There has been major progress in our understanding of the irritable bowel syndrome (IBS), and novel treatment classes have emerged. The Rome IV guidelines were published in 2016 and together with the growing body of Asian data on IBS, we felt it is timely to update the Asian IBS Consensus.
Key opinion leaders from Asian countries were organized into 4 teams to review 4 themes: symptoms and epidemiology, pathophysiology, diagnosis and investigations, and lifestyle modifications and treatments. The consensus development process was carried out by using a modified Delphi method.
Thirty-seven statements were developed. Asian data substantiate the current global viewpoint that IBS is a disorder of gut-brain interaction. Socio-cultural and environmental factors in Asia appear to influence the greater overlap between IBS and upper gastrointestinal symptoms. New classes of treatments comprising low fermentable oligo-, di-, monosacharides, and polyols diet, probiotics, non-absorbable antibiotics, and secretagogues have good evidence base for their efficacy.
Our consensus is that all patients with functional gastrointestinal disorders should be evaluated comprehensively with a view to holistic management. Physicians should be encouraged to take a positive attitude to the treatment outcomes for IBS patients.
The first Asian Consensus on Irritable Bowel Syndrome (IBS) was published in 2010.1 Since then, there has been major progress in our understanding of this condition and novel treatment classes have emerged. The international standard for diagnostic criteria in functional gastrointestinal disorders (FGIDs) was updated with the release of the Rome IV documents in 2016.2 FGIDs are now described as disorders of gut-brain interaction, shifting the emphasis to the gut, with greater prominence given to the intestinal microenvironment. Furthermore, there is now recognition of the roles of cross-cultural differences, the socio-cultural and environmental factors in the development and manifestation of IBS. The Asian Neurogastroenterology and Motility Association (ANMA) felt it is appropriate to examine the literature from an Asian perspective and to update the Asian IBS Consensus.
On April 1, 2016, ANMA convened a working team of 21 key opinion leaders from Asian countries on the basis of their scientific activities and published articles on IBS. Participants were organized into 4 teams to review 4 themes: symptoms and epidemiology, pathophysiology, diagnosis and investigations, and lifestyle modifications and treatments. The consensus development process was carried out by using a modified Delphi method.3
The consensus team members collected and reviewed original publications on IBS (in English and other languages) since the first consensus, through available global and domestic online literature-search systems. Manual search was also performed for publications that were not available online. Other important original and review articles from Asia and other parts of the world were also collected and reviewed. New publications that were published during the consensus process were also reviewed. Each team then generated 6 to 12 consensus statements through intra- and inter-team e-mail discussions.
On March 22, 2017, the working team met in Osaka during the ANMA Scientific Congress. All statements were presented along with supporting evidence, debated, and modified based on feedback. A grade of evidence was applied to every statement according to the GRADE Working Group.4 The final complete set of statements was subsequently circulated to all 21 members for anonymous voting. All members were asked to choose 1 of the following 6 levels of agreement on each statement: (a) accept completely, (b) accept with minor reservation, (c) accept with major reservation, (d) reject with major reservation, (e) reject with minor reservation, and (f) reject completely. The members were also asked to provide comments to each statement, if any. When the proportion of members who voted (a) or (b) was greater than or equal to 80.0%, the statement was regarded as acceptable and a consensus was considered to have been reached.
These characteristics of IBS symptoms are derived from the original studies by Manning and by Thompson.5,6 In the subsequent diagnostic criteria for IBS (Rome I to III), abdominal pain and/or discomfort are important components in the evaluation. In the Rome IV era, the term “discomfort” has been eliminated from the criteria because the term is thought to be ambiguous to patients.7 The current Rome IV definition for IBS required the patients to have recurrent abdominal pain, which is associated with defecation or a change in bowel habits. However, a recent global experts survey indicated that 53.8% felt that bloating was the most important feature of IBS, while only 25.6% felt that abdominal pain was.8 A study from China by using Rome III defined IBS, only 64.6% of them complained of recurrent abdominal pain and 44.2% with abdominal bloating alone.9 A large population-based internet survey from Japan also suggests that abdominal bloating has a great impact on the daily life of the patients with constipation-predominant IBS.10 Studies of IBS patients in India and Bangladesh suggested that frequency and/or severity of abdominal pain may not be so common, ranging from 33.0% to 70.0%, which will result in a low prevalence of Rome IV IBS in India.11 In a multicenter Indian study using various IBS diagnostic criteria, the Manning criteria had the highest sensitivity (91.0%), followed by Asian criteria (74.5%), Rome I (68.0%), Rome III (52.5%), and Rome II (40.0%) to diagnose IBS.12 The differences observed may be due to the fact that “abdominal pain” was not absolutely necessary for the diagnosis of IBS by both Manning and Asian criteria. Furthermore, “abdominal bloating” had been included in combination with “abdominal pain or discomfort” by the Asian criteria.1 Similar data has been reported from Romania.13 These data suggested that besides recurrent abdominal pain, abdominal bloating should also be included in the IBS diagnostic criteria, while the pain component in IBS may be de-emphasized in Asia.
Since the words for bloating symptom in several Asian countries have meanings overlapping with other abdominal symptoms, doctors in these countries should explore in detail to confirm whether the patient symptom is a real bloating symptom or not, according to the symptom concept described by the Rome committee.
According to Western studies, stool frequency of normal bowel habit varies from 3 stools per week to 3 per day.14 However, wide variation in normal bowel frequency is noted throughout Asian countries. For example, normal stool frequency is once per day in Chinese and twice per day in Iranians.15,16 In Indian community, 90.0% of healthy subjects had more than 1 bowel movement per day, less than 1.0% had number of bowel movement fewer than 3 per week, while the median stool frequency was twice a day in IBS patients, regardless of whether they had constipation or diarrhea.17 It has consistently being shown that stool form rather than stool frequency better represent colonic transit time.18,19 Therefore, evaluating stool form using the Bristol scale is suggested as the tool of choice in the classification of IBS subtypes in Asia. Bristol stool scale has been reported to be a better marker of constipation and slow colonic transit.19–21 A recent validation study has also shown that IBS patients could more often be classified as having constipation-or diarrhea-predominant bowel pattern by the Bristol stool form and by the patients’ own perception than by the stool frequency criteria.22
Several studies provide strong evidence that eating is an important trigger of symptoms in IBS patients.23–26 A study in Sweden required IBS patients to record in detail the timing of symptoms throughout the day for up to 6 weeks. This study demonstrated that pain was relieved with defecation on only 10.0% of occasions, whereas 50.0% of pain episodes developed within 90 minutes of eating.27 This study suggests that the pain experienced by IBS patients had a stronger temporal relationship to eating than to defecation. This could be a particular problem in Asia because Asian patients appear to present more frequently with upper abdominal pain than in Western patients.28,29 In a study from Taiwan, more than 50% of patients initially classified as dyspepsia were reclassified as IBS because their upper abdominal pain was exclusively relieved with defecation.30 We believe that it is important to highlight the relationship of symptoms to meals in IBS. Mistaking meal-related IBS symptoms as dyspepsia could lead to excessive investigation with tests, such as upper gastrointestinal (GI) endoscopy and ultrasound scans, inappropriate treatments, such as acid suppression, and unnecessary surgery, such as cholecystectomy.31,32
Globally the prevalence of IBS in women is approximately 1.5-to 3-fold higher than those seen in men.33,34 In Western populations, women usually report more IBS symptoms than men, irrespective of the employed diagnostic criteria.35 However, if the IBS prevalence is stratified according to geographic region, no significant sex difference can be observed in South Asia, South America, and Africa.33 In Asia, most studies showed no gender difference (female vs male in India: 7.9% vs 6.9%, 4.3% vs 4%, 3.2% vs 4.8%; Korea: 7.1% vs 6.0%; Hong Kong: 6.6% vs 6.5%; Pakistan: 13.1% vs 13.4%; Taiwan: 21.8% vs 22.8%; Singapore: 7.8% vs 9.4%; Malaysia: 10.6% vs 10.5%; Japan: 6.5% vs 5.5%).28,36–38 Untill now, only 2 reports showed significantly higher IBS prevalence in females.39,40
In Asia the prevalence of dyspeptic symptoms in IBS patients has been variously reported (India 58.0%, China 25.0–64.0%, and South Korea 14.0%).41–44 Furthermore Asian patients tend to present more with upper abdominal pain than Western patients. In a Taiwan study, Lu et al initially classified more than 50.0% of their patients as dyspepsia who were later reclassified as IBS when their upper abdominal pain was exclusively relieved with defecation.30 Similarly in a study performed in Singapore, 44.0% of patients who had functional chronic upper abdominal pain had IBS, while a later study demonstrated that more than 50.0% of IBS subjects localized their pain to the upper abdomen.45,46
Population-based studies demonstrated that 3.5% to 4.5% of the general adult population in India and Bangladesh have dyspepsia-IBS overlap.47,48 A community-based survey carried out involving 3000 people in Bangladesh, including both rural and urban populations, demonstrated that 42.0% of FD subjects had IBS and 27.0% IBS subjects had FD.48 Bowel symptoms frequency scores were higher in IBS-FD than IBS alone.47,48 In a hospital based study of patients with FD from China, postprandial fullness was a predictor of overlapping IBS.43 In a large study from Japan, abdominal bloating appears to be the most bothersome symptom in IBS with constipation (IBS-C) patients.10 Correspondingly, early satiety, epigastric pain, and bloating were important factors associated with IBS-FD overlap syndrome in Bangladesh.48 Bloating is a commonly encountered symptom in Asian IBS patients, in keeping with observations from Western countries. The challenge is not to misclassify these patients as functional dyspeptics when they actually suffer from IBS. An alternative is to view them as a spectrum of functional bowel disorders, focusing treatment on the main symptoms, or using combination therapy for the myriad of symptoms.
Experience of psychosocial stress and exacerbation of GI symptoms in IBS patients show higher correlation than that in healthy individuals.49 IBS patients show more exaggerated colonic motility in response to experimental stress than healthy subjects.50 A meta-analysis showed that colorectal distension in IBS patient is more likely to activate the anterior cingulate cortex, amygdala, and midbrain, which are important brain regions for stress response, but deactivates the medial and lateral prefrontal cortex than healthy controls.51 Furthermore, the right dorsolateral prefrontal cortex in IBS patients was less activated than healthy controls when subjects were exposed to the situation with necessity of cognitive flexibility and stress-coping.52
Systematic review indicated that psychosocial stress likely alters gut microbiota, increases mucosal permeability, motility, and induces visceral hyperalgesia in IBS patients.53–55 Systematic review of epidemiology supports psychosocial stress (adverse life events) as one of risk factors of post-infection IBS (PI-IBS).56 When the severity of IBS increases, the impact of psychological distress in IBS patients increases.57 The interaction between IBS and psychological symptoms are bi-directional. In a 12-year prospective study, functional GI disorder including IBS and functional dyspepsia at onset were found to increase the risk of developing depression and anxiety, while. depressive or anxiety disorder was a risk factor for the development of IBS.58 A 1-year prospective study indicates that in the majority of patients it is likely that IBS leads to depression and anxiety than the other way around.59
It is now appreciated that multiple pathophysiological mechanisms may operate in individual patients contributing to symptoms and their exacerbation, health care seeking behavior, and treatment response. The important role that the gut micro-environment plays in the pathophysiology has been increasingly recognized.60 In the recently published Rome IV guidelines, the term “functional” is de-emphasized, and FGIDs are now defined as “disorders of gut-brain interaction.”2
Multiple case-control studies from Asia and elsewhere demonstrated fecal microbial dysbiosis among patients with IBS as compared to controls.61–63 Since a fecal sample might not be representative of the small bowel, a few studies assessed small bowel aspirate among patients with IBS as compared to controls and showed dysbiosis even in the upper gut of patients with IBS.64 Multiple studies using quantitative upper gut aspirate culture and glucose and lactulose hydrogen breath tests also revealed occurrence of small intestinal bacterial overgrowth (SIBO) more often among patients with IBS than healthy subjects.65 Moreover, multiple studies documenting improvement in IBS symptoms following treatment with antibiotics including rifaximin also supports the role of gut dysbiosis in pathogenesis of IBS.66,67 Patients with IBS-D more often had SIBO than other sub-types of IBS.63,67 However, a few studies showed that methane production on lactulose hydrogen breath test is associated with constipation and its reduction with rifaximin accelerates colon transit time and improves constipation suggesting role of gut microbial dysbiosis even in a subset of patients with IBS-C.68,69
A large body of evidence supports the presence of immune activation, low grade inflammation, and increased gut permeability in the pathogenesis of IBS, particularly in PI-IBS and the diarrheapredominant sub-type.70–75 In a study from India, over-producer polymorphisms of IL-1 receptor antagonist (which controls inflammation) were found to be infrequent and under-producers frequent among patients with IBS than controls.76 The same study also revealed patients with SIBO had higher duodenal mucosal levels of IL-1α and β and the latter correlated with looser stools (Bristol type VI) and bloating.76 Another recent Indian study showed that altered immune activation in response to dysbiotic microbiota may promote intestinal inflammation in a subset of IBS patients.77 A Chinese study showed that IL-10, an anti-inflammatory cytokine level in serum, was significantly lower in SIBO-positive than negative IBS patients.78 Nerve growth factor is known to mediate visceral hypersensitivity and gut mucosal barrier dysfunction through interactions with mast cells and sensory nerves. In a recent Chinese study, elevated mucosal nerve growth factor has been suggested to interact with mast cells and sensory nerve fibers, contributing to visceral hypersensitivity and impaired gut barrier function in IBS-D.79
More than half a century ago, Chaudhary and Truelove described occurrence of IBS like syndrome following acute GI infection.80 Subsequently, Gwee et al81 reported that 27.0% of patients with acute gastroenteritis from Sheffield, England continued to have symptoms sufficient to fulfill the criteria for IBS for 6 months. Four studies on PI-IBS have been reported from Asia to date. In one cohort study from Beijing, China, the incidence of IBS by Rome II criteria among 295 patients following bacillary dysentery was 8.1% compared to 0.8% among controls.75 In a study from Seoul investigating an outbreak of Shigella infection among 181 health-care workers, the odds ratio of developing IBS was calculated to be 2.9 at 1 year.82 A 3-year follow-up study from Korea showed that PI-IBS may last for 3 years after onset.83 A recent study conducted in Bangladesh showed gastroenteritis patients developed PI-IBS and PI-FD more often than controls (16.5% vs 2.6% and 7.4% vs 0.6%, respectively).84 The same study also showed that 9.0% of patients developing Rome criteria-positive IBS after acute gastroenteritis actually developed post-infectious malabsorption syndrome (tropical sprue).
PI-IBS is defined as new development of IBS following acute infectious diarrhea, characterized by 2 of the followings, (1) diarrhea, (2) vomiting, (3) fever, and (4) positive stool culture for enteropathogens.85 PI-IBS is usually of diarrhoea-predominant subtype. In Asia, post-infective malabsorption, previously known as Tropical sprue, should be considered as a differential diagnosis.86 SIBO has been proposed as a possible link between the 2 conditions.85
Exaggerated visceral sensitivity is well known in patients with IBS as compared to controls based on studies on luminal distension using balloon and gas during colonoscopy and lactose hydrogen breath test.87,88 Such luminal distension has also been shown to reproduce patient’s abdominal pain. Visceral hypersensitivity in patients with IBS spans beyond the colon. It has been demonstrated in the esophagus, stomach, duodenum, and ileum, suggesting that these patients have irritable gut syndrome.89 Studies from Asia, like those from the rest of the world, also demonstrated hypersensitivity beyond the gut such as bladder dysfunction and fibromyalgia among patients with IBS. In an Indian study, following 50 g lactose ingestion, IBS patients experienced symptoms more than healthy subjects though the amount of breath hydrogen exhaled was comparable between the 2 groups.89 A Chinese study also showed similar results.90 Another Chinese study demonstrated that cold water intake lowered the visceral perception threshold.91 Abdominal pain could be elicited in 78.0% of patients with IBS in Singapore by distending the rectum with air insufflation.92
Evidence includes increased enterochromaffin cell numbers as well as rectal mucosal serotonin (5-hydroxytryptamine [5-HT]) in PI-IBS, presence of 5-HT-transporter-gene-linked polymorphic region mutation in IBS-C (in China and Korea), and altered serotonergic signaling (increased and decreased plasma serotonin levels in IBS-D and IBS-C respectively).71,93–95 Of particular interest in Asia is the possible role that 5-HT3 receptors may play in chili induced abdominal symptoms associated with IBS.96 However, a recent study compared enterochromaffin cells numbers in the colon of IBS and controls from subjects in Norway and Thailand demonstrated increased enterochromaffin cell numbers in IBS patients compared to controls only in Norwegian patients but not in Thai patients.97
Exaggerated gastro-colic reflex among patients with IBS is well known. In an American study, colonic spike and motor activity were higher following a meal among patients with IBS compared to healthy subjects.26 Diarrhea-predominant IBS patients have higher colonic motility than constipation-predominant subset. A Korean study showed that patients with diarrhea-predominant IBS showed higher colonic motility than those with constipation-predominant IBS.98 Lactose malabsorption are common among patients with IBS in Asia. An Indian study showed that though levels of breath hydrogen were comparable among patients with IBS and healthy controls, IBS patients showed greater frequency of symptom development following lactose load than healthy subjects.88 This may be related to greater degree of visceral hypersensitivity among IBS patients as has been demonstrated in a recent Chinese study.90 An Indian study demonstrated induction of IBS symptoms following chili ingestion.99 A study from Thailand also showed that chili ingestion produced more abdominal pain and burning in IBS-D patients than in healthy volunteers.100 Several Japanese studies showed that patients with IBS showed greater colonic motor response than healthy controls to experimental stress, and suggested that corticotropin releasing factor liberated from the hypothalamus to be the possible mediator.101,102
A few landmark studies showed that stool form is determined largely by colon transit time.19 A recent study, however, showed that the number of bacteria in the small bowel also determines stool forms; larger the number of bacteria in the small bowel, the looser the stools.64 Patients with IBS-D have shorter colonic transit time than those with IBS-C.103,104 Colonic transit time has been reported to be faster in Asian populations such as in India, Hong Kong, and Taiwan than in the West.105,106
Like somatic sensation, visceral sensation including that from the gut is primarily presented to sensory cortex. However, visceral sensation can also lead to varying degree of emotional arousal due to activation of the emotional arousal system (limbic system and paralimbic structures), particularly among patients with IBS. Due to advances in functional imaging studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), understanding of cerebral processing of visceral sensation in patients with IBS as compared to healthy controls have been possible.
A few Asian studies showed that patients with IBS have exaggerated cerebral activation and abnormal emotional area activation following visceral and somatic stimulation, which is agreement with the Western studies. A Japanese study using PET showed that colonic distension resulted in enhanced activation of specific brain regions, including the limbic system and prefrontal cortex.107 An fMRI-based study from China showed that rectal balloon distension resulted in increased activity in the anterior cingulate cortex, insula, prefrontal cortex, and thalamus, more so among IBS patients than controls.108 A study from Singapore showed abnormal cerebral activation on fMRI in anticipation of rectal pain among IBS patients during rectal stimulation.109 Cerebral and emotional response to pain is well known to differ among males and females. A recent Indian study on male IBS subjects and healthy controls showed differential brain response to rectal balloon distension and among patients with IBS-C and IBS-D.110
Several case-control studies both from the West and Asia showed that patients with IBS have more psychological co-morbidities than healthy subjects.111 It is important, however, to note that a cause and effect relationship cannot be assigned based on such case-control studies. Authors of a recent Australian study suggested that in most patients with functional GI disorders gut symptoms drives psychological morbidity rather than the brain being the primary origin of GI symptoms.59 However, studies on PI-IBS demonstrated that psychosocial co-morbidity are predictors of development of IBS following an episode of acute gastroenteritis.81 A Korean study showed that depressed women had greater severity of GI symptoms in relation to the degree of depression.112 Japanese studies also suggested role of psychosocial stress exacerbating IBS symptoms.113
Some of the Asian data, like the Western studies, do suggest a role of psychosocial factors determining consultation behavior among patients with functional GI disorders including IBS. Anxiety was the only independent predictor for medical consultation in a study from Hong Kong.114 In Pakistan, a high psychological distress score was a strong predictor of IBS in men, but not in women, while in India, there appeared to be more consulters in the higher socioeconomic classes.18,115 However, in Korea, India, and Japan, psychological factors appear to be less important to influence consultation for IBS.18,116,117 These data may suggest that psychological co-morbidity may influence health care seeking in addition to sociocultural factors.
It is well known that functional GI disorders, including IBS, occurs more often in families having members affected with these conditions. Though it has been argued that this may be related to environmental and socio-cultural factors, a role of genetic factors has also been considered. Polymorphisms in several genes involved inflammation, immune regulation, antigen recognition, defense mechanisms, tissue repair, neuro-transmission, lactose malabsorption etc have been studied in Asia.118 However, most of these studies suffer from limitation due to inadequate power resulting from relatively small sample size.
The Rome IV criteria eliminated the term “discomfort” to reduce ambiguity and improve consistency of the criteria across different languages. The frequency of abdominal pain should be at least 1 day per week during the past 3 months with onset at least 6 months earlier. In daily clinical practice, however, a pragmatic and flexible diagnostic approach should be adopted: pain is not universal in patients with IBS, who may have only abdominal discomfort or bloating as the predominant symptom, the threshold for symptom frequency and duration also needs validation in Asian countries.6,119
The BSFS is recommended as a reliable tool for evaluation of bowel habits. The subtyping of IBS is based on the stool consistency on days with abnormal bowel habits when the patients are not taking any medication used for the treatment of the bowel habit abnormalities. Based on the BSFS, IBS can be classified into IBS-D, IBS-C, mixed bowel habits, and unclassified. A recent study from Thailand suggested the BSFS type 3 is also associated with constipation. Thus, the correlation of BSFS with IBS classification in Asian patients may be different from that in the West. 120–122
For the majority of patients with IBS, a positive clinical diagnosis can be based on symptoms and physical examination, with limited investigations. Routine investigations are not warranted in all patients. However, a Canadian center analyzed the performance of symptom-based criteria in secondary-care centers and found a modest specificity of only 71–82% and positive predictive value of < 50%.123
The presence of alarm features should prompt for investigations including colonoscopy, whereas the absence of alarm symptoms and negative physical examination are associated with lower likelihood of organic disease in patients with IBS symptoms.1 However, data to support this approach are weak.124,125
In the primary-care setting, selected non-invasive laboratory tests to exclude organic causes in patients without alarm features include full blood counts with erythrocyte sedimentation rate, blood chemistry with C-reactive protein, and stool examination for occult blood and fecal calprotectin.126–129 Normal C-reactive protein and fecal calprotectin in patients with non-constipation IBS can help exclude inflammatory bowel disease.130 Evidence to support this approach is however weak.7
Stool examination for intestinal parasites should be performed in countries with high prevalence of intestinal parasites. However, the association of intestinal parasites with symptoms of IBS is still controversial and limited.131
Colonoscopy for exclusion of colorectal cancer is indicated in patients with symptom onset at age 50 years or older, regardless of other alarm features. In younger patients, colonoscopy is indicated in the presence of alarm symptoms or signs, positive family history of colorectal cancer, and poor symptom response to empiric medical therapy.1,132 Patients included in clinical trials must have a colonoscopy and/or other examinations as required by the entry criteria or study design.
Further work-up may be considered in selected patients for the diagnosis of other conditions such as SIBO, celiac disease, bile-acid diarrhea, malabsorption syndrome, and pancreatic or small bowel neoplasm. These investigations should be individualized according to the regional prevalence of each condition.64,85,133–135
Normal defecation requires coordination between contraction of the abdominal muscles that increase intra-rectal pressure and relaxation of the pelvic floor including the anal sphincter. Pubo-rectal dyssynergia is a common type of fecal evacuation disorder (FED). Different types of pubo-rectal dyssynergia are characterized by lack of increase in intra-rectal pressure or reduction in residual pressure in the anal canal during attempted defecation. An Indian study showed that the Rome III criteria for IBS were equally fulfilled among patients with constipation with or without FED.136 In a Thai study, of 50 patients with FED, 29 (58.0%) fulfilled Rome II criteria for IBS; patients with or without IBS demonstrated similar responses to biofeedback therapy.137 These Asian studies suggest that patients with FED may present as constipation-predominant IBS.138
NCGS is an increasingly recognized entity in the spectrum of gluten-related disorders, and is characterized by bowel symptoms similar to IBS. Evidence has emerged from several Asian countries for the presence of NCGS in patients fulfilling IBS criteria.133–135,139,140 The pathophysiology of NCGS is poorly understood and a causal relationship between NCGS and IBS is still a subject of debate.141 Moreover, the symptom benefit obtained from a gluten-free diet may be attributed to its low fermentable oligo-, di-, monosacharides, and polyols (FODMAP) content.
IBS is associated with significant impairment in the QOL, social functioning, sleep, and psychological well-being.142–144 Validated questionnaires should be considered as supportive instruments for quantitative and objective assessment of quality-of-life impairment and psychological distress. Short form 36, EuroQol 5 dimension, Hospital Anxiety and Depression Scale, Patient Health Questionnaire, and IBS-QOL have been used in Asian studies.
In the first Asian IBS consensus,1 it was generally agreed that the aims of IBS management are symptom relief as well as improving QOL, with the establishing of a good doctor–patient relationship being a cornerstone. Physicians were recommended to identify contributing factors and the patient’s specific concerns, so that the management of IBS may be individualized. Specifically, all bothersome symptoms should be targeted, taking into account specific IBS subtypes, symptom severity, and contributing factors including psychosocial issues. It was generally agreed that these remain fundamental to effective management of IBS. Since the last iteration, there has been substantial new information in dietary and pharmacological management.145
As diet is a frequent concern, a detailed dietary history was commended. New data involving diets in Western populations suggest that a diet low in FODMAPs may be effective in improving bloating, flatulence, and abdominal pain.146,147 As these are non-absorbable sugars, they are osmotically active, and subjected to fermentation in the colon, resulting in the production of metabolites and gases, that may contribute to causing diarrhea, abdominal pain, and bloating. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAPs diet, while diarrhea-predominant IBS appeared to benefit from improved stool consistency and frequency.147 Specifically to Asian populations, the role of a low FODMAPs diet in the management of IBS requires further study as studies are lacking.148,149 While in some communities (eg, India with high prevalence of vegetarianism) diets may be high in FODMAPs, others may traditionally be relatively low (eg, China and Japan).48,148,149 Lactose as a FODMAP is of specific relevance to Asia as lactase deficiency is almost universal in Asians.88,150 However, as the average daily consumption is relatively low, the role of lactose-containing dairy foods in Asia is uncertain. 48,151
Meta-analysis of antispasmodics as well as several Asian clinical trials support the efficacy of this class of drugs to relief IBS symptoms, especially when abdominal pain is the predominant symptom.145,152–157 As a class, anti-spasmodics have a favorable profile with number needed to treat (NNT) of 5 and number needed to harm of 17.5.152 However, some antispasmodics may have anticholinergic side effects.
Common antidiarrheal agents studied for the treatment of IBS were loperamide and smectite. Loperamide is an opioid agonist that is frequently used to control diarrhea both in infectious and non-infectious conditions. A limited number of randomized control trials (RCTs) are available that support its efficacy in IBS, and confidence in the estimate of effect was further limited by the small sample sizes.158–160 Data on the use in IBS of natural adsorbent clay compounds such as dioctahedral smectite that is frequently used to treat diarrhea in children, is very limited and suggests effect on abdominal discomfort or bloating.161,162
Serotonin is a neurotransmitter functioning in GI sensation, motility, and secretion. In the GI tract, 5-HT receptor subtype 3 and 4 mediate key functions that have been targeted for amelioration of IBS symptoms.163 5-HT3 antagonists have been shown to slow intestinal transit and to decrease abdominal pain.164,165 Examples of 5-HT3 antagonists that have been tested in IBS are alosetron, ramosetron, and ondansetron. Alosetron encountered serious side effect of ischemic colitis and is now available only in the USA. Ramosetron was newly developed in Japan for the treatment of IBS-D. In a trial comparing ramosetron with placebo, patients with IBS-D treated with ramosetron showed significant improvements in global IBS symptoms, abdominal pain, and bowel habits.166 A Japanese study for the effect of ramosetron on IBS-D patients also showed significantly increased rate of symptom improvements in ramosetron group (47.0%) than placebo group (27.0%).167 In a recent randomized, placebo-controlled study of 576 Japanese women with IBS-D, 2.5 μg ramosetron per day reduced abdominal pain and discomfort, increased stool consistency, and improved QOL as well as global IBS symptoms.168
Although in these studies, there have not been any reports regarding significant adverse reactions including ischemic colitis to this drug, significant proportions of 1 in 5 reported constipation after treatment of ramosetron.166–168 Ramosetron is also approved for managing patients with IBS-D in Japan, Korea, and Thailand.169 Ondansetron is an established anti-emetic with good safety record. In an investigator initiated RCT from the UK, a pragmatic approach was employed whereby starting at 4 mg once a day, the dose could be titrated up to 8 mg 3 times a day, ondansetron was found to be more effective than placebo in improving loose stools, bowel frequency and urgency.170
Tegaserod is a partial 5-HT4 agonist with high quality data from Asia for efficacy in IBS-C, both in women and men.171–173 Unfortunately, a controversial alert by Food and Drug Administration regarding cardiovascular safety has led to its withdrawal from most countries.174 An alternative, prucalopride is a selective 5-HT4 agonist, that has high quality efficacy data for relieving bloating, hard stool, and straining, symptoms commonly associated with IBS-C.175–179 While prominent side effects include diarrhea, headache, abdominal pain, and nausea, no cardiovascular safety concerns have been reported.174,177 Studies involving tegaserod and prucalopride, including 3 involving Asian subjects, provide evidence of efficacy in male subjects.173,178,179
Probiotics are live micro-organisms that confer health benefits. Several meta-analysis provide evidence that some probiotics have beneficial effect in IBS, but not all probiotics have demonstrated benefit.180 Thus, which species or combination was the most beneficial is unclear. Where a beneficial effect has been demonstrated, improvements in abdominal pain, bloating, and flatulence have been reported.
It is specifically noted that these meta-analyses were carried out on heterogeneous studies. While
A meta-analysis of 16 RCTs, found RR of IBS symptom not improving with antidepressants vs placebo was 0.67 and NNT of 4.186 The quality of the data appeared to be better for tricyclic antidepressant (TCA) than selective serotonin reuptake inhibitor (SSRI). Doses of TCA used in IBS trials were frequently below therapeutic range for depression; in particular, 3 Asian studies used low doses of TCAs.187–189 This suggests the possibility of a peripheral effect. On the other hand, doses of SSRIs used in IBS especially the studies from the West, were at anti-depressant levels.190,191 In one RCT of citalopram where non-depressed patients were excluded, there was no evidence of benefit.190 This suggests that SSRI may be acting at the central level. It should be noted that these agents are only used off label in many countries, and it is important to be familiar with known side-effects.
Linaclotide, a guanylate cyclase-C agonist, with very low oral bioavailability, acts locally in the intestinal tract to stimulate fluid secretion, increase colonic transit, and inhibit colonic nociceptors.192–194 In Asia, a recent study with linaclotide 290 μg, involving close to 700 patients from China, found significant efficacy over placebo for abdominal pain (60.0% vs 49.0%) and diarrhea was the commonest side effect (9.0%).195 This reinforces the findings of 2 pivotal studies where abdominal pain endpoints were met by about 54.0% on linaclotide vs 36.0–42.0% on placebo.196–198 Similarly, the commonest adverse event of linaclotide was diarrhea (19.7%).199
Lubiprostone is a luminally acting prostone that selectively activates the type-2 chloride ion channel (ClC-2 chloride channel) expressed in the small intestinal epithelial cells, thereby increasing the amount of water content it the intestinal lumen.200 In Asia, efficacy of lubiprostone for IBS-C has been evaluated in only 42 patients in a Japanese study with only the 48 μg dose showing superiority over placebo.201 Initial dose ranging studies had found that the 48 μg dose was associated with more GI adverse events than the 16 μg dose which was considered the optimal dose for efficacy and safety.202 Nausea was the commonest side effect, occurring in as many as 31%, and is dose dependent.203 Furthermore, long-term safety data is available only for the 16 μg dose, but not for the 48 μg dose.204 A recent systematic review and meta-analysis observed that while lubiprostone was efficacious in the short term, and except for bloating all other outcomes including abdominal pain did not appear to be different from placebo.205
Rifaximin is a rifamycin derived non-absorbable antibiotic which is associated with anti-inflammatory activity. Meta-analysis involving 5 high quality studies, found efficacy for global IBS symptoms, with secondary outcome analysis indicating that bloating could be the key symptom responding to rifaximin in non-constipated IBS.206 Adverse effects were similar among patients receiving rifaximin or placebo in all studies.207 Repeat treatments with rifaximin also appear to be safe.208,209 While the role of antibiotics was premised on the presence of low-grade SIBO, none of the pivotal studies actually evaluated this. One study from China reported that identifying SIBO among patients with IBS criteria produced better outcome.210 A study from India employing norfloxacin similarly observed better response in those with demonstrable SIBO.66 However, data on the efficacy of rifaximin for IBS in Asia are lacking. One study from Hong Kong found that a 2-week course produced significant relief of symptoms in functional dyspepsia, but in this study, patients with overlapping IBS were actively excluded. 211
Its heterogeneity makes it difficult to evaluate the efficacy of CAM as a single treatment class. The 4 commonest CAM treatments were evaluated. Chinese herbal medicine has the biggest evidence base and will be evaluated separately. Peppermint oil, thought to alleviate IBS symptoms by relaxing smooth muscles via calcium channels, has been shown in a meta-analysis to be efficacious for IBS.152 A review of Japanese herbal medicine (Kampo) found little clinical trial evidence for a role in IBS.212 Daikenchuto was reported to reduce symptoms of constipation in children, while Hangeshasin-to was reported to have anti-diarrheal effect in drug-induced diarrhea. Two single-blind clinical trials involving a total of 273 subjects found no difference between acupuncture and sham acupuncture.213,214
A meta-analysis of 14 RCTs of Chinese herbal medicines, involving 1551 subjects with IBS-D, found efficacy for global IBS symptoms, abdominal pain and diarrhea, but recognized that there was high heterogeneity and study sample sizes were generally small.215 One formulation known as Shugan Jianpi Zhixie had 7 trials of 954 IBS-D patients.216 Another formulation known as Tongxie Yaofang had 23 publications involving 1972 IBS-D patients.217 A very recently published RCT had 1044 patients with Rome III criteria IBS randomized to 3 treatments for 4 weeks, and found that Tongxie Yaofang was significantly better than placebo for improving abdominal pain and stool parameters, but not better than pinaverium for abdominal pain.218
A meta-analysis of 41 RCTs of psychotherapy for adults with IBS, found that none of the trials were at low risk of bias for every domain.219 The majority of studies were from USA, Sweden, and UK. On review of the demographic characteristics of study participants, it was acknowledged that the majority of patients were white and female. Asian experience with psychotherapy is limited to only one study each from Korea220 and from Japan.221 The Korean study employed cognitive behavioral therapy and recruited only female nursing students.220 This limits the generalizability of the outcome as the expectation is that these subjects were young and familiar with clinical science. The Japanese study employed autogenic training as a relaxation technique.221 The sample size was small (10 male and 11 female) and subjects were recruited from a psychosomatic department. Thus, the acceptance and understanding of this technique by a broader group of IBS subjects are unknown.
Another meta-analysis of 36 RCTs involving a variety of psychotherapies (including cognitive behavioral therapy, relaxation therapy, hypnotherapy, dynamic psychotherapy and mindfulness) involving a total of 2189 patients found that overall IBS symptoms did not improve in 52% compared with 76% receiving control in the form of symptom monitoring, physician’s usual management, supportive therapy or placebo.186 There were serious issues regarding the validity of the findings as none of the trials were at low risk of bias, 22 (61.0%) studies were based in tertiary care setting, 30 (83.0%) studies were unblinded and concealment of allocation was not stated in 24 (67.0%) studies. It remains unclear whether psychotherapy is effective for the treatment of IBS in primary care, with only 2 of the RCTs conducted entirely within this setting.222 A further concern was that 9 of the eligible studies originated from the same center, and when a subgroup analysis was conducted examining this issue there appeared to be a greater treatment effect in these 9 studies than in the 11 studies emanating from other centers.
A number of weaknesses common to several RCTs of psychological therapies were their failure to use the Rome criteria, absence of a power calculation, use of non-validated outcome measures, and inadequate blinding.222 Furthermore, the effect of psychotherapy on IBS symptoms in the long term remains unknown.219,222,223
Our consensus sought to represent current knowledge in a way that will be clinically useful to doctors treating IBS in Asia. The first and rate-limiting step in its management is to be able to make an early and confident diagnosis of IBS. Thus, it is important that physicians in Asia are able to recognize IBS based on the Asian experience, rather than parameters set by the West. In a landmark pan-Asian study, the pattern of symptom clusters in FGID patients was found to be quite different from the classification system proposed by the Rome committee.224 A greater emphasis was placed on meal-related symptoms by Asian patients with IBS criteria. In fact, subsequent reports from Australia and from a Rome Foundation study group also found that there are important issues with the Rome IV criteria.225,226 Future research in Asia should test the Asian symptom clusters against the Rome-proposed symptom clusters. We should also test whether socio-cultural and environmental factors influence the greater overlap between IBS and upper GI symptoms in Asia, and whether this makes it more challenging to recognize IBS here.
Asian data substantiate the global research that now places IBS as a disorder of gut-brain interaction, recognizing the key role of the intestinal micro-environment. Previous emphasis on the psychological disturbance could have contributed to a lack of interest in IBS within the GI community in Asia. The emergence of more effective treatments with peripheral targets should encourage greater effort to recognize IBS in our patients. Furthermore, our rich heritage of traditional Asian treatments, together with emerging data on the potential of herbal medicines, earmarks this as an important field of exploration for future treatments. All patients with IBS should be evaluated comprehensively with a view to holistic management.