World Gastroenterology Organisation Global Guidelines Irritable Bowel Syndrome

WGO IRRITABLE BOWEL SYNDROME (IBS) CASCADES Cascade Options for Resource-sensitive IBS Diagnosis High Resource Levels History, physical examination, exclusion of alarm symptoms, consideration of psychological factors. Full blood count (FBC), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), stool studies (white blood cells, ova, parasites, occult blood). Selenium homocholic acid taurine (tauroselcholic acid) test (SeHCAT; incorporating selenium-75) for the investigation of bile acid malabsorption (BAM) and measurement of bile acid pool loss. This test may have limited availability, even in areas with high resources. Thyroid function. Tissue transglutaminase antibody to screen for celiac disease. Esophagogastroduodenoscopy and distal duodenal biopsy in patients with diarrhea, to rule out celiac disease, tropical sprue, giardiasis, and in patients in whom abdominal pain and discomfort is located more in the upper abdomen. Colonoscopy and biopsy. Fecal inflammation marker (eg, calprotectin or lactoferrin) to distinguish IBS from inflammatory bowel disease (IBD) where the latter is prevalent. Hydrogen breath test for lactose intolerance and small-intestinal bacterial overgrowth (SIBO). Medium Resource Levels History, physical examination, exclusion of alarm symptoms, consideration of psychological factors. FBC, ESR or CRP, stool studies, thyroid function. Sigmoidoscopy. Low Resource Levels History, physical examination, exclusion of alarm symptoms, consideration of psychological factors. FBC, ESR, and stool examination. Note: Even in “wealthy” countries, not all patients need colonoscopy, which should be reserved in particular for those with alarm symptoms or signs and those over the age of 50. The need for investigations and for sigmoidoscopy and colonoscopy, in particular, should also be dictated by the characteristics of the patient (presenting features, age, etc.) and the geographical location (ie, whether or not in an area of high prevalence for IBD, celiac disease, colon cancer, or parasitosis). In general, the diagnosis is “safer” in patients with constipation, whereas in patients with severe diarrhea, there is a greater need to consider tests to exclude organic pathology. Cascade Options for Resource-sensitive IBS Management High Resource Levels Reassurance, dietary and lifestyle review, and counseling. Try a quality probiotic with proven efficacy. Symptomatic treatment of: Pain, with a locally available antispasmodic; for more severely affected patients, a low-dose tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) should be added. Constipation with dietary measures and fiber supplementation, progressing to osmotic laxatives such as lactulose. Although the evidence to support their use is weak, it may be worth addressing diarrhea with simple antidiarrheals. Psychological approaches (hypnotherapy, psychotherapy, group therapy) should be considered and consultation with a dietitian, where indicated. Add specific pharmacological agents, where approved: Lubiprostone or linaclotide for IBS with constipation (IBS-C). Rifaximin for diarrhea and bloating. Alosetron and eluxadoline for IBS with diarrhea (IBS-D). Medium Resource Levels Reassurance, dietary and lifestyle review, and counseling. Add a quality probiotic with proven efficacy. Symptomatic treatment of: Pain, with a locally available antispasmodic; for more severely affected patients, a low-dose TCA should be added. Constipation with dietary measures and fiber supplementation. Although the evidence to support their use is weak, it may be worth addressing diarrhea with bulking agents and simple antidiarrheals. Low Resource Levels Reassurance, dietary and lifestyle review, and counseling. Symptomatic treatment of: Pain, with a locally available antispasmodic. Constipation, with dietary measures and fiber supplementation. Although the evidence to support their use is weak, it may be worth addressing diarrhea with bulking agents and simple antidiarrheals. INTRODUCTION Definition: IBS is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation and/or a change in bowel habit. Sensations of discomfort (bloating), distension, and disordered defecation are commonly associated features. In some languages, the words “bloating” and “distension” may be represented by the same term. IBS is not known to be associated with an increased risk for the development of cancer or IBD, or with increased mortality. It generates significant direct and indirect health care costs. Although visceral hypersensitivity is accepted as prevalent, no universal pathophysiological substrate has been demonstrated in IBS.1 A transition of IBS to, and overlap with, other symptomatic gastrointestinal disorders (eg, gastroesophageal reflux disease, dyspepsia, and functional constipation) may occur. IBS usually causes long-term symptoms, which may occur in episodes. Symptoms vary and are often associated with food intake and, characteristically, with defecation. They interfere with daily life and social functioning in many patients. Symptoms sometimes develop as a consequence of an intestinal infection [postinfectious IBS (PI-IBS)] or are precipitated by major life events, occur during a period of considerable stress, or develop following abdominal and/or pelvic surgery. They may also be precipitated by antibiotic treatment. In general, there is a lack of recognition of the condition; many patients with IBS symptoms do not consult a physician and are not formally diagnosed. IBS Subclassification According to the Rome III criteria, IBS may be subtyped or subclassified on the basis of the patient’s stool characteristics, as defined by the Bristol Stool Scale: IBS-D: Loose stools >25% of the time and hard stools <25% of the time. Up to one third of cases. More common in men. IBS-C: Hard stools >25% of the time and loose stools <25% of the time. Up to one third of cases. More common in women. IBS with mixed bowel habits or cyclic pattern (IBS-M): Both hard and soft stools >25% of the time. One third to one half of cases. Unsubtyped IBS: Insufficient abnormality of stool consistency to meet criteria IBS-C or IBS-M It must be remembered, however, that patients commonly transition between these subtypes and that the symptoms of diarrhea and constipation are commonly misinterpreted in IBS patients. Thus, many IBS patients who complain of “diarrhea” are referring to the frequent passage of formed stools and, in the same patient population, “constipation” may refer to any one of a variety of complaints associated with the attempted act of defecation and not simply to infrequent bowel movements. In addition, bowel habit must be evaluated without using antidiarrheals or laxatives. On clinical grounds, other subclassifications may be developed, whether based on symptoms (eg, with predominant bowel dysfunction pain or bloating) or on precipitating factors [PI-IBS, food induced (meal induced), or stress related]. However, with the exception of PI-IBS, which is quite well characterized, the relevance of any of these other classifications to the prognosis or response to therapy in patients with IBS remains to be defined. It must also be remembered that the Rome III criteria are not commonly used in clinical practice. Furthermore, cultural issues may inform symptom reporting. In India, for example, a patient who reports straining or passing hard stools (often with a feeling of incomplete evacuation) is likely to complain of constipation even if he or she passes stools more than once daily. Finally, there is considerable overlap and a tendency to transition between IBS-C and functional constipation. Global Prevalence and Incidence The global picture of the prevalence of IBS is far from complete, as no data are available from several regions. In addition, comparisons of data from different regions are often problematic due to the use of different diagnostic criteria (in general, the “looser” the criteria, the higher the prevalence), as well as the influence of other factors such as population selection, the inclusion or exclusion of comorbid disorders (eg, anxiety), access to health care, and cultural influences. In Mexico, for example, the prevalence of IBS in the general population, measured using the Rome II criteria, was 16%, but the figure increased to 35% among individuals in a university-based community. What is remarkable is that the available data suggest that the prevalence is quite similar across many countries, despite substantial lifestyle differences. The prevalence of IBS in Europe and North America is estimated to be 10% to 15%. In Sweden, the most commonly cited figure is 13.5%. The prevalence of IBS is increasing in countries in the Asia-Pacific region, particularly in those with developing economies. Estimates of the prevalence of IBS (using the Rome II diagnostic criteria) vary widely in the Asia-Pacific region. Studies from India showed that the Rome I criteria for IBS identified more patients than the Rome II criteria. Reported prevalence rates included 0.82% in Beijing, 5.7% in southern China, 6.6% in Hong Kong, 8.6% in Singapore, 14% in Pakistan, and 22.1% in Taiwan. A study in China found that the prevalence of IBS, as defined by the Rome III criteria, in individuals attending outpatient clinics was 15.9%. Generally, data from South America are scarce, but this may be related to a publication bias, as many studies are not published in English2 or are not cited in commonly used search databases (eg, Medline). In Uruguay, for example, 1 study reported an overall prevalence of 10.9% (14.8% in women and 5.4% in men)—58% with IBS-C and 17% with IBS-D. In 72% of the cases, the age of onset was below 45 years. Also, a study from Venezuela reported an IBS prevalence of 16.8%, with 81.6% of those affected being women and 18.4% men.3 Studies on indigenous populations in Latin America revealed a high prevalence of IBS, which was similar to that in the rest of the population.4 Data from Africa are very scarce. A study in a Nigerian student population found a 26.1% prevalence, based on the Rome II criteria. A study among outpatients in the same country, based on the same criteria, reported a prevalence of 33%. Other Observations on IBS Epidemiology IBS mainly occurs between the ages of 15 and 65 years. The first presentation of patients to a physician is usually in the 30- to 50-year-old age group but in some cases, symptoms may date back to childhood. Prevalence is higher in women—although this result is not reproduced in some studies from India, for example. Although the estimated prevalence of IBS in children is similar to that in adults its frequency seems to be lower among older individuals. IBS Demographics, East-West Differences in Presenting Features Global information regarding presenting features also varies, and comparisons of studies based on community data, outpatient clinic data, and hospital statistics are fraught with difficulties. Typical IBS symptoms are common in healthy population samples, but the majority of sufferers with IBS are not actually medically diagnosed. This may explain apparent differences between countries in the reported prevalence. Most studies only count diagnosed IBS and not community prevalence. Some studies in non-Western countries indicate a close association between marked distress and IBS in men, in a manner similar to that found in women in Western studies. These same studies also indicate a trend to a higher frequency of upper abdominal pain and a lower impact of defecatory symptoms on a patient’s daily life. This may explain why overlap between functional dyspepsia and IBS is very common in China. Several studies suggest that among African Americans, in comparison with their white compatriots, stool frequency is lower and the prevalence of constipation is higher. In Latin America, except in Argentina, constipation predominance is more frequent than diarrhea predominance. Stool frequency seems to be greater in the Indian community as a whole—99% passed stools once or more per day. In Mexico, 70% of patients have anxiety, 46% depression, and 40% both and IBS has a significant economic impact, as it leads to high use of medical resources. Psychological distress, life events, and negative coping style may play important roles in the pathogenesis of IBS. These factors may also influence the individual’s illness behavior and the clinical outcome. DIAGNOSIS OF IBS Clinical History Although it is currently described as a single coherent entity, it is most likely that the disorder termed “IBS” comprises a number of discrete pathophysiological entities, which have not as yet been defined. Thus, a number of pathologic processes that we now recognize as quite distinct entities (eg, microscopic colitis, carbohydrate intolerance, and BAM) would formerly have been included within IBS. In assessing the patient with IBS, it is important not only to consider the primary presenting symptoms, but also to identify precipitating factors and other associated gastrointestinal and extragastrointestinal symptoms. It is vital also to seek out and directly question for the presence of alarm symptoms and to consider, in the relevant context, other explanations for the patient’s symptoms (eg, bile acid diarrhea, carbohydrate intolerance, microscopic colitis). Thus, the history is critical and involves both the identification of those features regarded as typical of IBS and also the recognition of “red flags,” or other features that suggest alternative diagnoses. Accordingly, the patient should be asked about the following: The Pattern of Abdominal Pain or Discomfort Pain that is chronic, intermittent rather than continuous, has occurred before and is relieved by defecation or passing of flatus is suggestive of IBS. In some individuals, pain may be well localized (eg, to the lower left quadrant of the abdomen), whereas in others the pain location tends to move around. Nocturnal pain is unusual in IBS and is considered a warning sign. Other Abdominal Symptoms Bloating and distension are common features of IBS. Distension can be measured; bloating is a subjective feeling. As defined in English, bloating and distension may not share the same pathophysiology and should not be regarded as equivalent and interchangeable terms, although in other languages they may be represented by a single word, or there may be no expression for bloating, as in Spanish. Nor does either necessarily imply that intestinal gas production is increased. Other symptoms, less specific for IBS, include borborygmi and latulence. Nature of the Associated Bowel Disturbance (ie, Constipation, Diarrhea, Alternating) and Abnormalities of Defecation Attention needs to be given to such issues as diarrhea for >2 weeks, mucus in the feces, urgency of defecation, and/or a feeling of incomplete defecation/evacuation (this symptom has been reported as particularly important in recent studies in Asian populations—51% in Singapore, 71% in India, 54% in Taiwan) Other Information From the Patient’s History and Important Warning Signs As well as seeking the usual “red flag” symptoms (unintended weight loss, blood in the stool or fever), one should identify if there is a family history of colorectal malignancy, celiac disease, or IBD. Furthermore, the relationships of symptoms, such as pain, to menstruation, drug therapy, consumption of foods that are known to cause intolerance (especially milk), artificial sweeteners, dieting products, alcohol, or recent travel, such as visiting the (sub)tropics, should be defined. The patient should be questioned about eating habits and a family history of IBS sought. IBS clearly aggregates within families, although its genetics are poorly understood and the mode of transmission is unclear. A history of the sudden onset in relation to exposure to gastroenteritis suggests PI-IBS. Be wary of a history of persistent diarrhea which, especially if relatively painless, should prompt more extensive investigations for other causes of diarrhea, such as celiac disease, microscopic colitis (especially in a middle-aged or older woman), bile acid diarrhea (due to impaired absorption of bile acids), or carbohydrate intolerance. Psychological Assessment Psychological factors have not been shown to cause or influence the onset of IBS. IBS is not a psychiatric or psychological disorder. However, psychological factors may play a role in the persistence and perceived severity of abdominal symptoms and contribute to impairment of quality of life and excessive use of health care services. For these reasons, coexisting psychological conditions are common in referral centers and may include: anxiety, depression, somatization, hypochondriasis, symptom-related fears, and catastrophizing. Tools that may assist in the psychological assessment include the Hospital Anxiety and Depression Scale (HADS), the Sense of Coherence (SOC) test, and the Patient Health Questionnaire (PHQ-15). Physical Examination A physical examination reassures the patient and helps detect possible organic causes and signs of systemic disease. Particular attention should, of course, be paid to the abdominal examination and a digital rectal examination including examination of the perianal region should be performed IBS Diagnostic Algorithm Figure 1 provides a general approach to the evaluation of the patient with IBS-type symptoms. Figure 2 attempts to prioritize evaluation based on regional variations in the prevalence of diseases and disorders that may share symptomatology with IBS.FIGURE 1: Diagnostic and initial approach to the management of the patient with IBS-type symptoms. As patient anxiety plays a significant role, reassurance and education are of key importance. CRP indicates C-reactive protein; ESR, erythrocyte sedimentation rate; FBC, full blood count; IBS, irritable bowel syndrome; *should only be performed if clinically appropriate.FIGURE 2: Approach to the diagnosis of IBS based on regional variations in disease prevalence. *Where relevant—that is, when there is a high prevalence of celiac disease, parasitosis, inflammatory bowel disease, or lymphocytic colitis. ESR indicates erythrocyte sedimentation rate; FBC, full blood count; FOBT, fecal occult blood test; IBS, irritable bowel syndrome.EVALUATION OF IBS A diagnosis of IBS is usually suspected on the basis of the patient’s history and physical examination, without additional tests. Confirmation of the diagnosis of IBS requires the confident exclusion of organic disease in a manner dictated by an individual patient’s presenting features and characteristics. In many instances (eg, in young patients with no alarm features), a secure diagnosis can be made on clinical grounds alone. There is a lack of robust evidence and prospective studies regarding the appropriate use of radiologic imaging in patients with IBS-like symptoms.5 Diagnostic Criteria In clinical research, the Rome III criteria are those most commonly used to make a diagnosis of IBS. However, is should be noted, firstly, that these are due to be updated in 2016 and that a systematic review (2012) of the diagnostic criteria for IBS demonstrated low validity and utilization of the Rome III criteria, and suggested that the Manning criteria were more widely validated and may be more clinically applicable.6 In clinical practice, whether in the setting of primary or specialist care, clinicians usually base a diagnosis of IBS on their evaluation of the whole patient (often over time) and consider a multiplicity of features that support the diagnosis (apart from pain and discomfort associated with defecation, or change in stool frequency or form). This approach includes a history of symptoms regarded as common in IBS and generally supportive of its diagnosis, as described above combined with the presence of behavioral features considered helpful in recognizing IBS in general practice, such as the presence of symptoms for >6 months, and their aggravation by stress or meals. A pattern of frequent consultations for nongastrointestinal symptoms, a history of previous medically unexplained symptoms, or an association with anxiety and/or depression may also raise suspicion for IBS. It must also be remembered that noncolonic complaints, such as dyspepsia (reported in 42% to 87%), nausea, and heartburn often accompany IBS. Nongastrointestinal symptoms, including lethargy, fatigue, backache and other muscle and joint pains, fibromyalgia, headache, urinary symptoms (eg, nocturia, frequency and urgency of micturition, incomplete bladder emptying), dyspareunia, insomnia, and a low tolerance to medications in general may also be evident. Additional Tests or Investigations In the majority of cases of IBS, no additional tests or investigations are required. An effort to keep investigations to a minimum is recommended in straightforward cases of IBS, and especially in younger individuals. Additional tests or investigations should be considered if symptoms begin after the age of 50, if warning signs (red flags), as listed above, are present, or if any abnormalities are detected on physical exam. The following tests (although commonly performed) are indicated only if supported by the clinical history and where locally relevant: FBC, serum biochemistry, thyroid function tests, and stool testing for occult blood and ova and parasites Additional tests or investigations may also be considered if the patient has persistent symptoms or is anxious despite treatment, a major qualitative change in chronic symptoms has occurred, or a new coexisting condition should be considered. Differential Diagnosis BAM Adult-onset BAM is now recognized as an important cause of an IBS-D-type presentation. A recent review study7 found evidence that >25% of patients with IBS-D have BAM. Etiologic factors that appear to contribute to the onset and persistence of chronic diarrhea symptoms are alterations in the enterohepatic circulation, accelerated intestinal transit, an increase in the bile acid pool, and low levels of fibroblast growth factor-19.8 Diagnostic tools that help in diagnosing BAM and differentiating it from IBS-D are assays of fecal bile acid concentration, 23-seleno-25-homo-taurocholic acid (SeHCAT) testing, and high-performance liquid chromatography for serum 7-α-OH-4-cholesten-3-one (C4)—in addition to the use of therapeutic trials (with the bile acid sequestering agents cholestyramine and colesevelam), and heightened awareness of the likelihood of BAM.9 Celiac Disease The main symptoms and signs of celiac disease are chronic diarrhea, failure to thrive (in children), and fatigue. It is estimated to affect approximately 1% of all Indo-European wheat-eating populations. It must be emphasized that nowadays many with celiac disease do not have classic features and present with “IBS-type” symptoms, including bloating and constipation, along with iron deficiency. A low threshold for investigation should therefore be maintained in high-prevalence (>1%) regions.10 Lactose Intolerance The main symptoms are bloating, flatulence, and diarrhea acutely related to consumption of milk and dairy products. Although genetic testing can now detect lactase deficiency, this is not necessarily predictive of intolerance, which is best tested using the lactose hydrogen breath test. Indeed, a substantial proportion of individuals who lack lactase can tolerate oral lactose despite bacterial fermentation. In countries with a high prevalence of lactase deficiency, inappropriately labeling IBS patients as lactose intolerant should be avoided, unless they are consuming substantial amounts of milk and/or milk products, as this could deprive the community of a cheap nutritious source of protein and nutrition in countries such as India. In all parts of the world, the prevalence of lactose malabsorption on breath tests has been consistently similar between IBS and non-IBS subjects. IBD (Crohn’s Disease, Ulcerative Colitis) There are very significant variations in prevalence worldwide. In a high-prevalence area, IBD, should be considered if diarrhea has persisted for >2 weeks or if rectal bleeding is reported and/or an inflammatory mass, weight loss, perianal disease, or fever is detected. In areas in which it is endemic, intestinal tuberculosis should also be considered, as its presentation may be similar to that of IBD. Colorectal Carcinoma Colorectal carcinoma should be considered in older patients who develop IBS-type symptoms for the first time later in life and/or in the presence of hematochezia or unintended weight loss. An obstructive-type pain may be a feature of the left-sided lesions, whereas anemia or iron deficiency is common with the right-sided lesions Microcytic (Lymphocytic and Collagenous) Colitis This disorder accounts for 20% of unexplained diarrhea in patients over the age of 70, is typically painless, and is most common in middle-aged females (M:F=1:15). Diagnosis is based on the pathologic examination of colonic biopsies Acute or Chronic Diarrhea Due to Protozoa or Bacteria Here the principal symptom is an acute onset of diarrhea and the diagnosis is confirmed by stool examination or duodenal biopsy. A review11 on the role of intestinal protozoa in IBS concluded that there was “a possible role for protozoan parasites, such as Blastocystis hominis and Dientamoeba fragilis” in the etiology of IBS. D. fragilis is known to cause IBS-like symptoms and has a propensity to cause chronic infections. It can be detected using nested polymerase chain reaction,12 where available, or alternatively using microscopy. The role of B. hominis as an etiological agent in IBS remains unclear, due to contradictory reports and the controversial nature of B. hominis as a human pathogen. The role of B. hominis may be genotype related.13 Although Entamoeba histolytica infections occur predominantly in developing regions of the world, the clinical diagnosis of amebiasis is often difficult, as symptoms in patients with IBS may closely mimic those in patients with nondysenteric amebic colitis. Clinical manifestations of Giardia intestinalis infection also vary from asymptomatic carriage to acute and chronic diarrhea with abdominal pain. Although stool testing for Giardia and Amoeba is recommended in India, self-medication with imidazoles is common, rendering the results difficult to interpret. It is essential that all patients with IBS in relevant areas should undergo parasitological investigations to rule out the presence of protozoan parasites. It is equally important that these tests are appropriately interpreted and that overtreatment is avoided. SIBO SIBO is rare unless the patient has a primary or secondary motility disorder, has been operated on (in particular with ileocecal resection or bariatric surgery), or has impaired immunity (such as immunoglobulin A deficiency). The classic features of SIBO are those of maldigestion and malabsorption. Some of the symptoms of SIBO (bloating, diarrhea) overlap with those of IBS, which has led to the suggestion that SIBO is related to IBS. However, it is generally believed that SIBO is not a common cause of IBS-like symptoms. Tropical Sprue Tropical sprue should be considered in returning travelers with persistent diarrhea. The symptoms and histologic findings of tropical sprue may resemble those of celiac disease. A diagnosis of celiac disease is unlikely in the absence of antiendomysium or antitissue transglutaminase antibodies, but conversely their absence increases the likelihood of tropical sprue.14 Diverticulitis The relationship between IBS and so-called “painful diverticular disease” is unclear; is painful diverticular disease no more than IBS in a patient who has diverticula? In diverticulitis, the classic symptoms and/or findings are episodic and acute to subacute during an episode, featuring left-sided abdominal pain, fever, and the presence of a tender inflammatory mass in the left lower quadrant. However, it is now evident that afflicted patients may have more chronic symptoms in between discrete episodes/attacks, and that left-sided and bilateral, but not right-sided diverticular disease, may increase the risk for IBS.15 Endometriosis Endometriosis will be suggested by the presence of cyclical lower abdominal pain and the detection of enlarged ovaries or nodules dorsal to the cervix on digital vaginal examination. Pelvic Inflammatory Disease Here the main symptoms and/or findings include: chronic lower abdominal pain, fever and upward pressure pain or adnexal tenderness, and swollen adnexa on digital vaginal examination. Ovarian Cancer In women over the age of 40, ovarian cancer should be considered in the differential diagnosis. In 1 survey, the following symptoms were more common among women with ovarian cancer: increased abdominal girth, bloating, urinary urgency, and pelvic pain. The combination of bloating, increased abdominal girth, and urinary symptoms was found in 43% of women with ovarian cancer, but in only 8% of a control population. Enterocolitis Associated With Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) This may account for diarrhea in elderly patients who are receiving treatment from neurologists and rheumatologists. Comorbidity With Other Diseases Patients with overlap syndromes tend to have more severe IBS. Thus, fibromyalgia has been reported in up to 20% to 50% of IBS patients and IBS is common in several other chronic pain disorders, such as chronic fatigue syndrome (51%), temporomandibular joint syndrome (64%), chronic pelvic pain (50%), as well as nonulcer dyspepsia and so-called gall-bladder and biliary dyskinesia In a meta-analysis, the prevalence of biopsy-proven celiac disease was found to be >4 times higher in patients who met the diagnostic criteria for IBS than in control individuals without IBS.16 There is a sig