Irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, as defined by no identifiable structural or biochemical abnormality. Epidemiologic surveys suggest that IBS is a common condition, with the prevalence reported to range between 5% to 30%. IBS is frequently encountered in clinical practice, accounting for almost a third of all gastroenterology cases seen in primary care, with a subsequent third of these being referred on to secondary care for further evaluation. The condition predominantly affects young to middle-aged adults, with the natural history of the disorder often following a chronic remitting-relapsing course.

The burden of illness of IBS is significant. Patients have decreased health-related quality of life (HRQOL) scores compared with healthy individuals and even those with chronic disorders such as diabetes and end-stage renal failure. In addition, patients with IBS generate a substantial economic burden, both because of direct health care costs and impaired work productivity. A systematic review addressing the economic cost of IBS in the United States and United Kingdom in the year 2002 found total direct and indirect costs per patient per year reaching $8750 and $3344, respectively.

The pathophysiologic mechanism of IBS is not completely understood, but is thought to be a dysregulation in the brain-gut axis manifested by alterations in the cerebral and autonomic response, immune function, visceral sensitivity and motility. Triggers of such alterations include genetic factors, chronic stress, enteric infections, and diet. Infectious gastroenteritis can lead to long-lasting alterations in gut immunity and function, and the clinical entity is commonly recognized as postinfectious IBS. Similar bottom-up mechanisms have been proposed for dietary triggers. Roughly two-thirds of patients with IBS perceive their symptoms to be related to meals, in particular foods rich in carbohydrates, as well as fatty foods, coffee, alcohol, and hot spices. However, identifying the dietary component triggering these IBS symptoms is difficult, with one method being that of dietary exclusion followed by selective rechallenges. The positive response rate for such a technique varies from 15% to 72%. It has been suggested that there may be a significant placebo effect, and such dietary approaches may be time consuming and cumbersome; for this reason, dietary approaches have not always been widely adopted into routine clinical practice. However, increased immunoglobulin (Ig)-G antibodies against dietary antigens such as wheat, beef, pork, and lamb were found to be more common in subjects with IBS than in controls, with subsequent selective dietary exclusion showing significant clinical benefit. This contemporary work has generated new interest in this dietetic approach to IBS.

Identification of patients with IBS is no longer considered to be a diagnosis based on the exclusion of organic disease but a positive diagnosis using symptom-based criteria. In 1978, Manning and colleagues first described specific symptoms, which were considered to increase diagnostic confidence. These key symptoms have been incorporated by a multinational working party into the Rome criteria. The Rome I criteria were revised as the Rome II Diagnostic Criteria for Functional Gastrointestinal Disorders and these have been used widely in clinical gastroenterology. More recently, the Rome III criteria have been devised and application in clinical studies has begun ( Box 1 ). The validity of symptom-based criteria has been substantiated by patient studies, long-term follow-up evaluation of patients with IBS, and factor analysis on healthy volunteers.

However, patients referred from primary care may not represent most IBS sufferers within the community and may be those with refractory symptoms, poorer HRQOL, more psychological distress, or reduced coping mechanisms. Knowing which patients will benefit from further investigations is challenging because the diagnostic yield in patients with IBS may be low. Nevertheless, previous studies have described disorders in patients who fulfill IBS diagnostic criteria. Examples of conditions that may mimic IBS include bile acid malabsorption, exocrine pancreatic insufficiency, and celiac disease (CD).

CD

CD, a chronic inflammatory disorder of the small bowel, can be defined as a state of heightened immunologic responsiveness to ingested gluten (from wheat, barley, or rye) in genetically susceptible individuals. In the past, CD was thought to be a rare condition with an estimated prevalence of 1 in 8000. With the advent of endoscopic small bowel biopsies and new serologic assays, the prevalence of this condition is now widely appreciated to be around 1%. Furthermore, it is now recognized that patients do not always have to present with classic gastrointestinal symptoms of malabsorption but may have nonclassic symptoms, including atypical gastrointestinal symptoms (such as bloating, abdominal discomfort, gas, or altered defecation), or may present insidiously with iron deficiency anemia, osteoporosis, ataxia, or peripheral neuropathy. Hence, because of symptom overlap, it can be clinically difficult to distinguish CD from IBS. The cornerstone of treatment of CD is lifelong adherence to a strict gluten-free diet (GFD). For most patients, a GFD leads to clinical and histologic remission, normalization of standardized mortality, a reduction in long-term health complications (ie, osteoporosis), and, in some studies, an improvement in psychological well-being and quality of life.

The diagnosis of CD requires a small bowel biopsy showing villous atrophy. There are several serologic tests that have been reported to be accurate in identifying patients who should then be referred for a duodenal biopsy. Serologic testing for CD has evolved over the years, starting with antigliadin antibodies (AGA) followed by endomysial (EMA) and tissue transglutaminase (tTG) antibodies. Because of their poor diagnostic accuracy, as shown by their lower sensitivity and specificity, AGA have largely been superseded by EMA and tTG for routine serologic testing in CD. However, AGA still plays a role in diagnosing non–celiac-related neurologic conditions (for example, gluten ataxia) in the absence of enteropathy.

HLA DQ2 or DQ8 are closely linked with CD, occurring in up to 98% of cases, but are also present in 25% of the normal population. Hence, an absence of these haplotypes could have a negatively predictive role when trying to exclude CD, particularly in patients who are already on a GFD before presentation and testing. However, testing for these susceptibility genes is not recommended in routine clinical practice because it is an expensive test, not readily available, and thus should be reserved for equivocal cases.

CD

CD, a chronic inflammatory disorder of the small bowel, can be defined as a state of heightened immunologic responsiveness to ingested gluten (from wheat, barley, or rye) in genetically susceptible individuals. In the past, CD was thought to be a rare condition with an estimated prevalence of 1 in 8000. With the advent of endoscopic small bowel biopsies and new serologic assays, the prevalence of this condition is now widely appreciated to be around 1%. Furthermore, it is now recognized that patients do not always have to present with classic gastrointestinal symptoms of malabsorption but may have nonclassic symptoms, including atypical gastrointestinal symptoms (such as bloating, abdominal discomfort, gas, or altered defecation), or may present insidiously with iron deficiency anemia, osteoporosis, ataxia, or peripheral neuropathy. Hence, because of symptom overlap, it can be clinically difficult to distinguish CD from IBS. The cornerstone of treatment of CD is lifelong adherence to a strict gluten-free diet (GFD). For most patients, a GFD leads to clinical and histologic remission, normalization of standardized mortality, a reduction in long-term health complications (ie, osteoporosis), and, in some studies, an improvement in psychological well-being and quality of life.

The diagnosis of CD requires a small bowel biopsy showing villous atrophy. There are several serologic tests that have been reported to be accurate in identifying patients who should then be referred for a duodenal biopsy. Serologic testing for CD has evolved over the years, starting with antigliadin antibodies (AGA) followed by endomysial (EMA) and tissue transglutaminase (tTG) antibodies. Because of their poor diagnostic accuracy, as shown by their lower sensitivity and specificity, AGA have largely been superseded by EMA and tTG for routine serologic testing in CD. However, AGA still plays a role in diagnosing non–celiac-related neurologic conditions (for example, gluten ataxia) in the absence of enteropathy.

HLA DQ2 or DQ8 are closely linked with CD, occurring in up to 98% of cases, but are also present in 25% of the normal population. Hence, an absence of these haplotypes could have a negatively predictive role when trying to exclude CD, particularly in patients who are already on a GFD before presentation and testing. However, testing for these susceptibility genes is not recommended in routine clinical practice because it is an expensive test, not readily available, and thus should be reserved for equivocal cases.

CD and IBS crossover

The association between CD and IBS was first reported in 2001, when sequential patients presenting with IBS in secondary care (n = 300) were investigated for CD. Participants were initially investigated for CD with immunoglobulins, IgA/IgG AGA and IgA EMA. Any participant who had a positive IgA AGA, IgA EMA, or IgG AGA in the presence of IgA deficiency was offered a small bowel biopsy to confirm the diagnosis of CD. Our group found CD to be present in 4.7% (14/300) of patients referred to secondary care fulfilling the Rome II criteria for IBS, a 7-fold increase compared with non–IBS-matched controls (0.67%, 95% confidence interval [CI] 1.6-28.0, P = 0.004). We then compared our findings with a population of healthy volunteers recruited from primary care (n = 1200). From 1200 volunteers in primary care, there were 12 new cases of CD. The prevalence of CD in this general population sample was 1% (95% CI 0.4-1.3%). The prevalence of CD among patients with IBS in primary care was 3.3%. These studies highlight the importance of a case-finding approach when considering patients with symptoms of IBS, in whom the diagnosis of CD may be missed. Since that time, others have published supportive evidence/validation studies from other international cohorts ( Table 1 ).

A recent systematic review and large meta-analysis found that the prevalence of biopsy-proven CD in cases meeting the diagnostic criteria for IBS was more than 4-fold that in controls without IBS. The recognized association between IBS and CD has led to a change in practice and guidelines. The National Institute for Health and Clinical Excellence in the United Kingdom and the British Society of Gastroenterology guidelines recommend the routine exclusion of CD in all patients referred with IBS. The American College of Gastroenterology (ACG) advise testing for CD in those with diarrhea-predominant IBS (D-IBS) or mixed bowel pattern IBS (M-IBS). However, this has recently been challenged by Cash and colleagues, who found the prevalence of CD in 492 US patients with nonconstipated IBS to be 0.41%, similar to that of healthy controls (0.44%). Given that testing for CD in IBS is cost-effective in areas where the prevalence of CD is 1% or greater, this may have implications on future ACG recommendations. However, this study is the first of its kind in the United States and further validation studies are required. What adds to the debate is that a primary care study in the United States noted the prevalence of CD in patients with IBS to be 2.7%. It may be that there is an ascertainment bias: in the United Kingdom, it is estimated that IBS accounts for at least 25% of a gastroenterologist’s workload in the out-patient department. The referral pattern in the United States seems to be significantly different to that seen in the United Kingdom, because Cash and colleagues recruited 492 patients from 4 centers over 5 years. Does this suggest that IBS is not a condition commonly referred to secondary care in the United States? Perhaps primary care physicians have already investigated patients for CD before referral? In addition, Cash and colleagues and others did not include patients investigated with constipation predominant IBS (C-IBS) for CD (see Table 1 ), but the largest multicenter CD epidemiologic screening study in the United States (involving 13,145 patients from 32 states) found CD to be present in 2.63% of patients complaining of constipation (40/1530). Furthermore, this group also noted constipation to be prevalent in 20.2% of newly diagnosed CD cases. Therefore, should patients with C-IBS be included or excluded from identifying CD cases? There is variation in the international literature. Jadallah and Khader recently noted that, in their group, the prevalence of CD in D-IBS was 6.8% (95% CI 3.36–10.23) but only 1.68% (95% CI 0.35–3.01) in C-IBS. Similar data were also noted by Shahbazkhani and colleagues, who found that C-IBS accounted for a third of the subsequently diagnosed CD cases. The diversity in the diagnostic criteria, referral patterns, number of patients, IBS subtypes, serologic tests, and histologic confirmation that are used to investigate patients with IBS for CD may account for the varying results seen in Table 1 . A standardized method would help to elucidate this.

The association of CD and IBS symptoms is biologically plausible, with many mechanisms being reported; for example, autonomic dysfunction, intussusception, exocrine pancreatic disease, small intestinal ulceration, and associated microscopic colitis. Our group found an increased prevalence of CD in patients referred with surgical abdominal pain, notably in those with unexplained or nonspecific abdominal pain.

The association between IBS and CD seems to operate in both directions, because patients with CD (on a GFD) are more likely than controls to describe IBS symptoms. A study by O’Leary and colleagues found 20% of patients with CD to also fulfill the Rome criteria for IBS, compared with 5% of healthy controls. This study also showed that patients with CD with IBS have a markedly lower HRQOL than their counterparts without IBS. This novel observation is also supported by research from our own group who recently reported in a cross-sectional study (n = 1031) that patients with CD and persisting IBS symptoms have worse Short Form 36 (SF-36) scores than those who only have CD.

These patients also report a higher frequency of medical consultations compared with CD patients without IBS. Predictors of IBS-type symptoms among adults with CD include mental disorder, female sex, and occasional nonadherence to a GFD. These data offer further support to the biopsychosocial model of IBS, with CD possibly playing its part by having a sensitizing effect on the bowel through mucosal inflammation.

NCGS: a new condition in the spectrum of gluten-related disorders

Until recently, the terms gluten sensitivity and CD were synonymous in the literature. Gluten was associated only with CD and wheat allergy; therefore, patients with gluten-induced gastrointestinal symptoms who produced normal values of tTG and IgE and showed normal histology were advised to continue integrating gluten foods into their diet, because gluten was not regarded as the cause for their condition.

However, most of those seeking medical attention for gluten-induced gastrointestinal symptoms do not have CD or wheat allergy. In a study with 94 adults affected by abdominal symptoms after cereal ingestion, Kaukinen and colleagues reported a prevalence of 9% with CD, 8% with latent CD, and 20% with cereal allergy. Sixty-three percent of study subjects could not be classified as allergic or as having CD, but were affected by gluten foods and clinically benefitted from a GFD.

Meanwhile, more recent evidence suggests the classification of 3 gluten-induced and heterogeneous conditions: CD, wheat allergy, and nonceliac gluten sensitivity (NCGS), a form of gluten intolerance that meets neither the diagnostic criteria for CD nor those for wheat allergy. NCGS is an umbrella term and can incorporate a wide range of symptoms including abdominal discomfort, bloating, pain, or diarrhea; it may also present with a variety of extraintestinal symptoms that may include headaches and migraines, lethargy and tiredness, attention deficit syndrome and hyperactivity, autism and schizophrenia, muscular disturbances, and bone and joint pain (see Table 2 ). For the purpose of this article, NCGS is referred to only in the context of gastrointestinal symptoms.

Table 2

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