07 Gastroenterology by Urvi Trivedi

SECTION 7

Gastroenterology 59.

Long Term PPI Use: Is it Really Safe? Ramesh Roop Rai

279

60.

PPIs and Antiplatelets Latest Concepts Randhir Sud

282

61.

Management if Irritable Bowel Syndrome: A Practical Approach Uday C Ghoshal

285

62.

Making a Positive Diagnosis of Irritable Bowel Syndrome Ujjwal Sonika, Vineet Ahuja

292

63.

Chronic Diarhoea â&#x20AC;&#x201C; An Approach Swaroop Kumar Baruah, Suman Talukdar

295

64.

Management of Ulcerative Colitis: Step-up or Step-down Approach? Bhaskar Nandi

300

65.

Medical Management of Acute Pancreatitis Rajoo Singh Chhina, Amit Bansal, Amanat Sidhu, Rajdeep Singh

306

C H A P T E R

Long Term PPI Use: Is it Really Safe?

Proton Pump Inhibitors (PPIs) are among the most prescribed medications. Millions of people are using it for two major indications viz. (1) Treatment of Dyspepsia, and (2) Prevention of Gastrointestinal (G.I.) Bleeding in patients prescribed Anti-Platelet Drugs (Aspirin Âą Clopedogril), Anti-inflammatory Drugs, Stress situations (in ICU). PPIs are prescribed for a prolonged period of time, with a belief that they are safe and have fewer side effects. That is why they are over-prescribed, often unnecessarily for a prolonged period. Once prescribed, most Indian patients continue to take PPIs for years even after symptomatic relief and would not re-consult the Physician. Most of the evidences supporting the adverse effects are observational studies. It is possible that PPI users are sicker than non-users or the adverse effects are caused by other drugs or confounding conditions. Multiple high quality observational studies, avoiding potential confounding factors have shown causal relationship of adverse effects with PPI use. PPIs have been associated with adverse effects on Kidney, cardiovascular system, Clostridium difficile infections, Hypo-magnesaemia and Calcium absorption. The possible potential mechanisms of AE of PPI's are listed in Table 1.

Ramesh Roop Rai

convulsions, cardiac arrhythmias and hypotension, Magnesium supplementation alone may not correct low serum magnesium levels unless the PPI is discontinued. US Food and Drug Administration (FDA) issued a warning in 2011 that use of PPIs may cause low serum magnesium levels if taken for prolonged period of time.

INFECTIONS

Clostridium Difficile Infection: Proton pump inhibitors (PPIs) reduce gastric acidity which may promote bacterial colonization in gastro-intestinal tract increasing the risk of infection. A metaanalysis of 39 studies showed a 74% higher risk of developing C. difficile infection as well as 2.5-fold higher risk of recurrent C. difficile infection among PPI users compared with non-users. FDA published a safety alert in 2015, warning for association of PPIs and C. difficile infection.

Pneumonia: Use of PPIs reduces gastric acidity and increases bacterial colonisation in stomach, which may also lead to increased rates of Pneumonia. A meta-analysis of 5 observational studies showed that risk of community acquired pneumonia was 34% higher among patients using PPIs compared with non-users. The risk was higher with increasing dose of PPIs. However, risk for hospitalacquired pneumonia was not increased. Contrary to this meta-analysis, a retrospective cohort study evaluated the risk for community acquired pneumonia among more than 4 million patients newly prescribed non-steroidal anti-inflammatory drugs.

In these patients, PPI therapy was started (presumably for prevention of dyspepsia, ulceration and bleeding), there was no increased risk of hospitalization for community-acquired pneumonia compared with non-users. The result of this study may be more reliable than other observational studies because study population did not have gastric or oesophageal disease. This study shows that the risk of pneumonia is probably not increased.

KIDNEY DISEASES

Use of PPIs is associated with an increased risk of acute kidney injury, possibly mediated through acute interstitial nephritis, which is 3 fold higher in PPI users compared with non-user. The risk of development of chronic kidney disease is 50% higher in PPI users. Patients taking twice daily PPIs are at higher risk compared to once daily PPI users. Longer the patient uses, higher is the risk. There is higher risk among PPI users compared to patients using histamine (H2 Antagonists). Use of PPIs may lead to chronic kidney disease through recurrent acute kidney injury and hypomagnesemia. Any patient with unexplained serum creatinine rise or urine analysis abnormalities, PPI induced ATN should be considered, prompting nephrology consultation.

HYPOMAGNESEMIA

Meta-analysis of 9 observational studies including 109798 participants found that PPI users had a 40% higher risk of development of hypomagnesemia compared with non-users. This increased the risk of kidney disease and non-recovery of renal functions after acute kidney injury, if not corrected in time. The development of severe Hypomagnesemia can lead to muscle weakness, tetany,

CARDIOVASCULAR EVENTS

Patients with coronary artery disease, who have undergone coronary stent placement, are generally prescribed antiplatelet therapy to reduce the risk of coronary events. Proton Pump Inhibitors are often prescribed along with

280

Table 1: Possible Potential Adverse Effects (AE) of Proton Pump Inhibitors Adverse Effect (ed risk with PPI’s compared to Non-users)

Possible Mechanisms

Possible Measure to Prevent AE of PPI’s

Bone Fractures

ed intestinal Ca absorption  ed bone density & ed risk of fractures

Avoid prolonged PPI use

Even after use of PPI for <1 yr

• Hip fractures

– 26%,

• Spine fractures – 58%

GASTROENTEROLOGY

• Fracture any site – 33% Clostridium difficile 74% higher risk & 2.5 fold higher risk of recurrence Community acquired Pneumonia 34% higher risk. No ed risk of hospital acquired pneumonia.

PPI’s reduce gastric acidity, promotes bacterial colonisation of C. difficile infection

FDA issued safety alert in 2015, warning of possible association of PPI’s & C. difficile infection and advised to avoid prolonged use of PPI’s

Reduced gastric acidity leads to ed bacterial colonisation in stomach which may increase risk of pneumonia

Avoid prolonged use of PPI’s

– 3 fold higher

• Avoid twice a day PPI & its prolonged use,

– 2.5 fold higher

• If possible replace PPI with H2RA, when less severe symptoms

– 50% higher risk

• Any unexplained rise of serum creatinine/urine abnormality suspect for prolonged use of PPI

Contrary to this other large study did not show such high risk. • Acute Interstitial Nephritis  • Acute Kidney Disease  • Chronic Kidney Disease Such AE not seen with use of H2RA Hypo-magnesaemia – 40% higher risk when PPI’s are used for a prolonged time

Hypo-magnesaemia increases the • Only replacement of Magnesium risk of acute kidney disease & nonwould not be effective unless the recovery of renal functions if it is not PPI is discontinued suspected & corrected in time

Reduced activation of Clopidogrel leads to 30% ed risk of Cardiovascular events (in observational studies but not in RCT)

Clopidogrel is metabolised to its active form by liver enzymes cytochrome P-450, which also metabolises PPI’s. This competitive inhibition reduces Clopidogrel activity.

Myocardial Infarction in general population (16% higher risk in PPi users)

Possibly arterial endothelial dysfunction

anti-platelet therapy to prevent gastrointestinal bleeding. Clopedogril is commonly used anti-platelet agent, which is metabolized to its active form by liver enzymes that also metabolize PPIs, suggesting that competitive metabolism by PPIs might lead to reduced activation of Clopedogril and thereby reduced anti-platelet effects. Pharmacological studies demonstrated that adding PPI to Clopidogril reduced platelet inhibition. This finding led the “FDA” in 2009 to warn against combining Clopidogril and PPIs. A meta-analysis of 31 observational studies found that patients using PPIs with Clopedogril have a 30% increased risk of cardiovascular events. Contrary to this observation, none of the 4 randomized clinical trials found an increases risk of coronary events,

• No clear clinical evidence for such a ed Clopidogrel activity • Used PPI in the morning and Clopidogrel in the evening before Dinner. Yet not established

when both drugs are co-prescribed. It is difficult to resolve these conflicting findings. The observational studies are much larger than the randomised trials and provide “real world” experience. However, the observation studies are prone to section bias, and confounding, which are minimized by randomization. In Summary, there is no clear evidence that PPIs increase risk of coronary events in patients on Clopidogril. A practical solution to avoid this competitive inhibition of PPI and Clopidogril, is to use PPI in morning and Clopidogril in evening.

RISK OF MYOCARDIAL INFARCTION

In 2015, a study from USA, in general population using large data of mining study indicates that persons using PPI’s appear to be associated with 16% higher risk of myocardial infarction as compared to persons using H2blockers.

its potential harms should be weighed before prescribing PPIs in a given patient. Avoid using PPIs in patients with less severe symptoms or the fear of recurrence of symptoms of dyspepsia or heartburn that has resolved.

REFERENCES

Katz MH. Failing th e acid test: benefits of proton pump inhibitors may not justify the risks for many users. Arch Intern Med 2010; 170:747-748.

Lazarus B, Yuan C, Wilson FP, e t al. Proton pump inhibitor use and the risk of chronic kidney disease [published online January 11,2016]. JAMA Intern Med doi:10.1001/ jamainternmed.2015.7193.

Antoniou T, Macdonald EM, Hollands S, e t al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open 2015; 3:E166-E171.

A meta-analysis published in 2015 wherein 18 observational studies which included more than 2.5 Lakhs patients with fractures found that PPIs compared with non-users; 26 % higher risk of hip fracture, a 58% higher risk of spine fractures and a 33% higher risk of fracture of any site, even after short term use of PPIs for less than 1 year.

Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail 2015; 37:1237-1241.

Kwok CS, Arth u r AK, Anibueze Cl, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107:1011-1019.

PPI & RISK OF DEMENTIA

Filion KB, Chateau D, Targownik LE, e t al; CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 2014; 63:552-558.

Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an

FRACTURES

PPIs reduces intestinal absorption of calcium, which may decrease bone density and increase risk of fractures. Many observational studies have shown an association between PPI use and increased risk of fractures. In 2010, FDA published a safety alert noting a possible increased risk of fractures among PPI users.

In 2016, a German study of more than 70 thousand patients have observed that older age women more than 80 years who were using PPI’s for more than 5 years, 77.9% women had a significantly increased risk of incidental dementia compared with patients not receiving PPI’s. The study suggests that the avoidance of PPI medications may prevent development of dementia in females. PPI should be used for short periods of time and if symptoms are less, either stop PPI or replace it with H2RA.

CONCLUSION

Available evidences suggest that PPIs are not that safe as claimed earlier. PPI use is associated with acute and chronic kidney disease, which is aggravated by hypomagnesaemia caused by prolonged PPI use, C. difficile infection and osteoporotic fractures. Physicians should take precautions in prescribing PPIs in high risk patients and serum creatinine, magnesium levels should be monitored in patients using high doses for a prolonged period. The benefits of PPI use compared to

8. update meta-analysis [published online October 13, 2015], Osteoporos Int. doi:10.1007/s00198-015-3365-x. 9.

Proton Pump Inhibitors Information. 2015; http://www. fda.gov/Drugs/DrugSafety/Information by Drug Class/ ucm213259.htm. Accessed November 12,2015.

10. Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome: a systematic review. Heart 2013; 99:520-527. 11. Melloni C, Washam JB, Jones WS, e t al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when co-administered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes 2015; 8:4755.

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PPI use is associated with 2.22 fold increased risk of cardiovascular mortality.

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C H A P T E R

PPIs and Antiplatelets Latest Concepts Randhir Sud

INTRODUCTION

Low dose aspirin (75 to 325mgs/d) alone or in combination with second generation thienopyridine clopidogrel is now frequently prescribed anti-throbotics in patients with ischaemic stroke, Ac Myocardial infarction, Acute coronary syndrome and after per-cutaneous coronary interventions (PCI) to minimize re-thrombosis risk. While these reduce the risk of CV events there is increased risk of GI bleeding. There is higher risk with dual antiplatelet agents and when corticosteroids, NSAIDs or anticogulants are co-prescribed as shown in the figure below. Previous history of GI bleed, h/o peptic ulcer disease and age above 60 years are strong risk factors for bleeding due to antiplatelet therapy. Aspirin causes direct mucosal injury in the GI tract causing ulcerations but Theinopyridines increase the risk of GI bleed by anti-thrombotic action and delay healing of pre-existing erosions and ulcers.

RISK OF GI BLEED WITH ANTIPLATELETS

Gastric acid suppression effectively reduces the risk of GI bleed by stabilization of platelet clot and healing of ulcers. H2RAs and PPIs are both effective in gastric acid suppression and ulcer healing. H2RAs are more effective than placebo in prevention of aspirin induced ulcers but PPIs cause more profound acid suppression and ulcer healing compared to H2RAs with significant risk

reduction for an UGI bleed. In a large case-control study in 2007 comparing 2779 patients of upper GI bleeding on endoscopy with 5532 controls, PPI use along with clopidigrel resulted in less upper GI bleeding (RR: 0.19; 95% CI: 0.07 to 0.49) than clopidogrel alone (Figure 1). A recent (2010) RCT demonstrated that co-prescription of Omeprazole with clopidogrel resulted in nearly 66% reduced risk of GI events including overt or obscure GI bleed and gastro-duodenal ulcers as compared to clopidogrel alone. Because of these benefits PPIs are often prescribed along with antiplatelets particularly in high risk patients. Clopidogrel and several PPIs share a common hepatic metabolic pathway through cytochrome-P450 (CYP450) enzymes CYP2C19 and CYP3A4, suggesting the potential for drug interaction and reduced efficacy and adverse CV outcomes. This resulted in 2009 a FDA warning on coprescription of Omeprazole with Clopidogrel. There has been intensive study of pharmacological interaction and clinical outcomes with conflicting data since then. To understand the intricacies of this drug drug interaction we need to understand metabolism and mechanism of both the molecules

Fig. 1: Case Control Study showing risk of GI Bleed with Antiplatelets

283

Fig. 2: Clopidogrel Metabolism

DRUG METABOLISM AND INTERACTION

Nearly 85% of pro-drug is hydrolysed by esterases into an inactive metabolite and rest is converted to its active metabolite through two step sequential oxidative pathway involving CYP 450 enzymes as shown below.

CLOPIDOGREL METABOLIC PATHWAY (FIGURE 2)

NEWER ANTIPLATELET AGENTS

Prasugrel and Ticagrelor are new antiplatelet agents approved for ACS patients undergoing PCI. Prasugrel is a third generation thienopyridine which is a pro-drug and needs one step of CYP 450 dependent hepatic metabolism to active metabolite conversion. In PRINCIPLEâ&#x20AC;&#x201C;TIMI 44 a study comparing anti-thrombotic activity, post PCI for ACS in patients taking Clopidogrel or Prasugrel with PPIs showed much less effect on anti-platelet activity of PPIs on Prasugrel compared to Clopidogrel.

PPIs are weak bases which are activated in the highly acidic environment of gastric parietal cell and metabolized in the liver by CYP 450 enzymes mainly CYP2C19 and CYP3A4 which it shares with Clopidogrel oxidation pathway. There are some differences in degree of CYP2C19 dependent metabolism of various PPIs but pharmacokinetic studies have been inconsistent and do not show superiority of one PPI over other. However Omeprazole and Esomeprazole have strongest competitive.

Ticagrelor is a non thienopyridine antiplatelet agent which does not need hepatic metabolism for conversion into active metabolite. It has rapid onset of action and more profound antiplatelet action and has similar risk of major bleeds as Clopidogrel. Its interaction with PPIs is not known.

CYP2C19 inhibition with resultant pharmacokinetic outcomes of decreased levels of clopidogrel active metabolite and preserved platelet reactivity ex vivo. Some studies have shown lesser competitive inhibition of CYP2C19 with Pantoprazole and Rabeprazole.

There has been inconsistent results of various clinical studies looking at the effect of PPIs co-prescription with thienopyridines on adverse CV events.

HEPATIC METABOLIC PATHWAY OF OMEPRAZOLE (FIGURE 3)

Clopidogrel biological activity will also depend upon a.

Intestinal absorption of pro-drug which may vary with ABCB 1 polymorphism Genetic polymorphism of CYP2C19. Three alleles; 2,3 and 4 have decreased

activity and produce less amount of active metabolite and therefore decreased anti-platelet activity. Competitive inhibition by Omeprazole will have maximum impact on individuals with such polymorphism. CYP2C19*2 is present in >50% asian, >33% African Americans and 24% Caucasians. However these factors influence only 12% in variation of platelet aggregability in response to ADP while Obesity, Diabetes and acute Ischaemia may have much greater effect. Recent SPICE trial (evaluation of influence of statins and PPIs on Clopidogrel anti-platelet activity) on 350 post PCI patients on aspirin and clopidogrel shows that 35 to 50% patients taking esomaprazole had >10% effect on antiplatelet effect of Clopidogrel while Pantoprazole and H2RAs and statins had no significant effect.

CLINICAL EVIDENCE OF PPI AND ANTIPLATELETS INTERCTION

Studies which have shown positive association are mostly observational and are likely to be influenced by selection bias and other confounding factors. In a study of 13608 post PCI patients (Lancet 2009) randomized to either Clopidogrel or Prasugrel, addition of PPIs did not effect cardio-vascular events or incidence of stroke In the only RCT (COGENT) comparing fixed dose Clopidogrel and Omeprazole (75/20) combination with clopidogrel alone there was no effect of PPIs on adverse CV events. There were significantly less adverse GI events (HR .34). However this trial fell short on enrolement numbers planned and was interrupted. Two recent meta-analysis also found no adverse effect of PPIs on CV events. There is no evidence of superiority of one PPI over other in clinical CV outcomes inspite of pharmacokinetic advantage of Pantoprazole and Rabeprazole over other PPIs. In a retrospective analysis of 20956 patients taking Clopidogrel PPIs did not influence CV events and all PPIs were same.

STRATEGIES TO MINIMISE INTERACTION

There have been various strategies to reduce PPI, antiplatelet agent interaction. Giving Pantoprazole or Rabeprazole instead of Omeprazole or eso-omeprazole or substituting Clopidogrel with Prasugrel may minimize potential pharmacokinetic interaction. Split dosing of PPIs and Clopiogrel at different time of the day also has inconsistent results.

CHAPTER 60

Clopidogrel is a pro-drug and its active metabolite binds irreversibly to purinergic P2Y receptor causing inhibition of ADP mediated platelet activation and aggregation.

284

Fig. 3: Omeprazole Metabolism

GASTROENTEROLOGY

RECOMMENDATIONS

There is evidence of pharmacokinetic interaction and measurable decreased anti-platelet activity (ex vivo) of Clopidogrel prescribed with PPIs . There are safety concerns of PPIs co-prescription with anti-platelet agents based on observational studies which only show mild to moderate clinical impact with HR <2. This may be due to study population heterogeneity and other confounding factors. Only RCT till date and two meta-analysis do not show clinically significant adverse CV events. However it is prudent to be cautious till more definitive evidence of safety emerges. Various cardiology and GI society guidelines recommend risk assessment of GI complications and potential risk of PPI co-administration. Routine use of PPIs in all patients on theinopyridines or even dual antiplatelets is not recommended. However PPIs must be given to patients at higher risk of GI complications and these are a.

Old age > 60 years

History of previous GI bleed on DAPT

Concomitant use of NSAIDS

Concomitant use of anti-coagulants

Patients with H. Pylori infection

In this group of patients risk of adverse GI events outweighs potential risk of decreased anti-thrombotic activity. There is unsubstantiated evidence that Pantoprazole or Rabeprazole may be safer and given short half life of most PPIs and Clopidogrel, dosing them at different time of the day may have un-proven but potential benefit in further reducing adverse drug drug interaction.

REFERENCES

Abraham. N S, Hlatky M A, Antman E M, Bhatt D L, Bjorkman D J, Clark C B, Furberg C D, et al ; ACCF/ACG/ AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines; Circulation 2010; 122:2619-2633

Moukarbel G V,and Bhatt D L; Antiplatelet Therapy and Proton Pump Inhibition : Clinician Update; Circulation 2012; 125:375-380

Levine G N, Bates E R, . Bittl J A, Brindis J G, Fihn S D, Fleisher L A et al ; ACC/AHA Guideline 2016 Focused Update on Duration of Dual Antiplatelet therapy in patients With Coronary Artery Disease; Circulation 2016; 134:e123â&#x20AC;&#x201C;e155

Scott S A, Obeng A O and Hulot J S ;Antiplatelet drug interactions with proton pump inhibitors : Expert Opin Drug Metab Toxicol 2014; 10:175â&#x20AC;&#x201C;189

C H A P T E R

Management if Irritable Bowel Syndrome: A Practical Approach

INTRODUCTION

According to recently describe Rome IV criteria published in May 2016, irritable bowel syndrome (IBS) is a chronic (onset at least 6 months ago and symptoms present during the last 3 months) functional bowel disorder in which recurrent abdominal pain is associated with defecation or a change in bowel habits (altered stool form and/or passage), which are not explained by any organic cause detected on routine investigations.1 However, it is being realized more and more that many of these patients, if investigated with highly sensitive investigations, may reveal organic causes that could not have been picked-up by routine investigations challenging the concept of functional basis for all patients with IBS.2, 3 These data suggest that IBS is multi-dimensional in nature with several micro-organic factors contributing to the pathogenesis.4 Although it is considered to be a functional disorder without increase in mortality, it has significant impact on quality of life.5-9 It is highly prevalent in almost all countries and is one of the most common disorders seen by gastroenterologists worldwide.6, 10-17 There has been major paradigm shift in understanding of epidemiology, pathophysiology, diagnosis and management of IBS in the last decade.6, 18, 19 This chapter will review some aspects of advances in diagnosis and treatment of this disorder.

DIAGNOSIS OF IBS

IBS used to be considered as a diagnosis of exclusion earlier. However, Manning’s criteria brought a revolution in diagnosis of IBS as it brought a paradigm shift; Manning’s criteria (Table 1) encourage a positive diagnosis of IBS without the need of multiple unnecessary investigations to exclude organic diseases before diagnosing IBS.20 In the Manning’s criteria, the authors found fulfilling four of these criteria often turned out to have functional disorder such as IBS on subsequent investigations. However, one must remember that in this study organic

Uday C Ghoshal

disorders excluded included peptic ulcer, gastrointestinal malignancy and stricture. Hence, in true sense, fulfilling Manning’s criteria does not exclude other organic diseases such as lactose intolerance, celiac disease, microscopic colitis, small intestinal bacterial overgrowth, fecal evacuation disorder, collagenous colitis and microscopic etc.20 Other limitation of Manning criteria is lack of any consideration for duration of symptoms, which is important to exclude organic disorders, which are expected to present with short duration of symptoms.20 Currently, Rome IV criteria (Table 2), developed after several iterations through Rome I, II and III criteria, are used to diagnose IBS.21-23

ALARM FEATURES

There are certain alarm features in presence of which, one should especially look for organic diseases before labelling patients as IBS. These ‘red flags’ include age 45 years or older, presence of anemia, blood in the stools, unintended weight loss, nocturnal symptoms, fever, abdominal mass, and a family history of colorectal cancer. The relevance of these alarm features may vary in different regions of the world and also from patient to patient. The differential diagnosis of IBS symptoms (Table 3) is broad, which can lead to multiple, but often unnecessary, diagnostic tests.24, 25 It is the role of clinician to curtail the battery of tests as per the patient’s clinical history and examination. Various expert committees have given guidelines regarding investigations in a suspected case of IBS.24, 25 For clinical trials, all patients should have at least full blood counts, erythrocyte sedimentation rate, C-reactive protein, and limited colonoscopic examination, and other investigations, if indicated.24

RECENT ADVANCES IN DIAGNOSIS OF IBS

Diagnosis of IBS is popularly made by symptom-based

Table 2: Rome IV criteria1 Table 1: The Manning criteria • Onset of pain associated with more frequent bowel movements • Onset of pain associated with more loose bowel movements • Relief of pain with defecation • Abdominal distension • Sense of incomplete evacuation • Passage of mucus

Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, associated with 2 or more of the following criteria: 1. Related to defecation 2. Associated with a change in frequency of stool 3. Associated with a change in form (appearance) of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

GASTROENTEROLOGY

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Fig. 1: Bristol stool types and method of sub-typing of IBS according to Rome IV system. IBS subtypes should be established according to stool consistency, using the Bristol stool form scale. Whether 25% of the stools are constipating types (type I and II) or 25% of the stools are diarrheal types (type VI or VII) determine IBS subtypes according to Rome IV criteria. Table 3: Differential Diagnosis of IBS Symptoms

Table 4: Multi-dimensional clinical profile (MDCP)

• Celiac disease

• Categorical Rome diagnosis

• Food intolerance

• Additional information that sub-classifies the diagnosis leading to more specific treatment (e.g. diarrhea-predominant, constipation-predominant, pain-predominant etc. overlapping)

• Lactose intolerance • Inflammatory bowel disease (IBD) • Infective colitis • Small intestinal bacterial overgrowth (SIBO)

• The personal impact of the disorder on the patient (severity)

• Colonic diverticulosis

• Physiological abnormalities or biomarkers

• Colorectal carcinoma

• Psychological influences of the disorder

• Giardiasis criteria with reasonable investigation to exclude organic disorders. In a proportion of patients, clinical evaluation and evaluation of past medical records including available investigations may be sufficient. However, there is a paradigm shift in understanding the pathophysiology of IBS in the recent time. Emerging evidence suggest that a sub-set of IBS may have micro-organic basis such as gut dysbiosis including small intestinal bacterial overgrowth (SIBO), low grade inflammation, dietary intolerance, abnormal gut transit, prior gastrointestinal infection and infestation, abnormal intestinal permeability and neurohormonal dysregulation.26-31 Recognizing some of these pathophysiological abnormalities may have important therapeutic implications. For examples, patients with SIBO and IBS are expected to respond more often with antibiotic treatment than those without SIBO.32-34 Moreover, with recent introduction of the explanatory model, which requires explaining the specific abnormality responsible for the symptom generation and aggravation necessitate physician to first understand the pathophysiological basis of symptoms himself/herself. It is also important to understand that patients with less severe symptoms,

those with considerable psychological co-morbidity may not require such extensive investigations and specific treatment for a micro-organic cause. Considering all these, the Rome IV algorithm, brought a new dimension to management of IBS, the multi-dimensional clinical profile (MDCP).35 MDCP necessitate the physician to assess several important issues in addition to the categorical diagnosis of functional gastrointestinal disorders such as IBS (Table 4). Sub-typing (Figure 1) is absolutely essential to treat patients with IBS as drugs useful in one sub-type of disease (e.g. IBS-C) would be counter-productive in another sub-type.21 Moreover, those with alternating (change in symptoms over weeks to months) and mixed type is more difficult to treat and may require pathophysiology modifying measures such as attempt at manipulating gut microbiota. Severity assessment is another important aspect of MDCP as patient with mild disease may be managed with less aggressive approach than those with severe disease. Most clinicians try to assess severity of IBS to plan for

Table 5: Severity assessment for IBS Functional Bowel Disorder Severity Index (FBDSI)42 IBS Symptom Severity Score (IBS-SSS)43 Health-related quality of life (IBS-QOL)5 Hospital Anxiety and Depression Scale (HADS)44 IBS 3645

including the burden of illness. There are several factors which may influence the severity of IBS symptoms. First, whether the patient or doctor think that severity assessment is important? Difference in perception of severity of symptoms between physicians and patients is far greater in patients with functional bowel disorders than in patients with organic diseases. Type of scale used to assess severity may have impact on results. Similarly, the social background and literacy status of patient is also important. Finally, the degree of disability or impairment is another factor that will influence IBS severity.41 Perhaps due to so many issues involved in severity assessment of IBS symptoms, till date no single set of criteria is universally accepted. Table 5 summarizes some of the criteria used for assessment of severity of IBS.

TREATMENT

Multi-disciplinary approach is often required for optimal treatment. Besides the treating physician expert opinion from dietician and psychologist may also be required. It is often best to focus on the predominant symptom: diarrhea (Figure 2), constipation, or pain/gas/bloat and then treat accordingly (Table 6). Variable response rates have been reported for each of these drugs in various trials. This may be due to use

Table 6: Current symptom based management of IBS Symptom

First Line

Second Line

Future

Constipation

Fiber

Bisacodyl

Osmotic laxative including polyethylene glycol

Sodium picosulfate

Elobixibat (ileal bile acid transporter inhibitor)

Lactulose/Lactitol

Lubiprostone

Stool softner eg, docusate

Tegaserod (withdrwan) Linaclotide Prucalopride (5-HT4 agonist)

Diarrhea

Loperamide

Alosetron

Diphenoxylate

Ramosetron Ondasetron Bile acid sequestrant (cholestyramine, cholestipol) Rifaximin Clonidine

Bloating

Treat constipation

Probiotic Antibiotic (rifaximin)

Pain

Antispasmodics Anticholinergics Mebeverine Pinnaverium Otilonium bromide Antidepressant â&#x20AC;˘ Tricyclic anti-depressants â&#x20AC;˘ SSRI SNRI

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investigations and recommend treatment but quite often it is subjective. Few studies have addressed this issue and no consensus criterion for assessing severity assessment of IBS is available. Although neglected in the development of diagnostic criteria for IBS, recent studies have demonstrated the clinical importance of IBS severity. It has been observed that patients who self-reported their IBS as severe or very severe incurred greater indirect medical costs in the form of decreased productivity compared to patients who reported their IBS as mild or moderate.36,37 Besides cost, severity of IBS is also determines impairment of health related quality of life (HRQOL).38 It has been shown in many studies that patients with severe IBS had lower HRQOL scores and incurred more direct medical costs.5,39,40 These studies emphasize the importance of severity in IBS, especially QOL, and also have implications for public health,

GASTROENTEROLOGY

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Fig. 2: Abnormalities in luminal micro-environment in diarrhea-predominant IBS, that are used as therapeutic targets with different pharmacological agents. Abbreviation used: FMT: fecal microbiota transplant (currently in experimental stage)

Fig. 3: High and low Fermentable Oligo-, Di- and Monosaccharides and Polyols (FODMAP) foods of different inclusion criteria and also due to regional, dietary and cultural factors. Another important aspect is that in most of the trials significant proportion of the placebo response rates have been observed. Therefore, more trials are required for many of the therapies that claim on their efficacy in treatment of IBS. Initial treatment for patients with IBS should include various combinations of antispasmodic, laxative, and anti-diarrheal agents as they are quite safe and relatively inexpensive. Antispasmodics are effective when pain is the predominant symptom.46,47 Antispasmodics encompass several different drug classes, including anti-muscarinics, smooth-muscle relaxants and anticholinergics. Common side effects, including dry mouth, dizziness, blurry vision, confusion (particularly in elderly patients), urinary retention, and constipation, often limit the usefulness of these agents in the treatment of IBS. The propensity of these agents to promote constipation makes them a less attractive option for patients with IBS-C. Bulking

agents are another group of commonly prescribed drugs especially for IBS-C. Evidence for this group of agents in IBS is surprisingly lacking. Moreover, they may even aggravate abdominal pain and bloating.46, 47 For the control of diarrhea, loperamide has the best quality of evidence, but has not been shown to improve abdominal pain or distension.48,49 Recently, a few drugs have been used in treatment of IBS which target serotonin receptors (Aloseteron, tegaserod, prucalopride).31,50 The major concern with some of these agents (e.g. tegaserod) has been the cardiovascular side-effects limiting their utility. Besides the above-mentioned peripherally acting agents, there are a quite a few centrally-acting therapies for IBS. Antidepressants (tricyclic anti-depressants and SSRI) have been shown to have efficacy in IBS even in absence of any psychiatric illness.51-53 Both group of anti-depressants were found to be equally effective. They act at multiple levels in IBS, such as by altering pain perception, by improving sleep, and by improving

Recently, rifaximin has been evaluated for treatment of IBS without constipation (TARGET 1 and Target 2).57 Rifaximin is a poorly absorbed antibiotic with broadspectrum activity against Gram-negative bacteria, Gram positive bacteria, and anaerobes. In these trials, 41% patients with IBS reported improvement with two-weeks course of rifaximin as compared to 30% in placebo arm. Symptoms recur in most patients within 2-3 months after therapy. Long term symptom relief with this antibiotic is still not known. Also no attempt was made to test for SIBO in this study. However, in spite of these limitations, this study is important as it brings a novel concept of treating a “functional disorder”, which is now believed to result from altered gut microbiota, with antibiotic. Lastly, dietary modifications have also been tried in IBS. Many people complain of adverse reactions to specific food. Gastrointestinal symptoms are the commonest manifestations of food intolerance. Studies from West show that dairy products and cereals are most important food items which aggravate the symptoms of IBS.58 In Asian countries, chilli and curry are the possible food triggers for pain in patients with IBS.59 Lactose intolerance has been found to be equally common in IBS and healthy controls but patients with IBS complain of symptoms more commonly following the lactose load.60 Similarly, some investigators have studied fructose intolerance in IBS.61 Presently, the role of fructose malabsorption in IBS is less understood. Recently, a new concept of dietary management of functional gastrointestinal symptoms “FODMAP approach” has been introduced (Figure 3).62 FODMAP stands for fermentable olio-di-monosacchrides and polyols. Basically, these consist of a group of rapidly fermentable short chain carbohydrates. Dietary FODMAPs induce prolonged hydrogen production in the intestine that is greater in IBS, influence the amount of methane produced, and induce gastrointestinal and systemic symptoms experienced by patients with IBS.63 In view of these dietary triggers involved in generation of symptoms in some patients with IBS, it is necessary to take detailed dietary history including excessive consumption of dairy and lactose-rich products, dietary fibres (especially in the form of bran or other cereals), and fructose or fructan-rich foods. Elimination of

high FODMAP foods and encouragement to use low FODMAP foods may help in improving symptoms of IBS, particularly abdominal bloating.

289

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Sanders DS. Celiac disease and IBS-type symptoms: the relationship exists in both directions. Am J Gastroenterol 2003; 98:707-8.

Barbara G, Feinle-Bisset C, Ghoshal UC, Quigley EM, Santos J, Vanner S, Vergnolle N, Zoetendal EG. The Intestinal Microenvironment and Functional Gastrointestinal Disorders. Gastroenterology 2016.

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Gwee KA. Irritable bowel syndrome in developing countries--a disorder of civilization or colonization? Neurogastroenterol Motil 2005; 17:317-24.

Levy RL, Von Korff M, Whitehead WE, Stang P, Saunders K, Jhingran P, Barghout V, Feld AD. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastroenterol 2001; 96:3122-9.

Vandvik PO, Wilhelmsen I, Ihlebaek C, Farup PG. Comorbidity of irritable bowel syndrome in general practice: a striking feature with clinical implications. Aliment Pharmacol Ther 2004; 20:1195-203.

Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology 2002; 122:1140-56.

10. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123:2108-31. 11. Gaburri M, Bassotti G, Bacci G, Cinti A, Bosso R, Ceccarelli P, Paolocci N, Pelli MA, Morelli A. Functional gut disorders and health care seeking behavior in an Italian non-patient population. Recenti Prog Med 1989; 80:241-4. 12. Gwee KA, Lu CL, Ghoshal UC. Epidemiology of irritable bowel syndrome in Asia: something old, something new, something borrowed. J Gastroenterol Hepatol 2009; 24:16017. 13. Ghoshal UC, Abraham P, Bhatt C, Choudhuri G, Bhatia SJ, Shenoy KT, Banka NH, Bose K, Bohidar NP, Chakravartty K, Shekhar NC, Desai N, Dutta U, Das G, Dutta S, Dixit VK, Goswami BD, Jain RK, Jain S, Jayanthi V, Kochhar R, Kumar A, Makharia G, Mukewar SV, Mohan Prasad VG, Mohanty A, Mohan AT, Sathyaprakash BS, Prabhakar B, Philip M, Veerraju EP, Ray G, Rai RR, Seth AK, Sachdeva A, Singh SP, Sood A, Thomas V, Tiwari S, Tandan M, Upadhyay R, Vij JC. Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol 2008; 27:22-8. 14. Masud MA, Hasan M, Khan AK. Irritable bowel syndrome in a rural community in Bangladesh: prevalence, symptoms

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any associated psychological illness.54 Another unique approach of treating IBS is psychotherapy. Aims of psychotherapy include reframing maladaptive beliefs, reduction of over-responsiveness to stress, reduction of maladaptive psychological responsiveness and modification of maladaptive behaviors.54 The specific content of the therapy is based on a biopsychosocial assessment of the patient’s background and current difficulties. Hypnotherpay is one of the important tools in psychotherapy.55 The essence of hypnotherapy is to create a relaxing and calming environment and allowing the patient to refocus away from uncomfortable symptoms and towards a more pleasant perception of his or her current state. There is little evidence for efficacy of such an approach in IBS.56 Major drawback of hypnotherapy is requirement of a well-trained mental health professional.

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pathophysiology, and treatment. Expert Rev Gastroenterol Hepatol 2014; 8:435-43.

15. Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology 1990; 99:409-15.

32. Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2013; 38:925-34.

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16. Talley NJ, Zinsmeister AR, Melton LJ, 3rd. Irritable bowel syndrome in a community: symptom subgroups, risk factors, and health care utilization. Am J Epidemiol 1995; 142:76-83. 17. Ghoshal UC, Singh R. Frequency and risk factors of functional gastro-intestinal disorders in a rural Indian population. J Gastroenterol Hepatol 2016. 18. Gwee KA. Defining IBS in India: a brave new world. Indian J Gastroenterol 2008;27:3-4. 19. Gerson CD, Gerson MJ, Awad RA, Chowdhury A, Dancey C, Poitras P, Porcelli P, Sperber A, Wang WA. Irritable bowel syndrome: an international study of symptoms in eight countries. Eur J Gastroenterol Hepatol 2008;20:659-67. 20. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2:653-4. 21. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130:1480-91. 22. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920-4. 23. Gwee KA, Ghoshal UC. The Rome criteria divides, distorts and dilutes the prevalence of irritable bowel syndrome. Saudi J Gastroenterol 2010; 16:143-4. 24. Gwee KA, Bak YT, Ghoshal UC, Gonlachanvit S, Lee OY, Fock KM, Chua AS, Lu CL, Goh KL, Kositchaiwat C, Makharia G, Park HJ, Chang FY, Fukudo S, Choi MG, Bhatia S, Ke M, Hou X, Hongo M. Asian consensus on irritable bowel syndrome. J Gastroenterol Hepatol 2010; 25:1189-205. 25. Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, Talley NJ, Quigley EM. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104:S135. 26. Shukla R, Ghoshal U, Dhole TN, Ghoshal UC. Fecal Microbiota in Patients with Irritable Bowel Syndrome Compared with Healthy Controls Using Real-Time Polymerase Chain Reaction: An Evidence of Dysbiosis. Dig Dis Sci 2015. 27. Srivastava D, Ghoshal U, Mittal RD, Ghoshal UC. Associations between IL-1RA polymorphisms and small intestinal bacterial overgrowth among patients with irritable bowel syndrome from India. Neurogastroenterol Motil 2014; 26:1408-16. 28. Ghoshal UC, Shukla R, Ghoshal U, Gwee KA, Ng SC, Quigley EM. The gut microbiota and irritable bowel syndrome: friend or foe? Int J Inflam 2012; 2012:151085. 29. Osadchuk MA, Burdina VO. [Irritable bowel syndrome with extraintestinal manifestations from a position of neuroendocrine pathology]. Eksp Klin Gastroenterol 2015; 29-34. 30. Ohman L, Tornblom H, Simren M. Crosstalk at the mucosal border: importance of the gut microenvironment in IBS. Nat Rev Gastroenterol Hepatol 2015; 12:36-49. 31. El-Salhy M, Hatlebakk JG, Gilja OH, Hausken T. Irritable bowel syndrome: recent developments in diagnosis,

33. Ford AC, Spiegel BM, Talley NJ, Moayyedi P. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2009; 7:1279-86. 34. Ghoshal UC, Srivastava D, Misra A, Ghoshal U. Randomized double-blind placebo-controlled trial of antibiotic treatment in patients with irritable bowel syndrome directed against small intestinal bacterial overgrowth diagnosed using upper gut aspirate culture. Neurogastroenterol Motil (submitted). 35. Drossman DA. Guidelines for use of the multi-dimensional clinical profile. In: Multi-dimensional clinical profile (MDCP) for the functional gastrointestinal disorders (1st Edition). North Carolina; Rome Foundation 2015:7-14. 36. Hahn BA, Kirchdoerfer LJ, Fullerton S, Mayer E. Patientperceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life. Aliment Pharmacol Ther 1997; 11:553-9. 37. Longstreth GF, Wilson A, Knight K, Wong J, Chiou CF, Barghout V, Frech F, Ofman JJ. Irritable bowel syndrome, health care use, and costs: a U.S. managed care perspective. Am J Gastroenterol 2003; 98:600-7. 38. Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, Whitehead WE, Janssens J, Funch-Jensen P, Corazziari E, et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993; 38:1569-80. 39. Drossman DA, Whitehead WE, Toner BB, Diamant N, Hu YJ, Bangdiwala SI, Jia H. What determines severity among patients with painful functional bowel disorders? Am J Gastroenterol 2000; 95:974-80. 40. Coffin B, Dapoigny M, Cloarec D, Comet D, Dyard F. Relationship between severity of symptoms and quality of life in 858 patients with irritable bowel syndrome. Gastroenterol Clin Biol 2004; 28:11-5. 41. Reilly MC, Bracco A, Ricci JF, Santoro J, Stevens T. The validity and accuracy of the Work Productivity and Activity Impairment questionnaire--irritable bowel syndrome version (WPAI:IBS). Aliment Pharmacol Ther 2004; 20:459-67. 42. Drossman DA, Li Z, Toner BB, Diamant NE, Creed FH, Thompson D, Read NW, Babbs C, Barreiro M, Bank L, et al. Functional bowel disorders. A multicenter comparison of health status and development of illness severity index. Dig Dis Sci 1995; 40:986-95. 43. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 1997; 11:395-402. 44. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361-70. 45. Groll D, Vanner SJ, Depew WT, DaCosta LR, Simon JB, Groll A, Roblin N, Paterson WG. The IBS-36: a new quality of life measure for irritable bowel syndrome. Am J Gastroenterol 2002; 97:962-71. 46. Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel

syndrome. Aliment Pharmacol Ther 1994; 8:499-510. 47. Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and metaanalysis. BMJ 2008;337:a2313. 48. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci 1984; 29:239-47. 49. Efskind PS, Bernklev T, Vatn MH. A double-blind placebocontrolled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996; 31:463-8.

51. Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and metaanalysis. Gut 2009; 58:367-78. 52. Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol 2004; 99:914-20. 53. Masand PS, Gupta S, Schwartz TL, Kaplan D, Virk S, Hameed A, Lockwood K. Does a preexisting anxiety disorder predict response to paroxetine in irritable bowel syndrome? Psychosomatics 2002; 43:451-5. 54. Grover M, Drossman DA. Centrally acting therapies for irritable bowel syndrome. Gastroenterol Clin North Am 2011; 40:183-206.

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56. Webb AN, Kukuruzovic RH, Catto-Smith AG, Sawyer SM. Hypnotherapy for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2007:CD005110. 57. Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364:22-32. 58. Nanda R, James R, Smith H, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut 1989; 30:1099-104. 59. Gonlachanvit S, Mahayosnond A, Kullavanijaya P. Effects of chili on postprandial gastrointestinal symptoms in diarrhoea predominant irritable bowel syndrome: evidence for capsaicin-sensitive visceral nociception hypersensitivity. Neurogastroenterol Motil 2009; 21:23-32. 60. Gupta D, Ghoshal UC, Misra A, Choudhuri G, Singh K. Lactose intolerance in patients with irritable bowel syndrome from northern India: a case-control study. J Gastroenterol Hepatol 2007; 22:2261-5. 61. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management. J Am Diet Assoc 2006; 106:1631-9. 62. Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol 2010;25:2528. 63. Ong DK, Mitchell SB, Barrett JS, Shepherd SJ, Irving PM, Biesiekierski JR, Smith S, Gibson PR, Muir JG. Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. J Gastroenterol Hepatol 2010; 25:1366-73.

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50. Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009; 104:1831-43; quiz 1844.

55. Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome. Lancet 1984; 2:1232-4.

C H A P T E R

Making a Positive Diagnosis of Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is amongst most common clinical condition presenting to physicians and gastroenterologists in day to day clinical practice. While IBS is not a life threatening disease, it leads to considerable expenditure and effects quality of life. It is thus important to have a basic knowledge of IBS so that patients can be given effective treatment and excessive futile investigations can be prevented.

DIAGNOSTIC CRITERIA

Various diagnostic criteria have been proposed to diagnose IBS. The first proposed criteria were Manning’s followed by Rome 1, Rome 2, Rome 3 and recently Rome 4 criteria (Box 1). Besides, an Asian consensus was also

Box 1: Diagnostic Criteria Manning’s criteria Includes any four of the following: a. Abdominal pain that is relieved with a bowel movement b. Pain associated with looser stools c. Pain associated with more frequent stools d. Sensation of incomplete evacuation e. Passage of mucus f. Abdominal distention No symptom duration is specified in Manning’s criteria Rome 4 Criteria: Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, associated with 2 or more of the following criteria: 1. Related to defecation 2. Associated with a change in frequency of stool 3. Associated with a change in form (appearance) of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. ASIAN consensus Recurrent abdominal pain, bloating, or other discomfort for ≥3 months associated with one or more of the following: a. Relief with defecation b. Change in stool form (show patient the Bristol Stool Scale) c. Change in stool frequency

Ujjwal Sonika, Vineet Ahuja

proposed in 2010 to account for cultural and linguistic differences between the west and Asia region.

CHANGES IN THE RECENT ROME 4 CRITERIA

In contrast to the earlier Rome III criteria, the term discomfort has been eliminated because not all languages have a word for “discomfort,” it has different meanings in different languages, and the term is ambiguous to patients. The current definition also involves a change in the frequency of symptoms; stating that patients should have abdominal pain at least 1 day per week during the past 3 months. This is in contrast to Rome III criteria, which defined IBS as the presence of abdominal pain (and discomfort) at least 3 days per month. Another notable change is that the phrase “improvement with defecation” has been modified to “related to defecation” as a large subset of IBS patients do not have an improvement in abdominal pain with defecation, but instead report a worsening. Similarly, the word onset was deleted from criteria 2 and 3 of the Rome III definition, as not all IBS patients report the onset of abdominal pain directly coinciding with a change in stool frequency or form.

DIFFERENCES BETWEEN ASIAN CONSENSUS AND ROME CRITERIA

The Asian consensus which was published in 2010 provided some very important insights which can be used in clinical practice. The most important difference is that Asian consensus also recognizes bloating as an IBS symptom apart from abdominal pain and discomfort. There is a common perception among clinicians that bloating is a symptom of an upper GI disorder. But in a review of Asian IBS series; it was found that bloating occurs almost as commonly as abdominal pain, and is an important reason for consultation. Another issue which has been recognized in Asian consensus is the site of abdominal pain or discomfort. It is noted that patient with IBS may not necessarily present with lower abdominal pain but instead a large proportion of them present with upper abdominal pain. The site of abdominal pain or discomfort is not included as a criterion in either Rome or Asian statement, but it is important to recognize that IBS patients can present with upper abdomen symptoms also. In a study from Taipei, more than 50 % of patients who were diagnosed initially

Table 1: Frequency of IBS using the Manning, Rome I, Rome II, and Rome III, and Asian criteria in patients with lower functional gastrointestinal disorder (n=1,618) in MIIBS study Diagnostic Criteria

Positive (%)

Negative (%)

Manning

1476 (91.2)

142 (8.8)

Rome 1

1098 (67.9)

520 (32.1)

Rome 2

649 (40.1)

969 (59.9)

Rome 3

849 (52.5)

769 (47.5)

Asian

1206 (74.5)

412 (25.5)

as functional dyspepsia based on upper abdominal discomfort were later found to have IBS. Thus, it is not advisable to exclude a diagnosis of IBS on the basis of site of abdominal pain. Rather it is necessary to ask about the relation of such symptoms with bowel movements and change in bowel habits (either a change in stool form or frequency) to determine the intestinal origin of symptoms.

APPLICABILTIY IN INDIAN SCENARIO

A multicentre study by Ghoshal et al compared Manning’s, Rome 1, Rome 2, Rome 3 and Asian consensus

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Recurrent abdominal pain, bloating, or other discomfort for ≥ 3 months associated with 1 or more of the following: • Related with defecation • Change in stool form (show patient the Bristol Stool Scale) • Change in stool frequency

ALARM FEATURES Patient age 45 years or older Blood in stools Unintended weight loss Nocturnal symptoms Fever Family history of colorectal caner • Presence of anemia • • • • • •

Yes

No Normal physical examinationa

Investigate/Refer to Gastroenterologist

Yes Irritable Bowel Syndrome

Subtype

(Based on stool form) Show Bristol stool chart to patientb

IBS – D More than 25% bowel movements are diarrhoea and less than 25 % are constipation

293

IBS – C More than 25 % bowel movements are constipation and less than 25 % are diarrhoea

IBS – M

More than 25 % bowel movements are constipation and more than 25 % are diarrhoea

IBS – U Not able to classify in any type

a, limited investigation in the form of complete blood count and ESR/CRP or fecal calprotectin has been recommended in Rome 4 statement b, Bristol stool form1-3: constipation; 5-7: diarrhea

Fig. 1: Algorithm for diagnosis and subtyping of IBS

GASTROENTEROLOGY

294

criteria for diagnosing IBS and found Manning’s criteria to be most sensitive in Indian patients. Rome 2 criteria were found to be least sensitive. Asian criteria identified the most number of patients after Manning’s (Table 1). The better performance of Manning’s and Asian criteria highlights that recognition of bloating as an IBS symptom. Based on this study, we can say that Manning’s and Asian consensus criteria are better suited for Indian patients in routine clinical practice. However, for the purpose of patient identification in IBS trials; the current Rome criteria which are most widely used should be applied.

MAKING THE DIAGNOSIS

We now know that multiple criteria have been proposed for the diagnosis of IBS and their major drawbacks and advantages. But these criteria are not routinely used in clinical practice as has been shown in both European as well as Asian studies. In Hong Kong, it was reported that only 21% of patients who fulfilled IBS criteria had received the diagnosis when seen by their medical practitioners. The key to diagnose IBS is to determine that the bowel is the site of origin of symptoms. The relation of abdominal pain or discomfort or bloating to bowel movements or change in stool frequency or consistency indicates that these symptoms are due to intestinal disease. A detailed history pertaining to alarm features and a through physical examination are also essential for diagnosis. Physical examination helps in excluding organic diseases and also builds patient-physician relationship which is the most important factor in successful treatment of these patients. Even in the absence of fulfillment of the criteria; a diagnosis of IBS can be made if it can be confidently established that symptoms are of bowel origin through proper history, absence of alarm features, normal physical examination and normal minimal investigations (if required). Based on this premise, we propose an algorithm which is easy to use in routine clinical practice to achieve a diagnosis of IBS (Figure 1).

IDENTIFICATION OF IBS SUBTYPE

Four subtypes of IBS are proposed: IBS –D (diarrhea predominant), IBS –C (constipation predominant), IBS-M (Mixed) and IBS –U (Unclassified). The subtypes were initially identified on the basis of stool frequency. But the sub typing of IBS using stool frequency is based on western habits and is often incorrect in Indian setting. Indian patients with constipation often report to have 1-2

bowel movements per day. In the Indian community, less than 1% of patients had stool frequencies of fewer than three per week, while among IBS patients, the median stool frequency was twice a day, regardless of whether they had constipation or diarrhea. Ghoshal et al identified that stool form (by Bristol stool chart) and patients’ own characterization of their disease are better methods for identification of IBS subtype rather than stool frequency. Rome 4 criteria also identify IBS subtype by stool form. Subtyping is necessary as it helps in making decisions regarding initial treatment.

TAKE HOME MESSAGE

It is necessary to make a diagnosis of IBS to start appropriate treatment and prevent unnecessary investigations.

Abdominal bloating is a common symptom of IBS, especially in Asian patients.

Upper abdominal symptoms do not necessarily rule out the diagnosis of IBS.

Diagnosis of IBS requires that symptoms are of bowel origin, absence of alarm features, and normal physical examination.

Minimal investigations may be required in a subset of patients in the form of blood counts and inflammatory markers (ESR/ CRP/ Fecal calprotectin).

6. Detailed investigations and colonoscopy is required only in the presence of alarm features or abnormalities on initial investigations. 7.

Subtyping should be done based on stool form, to guide initial treatment.

REFERENCES

Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R. Bowel Disorders. Gastroenterology 2016; 16:2225.

Gwee KA, Bak YT, Ghoshal UC, Gonlachanvit S, Lee OY, Fock KM et al. Asian consensus on irritable bowel syndrome. J Gastroenterol Hepatol 2010; 25:1189-205.

Ghoshal UC, Abraham P, Bhatia SJ, Misra SP, Choudhuri G, Biswas KD et al. Comparison of Manning, Rome I, II, and III, and Asian diagnostic criteria: report of the Multicentric Indian Irritable Bowel Syndrome (MIIBS) study. Indian J Gastroenterol 2013; 32:369-75.

C H A P T E R

Chronic Diarhoea – An Approach

INTRODUCTION

Diarrhoea is a common human experience. The word diarrhoea originates from the Greek terms dia (through) and rhein (to flow).For many, episodes of diarrhea last a day or 2 and rapidly subside without medical intervention. While for few others, diarrhoea will last for more than a few days or is complicated by fever, prostration, or rectal bleeding. Diarrhoea lasting for more

Swaroop Kumar Baruah, Suman Talukdar

than 4 weeks is termed as chronic diarrhoea. An acute diarrhoeal episode occurs once in every 18 months in an individual in developed countries. Chronic diarrhoea can occur in 3–5% of the population in any given year. Diarrhoea is defined as the passage of abnormally liquid or unformed stools at an increased frequency, i.e. more than three times in a 24 hour period. In Western populations,

Table 1: Classification of Chronic Diarrhoea 1. Osmotic

4. Inflammatory

• Medications

• Inflammatory bowel disease: Ulcerative colitis, Crohn’s disease,Microscopic colitis

Laxatives (Mg SO4, PO4), elixirs

• Undigested sugars

Diet foods/drinks/gum (sorbitol, mannitol, others); Enzyme dysfunction (e.g. lactose, fructose)

2. Secretory • Medications

Non-osmotic laxatives, antibiotics

• Small intestinal bacterial overgrowth • Endocrine:

• Malignancy: colon cancer, lymphoma • Radiation colitis/enteritis • Mastocytosis

Invasive or inflammatory infections: C.difficile, Cytomegalovirus, E.histolytica, Tuberculosis

• Ischemia 5. Motility disorders • Post-surgical (vagotomy, dumping)

Tumors: Carcinoid, Gastrinoma, Medullary thyroid cancer, VIPoma

• Scleroderma

Systemic: adrenal insufficiency, hyperthyroidism

• Hyperthyroidism

• Diabetes mellitus

• Bile salt malabsorption (ileal resection, idiopathic, postcholecystectomy)

6. Miscellaneous

• Non-invasive infections: Giardiasis, Cryptosporidiosis

• Functional diarrhoea

3. Steatorrhoea • Maldigestion

Decreased bile salts (cirrhosis, bile duct obstruction, ileal resection)

Pancreatic dysfunction (chronic pancreatitis, cystic fibrosis, ductobstruction)

• Malabsorption

Celiac sprue, Tropical sprue, Giardiasis, Whipple’s disease

Chronic mesenteric ischemia

Short bowel syndrome

Bacterial overgrowth (diabetes mellitus, scleroderma, prior bowel surgery)

Lymphatic obstruction

• Irritable bowel syndrome • Factitious

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Table 2: Drugs Causing Diarrhoea More Common Antacids, PPI Cephalosporins, Clindamycin, Ampicillin, Amoxycillin, Erythromycin Colchicine

GASTROENTEROLOGY

Metformin Non-steroidal anti-inflammatory drugs, 5-aminosalicylates Cholesterol-lowering agents (Clofibrate, Gemfibrozil, Lovastatin) Anti Neoplastic drugs Less common Angiotensin converting enzyme inhibitor Angiotensin receptor blocking agents Beta-adrenergic receptor antagonists, other antiarrhythmics Carbamazepine Lithium Vitamin and mineral supplements daily faecal weight does not exceed 200g, but in Indians this figure is somewhat higher and up to 400g per day may be acceptable.

CLASSIFICATION OF CHRONIC DIARRHOEA

The list of differential diagnosis for chronic diarrhoea is extensive. Depending on the Patho physiology, chronic diarrhoea can be broadly classified into six categories. Osmotic diarrhoea is suspected in a patient whose diarrhoea occur after meals but resolves with fasting. Secretory diarrhoea is suggested in a patient with large-volume watery diarrhoea which is painless and that persists even after fasting. It can be confirmed by demonstrating an increase in stool volume in absence of increased osmotic gap. Steatorrhoea is suggested by the occurrence of greasy or oily stools that have an offensive odour and float on the toilet water. Steatorrhoea can be confirmed by stool analysis. Quantitatively, steatorrhoea is defined as stool fat exceeding the normal 7 g/day. The presence of blood or pus in the stools, pain abdomen and fever is suggestive of inflammatory diarrhoea. It can be confirmed by the demonstration of leukocytes in stool or leukocyte proteins (such as lactoferrin or calprotectin), or by the visualisation of inflammatory changes in the colonic mucosa by endoscopy and biopsy. Inflammatory bowel disease, may have extra intestinal manifestation like uveitis, polyarthralgia, erythema nodosum etc. Microscopic colitis mostly occur in middleaged women and those on NSAIDs, statins, PPIs and SSRIs. Biopsy of a normal appearing colon is required for histologic diagnosis.

Motility disorders cause diarrhoea through either increased GI transit (e.g. post-vagotomy diarrhoea) or by slowing transit, thereby predisposing to small intestinal bacterial overgrowth (e.g. scleroderma). Diabetic diarrhoea may result from abnormal gut motility due to autonomic neuropathy, bacterial overgrowth and bile salt malabsorption. Irritable bowel syndrome (IBS) and functional diarrhoea are the common causes of chronic diarrhoea in Western countries. IBS is defined by the Rome Committee as a chronic condition characterized by abdominal pain and altered bowel habits; the pain characteristically is in association with a change in stool form or frequency, and is relieved by defaecation. Functional diarrhoea is defined as recurrent or continuous passage of loose or watery stools without abdominal pain or discomfort. Factitial diarrhoea accounts for up to 15% of unexplained diarrhoeas referred to tertiary care centers. It can occur as a part of Munchausen syndrome. Some patients may self-administer laxatives or adulterate the stool sample with water or urine to increase its volume.

CLINICAL APPROACH TO CHRONIC DIARRHOEA

History and examination-

A detailed history and thorough examination are crucial in the work up of patients with chronic diarrhoea. IBS commonly occur in the third and fourth decade, AIDSrelated diarrhoea is common in younger patients whereas the peak incidence of microscopic colitis is in the seventh and eighth decade of life. Colon cancer should be excluded in a patient with new onset of diarrhoea over the age of 50 years. IBS and microscopic colitis are more common in females. The presence of lymphadenopathy or significant weight loss could suggest chronic infection or malignancy. Family history is important in cases of inflammatory bowel disease, coeliac disease or neoplastic diseases. History and clinical examination should exclude systemic diseases like thyrotoxicosis, diabetes mellitus, parathyroid and adrenal disease which may cause chronic diarrhoea through various mechanisms. A detailed drug history should be obtained in all patients. History of alcohol abuse is important. Alcohol can cause diarrhoea by increasing gut motility, reducing activity of intestinal disaccharidases and decreased pancreatic function. The presence of malabsorption is usually evident by steatorrhoea which include pale, bulky malodorous stool. Fat laden stools float, are sticky and difficult to flush away. Patients with IBS have erratic stool pattern. Patientsâ&#x20AC;&#x2122; complain of abdominal cramps accompanied by either with diarrhoea or constipation. Abdominal pain is often relieved by defaecation. The symptoms of IBS as defined by the Rome IV criteria include recurrent abdominal pain that is present at least three days per month in the last three months, associated with a change in stool frequency or form which improves with defecation. Psychiatric symptoms like anxiety and depression are frequently associated with IBS and may be present in upto 67% cases.

Table 3: Physical Finding in Some of the Causes of Chronic Diarrhoea Findings

Implications

Muscle wasting, oedema -- Malnutrition Urticaria pigmentosa, dermatographism --

Mast cell disease (mastocytosis)

Pinch purpura, macroglossia --

Amyloidosis

Hyperpigmentation --

Glucagonoma

Malignant atrophic papulosis Dermatitis herpetiformis-Thyroid nodule, lymphadenopathy -Tremor, lid lag-Right-sided murmur, wheezing,flushing -Hepatomegaly -Arthritis -Lymphadenopathy-Abdominal bruit -Anal sphincter weakness--

Kohlmeier-Degos disease

Whipple’s disease - Normal calibre; thick, wild fold pattern; patchy micronodularity Scleroderma - Dilated, esp. duodenum; delayed peristalsis, hypomotility Lymphoma - Variable calibre; coarse folds; wall infiltrated, stiff; extraluminal masses; micronodularity Amyloidosis- Normal caliber; symmetrical fold thickening, no oedema; stiff walls; micronodularity

Medullary carcinoma of the thyroid

Lymphangiectasia- Increased luminal fluid; thick, oedematous folds

Hyperthyroidism

Crohn’s disease - Stenotic (string sign); deformed/ thickened folds; rigidity/ulceration of walls;

Endocrine tumor, amyloidosis Inflammatory bowel disease, yersinosis HIV, lymphoma, cancer Chronic mesenteric ischemia Faecal incontinence

Crohn’s disease is associated with pain in the right iliac fossa, while patients with malabsorption complain of dull, poorly localized abdominal discomfort. The presence of blood in stool necessitates further examination, usually by colonoscopy, although minor bleeding because of trauma is common in all diarrhoeal diseases. Dietary history is important to identify foods which may cause diarrhoea. Increased consumption of wheat fibre and certain fruits (grapes, plums, mangos, and cherries) can cause diarrhoea. Lactose is a disaccharide present in milk and is a common cause of diet induced diarrhoea. Diarrhoea due to lactose intolerance occurs if the patient consumes more than 12 g/day (240 ml of milk or its equivalent in other dairy foods). Physical examination should include evidence of weight loss, signs of malnutrition, anaemia, clubbing, or lymphadenopathy. Rectal examination is useful to exclude local tenderness that might suggest Crohn’s disease and rectal tone to rule out any sphincter defect which can cause incontinence. Moreover, it is important to differentiate between small and large bowel diarrhoea. In small bowel involvement, usually the frequency is less than 4 per day, large volume, bulky, frothy and greasy. In large bowel involvement, the frequency is more than 4 with small volume. Blood, mucous, pus may be present.

LABORATORY WORK-UP TO EVALUATE CHRONIC DIARRHEA

Routine Blood tests

Celiac disease - Dilated calibre; increased fluid; thin, effaced folds (moulage), segmentation of barium column, painless intussusception

Celiac disease

Carcinoid syndrome

Complete blood count, serum albumin, erythrocytes

297

Sometimes extraluminal mass Dysgammaglobulinemia- Increased luminal fluid; nodular lymphoid hyperplasia Giardiasis- Dilated duodenum; thick duodenal folds; spasm, rapid transit Zollinger–Ellison Syndrome - Dilated duodenum; thick duodenal folds; peptic ulcer; reticulated pattern Cystic fibrosis - Thick folds; nodularity in duodenum Abetalipoproteinemia- Fine mucosal graininess Mastocytosis- Thick gut wall; mucosal nodularity sedimentation rate, liver and kidney function tests, blood glucose and electrolytes. The presence of iron deficiency anaemia may indicate Coeliac disease.

Serological tests

Immunoglobulin A (IgA) anti-TTG is the preferred single test for detection of celiac disease in individuals over the age of 2 years. Total serum IgA should be measured at the same time to rule out IgA deficiency that might cause a falsely negative test. Anti- Saccharomyces cerevisiae antibodies are measured to diagnose IBD.

Stool examination

Fecal electrolytes can help to differentiate between osmotic and secretory diarrhoea. It is based on calculation of the osmotic gap. The stool osmotic gap: serum osmolarity (typically 290 mosmol/kg) - (2 x [fecal sodium + potassium concentration]). A faecal osmotic gap of < 50 mosmol/kg indicates a secretory diarrhoea while a gap of > 75 mOsm/kg indicates an osmotic diarrhoea.A low fecal pH (<7.0) ) is suggestive of carbohydrate malabsorption. Leucocyte enzyme, lactoferrin or calprotectin are used as surrogate markers of faecal leukocytes to diagnose mucosal inflammation. Fecal calprotectin has been found to be more sensitive.

CHAPTER 63

Migratory necrotizing erythema --

Addison’s disease

Table 4: Small Bowel Radiography

298

Imaging tests

A plain abdominal radiograph showing pancreatic calcifications is diagnostic of chronic pancreatitis. Barium studies have been used extensively in the past in the diagnosis of chronic diarrhoea. With the introduction of abdominal CT scans, the role of barium studies has become limited.

GASTROENTEROLOGY

CT and magnetic resonance enterography

CT and magnetic resonance (MR) enterography are useful in the diagnosis of chronic diarrhoea because of small bowel Crohn’s disease, eosinophilic gastroenteritis and in the detection of small bowel tumors, such as carcinoids.

Nuclear medicine imaging

Radio ligand scintigraphy is useful in detecting neuroendocrine tumors that express somatostatin receptors, such as gastrinomas and carcinoid tumors. SPECT-CT provides better localization of these tumours.

Endoscopy

Colonoscopy with biopsy is helpful for the diagnosis of IBD, neoplasia and microscopic colitis. Upper GI Endoscopy and duodenal biopsy can confirm a diagnosis of celiac disease. Duodenal biopsy may also aid in diagnosis of giardiasis and other protozoal infections and Whipple’s disease. Upper endoscopy also helps in collection of duodenal aspirate for quantitative for a diagnosis of small intestinal bacterial overgrowth.

Colorectal and terminal ileal biopsy

Colonoscopy and biopsy have a significant role in diagnosing conditions like IBD, microscopic colitis, inflammatory conditions and neoplasia. Multiple studies have evaluated the role of colonoscopy stating the yield of specific diagnoses of chronic diarrhoea in 15 – 31%.

Breath tests

Hydrogen Breath Tests (HBT) The breath tests help in diagnosing carbohydrate malabsorption and small intestinal overgrowth. However, the sensitivity and specificity however varies widely.

Pancreatic function tests

The standard secretin stimulation test is rarely used now a days whereas the modified endoscopic secretin stimulation test done using ERCP has limited diagnostic yield. Various other tests for pancreatic function include serum trypsin, faecal chymotrypsin and faecal elastase which again show limited utility in mild insufficiency. Pancreatic imaging using endoscopic ultrasound and MRI is used invariably to detect abnormal anatomy.

Bacteriology/Microbiology

In developing countries chronic bacterial, mycobacterial, and parasitic infections are common. Additionally some clinical situations require extensive search for a source of infection in case of diarrhoea of chronic origin. They include diarrhoea in immigrants from endemic areas, immunocompromised subjects, patients with HIV/ AIDS infection, men who have sex with men, and in individuals with chronic travellers’ diarrhoea. Giardiasis, amebiasis,

yersinosis, and C. difficile infections are frequent causes of chronic diarrhoea in immunocompetent hosts. Strongyloides is occasionally seen but is quite unusual. These five pathogens should be sought in such patients. Giardia is most reliably detected with a stool enzymelinked immunosorbent assay (ELISA) assay. Amoeba and Strongyloides are sought with serological tests and stool examination for ova and parasites. Three stool samples should be sent for microscopic examination. C. difficile is most reliably detected with a stool DNA amplification assay. Patients on immunosuppressant medications or those with HIV/AIDS infection have a greater likelihood of chronic infections. Enteropathogens that can cause acute, selflimited diarrhoea in immunologically normal individuals can cause chronic diarrhoea in these patients. These pathogens are Salmonella, Shigella, Campylobacter, E. coli, Yersinia, and others. These infections can last many weeks in the immunosuppressed host. Traditionally, these infections are detected with standard stool cultures. However, new molecular techniques may prove to be better in time, making standard stool cultures obsolete. Patients with HIV/AIDS suffer from potential infectious aetiologies related to their degree of immunosuppression. With lesser degrees of immunosuppression(CD4 count > 200 cells/mm3),the usual pathogens predominate. However if the CD4 count is < 200 cells/mm3, the spectrum includes mycobacterial and protozoan infections also along with the enteropathogens. These include MAC, cryptosporidium, cyclospora, isospora belli and microsporidium. Viral infections, such as CMV and Herpes simplex virus, and fungal infections, such as candidiasis and histoplasmosis, should be considered if other pathogens are not found.

MANAGEMENT ISSUES

The aetiology of chronic diarrhoea should be identified and treated accordingly. Dietary measures include the restriction of unabsorbed carbohydrates and sweets, avoidance of milk and milk products in patients with lactose intolerance, and fat restriction and supplementation of fat soluble vitamins and calcium in patients with steatorrhoea. Empirical therapy for chronic diarrhoea may be used when the diagnostic workup has failed to confirm the diagnosis, if no specific treatment is available or if the treatment has failed. Opiate anti diarrhoeal agents such as loperamide are frequently used. They are safe and effective but should not be used in infectious diarrhoea or in severe inflammatory bowel disease. Bile acid sequestrate like cholestyramine are useful in diarrhoea caused by bile acid malabsorption. Octreotide is used to control diarrhoea occurring in carcinoid syndrome, VIPomas and neuroendocrine tumors. Alpha2-adrenergic agonist, clonidine,is used to treat diabetic diarrhoea. Eluxadoline, a µ opioid receptor agonist is a new drug approved for use in patients with IBS. Diarrhoea in Zollinger-Ellison syndrome respond to treatment with proton pump inhibitors. Bacterial overgrowth is treated with antibiotics.

CONCLUSION

In conclusion, it is prudent to emphasize that the umbrella of chronic diarrhoea covers a vast range of disorders. A thorough history and clinical examination is absolutely necessary to arrive at a diagnosis. Though quite a number of laboratory investigations including imaging are available, judicious use of these investigations is the key. Examination of stool sample is vital. The management depends upon the aetiology.

REFERENCES

2. LR Schiller et al. Gastro 2013 APDW/WCOG Shanghai Working Party Report:Chronicdiarrhea: Definition, classification, diagnosis. Journal of Gastroenterology and Hepatology 2014; 29:6–25. 3. Fine KD, Schiller L. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464–86. 4. Camilleri M, Murray J A, Diarrhea and Constiption, Harrison’s Principles of Internal Medicine, (19th ed), 268272 5.

Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130:1480–91.

6. Persson J. Alcohol and the small intestine. Scand J Gastroenterol 1991; 26:3–15. 7.

Thomas PD, Forbes A, Green J, Howdle P, et al. Guidelines for the investigation of chronic diarrhea. Gut 2003; 52:1-5.

Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016; 150:1393-1407.

Spiller RC, Humes DJ, Campbell E et al. The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease. Aliment Pharmacol Ther 2010; 32:811– 20.

10) Shepherd SJ, Lomer MC, Gibson PR. Short-chain carbohydrates and functional gastrointestinal disorders. Am J Gastroenterol 2013; 108:707-17. 11. Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin Exp Gastroenterol 2012; 5:113-21.

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13. Mehta V, Mokharia VK. Approach to patients with Chronic Diarrhoea. Progress in Medicine 2016; 26:353-358. 14. Schiller LR. Definitions, pathophysiology, and evaluation of chronic diarrhoea. Best Pract Res Clin Gastroenterol 2012; 26:551–62. 15. Eherer AJ, Fordtran JS. Fecal osmotic gap and pH in experimental diarrhea of variouscauses. Gastroenterology. 1992; 103:545-51. 16. Caccaro R, D’Inca R, Pathak S, et al. Clinical utility of calprotectin and lactoferrin inpatients with inflammatory bowel disease: is there something new from the literature? Expert Rev Clin Immunol 2012; 8:579-85. 17. Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution, and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endosc 2000; 51:318-26. 18. Shale MJ, Walters JR, Westaby D. Adequacy of flexible sigmoidoscopy with biopsy for diarrhea in patients under age 50 without features of proximal disease. Gastrointest Endosc 2011; 73:757-64. 19. Schiller LR. Evaluation of small bowel bacterial overgrowth. Curr Gastroenterol Rep 2007; 9:373-7. 20. Draganov P, Patel A, Fazel A, et al. Prospective evaluation of the accuracy of the intraductal secretin stimulation test in the diagnosis of chronic pancreatitis. Clin Gastroenterol Hepatology 2005; 3:695-9. 21. Lieb JG, 2nd, Draganov PV. Pancreatic function testing: here to stay for the 21st century. World J Gastroenterol 2008; 14:3149-58. 22. Khanna S, Pardi DS, Rosenblatt JE, Patel R, Kammer PP, BaddourLM. An evaluation of repeat stool testing for Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol 2012; 46:846–9. 23. Chakravarty J,Sahu RP.Diarrhoea in HIV. Monograph on HIV 2016; 34-41. 24. Coste JF, Vuiblet V, Moustapha B et al. Microbiological diagnosis of severe diarrhoea in kidney transplant recipients by use of multiplex PCR assays. J Clin Microbiol 2013; 51:1841–926. Feasey NA, Healey P, Gordon MA. Review article: the aetiology, investigation and management of diarrhoea in the HIV-positive patient. Aliment Pharm Ther 2011; 34:587–603. 25. Lacy BE. Emerging treatments in neurogastroenterology: eluxadoline - a new therapeutic option for diarrheapredominant IBS. Neurogastroenterol Motil 2016; 28:26.

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1. Schiller LR, Sellin JH. Diarrhea. In: Feldman M, Friedman L, Brandt LJ, eds. Sleisenger&Fordtran’s Gastrointestinal and LiverDisease. Philadelphia: Saunders Elsevier, 2010; 211–32.

12. Hammer HF, Hammer J. Diarrhea caused by carbohydrate malabsorption. Gastroenterol. Clin North Am 2012; 41:611– 27.

C H A P T E R

Management of Ulcerative Colitis: Step-up or Step-down Approach?

ABSTRACT

Management of ulcerative colitis is determined by disease severity, extent of disease, frequency of relapses, prior drug therapy and presence of complications. A step-up approach in treatment is usually followed with algorithmic use of aminosalycilates, corticosteroids, azathioprine and biological or surgery. The concept of mucosal healing and advent of effective biologicals is bringing about a paradigm shift in our treatment goals and approach to ulcerative colitis. There is emerging evidence that early use of biological can induce rapid and sustained mucosal healing leading to a favourable alteration in natural course of the disease. There are strong limitations to this stepdown approach including definition and assessment of mucosal healing, opportunistic infection with biological and prohibitive cost of these drugs. There is a strong need for further studies to establish that step-down approach with early use of biologicals can alter the course of ulcerative colitis can be recommended for all cases. At this stage it is best reserved for severe and predicted severe cases of ulcerative colitis.

INTRODUCTION

Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the large gut. Rectum is involved in over 95% of patients with variable proximal progression in a symmetrical, circumferential and continuous manner to involve either part or entire colon. Treatment goals in UC have been to establish and maintain remission, improve quality of life, prevention of hospitalisation and colectomy. Conventional, stepup therapy with sequential and algorithmic use of steroids, aminosalicylic acid and immunomodulators like azathioprine is able to achieve this in only 60-80% of cases.1-3 The concept of mucosal healing has brought a paradigm shift in therapeutic goals and clinical endpoints in management of UC. There is growing evidence that mucosal healing can change the natural course of UC resulting in sustained remission and even prevention of colorectal carcinoma.4,5 In other words, if mucosal healing can be induced before irreversible mucosal damage due to chronic inflammation, natural course of UC can be altered for the better. Biologicals have the potential for early induction of mucosal healing 6-8. Whether its early use as in step-down therapy can alter the natural course of disease is a subject of intensive study in UC at this time.

ULCERATIVE COLITIS IN INDIA

Contrary to general perception, UC is relatively common

Bhaskar Nandi

with a reported incidence of 6.02 /104/year and prevalence of 44.3/105 population.9 The incidence and prevalence is highest in for the Asian subcontinent and similar to prevalence in the West. 9,10 The disease is limited to rectum in 18.3%, the left colon in 38.8% and involves the entire colon in 43.8%.11 The corresponding figures from the West are 30-60%, 1640% and 18-35% respectively. 12-14 The peak median age of onset is 2nd-3rd decade in India. The second peak in 6th decade as seen in the west has not been reported in Indian literature. The clinical course in UC is characterized by exacerbations and remissions, often spontaneous and sometimes triggered by intercurrent infections, drugs or in response to treatment. This intermittent disease course is seen in 47.2% and a chronic continuous inflammatory course is seen in 35.5% of patients.11 Extension of disease, frequent relapses, acute severe colitis at onset and colectomy imply a severe disease. Predictive factors for severity include younger age of onset, female gender, early relapse, higher endoscopy score and non-smokers.15

MUCOSAL HEALING â&#x20AC;&#x201C; REALISTIC OR AN IDEAL GOAL

There is no universally accepted and validated definition of mucosal healing (MH). It usually denotes absence of mucosal lesions of UC on sigmoidoscopy or colonoscopy (loss of vascularity, erythema, erosions and ulcerations). International Organisation of IBD (IOIBD) Task Force defined mucosal healing in UC as the absence of friability, blood, erosions, and ulcers in all visualized segments of the colonic mucosa.16 Many clinicians accept MH even in presence of mild friability and erythema. Different endoscopic indices for determining MH in UC have been used in clinical trials.4 Mayo Endoscopy Score17 is the most widely used tool in clinical studies, however, Ulcerative Colitis Endoscopic Index of Severity (UCEIS)18, that takes into account vascularity, blood in lumen and erosions or ulcerations is the only score that has been validated clinically (Table 1). It is accepted that clinical remission does not imply MH in UC. Clinical assessment underestimates disease activity as assessed by endoscopy or histology. Active endoscopic and histologic disease has been noted in 39% - 60% and 63% -90% of patients with UC in clinical remission respectively.19-21 Recent studies have demonstrated conclusively that MH in UC results in decrease in corticosteroid use, decrease in hospitalisation rates, increase in sustained clinical

301

Table 1: Ulcerative Colitis Endoscopic Index of Severity Likert Scale Anchor Points

Definition

Vascular pattern

Normal (0)

Normal vascular pattern with arborization of capillaries clearly defined, or with blurring or patchy loss of capillary margins

Patchy obliteration (1)

Patchy obliteration of vascular pattern

Obliterated (2)

Complete obliteration of vascular pattern

None (0)

No visible blood

Mucosal (1)

Some spots or streaks of coagulated blood on the surface of the mucosa ahead of the scope, which can be washed away

Luminal mild (2)

Some free liquid blood in the lumen

Bleeding

Luminal moderate or severe (3) Frank blood in the lumen ahead of endoscope or visible oozing from mucosa after washing intraluminal blood, or visible oozing from a hemorrhagic mucosa Erosions and ulcers

None (0) Erosions (1)

Normal mucosa, no visible erosions or ulcers Tiny f<S mm) defects in the mucosa, of a white or yellow color with a flat edge

Superficial uler (2)

Larger (>S mm) defects in the mucosa, which are discrete fibrin-covered ulcers when compared with erosions, but remain superficial

Deep ulcer (3)

Deeper excavated defects in the mucosa, with a slightly raised edge

remission, decrease in colectomy rates and decrease in development of colorectal carcinoma.5,22-25 A recent meta-analysis that included 13 studies comprising 2073 patients with active UC showed that patients with MH had pooled odds ratio of 4.50 for achieving long-term clinical remission (95% CI, 2.12–9.52), 4.15 for remaining free of colectomy (95% CI, 2.53–6.81),8.40 for achieving long-term MH (95% CI, 3.13–22.53), and 9.70 for achieving long-term corticosteroid-free clinical remission (95% CI, 0.94–99.67), compared with patients without MH. There was no difference in outcomes if patients achieved MH while receiving biologic versus non-biologic therapy.26 MH is a logical end-point in treatment of UC. It can be conveniently assessed by endoscopy and biopsy. Since rectum is usually involved and the lesions are mucosal as well as continuous, a sigmoidoscopic examination is sufficient in most cases of UC to determine MH. Limitation is in developing a universally accepted and validated definition of MH.

CONVENTIONAL STEP-UP THERAPY

Management of UC is determined by severity and extent of disease, prior response to therapy and quality of life indices. A sequential algorithmic step-up treatment with 5-aminosalycilate (topical or systemic), corticosteroids (topical or systemic) and immunomodulators like azathioprine or methotrexate constitute the conventional therapy (Figure 1). Biologicals are added if conventional

therapy fails to induce remission or maintain sustained remission. Surgery is reserved for patients with medical failure, complications and in fulminant acute colitis. Mucosal healing by conventional treatment is 20% -71% depending on severity of disease, clinical end-point, choice of drug and dosage used.27-30 The wide variation in mucosal healing rates is largely due to heterogeneity of the studies with respect to subjects studied, definition of mucosal healing and inter observer variation.

BIOLOGICALS AND MUCOSAL HEALING

Advent of biologicals (Table 2) has brought in a paradigm shift in management of ulcerative colitis. The efficacy of these drugs in inducing clinical remission has prompted change in clinical end-points in therapy of UC. The concept of mucosal healing as a therapeutic end-point that can alter the natural course of the disease has gained ground with the introduction of these monoclonal antibodies. Biologics (naive proteins, cytokines, growth factors, and antibodies) interfere with molecules that are involved in the disease pathogenesis. Initially, biologics targeting tumor necrosis factor- α (TNF α ) were approved for patients with persistent active disease despite conventional treatment. Subsequently, many novel biological therapies targeting different immunological pathways were introduced. All showed significant success in achieving sustained clinical remission or mucosal healing (Table 3).

CHAPTER 64

Descriptor (Score Most Severe Lesions)

GASTROENTEROLOGY

302

ULCERATIVE COLITIS

MILD-MODERATE

CHRONIC ACTIVE

5-ASA Topical Proctitis / Left colitis Oral ± Topical Extensive

Steroids for induction Add Azathioprine (or Methotrexate)

RESPONSE

NO RESPONSE

Taper steroids Maintenance 5-ASA (Topical/Oral)

Steroids (Topical /Oral Left colitis / Extensive) RESPONSE

NO RESPONSE

RESPONSE

SEVERE / FULMINANT IV Hydrocortisone or IV Methylprednisolone

RESPONSE NO RESPONSE

5-ASA + Azathioprine

Infliximab* Or Surgery

Fig. 1: Treatment of Ulcerative Colitis (Step-up approach) both studies, patients who of received infliximab were more *In Severe/Fulminant colitis Cyclosporin may be used in thiopurine naïve patients instead infliximab Table 2: Biologics in Ulcerative Colitis likely to have a clinical response at week 30 (P< or =0.002 Anti-TNF Inhibitors Infliximab. Adalimumab, FIGURE 1: Treatment of Ulcerative Colitis (Step-up approach)for all comparisons). In ACT 1, more patients who received Golimumab 5 mg or 10 mg of infliximab had a clinical response at Anti-adhesion molecules Natalizumab week 54 (45% and 44% respectively) than did those who (recombinant IgG4 received placebo (20%, P<0.001 for both comparisons). In monoclonal antibody to the ACT-1 and ACT-2 trials, the proportion of patients α4 integrin) in clinical remission at week 30 of therapy was 4-fold Vedolizumab (anti α4â7 greater for patients with MH at week 8 (48.3 vs. 9.5%, integrin antibody) respectively). Etrolizumab ULTRA 1 study concluded that ADA160/80 was safe Janus kinase inhibitors Tofacitinib and effective for induction of clinical remission in Others Abatacept, Tocilizumab patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or Experience in India with biologicals is limited and is immunosuppressants.32 It was an 8-week, multicentre, restricted to infliximab in published literature. Sood has randomised, double-blind, placebo-controlled study in reported reduction in colectomy in his patients with patients with moderate to severe UC non-resposive to steroid refractory UC treated with infliximab. Adalilumab conventional therapy. 390 patients were randomised has been reportedly used in some centres. (1:1:1) to ADA160/80, ADA80/40, or placebo. At week 8, Two randomized, double-blind, placebo-controlled trials, 18.5% of patients in the ADA160/80 group (p = 0.031 vs Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT placebo) and 10.0% in the ADA80/40 group (p = 0.833 vs Surgery 2), evaluated the efficacy of infliximab for induction and placebo) were in remission, compared with 9.2% in the maintenance therapy in adults with moderate to severe placebo group. ulcerative colitis.31 In each study, 364 patients with ULTRA 2 was a randomized, double-blind, placeboBiologicals concurrent medications received placebo or infliximab (5 controlled trial to evaluate the efficacy of adalimumab in mg or 10 mg per kilogram body weight) intravenously STEPofUP STEP DOWN induction and maintenance of clinical remission in 494 at weeks 0, 2, and 6 and then every eight weeks through patients with moderate-to-severe ulcerative colitis who week 46 (in ACT 1) or week 22 (in ACT 2). Patients were received concurrent treatment with oral corticosteroids followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In or immunosuppressants.33 Patients were stratified based Corticosteroids ACT 1, 69% and 61% of patients who received 5 mg and on prior exposure to TNF-α antagonists (either had or 10 mg of infliximab respectively had a clinical response Immunomodulators had not been previously treated with anti-TNF-α) and at week 8, as compared with 37% of those who received randomly assigned to groups given adalimumab 160 mg placebo (P<0.001 for both comparisons with placebo). In at week 0, 80 mg at week 2, and then 40 mg every other ACT 2, 64% and 69% of patients who received 5 mg and week or placebo. Primary end points were remission at 10mg of infliximab respectively had a clinical response weeks 8 and 52. Overall rates of clinical remission at week at week 8, as compared with 29% of those who received 5-Aminosalycilates 8 were 16.5% on adalimumab and 9.3% on placebo (P = placebo (P<0.001 for both comparisons with placebo). In

MODERATE

CHRONIC ACTIVE

Topical is / Left colitis Topical ive

NSE

SEVERE / FULMINANT

303

Steroids for induction Colitis IV Hydrocortisone or Table 3: Efficacy of Biologics in Ulcerative

Drug

Add Azathioprine Study Steroids (Topical /Oral (or Methotrexate) Left colitis / Extensive)

Infliximab

NO RESPONSE

IV Methylprednisolone

ACT 1(N=364)

RESPONSE

steroids enance 5-ASA al/Oral)

Mod-Severe

NO RESPONSE

RESPONSE

Protocol

Efficacy

5mg/kg 0,2,6 weeks, every 8 weeks x 46 weeks

69% at week 8 (Placebo 37%)

5mg/kg x 22 weeks

64% at week 8 (Placebo 29%)

RESPONSE NO RESPONSE

5-ASA

ACT 2 (N=364) + Azathioprine Mod-Severe

Adalimumab

Infliximab* Or Surgery ULTRA

45.5% at week 54 (Placebo 20%) 47.1% at week 30

1 (n= 390) Mod-severe

160/80, 80/40, Placebo S/C every 2 weeks

vere/Fulminant colitis Cyclosporin may be used in thiopurine ULTRA 2 naĂŻve patients instead of infliximab40

16.5% at week 8 (Placebo 9.3%)

E 1: Treatment of Ulcerative Colitis (Step-up approach)

17.3% at week 52 Placebo 8.5%)

Golimumab

PURSUIT

200 mg week 0, 100 mg week 2

51% week 6

N=1065 Mod-Severe

Vedolizumab Tofacitinib

PURSUIT MAINT. N=464 Mod 100 mg every 4 weeks after Severe induction

49.7% week 52

GEMINI N=895 Mod-Severe

300 mg IV at 0 and 2 weeks, then 4 or 8 weekly IV

47.1% at week 6

15 mg BD x 8 weeks

78% at week 8

Sandborn et al N=194 ModSevere

41.8-44.8% at week 52

STEP-UP OR STEP-DOWN â&#x20AC;&#x201C; CLINICAL PERSPECTIVE

Surgery Biologicals STEP UP

STEP DOWN Corticosteroids Immunomodulators

Whilst the Step-Down approach may seem to be logical and exciting given its potential for achieving sustained mucosal healing and potential to favourably alter the natural course of disease, a critical analysis will reveal the following limitations: 1.

Mucosal healing is achieved in a sizable number of patients even with conventional step-up therapy. It may be presumed that step-down approach may achieve this more rapidly, however, no such hard evidence exists.

Our experience with biologicals in rheumatology tells us that these drugs are capable of changing the natural history of immune mediated disorders. There is emerging evidence of similar effect in ulcerative colitis, nevertheless more data and validation is required before step-down approach can be adopted for all cases.

A universally acceptable definition of mucosal healing is still elusive. Assessing mucosal healing is equally worrisome. Endoscopy is invasive and patients are reluctant to submit themselves for repeated endoscopic and histologic assessment.

Cost of biologicasl is prohibitive and out of reach of most patients in India.

Risk of developing tuberculosis and opportunistic infection is significant and meticulous pretreatment and during the course of treatment surveillance is mandatory.

5-Aminosalycilates

Steptherapy downintherapy inColitis Ulcerative Colitis FIGURE 2:Fig. Step2:down Ulcerative .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004).

STEP-DOWN APPROACH: CLINICAL RATIONALE

Mucosal inflammation damages mucosa and begets further inflammation giving rise to persistent disease activity, complications and risk of developing colorectal carcinoma in ulcerative colitis. To favourably change the natural course of the disease it is necessary to interrupt this vicious cycle of mucosal inflammation during the early stage of the disease before irreversible mucosal damage takes place. Biologicals, with their efficacy to induce MH, quick onset of action, ability to maintain remission have the potential to meet this target. Once remission is achieved, it can be maintained with continuing biological or stepping down to immunomodulators like azathioprine. If biological fail to induce or maintain remission patient can be taken up for colectomy (Figure 2).

Further clinical trials conclusively establishing the superiority of biological over aminosalicylates, steroids

CHAPTER 64

mg s/c every 2 weeks after induction

18.5% at week 8 (160 mg) vs 9.2% (placebo)

GASTROENTEROLOGY

304

and immunomodulators is required to strengthen the protocols of step-down therapy in UC. Mucosal healing needs to be better defined and validated with clinical outcome. Identification of surrogate biochemical markers of mucosal healing is warranted to avoid repeated invasive endoscopies. Lastly, affordable biological need to be introduced in the market for wider clinical use. In conclusion, step-down therapy may be an exciting approach to treat ulcerative colitis but at this stage it may be restricted to patients with severe or predicted severe disease.

during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm. Bowel Dis 2007; 13:481–9. 15. Wanderas MH, Moum BA, Hoivik ML. Predictive factors for a severe clinical course in ulcerative colitis: Results from population-based studies. World J Gastrointest Pharmacol Ther 2016; 7:235-241. 16. D’Haens G, Sandborn WJ, Feagan BG, et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132:763–86.

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17. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987; 317:1625–1629.

Sandborn WJ, Ghosh S, Panes J. Tofacitinab, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367:616-624.

18. Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (UCEIS). Gut 2012; 61:535–42.

Stidham RW, Lee TC, Higgins PD. Systematic review with network meta-analysis: the efficacy of anti-tumor necrosis factor-alpha agents for the treatment of ulcerative colitis. Aliment Pharmacol Ther 2014; 39:660-671

Osterman MT. Mucosal healing in Inflammatory Bowel Disease. J Clin Gastroenterol 2013; 47:212-221.

Walsh A, Palmer R, Travis S. Mucosal healing as target for therapy in colonic inflammatory bowel disease and methods to score disease activity. Gastrointest Endoscopy Clin N Am 2014; 24:367-378.

Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved longterm clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194e201.

Park SC, Jeen YT. Current and emerging biologics for Ulcerative Colitis. Gut and Liver 2015; 9:18-27

8. Ghosal UC, Verma A. Biologicals in treatment of acute ulcerative colitis. Trop Gastroenterology 2015; 36:80-85 9.

Sood A,Midha V, Sood N, Bhatia AS, Avasthi G. Incidence and prevalence of Ulcerative Colitis in Punjab, North India. Gut 2003; 52:1587-1590.

10. Ahuja V, Tandon RK. Inflammatory Bowel Disease in AsiaPacific area: A comparison with developed countries and regional differences. J Dig Dis 2010; 11:134-147. 11. Makharia GK1, Ramakrishna BS, Abraham P, Choudhuri G, Misra SP, Ahuja V, Bhatia SJ, Bhasin DK, Dadhich S, Dhali GK, Desai DC, Ghoshal UC, Goswami BD, Issar SK, Jain AK, Jayanthi V, Loganathan G, Pai CG, Puri AS, Rana SS, Ray G, Singh SP, Sood A; Indian Society of Gastroenterology Task Force on Inflammatory Bowel Disease. Survey of inflammatory bowel diseases in India. Indian J Gastroenterol 2012; 31:299-306. 12. Moum B, Ekbom A, Vatn MH, Elgjo K. Change in the extent of colonoscopic and histological involvement in ulcerative colitis over time. Am J Gastroenterol 1999; 94:1564–9. 13. Henriksen M, Jahnsen J, Lygren I et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm. Bowel Dis 2006; 12:543–50. 14. Jess T, Riis L, Vind I. Changes in clinical characteristics, course,and prognosis of inflammatory bowel disease

19. Truelove SC, Richards WCD. Biopsy studies in ulcerative colitis. Br Med J 1956; 1:1315–1318. 20. Matts SGF. The value of rectal biopsy in the diagnosis of ulcerative colitis. Q J Med 1961; 30:393–407. 21. Dick AP, Holt LT, Dalton ER. Persistence of mucosal abnormality in ulcerative colitis. Gut 1966; 7:355–360. 22. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved longterm clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194–201. 23. Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004; 53:1813–6. 24. Ardizzone S, Cassinotti A, Duca P, et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011; 9:483–489. 25. Meucci G, Fasoli R, Saibeni S, et al. Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: a prospective, multicenter study. Inflamm Bowel Dis 2012; 18:1006–1010. 26. Shah SC, Colombel JF, Sands BE, Narula N. Mucosal Healing Is Associated With Improved Long-term Outcomes of Patients With Ulcerative Colitis: A Systematic Review and Meta-analysis. Clinical Gastroenterol Hepatol 2016; 14:1245–1255. 27. Sandborn WJ, Kamm MA, Lichtenstein GR, et al. MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate active ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther 2007; 26:205–215. 28. Kamm MA, Lichtenstein GR, Sandborn WJ, et al. Effect of extended MMX mesalamine therapy for acute, mildtomoderate ulcerative colitis. Inflamm Bowel Dis 2009; 15:1– 8. 29. Lichtenstein GR, Ramsey D, Rubin DT. Randomised controlled trial: delayed-release oral mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing—ASCEND I and II combined analysis. Aliment Pharmacol Ther 2011; 33:672–678. 30. Ardizzone S, Maconi G, Russo A, et al. Randomised

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CHAPTER 64

Medical Management of Acute Pancreatitis

C H A P T E R

Rajoo Singh Chhina, Amit Bansal, Amanat Sidhu, Rajdeep Singh

DEFINITION

Acute pancreatitis is defined as an acute inflammation of pancreas along with involvement of other regional tissues or organs. Clinically it is presence of two of the following three features: (1) severe and constant epigastric or left upper quadrant pain with radiation to the back, chest, or flanks; (2) serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal; and (3) characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT) and magnetic resonance imaging (MRI) or transabdominal ultrasonography.

as the elderly, or those with a history of cardiac and / or renal disease in order to avoid complications such as volume overload, pulmonary edema, and abdominal compartment syndrome. Response to fluid resuscitation should be assessed by non-invasive response monitoring (heart rate <120 bpm, mean arterial pressure 65-85 mm Hg, urine output 0.5-1 mL/kg/h) along with monitoring of hematocrit and BUN.

Analgesia

A: Analgesia

Pain is the most troublesome symptom of acute pancreatitis which may lead to impaired respiratory function by restriction of abdominal wall movement. Therefore, adequate analgesia is important during the first few days of clinical presentation. It should be according to the need of the patient. Both opiates and non-opiates can be used inspite of some theoretical risks of exacerbation of pancreatitis by morphine, which can increase pressure in the sphincter of Oddi.

N: Nutrition

Nutrition

MANAGEMENT OF ACUTE PANCREATITIS

There is a mnemonic for components of management of acute pancreatitis: P: Perfusion

C: Clinical Assessment R: Radiological Assessment E: ERCP A: Antibiotics S: Surgery

Perfusion

Maintenance of adequate perfusion is the most important determinant of outcome in acute pancreatitis in the first 72 h. There occurs frequent hypovolemia in patients with acute pancreatitis because of multiple factors including vomiting, reduced oral intake, third space loss of fluids, increased respiratory losses, and diaphoresis that requires aggressive hydration. A combination of microangiopathic effects and edema of the inflamed pancreas decreases pancreatic blood flow leading to increased cellular death, necrosis, and ongoing release of pancreatic enzymes activating numerous cascades. Early aggressive intravenous fluid resuscitation provides circulatory support which prevents serious complications such as pancreatic necrosis. The preferred fluid for resuscitation is Ringer’s lactate. Infusion rates during the first 24 hours in hospital should be sufficient to restore circulating volume and urine output (250 – 500 ml per hour). Early aggressive intravenous hydration is most beneficial during the first 12 – 24 h, and may have little benefit beyond this time period. In a patient with signs of severe volume depletion such as hypotension and tachycardia, more rapid repletion may be needed. Aggressive early hydration will require caution for certain groups of patients, such

Earlier pancreatic rest (NPO) was considered an important part of management of acute pancreatitis based on a hypothesis that stimulation of pancreatic exocrine secretory function by food may lead to worsening of acute pancreatitis. But experimental studies have shown that Acute Pancreatitis leads to decreased pancreatic exocrine function and does not get stimulated by food. Moreover, bowel rest is associated with intestinal mucosal atrophy and increased infectious complications because of bacterial translocation from the gut. Provision of early enteral nutrition leads to shorter hospital stay, decreased infectious complications, decreased morbidity, and decreased mortality. In mild AP, oral feedings can be started immediately once nausea, vomiting and pain has resolved. In mild AP, initiation of feeding with a low-fat solid diet appears as safe as a clear liquid diet. In severe AP, tube feeding should be started as soon as possible to prevent infectious complications. Parenteral nutrition should be used only if enteral route is not available or not tolerated or doesn’t meet caloric requirements. Both nasogastric and nasojejunal tube feeding are equally safe and effective except for increased risk of aspiration in nasogastric feeding.

Clinical Assessment

It is based mainly on assessment of the severity of pancreatitis. According to revised Atlanta Classification, severity of acute pancreatitis can be divided into three groups: mild, moderately severe and severe pancreatitis (Table 1). Several scoring systems are available to predict which

Table 1: Definitions of severity in acute pancreatitis: comparison of Atlanta and recent Revision

Table 3: Local Complications of Acute Pancreatitis

Atlanta Criteria (1993)

Atlanta Revision (2013)

Mild Acute Pancreatitis

• Sterile necrosis

• Absence of organ failure*

• Absence of organ failure

• Absence of local complications

Severe Acute Pancreatitis

Moderately Severe Acute Pancreatitis

 Splenic artery or splenic artery pseudoaneurysm rupture

• Local complications and/or

 Splenic vein rupture  Portal vein rupture

• Organ Failure

• Transient Organ Failure (<48h)

 Splenic vein thrombosis leading to gastroesophageal variceal bleeding

GI bleeding (>500cc/24hr)

Severe Acute Pancreatitis

 Pseudocyst or abscess hemorrhage

Shock –SBP ≤ 90mm Hg

Persistent Organic Failure > 48h

 Postnecrosectomy bleeding

• Infected necrosis • Abscess • Gastrointestinal bleeding  Pancreatitis-related

 Nonpancreatitis-related  Mallory-Weiss tear

Creatinine ≥ 2mg/dl *Definitions of organ failure: Respiratory: arterial oxygen pressure/fractional inspired oxygen ≥300; Circulatory: systolic blood pressure <90 mm Hg and not fluid responsive; Renal: plasma Creatinine concentration ≥1.9 mg/dl

Table 2: Various Scoring System and their significant values Type of Scoring system

• Pseudocyst

Score

 Alcoholic gastropathy  Stress-related mucosal gastropathy • Splenic complications  Infarction  Rupture  Hematoma

BISAP Score

≥3

• Fistulization to or obstruction of small or large bowel

Modified Marshall Score

• Right-sided hydronephrosis

APACHE II Score

≥8

Ranson Criteria

HAPS Score

≥2

patients will develop severe disease (Table 2). These include clinical scores such as APACHE II, Ranson criteria, HAPS score, BISAP score, modified Glasgow scores and the CT based score (Balthazar score, Mortele Score). Out of these, BISAP is easiest to apply and can be used on initial presentation. BISAP relies on the BUN level, impaired mental status, SIRS, age over 60 years and pleural effusions to stratify patients, and has a prognostic accuracy similar to the other scoring systems. While Ranson’s score is the oldest and most validated but has limitations that require 48 h for accurate scoring. There is no definitive consensus as to which scoring system should be used. All have a good negative predictive value but low positive predictive value. However, it is recommended that risk assessment be performed for all patients with pancreatitis to stratify them into higher and lower risk categories. Apart from this scoring system, single parameters like hematocrit > 44%, raised BUN (>20 mg/dl) may also help to predict severe pancreatitis.

Radiological Assessment

It has two roles in management o acute pancreatitis: to diagnose and evaluating local complications. While

ultrasound is the most common modality used for the diagnosis of pancreatitis but in doubtful cases CECT abdomen may be required for confirming the diagnosis. USG and CECT may also indicate the etiology of pancreatitis like gallstones. The second major role of radiological investigations is to evaluate local complications. Based on CECT or MRI findings local complications are acute peripancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection and walled-off necrosis (Table 3).

ERCP

ERCP in acute pancreatitis is related to the management of choledocholithiasis. In the absence of cholangitis and / or jaundice, MRCP or EUS rather than diagnostic ERCP should be used to screen for choledocholithiasis if highly suspected .

Antibiotics

Antibiotics should be given for an extrapancreatic infection, such as cholangitis, catheter-acquired infections, bacteraemia, urinary tract infections, and pneumonia. Routine use of prophylactic antibiotics in patients with severe AP is not recommended. Serum Procalcitonin is the best single marker for predicting infection in pancreatitis. In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis, such as carbapenems, quinolones, and metronidazole, may

CHAPTER 65

PaO2 ≤ 60%

307

308

be useful in delaying or sometimes totally avoiding intervention, thus decreasing morbidity and mortality. Routine administration of antifungal agents along with prophylactic or therapeutic antibiotics is not recommended..

Surgery/Interventions

GASTROENTEROLOGY

Step up approach ,in management of acute pancreatitis should be followed as 1.

Catheter drainage

Minimal invasive necrosectomy

Open necrosectomy

PROGNOSIS

Early evaluation and risk stratification for patients with acute pancreatitis are important to differentiate patients with mild versus severe disease because patients with severe disease often need intensive care treatment (Figure 2). The overall mortality in patients with acute pancreatitis is 10-15%. Patients with biliary pancreatitis tend to have a higher mortality than patients with alcoholic pancreatitis. This rate has been falling over the last 2 decades as improvements in supportive care have been initiated. In patients with severe disease (organ failure), who account for about 20% of presentations, mortality is approximately 30%. Approximately 20-25% of patients with acute pancreatitis have a severe form of the disease which usually necessitates high dependency or intensive care management in the first week or two of illness. The measurement of C-reactive protein is also helpful and it has recently been shown that the combining

of the Glasgow scoring system with CRP results in 80% or better sensitivity and specificity for those who develop major clinical complications. The body mass index (BMI) when over 30 kgs/m2 is also a useful marker of an adverse outcome, and CT scanning is another method of grading severity. In patients with pancreatic necrosis without organ failure, the mortality approaches zero.

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