irritable bowel syndrome: the clinical approach

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Panminerva Medica 2018 December;60(4):213-22 DOI: 10.23736/S0031-0808.18.03541-3

© 2018 EDIZIONI MINERVA MEDICA Online version at http://www.minervamedica.it

REVIEW

Irritable bowel syndrome: the clinical approach Alessandro ADRIANI 1, Davide G. RIBALDONE 2, Marco ASTEGIANO 1, Marilena DURAZZO 3, Giorgio M. SARACCO 1, 2, Rinaldo PELLICANO 1 * 1Unit

of Gastroenterology, Molinette Hospital, Turin, Italy; 2Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy; 3Department of Medical Sciences, University of Turin, Turin, Italy *Corresponding author: Rinaldo Pellicano, Unit of Gastroenterology, Molinette-SGAS Hospital, Via Cavour 31, 10126 Turin, Italy. E-mail: [email protected]

A B S T RAC T Irritable bowel syndrome (IBS) is a chronic and debilitating functional gastrointestinal disorder which presents with abdominal pain associated with alteration of bowel habits. IBS is a common condition affecting 9-23% of the general population, being the 80% female, with considerable impact on quality of life and health care costs. The exact pathogenesis of IBS remains elusive, but is clearly multifactorial and includes environmental and host factors. Management of patients with IBS is challenging since diagnosis and treatment could require several approaches with unsatisfactory results. In any case, the diagnosis of IBS is based on the positive identification of symptoms consistent with this condition and by excluding an underling organic disease. Before choosing therapeutic options, a strong reassuring physician-patient relationship is crucial. The therapeutic approach of IBS may consist of both non-pharmacological therapies and pharmacotherapy and should be based on prevalent symptomatology. Lifestyle modifications such as stress reduction and increased physical activity seem to be useful to improve symptoms and should be encouraged. The same for dietary modifications that represent an important first-line therapeutic option. The pharmacological treatment should take into account the predominant symptom and test one drug at a time with a predefined time point for effectiveness evaluation and dosage adjustment. This clinical review offers an updated overview on epidemiology, pathogenesis, diagnosis and treatment of IBS. (Cite this article as: Adriani A, Ribaldone DG, Astegiano M, Durazzo M, Saracco GM, Pellicano R. Irritable bowel syndrome: the clinical approach. Panminerva Med 2018;60:213-22. DOI: 10.23736/S0031-0808.18.03541-3) Key words: Irritable bowel syndrome - Constipation - Diarrhea - Abdominal pain.

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rritable bowel syndrome (IBS) is defined by the presence of abdominal pain associated with alteration of bowel habits without an underlying structural pathology.1, 2 IBS is a common condition that affects 9-23% of the general population with considerable impact on quality of life and health care costs. Of those who do visit physicians about 80% are female.3-5 Despite the relatively high prevalence IBS remains an important medical challenge in term of diagnosis and treatment.6 The factors that are thought to be involved in its pathogenesis are heterogeneous. They include both environmental and host factors such as food intolerance, antibiotics, enteric infections, altered pain perception and altered brain-gut interaction, dysbiosis, psychosocial stressors, increased intestinal permeability, increased gut mucosal immune activation and visceral hypersensitivity.7

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Several studies have been published in the last years on IBS and the new Rome IV symptom-based criteria have been published in 2016 bringing changes in the diagnostic criteria for IBS.8 This review of the literature provides an updated overview of IBS focusing on its epidemiology, pathogenesis, diagnosis and treatment.

Literature search To identify all appropriate papers, a PUBMED search of all studies published from 1965 to 2018 was conducted. The final date was 5 August 2018. The following medical subject headings were used singularly or associated: irritable bowel syndrome, IBS, constipation, diarrhea, abdominal pain, abdominal distension. When available, systematic reviews and meta-analyses were used to summarize the evidence.

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Epidemiology, definition and clinical features The global prevalence of IBS is about 11%,3 with a range of 9 to 23%,9 but it varies largely among countries depending on diagnostic criteria, gender, and age.3 Most of the studies have been conducted in Northern Europe or Southeast Asia, with a significant heterogeneity in term of study design. The lowest prevalence occurs in Southeast Asia (7.0%) and the highest in South America (21.0%).3 IBS is defined as a chronic and debilitating functional gastrointestinal (GI) disorder which presents with abdominal pain associated with alteration of bowel habits regarding stool frequency and/or stool consistency. Symptom onset should occur at least 6 months before diagnosis and symptoms should be present during the last 3 months.8 The exclusion of underlying structural pathologies requires the absence of alarm symptoms such as unintentional weight loss, anemia, fever, nocturnal symptoms, GI bleeding, and onset of symptoms after age 50.9-12 Depending on predominant symptomatology IBS is divided into four subgroups: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), IBS with a mixed pattern (IBS-M) of constipation and diarrhea, and unclassified IBS (IBS-U), without any of the previous symptoms.1, 2 Sometimes, IBS develops acutely after an infective syndrome (postinfectious IBS, IBS-PI), characterized by two or more of fever, vomiting, diarrhea or positive stool culture. Moreover, other conditions are often associated with IBS, such as somatic comorbidities (fibromyalgia, chronic pelvic pain and chronic fatigue syndrome),13 other GI disorders (gastroesophageal reflux,14 noncardiac chest pain,15 and dyspepsia16), psychological and psychiatric symptoms (depression, anxiety, somatization).17 In most cases, IBS presents as a chronic relapsing disease in which symptoms may change over time,7 with a worsening in 2% to 18% of patients, a stable history in 30% to 50% and an improvement in 12% to 38% of cases.18 Furthermore, the predominant symptomatology may varies leading to a different IBS subtype, most commonly from IBS-C or IBS-D to IBS-M,19 less frequently switching from IBS-C to IBS-D or vice versa.20 A possible bias in “follow-up” and “natural history” studies is represented by treatments introduced by patient or clinician, making difficult to attribute symptoms variation to medical interventions or natural history of IBS.7 The economic and human burden of IBS is reflected with substantial costs for patients, healthcare systems and society.21

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Table I.—Pathogenesis of irritable bowel syndrome. Environmental factors Psychosocial distress Enteric infections Antibiotics Diet and food intolerance Host factors Visceral hypersensitivity and altered pain perception Intestinal dysmotility Mucosal immune disfunction Altered brain-gut interaction Dysbiosis Increased intestinal permeability

Pathogenesis The pathogenesis of IBS is heterogeneous and traditionally related to either environmental or host factors (Table I). Psychosocial factors may be important in the development of IBS although their etiological relevance in GI dysfunction remains uncertain. The literature data show that anxiety and depression are quite common in IBS22 with higher levels than in healthy controls.23 Within the IBS-D subgroup, some patients seem to show an increased intestinal membrane permeability associated with higher visceral and thermal hypersensitivity, which may lead to more severe IBS symptoms, altered pain perception and hypersensitivity to somatic and visceral stimuli.24 The brain-gut relationship is another important feature underlined by mutual interactions between central nervous system and the gut itself, with the microbiota as an important “influencer” of these interactions through neural, endocrine, immune, and humoral links.25-29 As reported above, some patients (about 10%) develop IBS after an infectious illness, and 3%-36% of enteric infections are followed by the onset of persistent new IBS symptoms.30 Different microbes influence the time trend features of IBS, leading viral infections more frequently to temporary symptoms, while bacterial enteritis and protozoan and helminth infections may be followed more often by prolonged IBS-PI.30 A hypothetical pathogenetic explanation is linked to a possible residual mucosal inflammation or persistent alterations of mucosal immunocytes, enterochromaffin and mast cells, enteric nerves, and the GI microbiota,31 with a crucial role of the immune hyperactivation, although several studies are needed.32 Small intestine bacterial overgrowth (SIBO) is prevalent in IBS, but it remains unclear whether the former has a pathogenetic role on the latter, being the relationship between SIBO and IBS highly inconsistent among studies.33

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There is no evidence of the fact that SIBO would be absent before IBS symptoms, and present after IBS onset, and there is not a dose-response relationship between small intestinal microbiota and IBS symptoms.33 So, bacteria may contribute to some IBS symptoms, but in a multifactorial context. The gut microbiota is a complex living ecosystem that actively influences and mediates several physiological functions.26, 34 An altered gut microbiota composition, also known as dysbiosis, could promote development and maintenance of symptoms in IBS, despite the lack of randomized, placebo-controlled studies.27, 34 Specific dietary constituents such as fiber, proteins and short-chain carbohydrates may cause GI symptoms,35-38 and food intolerances are common in IBS patients. Poorly absorbed carbohydrates, with their osmotic effects, may trigger symptoms linked to increased fermentation in the small bowel or colon in subjects with abnormalities in gut function and hypersensitivity.38 Conversely, true food allergies in IBS are rare.39 Motility dysregulation, through serotonin (5-HT) plasma concentration and its effects on 5-HT3 and 5-HT4 receptors, is another mechanism involved in different types of IBS. IBS-D and IBS-C patients show higher and lower levels of plasmatic 5-HT respectively,40-42 considering these receptors as a therapeutic target of prokinetic agents (5-HT4 receptor agonists) or 5-HT3 receptor antagonists to slow GI transit and reduce visceral sensation.30

Diagnosis Clinical diagnostic criteria have evolved through the progressive revisions of the Rome guidelines — the expert consensus criteria for diagnosing functional GI disorders (FGIDs) that include esophageal, gastroduodenal, bowel, biliary, and anorectal disorders — until the most recent Rome IV criteria,8 released in May 2016. The official Rome IV publications by the Rome Foundation adopted a gradual shift from the classical definition “Functional Gastrointestinal Disorders” to “Disorders of Gut-Brain Interaction,”8 underlying the importance of multiple specific pathophysiological processes such as dysbiosis, increased gut permeability, altered immune function, and neural and hormonal interaction between the brain and the gut, as mentioned above. Diagnostic criteria for IBS are shown in Table II. The main differences between Rome III and Rome IV criteria concern two major changes: first, the term “abdominal discomfort” has been deleted from the definition due to the

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Table II.—Diagnostic criteria for irritable bowel syndrome (based on Rome IV criteria).8 Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, with symptom onset at least 6 months before diagnosis associated with 2 or more of the following criteria Related to defecation Associated with a change in frequency of stool Associated with a change in form (appearance) of stool

imprecise nature of the term itself and different meaning in different languages and among individuals; moreover, it is unclear if the distinction between discomfort and pain is qualitative or quantitative, so abdominal pain is now necessary to make diagnosis of IBS.8 The second important change concerns the frequency of abdominal pain, stating that it should be present at least 1 day per week during the past 3 months,8 compared with Rome III criteria in which abdominal pain should be present at least 3 days per month. This was based on data from the Rome normative GI symptom survey.43 Furthermore, the phrase “improved with defecation” was replaced with the definition “related with defecation” as a substantial proportion of IBS patients report a worsening in abdominal pain with defecation instead of an improvement.44, 45 As already mentioned, in Rome III criteria IBS was divided in subgroups depending on prevalent symptomatology based on proportion (more than 25%) of bowel movements with abnormal stool consistency according to Bristol Stool Form (BSF) Scale (Figure 1, types 1 and 2: hard, lumpy stool; types 6 and 7: loose, watery stools): IBS with constipation (IBS-C), IBS with diarrhea (IBSD), IBS with mixed constipation and diarrhea (IBS-M), and unsubtyped IBS (IBS-U). However, with these criteria, most subject were defined as IBS-U and only few patients fulfilled criteria for IBS-M as IBS-patients haType 1

Type 5

Type 2 Type 6 Type 3 Type 4

Type 7

Figure 1.—Bristol Stool Form Scale. Type 1: separate hard lumps, like nuts; type 2: sausage like but lumpy; type 3: sausage like with cracks in the surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear-cut edges; type 6: mushy stool with ragged edges; type 7: watery stool, no solid pieces.


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bitually report normal stool consistency,46 whereas using the same cut-off in diagnostic questionnaires the IBS-M subgroup was over represented.47 In Rome IV, the same subgroups were maintained except for the IBS-U renamed unclassified IBS. In clinical trials the IBS subtypes should be based on two weeks’ stool diaries19 using the BSF Scale but the predominant bowel habit on days with at least one abnormal bowel movement should be used for subtyping (days with bowel movement but normal stool consistency is not counted). Obviously, the patients must be evaluated off medications such as laxatives or antidiarrheal agents. In Rome IV criteria, stools should be hard or loose in more than 25% of bowel movements in IBS-C or IBSD, respectively. For IBS-M there should be >25% loose stools and >25% hard stools and for IBS-U 2,400 IBSD patients a combined response (for both abdominal pain and diarrhea).8 The most common adverse events were constipation, nausea and abdominal pain, whereas serious but rare side effects were sphincter of Oddi dysfunction or self-limited pancreatitis.8 Hence, this drug should not be used in patients with bile duct obstruction, pancreatitis, severe liver impairment or severe constipation. Rifaximin, a nonabsorbable antibiotic recently approved by the Food and Drug Administration (FDA) for the treatment of IBS-D, showed significantly relief of global IBS symptoms and bloating after 2 weeks of treatment and during the first 4 weeks of follow-up.80 The efficacy, compared to placebo, persisted up to ten weeks although a gradual loss of symptom response was noted.


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With this drug, a recurrence of symptoms can be retreated with superior efficacy compared to placebo.81 Nausea is the most common side effect reported.

within a week of treatment initiation for stool frequency, whereas for abdominal pain and bloating it may take 8 to 12 weeks. The most reported side effect is diarrhea.

Pharmacotherapy for IBS-C

Pharmacotherapy for abdominal pain

Considering that most patients with IBS-C have a normal transit time,82 fiber supplementation and bulking agents are often used as first line therapy in this context. In a meta-analysis soluble fiber (psyllium and ispaghula) showed modest improvement in global IBS symptoms,58 whereas, since they can exacerbate IBS symptoms (especially flatulence and abdominal pain),59 insoluble fiber (bran) should be avoided. Fiber dosage should be titrated gradually up to a total daily intake of 30g. Polyethylene glycol (PEG) is an osmotic laxative used either as first-line in IBS-C or as second-line when treatment with fiber and bulking agents fails. Clinical trials showed improvements on stool frequency and stool consistency but not on abdominal pain or bloating.83 PEG is typically well tolerated but can cause dose-dependent bloating, gas and loose stools. Prucalopride, a highly selective 5-HT4 agonists, is approved in Europe for symptomatic treatment of patients with chronic constipation as second- or third-line after laxatives failure. In contrast to nonselective 5-HT4 agonists (cisapride, withdrawn due to cardiac arrhythmias;84 tegaserod limited in use due to ischemic cardiac events85), it has not been associated with adverse cardiovascular events.85, 86 Large, multicenter randomized controlled trials (RCTs) have shown the efficacy and safety of prucalopride in chronic idiopathic constipation,87 and its long-term effects,88 but no trial has been published in the context of IBS-C. Lubiprostone is a selective type 2 chloride-channel (ClC-2) activator that stimulates intestinal fluid secretion, acting as a stool lubricant and facilitating its evacuation. This drug has been approved in USA and Switzerland (8 mg twice daily) for treatment in women with IBS-C with evidence of higher overall response compared with placebo.89 Possible adverse effects are nausea and diarrhea, more frequent at higher dosage (8% with an 8-μg dose and 33%with a 24-μg dose) and away from food. Linaclotide is a new type of intestinal secretagogue that acts as a guanylate cyclase-C agonist increasing cyclic guanosine monophosphate production. The consequence is an increased intestinal chloride secretion through the cystic fibrosis transmembrane regulator. In IBS-C, at the dose of 290 µg daily, linaclotide improves stool frequency and consistency, ease of defecation and abdominal pain, discomfort and bloating.90 The maximum benefit occurs

Antispasmodics (dicycylomine, otilonium, mebeverine) are used in all IBS subtypes to treat symptoms such as abdominal pain and spasm. As they reduce GI contractility, these drugs are useful for postprandial symptoms related to exaggerated gastrocolonic reflex. The mechanism of action includes either anticholinergic or calcium channel blocking properties and the efficacy is superior to placebo for the prevention of recurrent IBS symptoms.58 Peppermint oil is another compound with antispasmodic properties for global improvement of IBS symptoms and abdominal pain.58 Heartburn and reflux symptoms are the most frequent adverse effects.91 The actions of trimebutine [3,4,5-trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutylester] on the GI tract are mediated via (i) an agonist effect on peripheral μ, k and δ opiate receptors and (ii) release of GI peptides such as motilin and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and glucagon. Trimebutine accelerates gastric emptying, induces premature phase III of the migrating motor complex in the intestine and modulates the contractile activity of the colon. Trimebutine has also been shown to decrease reflexes induced by distension of the gut lumen in animals and it may therefore modulate visceral sensitivity. Clinically, trimebutine has proved to be effective in the treatment of both acute and chronic abdominal pain in patients with functional bowel disorders, especially IBS, at doses ranging from 300 to 600 mg/day.92 Centrally acting agents such as antidepressants are a therapeutic option due to their effect on pain perception, mood, and motility, acting on dysregulation of the braingut axis. Both tricyclics antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) showed efficacy in treating IBS symptoms,93 whereas few data are available for selective norepinephrine reuptake inhibitors (SNRIs).94 The choice of different type of antidepressant could be addressed by the stool habits, the presence of insomnia, or comorbid anxiety taking advantage of adverse effects. For example, as TCAs can cause constipation, they might be useful in IBS-D patients. Furthermore, also patients with insomnia, anorexia, or weight loss may find advantage with TCAs. On the other hand, SSRIs may be a better choice for IBS-C patients due to their prokinetic effects and for IBS subjects with significant anxiety. Starting with the lower dose and gradually increasing it if an adequate

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Table III.—Therapies for irritable bowel syndrome based on predominant symptom. Diarrhea Peripheral opioid agonist: loperamide (2-4 mg/d, up to 16 mg/d) Bile acid sequestrants: • cholestyramine (9 g bid-tid) • colestipol (2 g qd-bid) • colesevelam (625 mg qd-bid) 5-HT3 receptor antagonists: • alosetron (0.5-1 mg bid) • ondansetron (4-8 mg tid) • ramosetron 5 mg qd Mixed opioid agonists/antagonists: eluxadoline (100 mg bid) Antibiotics: rifaximin (550 mg tid for 14 d) Constipation Soluble fiber: psyllium (up to 30 g/d in divided doses) Laxatives: polyethylene glycol (17-34 g/d) Type 2 chloride-channel activator: lubiprostone (8 µg bid) Guanylate cyclase-C agonist: linaclotide (290 µg qd) Abdominal pain Antispasmodics: • dicycylomine (10-20 mg qid) • otilonium (40-80 mg bid-tid) • mebeverine (135 mg tid) Peppermint oil: 250-750 mg, bid-tid Tricyclic antidepressants: • desipramine (25-100 mg/d) • amitriptyline (10-50 mg/d) Selective serotonin reuptake inhibitor: • paroxetine (10-40 mg/d) • sertraline (25-100 mg/d) Other treatments Probiotics: multiple products available

response is not seen, is considered a wise approach.7 Taking into account the role of the gut-brain axis, immune, neural, and endocrine pathways in the pathogenesis of IBS, the possible beneficial effect of benzodiazepines (BZD) in this axis should be considered. BZD receptor modulators can be helpful, especially in the diarrhea-dominant form of IBS, by affecting the inflammatory, neural, and psychologic pathways. However, controversies still exist.95 A summary of treatment options based on predominant IBS symptom is showed in Table III.

Other treatments Since the role of gut microbiota in the pathogenesis of IBS is a relevant topic, probiotics are widely used in this context.96 Multiple mechanisms may lead to benefit97 and a meta-analysis including 43 clinical trials showed that different probiotic products had efficacy on global IBS symptoms, pain, bloating, and flatulence.98 In a previous casecontrol study, our group has shown that a combination of

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L-tryptophan, inulin, angelica, vegetal charcoal, groups B vitamins and probiotics (Lactobacillus sporogenes, Lactobacillus acidophilus, Streptococcus thermophilus), in a cohort of patients with IBS reduced significantly abdominal pain, abdominal distension and constipation.99 These beneficial effects could be explained through the modulation of several activities. Its peculiarity resides in the influence on serotonin (5-HT) production, due to the essential amino acid tryptophan. Serotonin has a key role in the pathogenesis of IBS because while in the GI tract influences the peristaltic activity, it is also involved as neurotransmitter in the central nervous system and is well-known its implication in platelet aggregation. The fact that probiotics appear to be safe contributes to their wide use. The biopsychosocial model describes the interaction between psychosocial and physiological factors associated with IBS. It explains how the early life factors such as genetic predisposition and social learnings, the psychological factors associated with life stress, and the gut pathophysiology such as dysmotility, visceral hypersensitivity and brain-gut interactions, interact each other influencing GI symptomatology, patient response and illness outcome.100 Psychological therapies provide an alternative or adjunctive treatment for IBS patients and are mainly cognitive behavioral therapy (CBT), psychodynamic psychotherapy, relaxation therapy, mindfulness and gut-directed hypnotherapy. Psychological interventions may be slightly superior to usual care at the end of treatment,101 and a meta-analysis considering 32 separate trials showed that CBT, hypnotherapy, multicomponent psychological therapy and dynamic psychotherapy were all effective treatments for IBS.93 Despite this, poor patient and clinician acceptance of the need for treatment, the costs and the duration of the treatment itself could limit the adoption of these therapies in clinical practice. Complementary and alternative therapies are often used by many IBS patients despite the lack of evidence.102 Some of these treatments have been summarized in Cochrane reviews. Acupuncture was no better than sham acupuncture in improving symptoms or quality of life,103 whereas Chinese herbal remedies have yielded showed efficacy in alleviating IBS symptoms.104 However, further studies are desirable with adequate control groups and validated study endpoints.

Conclusions IBS is a common disorder with a considerable impact on quality of life and health care costs. Despite new Rome


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IV symptom-based criteria have been recently approved, IBS remains a relevant challenge both for diagnosis and treatment. A useful clinical approach should consider a combination of the diagnostic criteria (with clinical history and physical examination), a limited number of diagnostic tests, and a careful follow-up. For most patients, when diagnostic criteria are fulfilled and alarm symptoms are absent, the need for diagnostic tests should be minimal. The therapeutic approach of IBS may consist of both non-pharmacological therapies and pharmacotherapy, remembering that a strong physician-patient relationship is fundamental for effective treatment and realistic expectations. As the therapy should be based on prevalent symptomatology, several IBS-specific agents showed efficacy in randomized controlled trials, although further studies are desirable to better customize the therapy and provide the most significant benefit.

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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Article first published online: September 24, 2018. - Manuscript accepted: September 4, 2018. - Manuscript received: September 4, 2018.

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irritable bowel syndrome: the clinical approach

irritable bowel syndrome: the clinical approach

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