Pathogenesis and management of irritable bowel syndrome

Irritable bowel syndrome (IBS) is characterised by abdominal discomfort associated with altered bowel habits, and has a world-wide prevalence between 10 and 15%.[1] In a populationbased study from Mumbai, the prevalence was observed as 7.4%.[2] IBS and the associated psychological conditions account for significant impairment in the quality of life[3] with overuse of healthcare resources.[4]

The exact cause of IBS is not known. Multiple factors, like genetic, gut motility, visceral hypersensitivity, psychosocial factors and immune-mediated factors, are thought to contribute to the symptom complex of IBS.

Genetic factors

Aggregation of IBS cases within families is well known. Whorwell et al has shown that 33% of IBS patients have a family history of IBS compared with 2% among controls.[5] An Olmsted County study found that the prevalence of IBS among patients’ relatives was 17% as compared to 7% amongst spouses’ relatives. The authors concluded that familial aggregation of IBS occurs, but this may be partly due to familial aggregation of somatisation.[6] Children of IBS patients suffer a higher frequency of gastrointestinal complaints and make a larger number of visits to the doctor.[7] In Japan, the history of bowel problems in parents was a risk factor for development of IBS among children.[8]

Twin studies comparing monozygotic (MZ) versus dizygotic (DZ) twins were used to understand the genetic component of IBS. The concordance rate of IBS among MZ twins was found to be higher (range 33.3% to 22.4%), as compared to that in DZ twins (range 13.3% to 9.1%).[9,10] Levy et al found that an afflicted parent was a stronger predictor of IBS than a twin with IBS. They concluded that heredity contributes to IBS development, but social learning has an important influence.[11]

A study from the UK showed that the prevalence of IBS was similar among MZ and DZ twins (17% vs. 16%).[12] A recent study has shown that IBS is more common in MZ twins, but statistical significance was lost when data were adjusted for anxiety and depression.[13]

Candidate genes in the serotonergic, adrenergic, ionic channels and inflammatory pathophysiological systems have been evaluated.

In the GI tract, serotonin (5HT) acts as a paracrine hormone. Increased 5HT levels in the bowel in IBS are associated with cramps, urgency, diarrhoea and colonic contractions. Serotonin reuptake transporter (SERT) is involved in the removal of 5HT. 5HT transporter gene linked polymorphic region (5HTTLPR) polymorphism has been associated with diarrhoea in women with IBS. HTTLPR insertion polymorphism is associated with decreased colonic transit, but deletions have no affect on motility.[14] Polymorphism involving the gene of a_2cadrenoreceptor is apparently associated with constipation. There is greater prevalence of genotypes with high production of TNF a and low production of IL-10 in IBS patients.[15] A recent addition to the list has been mutations in sodium channel in interstitial cells of Cajal and smooth muscle cells SCN5A.[16] In most of the studies the sample size and design has not been able to give satisfactory conclusions. Till date an ‘IBS gene’ has not been defined, and there is a need for further studies.

Abnormal gut motility

Colonic dysmotility was initially thought to be the predominant feature because of altered bowel habits. Changes in the colon have been noted now and then, and altered motility has been detected in the small bowel and stomach of some patients with IBS.

The most consistent feature seen in the colon is an exaggerated motor response to eating.[1,17,18,19] Patients with diarrhea-predominant IBS (IBS-D) may show a greater number of high amplitude propagative contractions (HAPCs) and reduced colonic transit time,[19,20,21] whereas the constipationpredominant ones (IBS-C) have fewer HAPCs and delayed colonic transit.[20,21,22,23] Among IBS-D patients, postprandial levels of platelet depleted plasma 5HT, a possible colonic motility mediator were higher when compared to IBS-C.[24,25]

A number of nonspecific findings have been demonstrated in the small intestine of IBS patients, like increased frequency and duration of cluster contractions, increased frequency of migrating motor complexes, retrograde duodenal and jejuna contractions, prominent high amplitude waves in the terminal ileum and exaggerated jejunal motor response to meal ingestion.[26,27,28] A small number of IBS patients may possibly be part of the spectrum of chronic idiopathic intestinal pseudoobstruction.[29] In some patients colonic distension does not decrease duodenal motility, implying an impaired intestine-intestinal reflex.[30]

The stomach shows delayed gastric emptying in some cases; this may correlate with the increased dyspeptic symptoms among IBS patients.[31]

The clinical relevance of these motor abnormalities is not known. In addition, it is not clear whether these finding relate to the pathophysiology of IBS or are a mere epiphenomenon. The possibility of a fundamental abnormality of enteric neuromuscular function in some IBS patients cannot be discounted; however, it is likely to afflict only a minority. A heightened visceral sensation may play an important role in the perception of these motor events.

Visceral hypersensitivity

Abdominal discomfort is one of the defining entities in IBS. Visceral hypersensitivity[32] and visceral hyperalgesia[33] are commonly associated with IBS, and play as major role in causing abdominal discomfort and pain.

Peripheral sensitisation could be due to the action of inflammatory mediators on nerve endings in the gut wall, like when symptoms develop after an episode of gastroenteritis.[34] Lymphocytes have been found in intra and periganglionic regions of myentric plexuses on full thickness colonic biopsies from patients with severe IBS.[35] Nippostrongylus brasiliensis, which causes mucosal infection in mice, was used to study the role of mechanosensitivity versus chemosensitivity in visceral hypersensitivity; chemosensitivity, through vagal afferents rather than spinal afferents, was found to play a major role in stress-induced post-inflammatory visceral hypersensitivity.[36]

Nerve pathways from the emotional motor cortex descend via periaqueductal gray matter and nucleus raphae magnus to the dorsal horn cells where they can amplify or suppress afferent signals from the gut.[37] These descending pain systems are closely integrated, and mediate and affect stress responses; thus patients with IBS may show increased motor, sensory, and autonomic reactivity via these central modulatory systems.[38]

Positron emission tomography (PET), magnetoencephalography, and functional MRI, have provided insights into the brain’s response to visceral stimuli. Visceral hypersensitivity as measured by rectal balloon distension is common in patients with IBS.[33] In general there is an association of increased anterior cingulate cortex activation to rectal distension in IBS patients relative to controls.[39] In a study using PET to examine changes in perception and brain activation, repeated rectal inflation resulted in the habituation of visceral perception and central arousal.[40]

Psychosocial factors

Many psychological and social variables have been recognized as significant factors in IBS predisposition, precipitation, and perpetuation. Almost 40% to 94% of IBS patients have psychological abnormalities; depression being the most commonest, followed by anxiety and somatisation disorders.[41]Stressful life events were found to be unusually high among patients with IBS, sexual abuse was reported in about half the women with functional GI disorders compared to the onethird with organic disorders.[42] A history of abuse was associated with significantly poorer health outcome in terms of pain scores, days in bed, psychological distress, healthcare use and reduced quality of life.[43] Stressful life events other than abuse, such as breaking up following an intimate relationship more often preceded the onset of IBS than organic GI illness.[44] Anxiety, somatisation, perceived stress and negative illness beliefs were all significant risk factors for the development of IBS six months after Campylobacter gastroenteritis.[45]

Acute stress, either physical or psychological, alters gutspecific efferent autonomic innervation in both controls and patients with IBS. However, normalization is delayed in IBS, who show heightened visceral sensation, suggesting the involvement of a different regulatory mechanism.[46] Patients with IBS-D display enhanced proinflammatory cytokine release. In one study, lipopolysaccharide-induced TNF- a production was associated with anxiety in patients with IBS.[47] Psychological stress may thus induce an exaggerated response to bacterial antigens in the absence of altered baseline cytokine levels. Therefore, psychological factors may modulate inflammatory responses to bacterial antigens and at least partly explain the increased incidence of post-infective IBS in patients with psychological co-morbidity. Recent treatment outcome studies indicate certain forms of psychological treatment including hypnotherapy and cognitive– behavioral therapy (CBT), which are effective in treating IBS.[48]Hence there is evidence that psychological factors have a role in IBS, but whether it is an epiphenomenon or has a pathophysiological role in the development of symptoms has yet to be delineated.

Brain-gut axis

The hypothalamic pituitary adrenal (HPA) axis is one of the systems that mediates physical and psychological stress. It is also affected by central and peripheral stimuli. Stress can influence both innate and specific immune responses via the HPA axis and the sympathetic nervous system. The basal cortisol level has been shown as elevated with blunted ACTH levels in some studies,[49,50] and blunted in others.[51] After ovine CRF injection, some studies found increased plasma ACTH but normal cortisol levels,[52] whereas others demonstrated both blunted plasma ACTH response and plasma and salivary cortisol levels.51 Similarly in response to simultaneous mental stress and rectal distension, one study found increased plasma ACTH, but not cortisol levels in IBS patients,[53] while the other found no difference in either ACTH or cortisol level when compared with the controls.[54] It thus appears that the HPA axis is dysregulated in IBS.

In a recent study,[55] the plasma levels of IL-6, IL-6R, and IL- 8 were elevated in IBS patients compared with controls, levels of IL-10 and TNF- a however were not different between the two groups. The plasma cortisol level was suppressed in both patients and controls in response to dexamethasone administration.[55] It therefore appears that IBS is characterized by a pro-inflammatory cytokine response and an exaggerated stress response manifested by increased stimulated HPA axis hormones.

Post infective IBS

A small subgroup of IBS patients relates the onset of their symptoms to a bout of infectious gastroenteritis. A case control study using Rome II criteria for IBS showed an incidence of new post-infectious IBS of 16.7% over 6 months compared with just 1.9% of controls.[56] The cumulative incidence of IBS one year after an epidemic of salmonella gastroenteritis was 11.6% in post-infectious patients and 1.5% in controls, yielding a relative risk of 7.8.[57] A recent meta-analysis found that the median prevalence of IBS in the gastroenteritis group was 9.8% (interquartile range, 4.0 –13.3), compared with 1.2% (interquartile range, 0.4 –1.8) in the control group (p< 0.01); the pooled odds ratio was 7.3 (95% CI 4.7–11.1).[58] The risk factors included severity of the initial illness, bacterial toxigenicity, female gender, adverse psychological factors (including neuroticism, hypochondriasis, anxiety and depression), and adverse life events.[59,60] Increased mucosal lymphocytes are noted in colonic biopsies, along with enterochromaffin hyperplasia, these changes persist in IBS patients even after the infection has resolved.[61,62] Increased enterochromaffin cell numbers are associated with increase in postprandial 5HT release, an abnormality shown both in post-infective IBS and in IBS-D.[63]

Increased gut permeability is found frequently among patients following bacterial gastroenteritis.[64] This increased permeability allows access of bacterial products to the lamina propria, and can perpetuate chronic inflammation. Recent studies suggest that, regardless of bowel habit subtype, some IBS patients may show evidence of an ongoing immune activation. Studies from India also show that the circulating levels of IL-2 and IFN gamma are increased in IBS when compared to healthy controls. Similarly substance P was significantly increased and IL 10 levels reduced in IBS patients. This suggests that there may be a role for inflammation in the pathophysiology of IBS.[65,66] As stress and mucosal abnormalities are known to interact and contribute equally to the development of post-infective IBS,[60] it is possible that stress, by activating mast cells, may contribute to persistently increased gut permeability and hence to immune activation.

Management of IBS

A good history and examination is the key to diagnosis of IBS without resorting to extensive tests. A detailed and accurate history must be sought in every case. It is important to determine the reason for consultation at the time and to elicit any associated psychological factors; this is very helpful in future management strategies. Optimal eye contact, body language which conveys empathy, and open ended questioning designed to elicit the patient’s ideas have shown to reduce re-consultation rates.[67] Recognition of associated extracolonic symptoms with IBS is important, as this can avoid unnecessary investigation as well as inappropriate referral to other specialties.

Most of the history is directed at determining the presence of any alarm symptoms which might point towards an organic disorder like rectal bleeding, anaemia, weight loss, fever, family history of colon cancer, nocturnal symptoms, onset of the first symptom after 50 years of age, short duration of symptoms and a major change in symptoms.

It is helpful to classify the predominant symptom type, based on the Bristol stool form score, whether the patient has IBS with constipation, diarrhoea, mixed or alternator. Physical examination is usually unimpressive.

The concept that IBS as a diagnosis of exclusion is not acceptable any more. Investigating a case of IBS yields few results if any.[68] A complete blood count should is necessary in all elderly patients.[69] As the pretest probability of inflammatory bowel disease, colorectal cancer, and infectious diarrhoea is less than 1% among IBS patients without alarm symptoms,[1] invasive investigations should be reserved for patients with alarm symptoms, and IBS with diarrhoea. Western studies have shown that the prevalence of celiac disease (CD) is 5% compared to <1% among healthy controls. Hospital-based Indian studies looking at CD in IBS also noted the presence of CD in 3.2% IBS patients.[70,71] Hence CD serology should be done in populations with significant CD risk. Lactose intolerance among Indian patients was the same as in healthy controls[72] and small intestinal bacterial overgrowth among IBS patients was higher than in healthy subjects (11% vs. 1%),[73] but significantly lower than in Western studies (43%).[74]

Pharmacological therapy

Reassurance by the physician provides relief for patients with mild symptoms.[75] The goal of IBS treatment is to improve global IBS symptoms. In all cases of IBS, it is important to establish realistic and consistent treatment goals. Treatment of IBS with currently available drugs usually is targeted to the management of predominant symptoms such as constipation, diarrhoea, and abdominal pain.

Constipation

Fibre and bulking agents are commonly used for patients with IBS-C, though their efficacy is controversial. Fibre is thought to cause a decrease in intracolonic pressure and also a decrease the in oro-anal transit time. Review of literature shows that fibre causes minimal improvement in global IBS symptoms especially abdominal pain, some types of fibre (wheat corn and bran) may even cause worsening of bloating.[76] Currently osmotic laxatives like polyethylene glycol are being used to treat constipation.

Tegaserod is a 5-HT4 agonist, and stimulates intestinal secretion of water and chloride and decreases the nociceptive response to rectal distension. A Cochrane review concluded that tegaserod appears to improve overall symptoms of IBS, and the frequency of bowel movement in those with chronic constipation, clinical importance of these modest improvements is not clear.[77] There is currently limited data of its effect on the quality of life, also scant information of its efficacy in men. The primary side effect of tegaserod is diarrhoea, but it is usually transient and resolves with ongoing treatment. Tegaserod was found to cause an increase in adverse cardiovascular events and now has restricted use in the treatment of IBS-C and chronic idiopathic constipation in women less than 55 years of age without known cardiovascular problems.[78]

Lubiprostone, a member of a new class of bicyclic fatty acid derivatives known as prostones, acts on type-2 chloride channels located on the apical side of gastrointestinal epithelial cells, and increases secretion of electrolyte-rich fluid into the small intestine, promoting increased motility.[79] It was recently approved for treatment of IBS-C[80] based on the results of two RCTs involving 1154 patients diagnosed with IBS-C treated with 8 mg twice daily.[81] Common side effects of lubiprostone include nausea, diarrhoea, and abdominal pain. Other rare side effects include urinary tract infections, dry mouth, syncope, peripheral oedema, dyspnea, and palpitations. Lubiprostone has not been approved for use in children or men. It should not to be administered to patients suffering from severe diarrhoea or patients with known or suspected bowel obstruction. Lubiprostone has also beenapproved for the treatment of chronic idiopathic constipation at 24 mg twice daily.

Diarrhoea

Loperamide has been shown to benefit IBS cases with diarrhea without any effect on pain,[82,83] there is however no evidence from RCTs. Low dose loperamide at 2-4 mg every 4- 6 hours, up to a maximum of 12 g/day, is beneficial in troublesome diarrhoea. These agents are most useful if taken before the anticipated stressful event that causes the diarrhoea.

Alosetron, a selective 5-HT3 receptor antagonist, results in increased small bowel and colonic transit times, decrease in intestinal secretion, increased stool firmness, and an increase in colonic compliance.[84] Alosetron was shown to cause significant global improvement in IBS-D trials.[85] Due to reports of ischemic colitis and bowel perforation its use is now confined to women with severe diarrhoea-predominant IBS who have had symptoms for at least 6 months and who have not shown a response to conventional therapy (in particular, antidiarrhoeal agents).

Abdominal pain

Spasmolytics work by decreasing intestinal smooth muscle activity, two classes are commonly used, anticholinergics (hyoscyamine, dicyclomine, cimetropium) and direct smooth muscle relaxants (mebeverine, pinaverine, octylonium bromide). Results from studies have been contradictory; a Cochrane meta-analysis demonstrated that spasmolytics were beneficial for abdominal pain[86] whilst other studies have not.[87]

Tricyclic antidepressants (TCAs) when used at low doses (10 – 75 mg of amitryptyline) result in antihyperalgesia, improvement in sleep, normalisation of gastrointestinal transit, and when used at higher doses (e.g. 100 mg or more at bedtime) helps in coexisting depression and anxiety. They are thought to benefit predominantly IBS-D patients, anticholinergic side effects limit their use in IBS – C patients. TCAs should be used cautiously in the elderly, even with low doses, side effects of constipation, dry mouth, drowsiness, and fatigue occur in over one third of patients. Cochrane review and other reviews[86,88] did not show any benefit of TCAs when compared to placebos. TCAs may be more helpful in IBS patients with somatic pain and who have insomnia.

Selective serotonin reuptake inhibitors (SSRIs) cause global improvement in IBS symptoms without significant changes in bowel habits or pain.[89,90,91,92] Severe IBS patients with somatisation were the ones who benefitted the most. The exact mechanism is unknown, whether it is by decreasing depression and anxiety or otherwise.

Psychotherapy

Four specific psychological therapies have been tested in case controlled studies for the treatment of IBS, and these consist of cognitive-behaviour therapy, gut-directed hypnosis, psychodynamic therapy and relaxation training.

Cognitive–behaviour therapy (CBT) is a form of psychotherapy where the patient’s biased and negative thought patterns that amplify physical symptoms and undermine effective life functioning and psychological well-being are corrected. Among all forms of psychological therapy, the type most extensively studied is CBT, which also has shown the greatest benefit. The benefit seen with psychological treatment seems to be similar to or greater than that reported with medications studied specifically for bowel symptoms in IBS, although there are no true placebo controls in trials of psychotherapy. A recent meta-analysis of 17 CBT trials for IBS, yielded an odds ratio of 12.0 (5.6 –26.0); the average number of patients that had to be treated with CBT or hypnotherapy for one patient to achieve improvement over control groups was estimated as two.[93]

At present there is limited data to recommend the use of probiotics. A recent meta-analysis of probiotics in IBS demonstrated their efficacy, but the magnitude of benefit and the most effective species are uncertain.[94] There is as yet no role of antibiotics in the treatment of IBS.

In conclusion, the treatment of IBS is not an easy task. New drugs in the pipeline may make treatment of IBS less challenging in the future.

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