signs, and laboratory findings. The differential diagnosis for IBS-like symptoms is significant and should always be considered when evaluating patients (Box 4).

    Box 4
    Differential Diagnosis for Irritable Bowel Syndrome
    • Colon malignancy
    • Lymphoma of the gastrointestinal tract
    • Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
    • Diverticulitis
    • Peptic ulcer disease
    • Biliary or liver disease
    • Chronic pancreatitis
    • Celiac disease
    • Small-bowel bacterial overgrowth
    • Parasites
    • Endometriosis
    • Medication-induced symptoms
  6. 6
    Treatment

    Treatment of IBS involves a multilevel approach. One of the most important components is the establishment of a strong physician- patient relationship; this is done by being nonjudgmental and allowing for a patient-centered interview. Be sure to acknowledge the patient’s symptoms, identify whether any of them are stress-related, and determine whether comorbid psychological symptoms exist.

    Addressing psychosocial factors may improve health status and treatment response. Another component of treatment involves dietary modification. Although some patients may identify certain foods that precipitate or exacerbate their symptoms, reduction or exclusion or specific foods has not shown significant benefit in the literature.

    However, there is increasing evidence to support a diet low in fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), including a recent randomized controlled trial that showed a diet low in FODMAPs in patients with IBS effectively reduced functional gastrointestinal symptoms.2 Pharmacotherapy is guided by the predominant symptom; placement of each patient into an IBS subcategory is useful (Table 1). In addition, alternative therapies, including complementary medicines and psychotherapy, are often coupled with the available FDA-approved pharmacotherapy in an effort to treat IBS (Box 5).

    Box 5
    Alternative Management of Irritable Bowel Syndrome
    Complementary Medicines

    • Herbal medicines
    • Megavitamins
    • Folk remedies
    • Microbial food supplements (prebiotics, probiotics, fungi)

    Psychotherapy

    • Cognitive behavioral therapy
    • Relaxation therapy
    • Contingency management
    • Biofeedback
    • Hypnosis

    Table 1

    Pharmacotherapy for Irritable Bowel Syndrome According to Symptom

     

    1  Not FDA approved for this indication.

    2  Not available in the United States.

    3  Exceeds dosage recommended by the  manufacturer.

    7  Available as a dietary supplement.

    • Available only to physicians enrolled in the Prescribing Program for Lotronex.

    Although almost all of these agents have been tested in randomized, controlled studies, only three – alosetron (Lotronex), lubiprostone (Amitiza), and linaclotide (Linzess) – are currently approved by the FDA for treatment of IBS. Alosetron is a serotonin 5- HT3 antagonist that received FDA approval for treatment of IBS with diarrhea in adult women at a dose of 1.0 mg twice daily. Because of reports of ischemic colitis and bowel perforations, it was removed from the market. It has now been reintroduced on a restricted basis for use in patients with refractory disease. The recommended dosing is to begin with 0.5 mg once daily and slowly increase the dose to 1.0 mg twice daily if necessary. Lubiprostone, a prostaglandin-derived bicyclic fatty acid, is FDA approved for use in women with IBS with constipation at a dose of 8 mcg twice daily. Lubiprostone acts on epithelial surface chloride channels to increase intraluminal chloride and water in the small intestine and colon, and leads to decreased intestinal transit time and quicker passage of stool. There have been no serious adverse effects reported in placebo-controlled, randomized, controlled trials or long-term extension studies of lubiprostone, and there are currently no restrictions on the duration of use. The most common side effects are mild to moderate diarrhea and nausea, and it is recommended to take with food.3 Linaclotide is another novel agent that is FDA approved for treatment of IBS with constipation at a dose of 290 mcg daily. Linaclotide binds and agonizes guanylate cyclase on the intraluminal surface of the intestinal epithelium and subsequently leads to chloride and bicarbonate secretion into the intestinal lumen.

    This results in increased intraluminal fluid and decreased intestinal transit time. Linaclotide may also decrease visceral pain sensation.4 Another agent, Tegaserod, a 5-HT4 agonist, was previously approved by the FDA for treatment of IBS with constipation in women, however it was subsequently removed from the market because of increased serious cardiovascular side effects.

  7. 7
    References

    Gershon M.D., Tack J. The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.

    Halmos E.P., Power V.A., Shepherd S.J., Gibson P.R., Muir J.G. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146:67–75 e65.

    Horwitz B.J., Fisher R.S. The irritable bowel syndrome. N Engl J Med. 2001;344:1846–1850.

    Longstreth G.F., Thompson W.G., Chey W.D., et al. Functional bowel disorders. In: Drossman D.A., Corazziari E., Delvaux M., et al., eds. Rome III: The functional gastrointestinal disorders. 3rd ed. McLean, VA: Degnon; 2006:487–555.

    Mayer E.A. Irritable bowel syndrome. N Engl J Med.

    2008;358:1692–1699.

    Park M., Camilleri M. Genetics and genotypes in irritable bowel syndrome: Implications for diagnosis and treatment.

    Gastroenterol Clin North Am. 2005;34:305–317.

    Quigley E.M., Flourie B. Probiotics and irritable bowel syndrome: A rationale for their use and an assessment of the evidence to date. Neurogastroenterol Motil. 2007;19:166–172.

    Rothstein R.D., Friedenberg F.K. Linaclotide: a novel compound for the treatment of irritable bowel syndrome with constipation. Expert Opin Pharmacother. 2013;14:2125–2132.

    Schey R., Rao S.S. Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. Dig Dis Sci.

    2011;56:1619–1625.

    Videlock E.J., Chang L. Irritable bowel syndrome: Current approach to symptoms, evaluation, and treatment.

    Gastroenterol Clin North Am. 2007;36:665–685.

    Wilcz-Villega E., McClean S., O’Sullivan M. Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant

    IBS. Neurogastroenterol Motil. 2014;26:316–325.

    1  Not FDA approved for this  indication.

    2  Not available in the United  States.

    3  Exceeds dosage recommended by the  manufacturer.

    4  Not yet approved for use in the United  States.

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