Section 10

Section Editor: Rajesh Upadhyay Gastroenterology

124. Type 2 Diabetes Mellitus Originates 135. Proton Pump Inhibitors—Long-term Use: from Fatty Liver Boon or Bane? Rajesh Upadhyay, Ankit Gupta Manish Manrai, Rohit Upreti 125. Non-Pharmacological Management of 136. Eosinophilic Esophagitis— NAFLD/NASH (Diet, Exercise, and Role of An Underdiagnosed Entity Intermittent Fasting) Goundappa Loganathan, H Leena Shree Sundeep Kumar Goyal 137. Non-Cirrhotic Portal Hypertension in India 126. Medical Management of Acute Pancreatitis Srikant Mohta, Anoop Saraya D Nageshwar Reddy, Hardik Rughwani 138. Drug-induced Liver Injury 127. Functional Gastrointestinal Disorders Harshad Devarbhavi Uday C Ghoshal 139. Achalasia Cardia—Diagnosis and 128. Variceal Bleed Management Endoscopic Treatment Srikanth Gopi, Deepak Gunjan Mohan Ramchandani, Partha Pal 129. Hepatorenal Syndrome: Current 140. Non-Variceal Upper GI Bleed—Clinical Approach Diagnosis and Management Bhabadev Goswami, Preeti Sarma Shri Krishna Gautam 141. Recent Updates in Management of IBS 130. Hepatic Encephalopathy: Management Nikhil Gupta, Manisha Dwivedi, SP Misra Sudhir Maharshi, Barjesh Chander Sharma 142. Evaluation of Occult GI Bleed 131. The Healthy Indian Gut Microbiota Sanjay Bandyopadhyay Rupjyoti Talukdar 143. Endoscopic Ultrasound for the Internist 132. Celiac Disease: Who to Screen and How to Screen? Surinder S Rana Ashish Agarwal, Archita Makharia, Govind K Makharia 144. Gastroesophageal Reflux Disease—What’s New! 133. Differentiating Crohn’s Disease from Intestinal Piyush Dadhich, Shraddha Sharma, Shreyans Singhvi, Tuberculosis: A Diagnostic Challenge Gautam Bhandari, Sunil Kumar Dadhich Pabitra Sahu, Saurabh Kedia, Vineet Ahuja 145. Post-Infectious Irritable Bowel Syndrome 134. Acute Liver Failure and Acute-on-Chronic-Liver BK Tripathi Failure in India: How They Are Different from West? Subrat Kumar Acharya

Section-10.indb 785 28-01-2021 12:10:33 Section-10.indb 786 28-01-2021 12:10:33 CHAPTER

Type 2 Diabetes Mellitus 124 Originates from Fatty Liver

Rajesh Upadhyay, Ankit Gupta

Abstract The relationship between diabetes mellitus and liver disease is bidirectional, both supporting and accelerating the development of each other. The key pathogenic mechanism is insulin resistance (IR). The main factor leading to IR is accumulation of fat in the liver. The hepatic fat predominately comes from three sources • Dietary fat, • De-novo lipogenesis due to high insulin level and • Fatty acid generation from adipose tissue lipolysis. Fat in the liver impairs insulin signaling, leading to IR. Liver is the largest metabolic organ leading to IR. The resultant IR worsens hyperinsulinemia, which affects various metabolic processes in the liver. The IR prevents glucose transport from blood to liver, thus leading to poor trapping in liver and consequent rise in blood sugar. In addition increased free fatty acids inhibit the insulin action on liver, and insulin-induced suppression of glucagon is impaired, thus leading to increased production of hepatic glucose which has a major contribution in fasting hyperglycemia. Evidence suggests that improvement in fatty liver reduces IR and prevents development and/or improvement of diabetes mellitus. There are numerous observational studies suggesting that fatty liver is an independent risk factor for development of diabetes. Chronic liver disease is associated with development of diabetes (secondary diabetes). Glucose intolerance can be seen in about 80% of patients, and diabetes in about 30% of patients with chronic liver disease. Thus, fatty liver may be considered the main organ responsible for IR and T2DM. Diabetes should be considered a reversible metabolic state due to excess intra-organ fat, especially fatty liver.

Introduction T2DM and NAFLD. The relationship between diabetes mellitus and liver disease is bidirectional, both supporting The interest in relationship between chronic liver disease and diabetes mellitus has increased since last decade. and accelerating the development of each other. What Chronic liver disease particularly NAFLD is associated remains unclear is the chicken-egg conundrum—which with diabetes mellitus. In the United States, NAFLD is the comes first? In other words, does diabetes lead to fatty liver most common cause of chronic liver disease and affects or fatty liver causes diabetes? An understanding of this between 80–100 million individuals.1 According to an requires a deep study of the physiology and pathogenesis estimate in India, approximate 30% of the population is of both conditions and developing clear concepts. having NAFLD and its prevalence approaches to 64% in Although IR is the common pathogenetic mechanism for diabetics.2 The association is based on insulin resistance both these conditions; however, it is the liver which is the (IR), which is the common underlying mechanism for both key player for IR.

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Liver is the Main Organ Producing IR to the fatty pool. Fatty acid accumulation occurs in the liver cells which would normally be oxidized to produce Being the largest metabolic organ of human body, it plays energy. However, the oxidative stress and mitochondrial an important role in glucose metabolism. It is the site for dysfunction in fatty liver prevents oxidation. The fatty acid glycogenesis, glycogenolysis, and gluconeogenesis. It has is therefore esterified into triglycerides and stored in the an immense capacity to store sugar in times of excess and liver cells. Fat in the liver impairs insulin signaling, leading push out glucose into circulation in deficient condition. to IR. The resultant IR worsens hyperinsulinemia, which Therefore, in states of fasting or hypoglycemia, liver affects various metabolic processes in the liver. First, it releases glucose into the circulation by glycogenolysis stimulates the enzyme hexokinase, which phosphorylates and/or gluconeogenesis. On the other hand, it is also the glucose. In addition, it also activates the enzymes main organ which prevents rapid rise of blood glucose phosphofructokinase and glycogen synthase, which are after food ingestion. Whatever glucose is absorbed from involved in glycogen synthesis. When glycogen stores are the intestines it goes through the portal vein to the liver saturated, the excess glucose is then shunted to fatty acid where, almost all of it is retained. The rise in prandial synthesis, which further adds to liver fat. plasma glucose reflects only a minor component of The liver mediated IR is a manifestation of the inherent the absorbed glucose. It is pertinent to note that the ability of liver to protect itself from ongoing onslaught of first glycemic abnormality in T2DM is postprandial further sugar/fat accumulation in liver cells, which is likely hyperglycemia, which may actually indicate insufficient to cause cell disintegration. The stored fat is therefore trapping of glucose by the liver. The insufficient trapping transported out from the cell in the form of free fatty of glucose in the liver is due to the liver mediated IR. The acid and VLDL, which causes tissue IR in various organs main factor leading to IR is accumulation of fat in the liver. (Fig. 1). The IR prevents glucose transport from blood to This brings us to the basic question as to what causes liver, thus leading to poor trapping in liver and consequent fatty liver (Flowchart 1). High carbohydrate/high fat diet rise in blood sugar. increases insulin production, which pushes sugar from blood into liver. The liver cells are filled up with stored glycogen. The hepatic fat predominately comes from three Increased Hepatic Glucose Output in sources: Diabetes „„ Dietary fat, It is also well known that hepatic glucose output is „„ De-novo lipogenesis due to high insulin level, and increased in T2DM, and it has a major contribution „„ Fatty acid generation from adipose tissue lipolysis. in fasting hyperglycemia. Increased free fatty acids In addition the role of absorbed fructose is also inhibit the insulin action on liver, and insulin-induced important. Fructose unlike glucose can only be suppression of glucagon is impaired, thus leading to metabolized by the liver and not by other tissues. In fatty increased production of hepatic glucose excessive release liver, there is already high hepatic glucose/glycogen; of glucose from liver further increases blood sugar levels hence, fructose can only be converted into fat which adds although the levels may still be maintained within the normal range due to compensatory high pancreatic beta Flowchart 1: What causes fatty liver? cell production of insulin.

Phases of T2DM and the Role of Pancreatic Fat It is well known that in diabetics, there is a prolonged period of 12–14 years of IR with compensatory hyperinsulinemia keeping the blood sugar within the normal range with gradually increasing HbA1c to prediabetic levels. Then comes the pancreatic beta cell failure resulting in reduced

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Fig. 1: Sources and fate of free fatty acids in liver

insulin production causing overt diabetes (Fig. 2). The question is what causes beta cell failure? Various theories in literature have been suggested especially the burnout theory due to persistent insulin overproduction by the pancreatic beta cells leading to cell death causing reduced insulin production. If this was so then T2DM would clearly be an irreversible condition. On the contrary, there is evidence of increase in insulin secretion post- bariatric surgery or following a hypocaloric diet.3,4 Such interventions have the ability to reverse diabetes completely. Hence, a more plausible explanation would be that the beta cells have been rendered metabolically inactive due to reversible factors. Evidence suggests that fatty acids prevent beta cell proliferation. In the genetic model, Zucker diabetic fatty rats rapid increase in pancreatic fat leads to development of diabetes. When food intake is restricted in this model, diabetes Fig. 2: Two phases of type 2 diabetes did not develop. This also suggests that a significant

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mass of beta cells is not permanently damaged but hepatic insulin sensitivity. Weight loss interventions became metabolically inactive. Thus, pancreatic fat (PF) are also associated with improvement in liver histology accumulation is an important precursor for development and transaminases. Metformin an oral antidiabetic drug of diabetes. The amount of PF is greater in diabetics and reduces plasma glucose via activation of AMP kinase, increases with the duration of diabetes. Patients with PF and reduces hepatic glucose synthesis. This enzyme also have a higher prevalence of T2DM than non-PF controls decreases lipid synthesis and enhances fat oxidation. (12.6% vs. 5.2%) and T2DM was independently associated Metformin treatment thus can improve insulin sensitivity with PF.5 A cohort of patients with biopsy proven NASH and liver transaminases in patients with fatty liver disease. had more PF in diabetics compared to patients without Thiazolidinediones are insulin sensitizers and can diabetes.6 The fatty liver cells are overdistended with fat improve hepatic as well as peripheral insulin sensitivity. which is then transported to different organs including They can induce adipocyte differentiation, reduce free the pancreas as free circulating fatty acids and VLDL fatty acid levels, and thus decrease their delivery to liver. particles which lead to tissue IR and PF accumulation. They also increase adiponectin levels and can increase There is evidence to suggest this cross talk between the lipid oxidation of fatty acid in liver. They also reduce TNF- fatty liver and PF.7 Fat in pancreas may lead to metabolic alpha and C-reactive protein, which play important role suppression of beta cells causing pancreatic failure in IR. Therefore, there are ample evidences to suggest2 and reduced insulin production leading to T2DM. This that targeting fatty liver can lead to improvement of IR. hypothesis appears attractive but needs to be evidence It is a well-known fact that persons with fatty liver have based. There are studies on post-bariatric surgery patients higher prevalence of T2DM (22.4%) and NASH (43.6%) as demonstrating lowering of pancreatic triglyceride content compared to 8.5% in general population.12 This suggests with simultaneous increase in insulin secretion. Bariatric that fatty liver is a risk factor for T2DM and increases the surgery leads to fat mobilization from various tissues and risk of development of T2DM by 2–3 folds. The risk of liver/pancreas are the earliest targets of mobilization development of T2DM may be even higher in patients leading to reduction in liver and PF causing improvement with more severe liver disease which suggests that fibrosis in insulin sensitivity and insulin production. Hence, increases the risk. About 30% patients with cirrhosis of improvement in blood glucose in post-bariatric surgery liver have diabetes.13 patients occurs early even before body weight loss and this improvement in blood glucose has linear correlation with Evidence Suggesting Fatty Liver reduction in fat content of liver and improved sensitivity Leads to T2DM to insulin and the normalization of fasting blood glucose Over the past 15 years there have been numerous 8 which occurred within 7 days. PF content reduction observational studies suggesting that fatty liver is an occurred in 8 weeks and was accompanied by restoration independent risk factor for development of diabetes 9 of first phase insulin. (Table 1). Treatment of Fatty Liver can Ameliorate IR Secondary Diabetes is Related to and Prevent Diabetes Liver Disease In a rodent model, it was found that there was early Liver is the most important organ for regulation of blood development of hepatic IR without significant changes sugar. It is therefore, a simple understanding that chronic in insulin-stimulated glucose utilization or body weight liver disease is associated with impaired glucose tolerance in rodents fed with high fat diet.10 In a study in T2DM and development of diabetes. Glucose intolerance can be patients subjected to a moderately hypocaloric and very seen in about 80% of patients, and diabetes in about 30– low-fat diet, 81% reduction in intrahepatic fat content 60% of patients with chronic liver disease.14,15 Apart from and improvement in basal and insulin-stimulated hepatic fatty liver disease, other conditions like hemochromatosis, glucose metabolism was noted; however, effects on cystic fibrosis, chronic liver disease due to alcohol abuse, insulin-stimulated peripheral glucose uptake were chronic hepatitis C, and glycogen storage disorders are not significant.11 So dietary modification can improve also associated with development of diabetes.

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TABLE 1 Observational studies of the association between NAFLD and T2DM

Study Study population Length of follow-up Main findings (diagnosis)

Fan et al. (2007) Age and sex matched 1,146 7 years, ultrasound based Higher incidence of T2DM in NAFLD group Chinese study individuals with and without NAFLD NAFLD diagnosis (OR 4.6, 95% CI 3.0–7.1)

Shibata et al. (2007) 3,189 male ≥ 40 years age 8 years, ultrasound based NAFLD significantly increases the risk of Japanese study NAFLD diagnosis T2DM (HR 5.5, 95% CI 3.6–8.5)

Kim et al. [2008] 5,372 individuals 5 years, ultrasound based NAFLD was independent risk factor for T2DM South Korean study NAFLD diagnosis (HR 1.51, 95% CI 1.04–2.20).

Yamada et al. (2010) 12,375 individuals 5 years, ultrasound based Fatty liver is independent risk factor for Japanese study NAFLD diagnosis development of T2DM (OR 1.91, 95% CI 1.56–2.34)

Sung et al. (2011) 11,091 individuals 5 years, ultrasound based Increased risk of T2DM in NAFLD (OR 2.05, South Korean Study NAFLD diagnosis 95% CI 1.3–3.1)

Bae et al. (2011) 7,849 individuals 5 years, ultrasound based Increased risk of T2DM in NAFLD (HR 1.33, South Korean Study NAFLD diagnosis 95% CI 1.07–1.66)

Sung et al. (2012) 12,853 individuals 5 years, ultrasound based NAFLD was independently associated with South Korean Study NAFLD diagnosis incident T2DM (OR 2.42, 95% CI 1.7–3.36)

Ekstedt et al. (2006) Retrospective study, 13.7 years, liver biopsy At follow-up, 58% of patients developed Swedish study 129 individuals based NAFLD diagnosis T2DM and 20% developed impaired glucose tolerance

Alessandro Mantovani, 19 observational studies Median 5 years NAFLD associated with two fold increase risk et al. (2018) (296,439 individuals) of diabetes Meta-analysis

Sung et al. (2019) 70,303 adults 3.3 years Diabetes risk increased with increasing South Korean Study insulin resistance (HR-6.6)

Flowchart 2: Triumvirate pathology of T2DM Conclusion The traditional triumvirate features in the pathogenesis of diabetes, viz. IR, diminished insulin release from pancreatic islet beta cells and increased hepatic glucose output (Flowchart 2) gave way to the ominous octet proposed by deFronzo in his Banting Lecture a decade back.16 However, it is imperative to note that the triumvirate features had the liver contributing to categorically all the features. The octet may provide the treating physicians with different ways to tackle the treatment of diabetes, but it will be pertinent to understand that the liver- pancreas axis is involved in most of the features of the octet. Thus, liver is an important organ involved in glucose homeostasis and plays an important role in the pathogenesis of T2DM. In fact, reversal of fatty liver may help ameliorate IR, and may aid in the prevention of development of type 2 diabetes. Thus, fatty liver may be considered the main organ responsible for IR and T2DM. Diabetes should be considered a reversible metabolic state due to excess intra-organ fat especially fatty liver.

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References 9. Steven S, Hollingsworth KG, Small PK, et al. Weight loss decreases excess pancreatic triglycerol specificallty in type 2 diabetes. 1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Diabetes Care. 2016:39;158-65. Gastroenterol Hepatol. 2013;10:686-90. 10. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin 2. Patel H, Verma YN. Prevalence of non-alcoholic fatty liver disease in resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004; type-2 diabetes mellitus patients. Int J Res Med Sci. 2018;6:1322-6. 279:32345-53. 3. Douros JD, Tong J, D’Allesio D. The effects of bariatric surgery on 11. Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic islet function, insulin secretion, and glucose control, endocrine hepatic steatosis, hepatic insulin resistance, and hyperglycemia reviews. Endocr Rev. 2019;40(5):1394-1423. by moderate weight reduction in patients with type 2 diabetes. 4. Steven S, Hollingsworth KG, Al-Mrabh A, et al. Very low-calorie Diabetes. 2005;54:603-8. diet and 6 months of weight stability in type 2 diabetes: 12. Gastadelli A, Cusi K. From NASH to diabetes and from diabertes to pathophysiological changes in responders and non responders. NASH: mechanisms and treatment options. JHEP Rep. 2019;1(4): Diabetes Care. 2016;39(5):808-15. 312-28. 5. Wang CY, Ou HY, Chen MF, et al. Enigmatic ectopic fat: prevalence 13. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, et of nonalcoholic fatty pancreas disease and its associated factors in al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical a Chinese population. J Am Heart Assoc. 2014;3:e000297. implications and management. World J Gastrenterol. 2009:15(3) 6. Idilman IS, Tuzun A, Savas B, et al. Quantification of liver, pancreas, 280-8. kidney and vertebral body MRI-PDFF in non alcoholic fatty liver 14. Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev. disease. Abdom Imaging. 2015;40;1512-9. 1994;2:1-18. 7. Jaghutriz B, Wagner R, Machann J. Association of pancreatic fat with 15. García-Compean D, Jaquez-Quintana JO, Maldonado-Garza H. impaired insulin secretion depends on liver fat and circulating fatty Hepatogenous diabetes: current views of an ancient problem. Ann acids. Diabetes. 2018:67(Suppl 1). Hepatol. 2009;8:13-20. 8. Lim EL, Hollingworth KG, Arbisala BS, et al. Normalisation of beta 16. DeFronzo RA. From the triumvirate to the ominous octet: a new cell function in association with decreased pancreas and liver paradigm for the treatment of type 2 diabetes mellitus. Diabetes. triglycerol. Diabetologia. 2011;54:2506-14. 2009;58:773-95.

Section-10.indb 792 28-01-2021 12:10:36 CHAPTER Non-Pharmacological Management of NAFLD/NASH (Diet, Exercise, and Role of 125 Intermittent Fasting)

Sundeep Kumar Goyal

Abstract Nonalcoholic fatty liver disease (NAFLD) and its complications are growing with increasing prevalence of obesity. Multiple factors and pathways are involved in pathogenesis of disease. In the absence of effective pharmacotherapy that addresses all or most of the components of disease and reverses the inflammation and fibrosis, primary approach to treat NAFLD focuses on promoting weight loss through diet and lifestyle interventions. The choice of therapy is dependent on degree of overweight, comorbidities, and patient preferences. This chapter will review the dietary therapy and lifestyle changes of NAFLD.

Introduction with imbalance between calorie intake and expenditure that leads to obesity, insulin resistance, and other Nonalcoholic fatty liver disease (NAFLD) and its metabolic disorders.2 Obesity doubles the prevalence of complications are growing with increasing prevalence of NASH and its progression to cirrhosis, liver failure, and obesity worldwide. Under the umbrella of NAFLD, there hepatocellular carcinoma (HCC).3 Prior to development of are two histological phenotypes: cirrhosis, clinical outcomes of disease are mostly related to „„ Steatosis (nonalcoholic fatty liver, NAFL) and cardiovascular system. With the advancement of fibrosis „„ Steatosis with inflammation, ballooning and fibrosis stage or cirrhosis development, liver-related outcomes (nonalcoholic steatohepatitis, NASH). increase exponentially.4 The ideal goal of treatment NAFLD often occurs concomitantly with other end is to subside inflammation, regression of fibrosis, and organ diseases like diabetes, hypertension, coronary cirrhosis with simultaneously addressing concomitant artery disease, and chronic kidney disease. These are metabolic disorders and cardiovascular mortality.5 often connected to common biology linked to metabolic Histology based data have showed that weight loss is the stress and systemic inflammation. So term NAFLD is only modality at present that has favorable impact on proposed to rename as metabolic dysfunction associated reducing hepatic as well as extrahepatic complications.6,7 fatty liver disease (MAFLD) to give clearer concept of In a prospective study of 293 patients, degree of weight liver manifestations of this multisystem disease.1 Natural loss was independently associated with improvements in history of disease is influenced by various factors like age, all NASH-related histological parameters.8 Nevertheless, sex, ethnicity, diet, hormonal status, genetic, epigenetic in the study just 10% of patients reached a 10% weight loss factors, gut microbiome, alcohol, and metabolic status and 70% of the cohort did not lose 5% of total body weight and leads to heterogeneous clinical phenotype. (Fig. 1). Aim and objectives of dietary restriction and exercise: Approximately 22 kcal/kg (±20%) is required to Patients with NAFLD/MAFLD are metabolically unhealthy maintain a kilogram of body weight in a normal-weight

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cause rapid weight loss, due to breakdown of glycogen, ketosis development, and fluid loss. In addition, very low- carbohydrate diets are associated with a small increase in energy expenditure.14 Side effects may be more with low- carbohydrate diet like constipation, headache, muscle cramps, diarrhea, weakness, and rash. There is some data to suggest that low-carbohydrate diet have early weight independent effect on liver steatosis and insulin resistance but after more than 7% weight loss this benefit is similar like hypocaloric low-fat diet.15 A low-carbohydrate diet may be planned either by reducing the total amount of carbohydrate or by 8 Fig. 1: Effect of weight loss on NASH consuming foods with a lower glycemic index (GI) or glycemic load. High-glycemic-load foods increase postprandial glycemia and insulinemia, particularly in adult. An average deficit of 500 kcal/day should result patients with insulin resistance. Since the duration of post- in an initial weight loss of about 0.5 kg/week. Both lean meal satiety is related to postprandial glycemia, low-GI body mass and body fat decreases with weight loss and foods have been hypothesized to reduce hunger signals reach plateau after 3–6 months. Further caloric restriction and delay the onset of the next meal. Meals with high GI and increased physical activity required to overcome this were found to be associated with high-grade liver steatosis plateau effect.9 Aim of weight loss is to preserve muscle (assessed by ultrasound), particularly in insulin-resistant mass and decrease visceral fat. subjects.16 Types of diet: Planning a diet requires the selection of Fructose: Fructose mainly derived from table sugar (50% caloric intake and then choice of foods according to fructose) and corn syrup (55% fructose). High intake of local culture and palatability. Replacement of food by sugar-sweetened foods in general contributes to weight low-calorie meals containing 250–350 kcal/package in gain and high liver fat due to their high-energy density, form of nutrition bars, frozen food, and prepackaged glycemic load, and palatability. Fructose role has been meals resulted in early initial weight loss, which then implicated in alteration of gut microbiome, increasing 10 was maintained over long term (4 year follow-up). gut permeability, endotoxemia and hyperuricemia.17,18 The Mediterranean diet includes consuming high Soft drinks contain caramel coloring rich in advanced level of monounsaturated fat relative to saturated fat; glycation end products, which increases insulin resistance moderate consumption of alcohol, mainly as wine, a high and liver injury.19 consumption of vegetables, fruits, legumes, and grains, a Fat: The quality of fat consumed and its food sources moderate consumption of milk and dairy products, mostly appear to be more important for health than total fat in the form of cheese, and a relatively low intake of meat intake. Trans fatty acids and saturated fatty acids have and meat products. Adherence to the Mediterranean been associated with metabolic derangement (increase dietary pattern leads to a significant decrease in liver fat LDL, low HDL), and an elevated cardiovascular risk.20 and insulin resistance among overweight patients with Saturated fat promotes visceral and liver fat deposition.21 NAFLD.11 Assessment of dietary pattern in NASH patients showed higher saturated fat and cholesterol intake and lower Dietary Composition polyunsaturated fatty acids (PUFA), fiber, vitamin C and E Carbohydrate: Low- and very low-carbohydrate (60–130 consumption.22 gm and <60 gm, respectively) diets have been more Monounsaturated fatty acids (oleic acid, palmitoleic effective for short-term weight loss than low-fat diets, but acid in canola and olive oil) consumption favors not for long-term weight loss, compared with a low-fat accumulation of fat in adipose tissues rather than the diet.12,13 Restriction of carbohydrates less than 50 gm/day- liver in animal models.23 In type 2 diabetic patients, an

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isocaloric diet enriched in MUFA compared with a diet 125% consumed on “feast” days) and time-restricted higher in carbohydrate and fiber was associated with a feeding (TRF) (cessation of eating by a certain time significant fat reduction in liver (measured by proton each day) have been used as approaches to weight loss. magnetic resonance spectroscopy) despite a stable Short-term TRF trials have shown that the alignment of weight in both groups.24 Polyunsaturated fatty acids (n- the feeding period with circadian rhythms may result in 6: linoleic acid, arachidonic acid and n-3: α-linolenic weight loss and improve metabolic parameters.35 The acid, eicosapentaenoic acid, docosahexaenoic acid) mechanisms by which intermittent fasting affect health are abundant in fish oil. Low intake n-3 fatty acids and may include improved insulin sensitivity and anti- higher n-6/n-3 ratio is found in NAFLD patients than inflammatory effects. healthy controls.25 It is associated with a proinflammatory Summary of diet recommendations for NASH:2 state and increased lipogenesis leading to steatosis.26 „„ Calorie restriction (500–1000 kcal/day) Conversely, n-3 PUFAs down-regulate sterol regulatory „„ Low-carbohydrate (<40%) diet—replace calories with element binding protein 1c (SREBP-1c) and up-regulate PUFA, MUFA peroxisome proliferator activated receptor α (PPAR-α) „„ Low-fat diet—replace calories with low-GI foods that would favor fatty acid oxidation and reduce steatosis.27 „„ Reduce trans FA (<1%), saturated fats (<7%), and PUFA Supplementation is effective in reducing total liver cholesterol (<200 mg/day) fat but not beneficial in histological improvement in terms „„ Proteins from fish, poultry, nuts, and legumes & restrict of inflammation and fibrosis.28 unprocessed red meats (<300 g/week), processed High cholesterol consumption (>500 mg/day) was meats (<2/week) associated with higher risk of cirrhosis or liver cancer, „„ Increase the intake of cereal-derived non-soluble fiber instead of total fat consumption.29 (whole grain) (25 g/day) Protein: High-protein diets have been recommended for „„ Vegetables (3–5 servings/day), fruits (2–4 servings/ the treatment of obesity because they are more satiating day), nuts (4 servings/week), olive oil, and low-fat and stimulate thermogenesis. Higher-protein diets dairy products. may improve weight maintenance. Total red meat and processed red meat intake are both positively associated Physical Activity 30 with risk of coronary artery disease. Sedentary behavior is a component of reduced life Fiber has several beneficial metabolic effects, including expectancy. The energy expenditure is sum of resting increased satiety, increased incretin secretion, reduced metabolic rate (RMR), the thermic effect of feeding (TEF), absorption rate of CHO and proteins, modulation of gut and physical activity. Exercise (aerobic and resistance) is microbiota, and increased fermentation products, such as planned form of physical activity. While it may be difficult butyrate. to lose weight with exercise alone, exercise programs Increased coffee consumption has been associated added to moderate to severe caloric restriction have inversely with the risk of cirrhosis or progression of fibrosis additional effect upon weight loss.36 If a patient burn 100 31 but not with steatosis. In epidemiological studies, coffee calories during exercise each day (700 calories per week), consumption is associated with a lower risk of metabolic it would take almost 5 weeks to utilize the energy (3,500 32 syndrome. Animal studies suggest, coffee exerts its calories) in half kg of fat. Exercise alone, in the absence of effects by reducing hepatic fat accumulation, systemic and any change in body weight or composition, may enhance 33 liver oxidative stress and liver inflammation. Drinking peripheral insulin sensitivity and glucose homeostasis 34 coffee reduces HCC risk. For the majority of healthy mediated by insulin-receptor up regulation in muscle adults, consuming less than 400 mg of caffeine a day tissue, enhancing whole-body lipid oxidation, decreased appears to be safe. hepatic triglyceride accumulation and lower hepatic FFA uptake (Fig. 2). Increased physical activity attenuates the Intermittent Fasting diet-induced loss of muscle mass, which in turn increases Intermittent fasting strategies, including alternate-day physical functioning and insulin sensitivity.37 Both aerobic fasting (25% of total energy consumed on “fast” days and or resistance exercise are effective in reducing liver

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Fig. 2: Exercise effect in NAFLD and effect on liver, adipose tissue, and muscles

fat.38 The addition of resistance exercise to weight-loss References programs can help prevent the reduction in muscle and . 1 Eslam M, Sanyal AJ, George J, et al. MAFLD: A consensus-driven bone mass. Patients with poor cardiorespiratory reserve proposed nomenclature for metabolic associated fatty liver may better tolerate resistance exercise. Weight training disease. Gastroenterology. 2020;158(7):1999-2014. results in greater increases in fat-free mass.39 . 2 Barrera F, George J. The role of diet and nutritional intervention The recommendation by American Heart Association for the management of patients with NAFLD. Clin Liver Dis. of intense cardiorespiratory activity (aerobic & resistance) 2014;18(1):91-112. 3. Barrera FGJ. Non-alcoholic fatty liver disease: more than just ectopic for at least 150 minutes (preferably 300 minutes) per fat accumulation. Drug Discov Today Dis Mech. 2013;10(1-2):47-54. week, or at least 75 minutes (preferably 150 minutes) is 4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis 40 adapted by EASL for NASH patients. The clinician needs stage in nonalcoholic fatty liver disease: systematic review and to be aware for identifying high-risk patients who may meta-analysis. Hepatology. 2017;65(5):1557-65. require a more thorough evaluation before beginning an . 5 Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and exercise program. The major hurdle is obtaining long- opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American term compliance—especially in individuals who are not Association for the Study of Liver Diseases-U.S. Food and Drug accustomed to regular intense exercise. Administration Joint Workshop. Hepatology. 2015;61(4):1392-405. 6. Harrison SA, Fecht W, Brunt EM, et al. Orlistat for overweight subjects Conclusion with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49(1):80-6. The primary approach to treat NAFLD focuses on the control of . 7 Promrat K, Kleiner DE, Niemeier HM, et al. Randomized the underlying risk factors like diabetes, hyperlipidemia, obesity, controlled trial testing the effects of weight loss on nonalcoholic and other comorbidities through diet and lifestyle changes. steatohepatitis. Hepatology. 2010;51(1):121-9. After the initial weight-loss phase, the weight-maintenance . 8 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight phase is key for preventing long-term complications. Strategies loss through lifestyle modification significantly reduces features of to enhance long-term adherence to lifestyle interventions, with nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367-78. a multidisciplinary approach should be included. 9. Hall KD, Sacks G, Chandramohan D, et al. Quantification of the effect of energy imbalance on bodyweight. Lancet. 2011;378(9793):826-37.

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10. Flechtner-Mors M, Ditschuneit HH, Johnson TD, et al. Metabolic 26. Molendi-Coste O, Legry V, Leclercq IA. Why and how meet and weight loss effects of long-term dietary intervention in obese n-3 PUFA dietary recommendations? Gastroenterol Res Pract. patients: four-year results. Obes res. 2000;8(5):399-402. 2011;2011:364040. 11. Ryan MC, Itsiopoulos C, Thodis T, et al. The mediterranean diet 27. Pettinelli P, Del Pozo T, Araya J, et al. Enhancement in liver SREBP-1c/ improves hepatic steatosis and insulin sensitivity in individuals with PPAR-alpha ratio and steatosis in obese patients: correlations with non-alcoholic fatty liver disease. J hepatol. 2013;59(1):138-43. insulin resistance and n-3 long-chain polyunsaturated fatty acid 12. Bueno NB, de Melo IS, de Oliveira SL, et al. Very-low-carbohydrate depletion. Biochim Biophys Acta. 2009;1792(11):1080-6. ketogenic diet v. low-fat diet for long-term weight loss: a meta- 28. Parker HM, Johnson NA, Burdon CA, et al. Omega-3 supplementation analysis of randomised controlled trials. Br j nutr. 2013;110(7): and non-alcoholic fatty liver disease: a systematic review and meta- 1178-87. analysis. J Hepatol. 2012;56(4):944-51. 13. Hu T, Mills KT, Yao L, et al. Effects of low-carbohydrate diets versus 29. Ioannou GN, Morrow OB, Connole ML, et al. Association between low-fat diets on metabolic risk factors: a meta-analysis of randomized dietary nutrient composition and the incidence of cirrhosis or liver controlled clinical trials. Am J Epidemiol. 2012;176(Suppl 7):44-54. cancer in the United States population. Hepatology. 2009;50(1): 14. Hall KD, Chen KY, Guo J, et al. Energy expenditure and body 175-84. composition changes after an isocaloric ketogenic diet in 30. Bernstein AM, Sun Q, Hu FB, et al. Major dietary protein sources overweight and obese men. The Am J Clin Nutr. 2016;104(2):324-33. and risk of coronary heart disease in women. Circulation. 15. Kirk E, Reeds DN, Finck BN, et al. Dietary fat and carbohydrates 2010;122(9):876-83. differentially alter insulin sensitivity during caloric restriction. 31. Bambha K, Wilson LA, Unalp A, et al. Coffee consumption in NAFLD Gastroenterology. 2009;136(5):1552-60. patients with lower insulin resistance is associated with lower risk of 16. Valtuena S, Pellegrini N, Ardigo D, et al. Dietary glycemic index and severe fibrosis. Liver Int. 2014;34(8):1250-8. liver steatosis. Am J clin nutr. 2006;84(1):136-42. 32. Shang F, Li X, Jiang X. Coffee consumption and risk of the metabolic 17. Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver syndrome: a meta-analysis. Diabetes Metab. 2016;42(2):80-7. disease. Hepatology. 2013;57(6):2525-31. 33. Vitaglione P, Morisco F, Mazzone G, et al. Coffee reduces liver damage 18. Choi JW, Ford ES, Gao X, et al. Sugar-sweetened soft drinks, diet in a rat model of steatohepatitis: the underlying mechanisms soft drinks, and serum uric acid level: the Third National Health and the role of polyphenols and melanoidins. Hepatology. and Nutrition Examination Survey. Arthritis Rheum. 2008;15;59(1): 2010;52(5):1652-61. 109-16. 34. Setiawan VW, Wilkens LR, Lu SC, et al. Association of coffee intake 19. Hyogo H, Yamagishi S, Iwamoto K, et al. Elevated levels of serum with reduced incidence of liver cancer and death from chronic advanced glycation end products in patients with non-alcoholic liver disease in the US multiethnic cohort. Gastroenterology. steatohepatitis. J Gastroenterology and Hepatol. 2007;22(7):1112-9. 2015;148(1):118-25. 20. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart 35. Stockman MC, Thomas D, Burke J, et al. Intermittent fasting: is the disease of increasing polyunsaturated fat in place of saturated fat: wait worth the weight? Curr Obes Rep. 2018;7(2):172-85. a systematic review and meta-analysis of randomized controlled 36. Catenacci VA, Wyatt HR. The role of physical activity in producing trials. PLoS Medicine. 2010;23;7(3):e1000252. and maintaining weight loss. Nat Clin Pract Endocrinol Metabol. 21. Rosqvist F, Iggman D, Kullberg J, et al. Overfeeding polyunsaturated 2007;3(7):518-29. and saturated fat causes distinct effects on liver and visceral fat 37. Pownall HJ, Bray GA, Wagenknecht LE, et al. Changes in body accumulation in humans. Diabetes. 2014;63(7):2356-68. composition over 8 years in a randomized trial of a lifestyle 22. Musso G, Cassader M, Rosina F, et al. Impact of current treatments intervention. Obesity. 2015;23(3):565-72. on liver disease, glucose metabolism and cardiovascular risk in non- 38. Bacchi E, Negri C, Targher G, et al. Both resistance training and alcoholic fatty liver disease (NAFLD): a systematic review and meta- aerobic training reduce hepatic fat content in type 2 diabetic analysis of randomised trials. Diabetologia. 2012;55(4):885-904. subjects with nonalcoholic fatty liver disease. Hepatology. 23. Bessesen DH, Vensor SH, Jackman MR. Trafficking of dietary oleic, 2013;58(4):1287-95. linolenic, and stearic acids in fasted or fed lean rats. Am J Physiol 39. Ballor DL, Keesey RE. A meta-analysis of the factors affecting Endocrinol Metabol. 2000;278(6):1124-32. exercise-induced changes in body mass, fat mass and fat-free mass 24. Bozzetto L, Prinster A, Annuzzi G, et al. Liver fat is reduced by an in males and females. Int J Obes. 199115(11):717-26. isoenergetic MUFA diet in a controlled randomized study in type 2 40. European Association for the Study of the Liver (EASL); European diabetic patients. Diabetes Care. 2012;35(7):1429-35. Association for the Study of Diabetes (EASD); European Association 25. Cortez-Pinto H, Jesus L, Barros H, et al. How different is the dietary for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice pattern in non-alcoholic steatohepatitis patients? Clin Nutr. Guidelines for the management of non-alcoholic fatty liver disease. 2006;25(5):816-23. J Hepatol. 2016;64(6):1388-402.

MU-125.indd 797 29-01-2021 15:00:02 CHAPTER

Medical Management of 126 Acute Pancreatitis

D Nageshwar Reddy, Hardik Rughwani

Abstract Acute pancreatitis is a common disease, major etiologies being gallstones or alcohol ingestion. Diagnosis is based on clinical symptoms, elevated pancreatic enzymes, and imaging findings. Revised ATLANTA classification (2013) has defined the types, severity, organ failure, and complications of acute pancreatitis. Majority of patients have self-limiting disease while some may develop severe disease, causing organ failure and complications such as pseudocyst or wall-off necrosis (WON). Treatment involves early enteral nutrition, intravenous fluids, analgesics, with avoidance of use of antibiotics. Endoscopic and/or surgical interventions are required in case of complicated unresolving pancreatic collections.

Introduction includes assessment of the severity clinically and provides objective terms to define the local complications of AP, Acute pancreatitis (AP) is a common gastrointestinal tract which are described as follows. (GIT) disease causing enormous physical, emotional, and socioeconomic human burden. The first clinical description of AP was given by Dutch anatomist Nicholaeus Definitions and Classification: Proposed Tulp in 1652. Incidence of AP varies from 30–80/100,000 to be Used in Clinical and Research population. In India, approximately 74% of patients of Communications AP are men with the mean age being 40 years, which is a younger age group compared to other parts of the world. Diagnosis of AP The diagnosis of AP requires two out of following three Definitions1 features: „„ Pain abdomen suggestive of AP (acute onset severe, ATLANTA classification defining the severity and persistent, epigastric pain, aggravated with food complications of AP was first described in 1992. Since intake, and radiating to the back); then there has been continuing research in this field and „„ Pancreatic enzymes activity (serum lipase and serum has resulted in improvement of knowledge about the amylase) more than three times elevated than normal disease process, and hence management of AP. Also, there range; and has been a major improvement in imaging modalities, „„ Imaging findings on contrast-enhanced computerized which has helped to classify and define disease severity tomography (CECT), magnetic resonance imaging and complications in a clarified way as a part of revised (MRI), or trans abdominal ultrasonography, showing ATLANTA classification proposed in 2013. This revision characteristic changes of AP.

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Routinely use of CECT in patients of AP is unjustified, Complications as the diagnosis is apparent and most patients have a mild, non-complicated course. But if there is lack of Organ Failure—Definition improvement after 48–72 hours (e.g., persistent pain, Organ failure is defined based on the assessment of three nausea, fever, inability of start oral feeds), imaging using major organ systems: CECT or MRI is recommended for assessment of local „„ Cardiovascular complications such as peripancreatic fluid collection or „„ Respiratory, and pancreatic necrosis. „„ Renal. Modified Marshall scoring system (Table 1) is used to define organ failure. Onset of AP Local Complications—Definition The onset of AP is defined by the time when the typical The concept of local complications following AP was abdominal pain first begins and not by the time when defined by the Original ATLANTA classification (1992). patient first seeks hospital care. This time of onset of pain Since then with the advancement of the understanding abdomen is crucial to define the further complications of of pathophysiology and improvement of imaging has led AP. to better characterize the local complications as acute peripancreatic fluid collection, pancreatic pseudocyst Types of AP (Fig. 1), acute necrotic collection, and walled-off necrosis AP can be subdivided into two types based on presence or (Fig. 2) based on the presence and absence of necrosis absence of necrosis: and time from the onset of pain abdomen, each of which „„ Interstitial pancreatitis—in the absence of pancreatic has been defined by the revised ATLANTA classification1 necrosis, the edematous pancreas in mild disease, is (2013) (Table 2). Gastric outlet obstruction, splenic vein defined as interstitial pancreatitis; and portal vein thrombosis are some of the other local „„ Necrotizing pancreatitis—in about 5–10% of patients, complications of AP. AP evolves to produce necrosis of pancreatic parenchyma, the peripancreatic tissue or both. Systemic Complications—Definition Pancreatic necrosis is defined as focal or diffuse areas Any exacerbation of previous comorbid conditions such as of nonviable parenchyma which is 30% of the pancreas or chronic lung disease, or coronary artery disease, by AP is 3 cm in size. defined as systemic complications.

TABLE 1 Modified Marshall scoring system1

Organ systems Scores 0 1 2 3 4

Respiratory (FiO2/PaO2) >400 301–400 201–300 101–200 ≤100 Renal (creatinine mg/dL) <1.4 1.4–1.8 1.9–3.6 3.6–4.9 >4.9 Cardiovascular (systolic BP mm Hg) >90 <90, fluid <90, not fluid <90, pH<7.3 <90, pH<7.2 responsive responsive

FiO2 calculation for non-ventilated patients

Supplemental oxygen (L/min) FiO2 (%) Room air 21 2 25 4 30 6–8 40 9–10 50

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Fig. 1: Contrast enhanced CT axial images showing small Fig. 2: Contrast enhanced CT axial images showing large pseuodcysts in the uncinate process and neck of pancreas peripancreatic walled off necrosis (WON) around body and tail of pancreas

TABLE 2 Terminology based on fluid collection1 (local complications)

Type of pancreatitis First 4 weeks After 4 weeks Interstitial pancreatitis Acute peripancreatic fluid collection Pseudocyst Necrotizing pancreatitis Acute necrotic collection (ANC) Walled off necrosis (WON)

Phases2 (MOF) is defined when more than one organ develops failure. The disease process of AP is not fixed and can vary from patient to patient. Arbitrarily the disease course can be divided into two overlapping phases with two peaks of Late Phase mortality: Early and Late phase. These two phases are By definition, the late phase occurs only in patients with considered separately. moderately severe or severe AP. It is characterized by the persistence of local complications or systemic signs of Early Phase inflammation. The early phase involves first week of disease presentation, but may sometimes be prolonged into the second week Severity of AP—Definition also. During the early phase, manifestations are due It is prudent to define and distinguish patients of AP based to the response to local pancreatic inflammation and on severity. The ATLANTA classification has defined three injury. Pancreatic inflammation, in turn, activates major types of severity—mild, moderate, and severe AP cytokine cascade, which clinically manifests as systemic (Table 4). inflammatory response syndrome (SIRS) (Table 3). There is an increased risk of developing organ failure if SIRS is 2 persistent. The presence and duration of organ failure in Etiology the early phase determines the severity of AP. If the organ The most common causes of AP are gallstones (40– failure resolves within 48 hours, it is defined as “Transient 70%) and alcohol (25–35%). Other etiologies being post organ failure,” and if it persists for more than 48 hours, it ERCP (5%), post trauma, especially in children (1%), is defined as “Persistent organ failure.” Multiorgan failure idiopathic (25%), and miscellaneous (5%). Alcohol-related

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TABLE 3 SIRS1 TABLE 4 Grades of severity1,2

Signs of systemic inflammatory response syndrome (SIRS) Severity Local/systemic Organ failure complications SIRS—defined by presence of two or more criteria: Mild acute No No zz Heart rate >90 beats/min zz Core temperature <36°C or >38°C Moderately acute Yes Transient (<48 hrs) 3 zz White blood count <4000 or >12000/mm Severe acute Yes Yes (>48 hrs) zz Respirations >20/min or PCO2 <32 mm Hg (15–20%)

pancreatitis usually manifests as a spectrum, ranging from Fluid Resuscitation—Importance of distinct episodes of AP to chronic pancreatitis causing Intravenous Hydration irreversible changes silently. Multiple factors are responsible for often causing hypovolemia in patients affected by AP, such as vomiting, Risk Stratification and Predicting Severe AP third space loss, decreased oral intake, diaphoresis, and For initial management and hospitalization, laboratory increased respiratory losses. Besides, inflammation of investigations and imaging studies can be useful but pancreas causes pancreatic edema and microcirculatory are unreliable to predict the severity of AP. Laboratory effects causing decreased blood flow, which in turn investigations like hematocrit, blood urea nitrogen (BUN), causes cell death, pancreatic tissue necrosis and creatinine or CRP in the 1st 48 hours can be normal. Also, pancreatic enzymes release, activating further numerous cross sectional imaging cannot determine severity early in inflammatory cascades. disease course as necrosis is usually absent on admission In AP, there is a median fluid loss of 3.2 liters.4 and may take 2–3 days to develop. Thus, as there is an The fluid should be given as 15–20 mL/kg bolus dose absence of any definite test to determine the severity of AP, followed by 1.5–3 mL/kg/hour, depending on the clinical assessment of third space fluid losses, shock and response for the first 12–24 hours. Although the most signs and symptoms suggestive of organ dysfunction is of effective approach to early fluid resuscitation has yet paramount importance. to be determined, studies have suggested that lactated Ringer’s maybe the preferred solution for initial Management (Flowchart 1) hydration.5 Owing to its bicarbonate content and stable pH, this isotonic solution, when compared to normal Pain Management (Analgesia) saline, may prevent the development of metabolic Abdominal pain is the presenting and distressing symptom acidosis, which can complicate care in patients receiving in patients with AP. Effective and successful analgesia is an large-volume resuscitation using isotonic saline. important component of the management of AP. An added Also, there are theoretical advantages in stabilizing desirable effect of the analgesic could be its impact on the the pancreas by preventing acidosis, which increases underlying inflammatory process. Both opioid analgesics degranulation, enzyme release. The goal of fluid therapy and nonsteroid anti-inflammatory agents (NSAIDs) have is to achieve a mean arterial BP of minimum 70 mm been used in patients with AP for pain relief. However, Hg, hematocrit of 40–42, urine output—0.5–1 mL/min.6 the evidence for their efficacy and safety profile is limited. Monitoring of fluid therapy can be done using invasive The concern with NSAIDs is adverse events such as methods like central venous pressure, stroke volume, gastrointestinal bleeding and acute kidney injury. Opiates arterial pressure wave-form, and noninvasive methods have shown by a randomized controlled trial to have better like IVC diameter: <1.5 cm or >50% index-deficit, lung analgesic effect and safety profile compared to NSAIDs3 for ultrasound for fluid overload. Elderly patients and those AP. Nalbuphine (an opioid with µ receptor antagonism) is with history of cardiac and/or renal disease should be a latest armamentarium useful for AP pain. taken carefully resuscitated.

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Flowchart 1: Management of acute pancreatitis

CT, computerized tomography; ERCP, endoscopic retrograde cholangiopancreatography; FNA, fine needle aspiration; IV, intravenous; NBM, nil by mouth; NG, nasogastric; NJ, nasojejunal; SIRS, systemic inflammatory response syndrome12

Antibiotics—Role in AP Management improvement and having persistent fever and increasing Routine use of prophylactic antibiotics in patients with WBC counts, infected pancreatic or peripancreatic mild AP and also severe AP is not recommended. Also, necrosis should be suspected. Serum procalcitonin may in patients having sterile necrosis, the use antibiotics to be helpful as a useful marker. In these patients, there are prevent the evolution of infection is not recommended. two ways to manage: (a) CT-guided fine needle aspiration After 7–10 days of hospital stay, in patients with lack of (FNA) with culture sensitivity can be used to start suitable

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antibiotics, or (b) Empirical use of antibiotics can be done Endoscopic Retrograde Cholangiopancreatography after obtaining necessary blood or urine culture sensitivity (ERCP)–Role in AP for disease causing agents, without CT-guided FNA. As per the latest recommendations, patients with Infected necrosis warrants use of antibiotics which can concurrent AP and acute cholangitis with high clinical penetrate the necrosis, such as carbapenems, quinolones, suspicion of choledocholethiasis should undergo ERCP and metronidazole, as per the local pattern of sensitivity of organisms. Timely use of antibiotics in such cases can with biliary stenting within 24 hours of admission as a delay or sometimes avoid interventions, hence reducing therapeutic procedure. Usually, in patients with gallstone morbidity and mortality. Evidence of extra-pancreatic pancreatitis who lack laboratory or clinical evidence infections like urinary tract infections, cholangitis, of ongoing biliary obstruction, magnetic resonance catheter-acquired infections, bacteremia, and pneumonia cholangiopancreatography (MRCP) or endoscopic necessitates antibiotics. Routinely antifungal agents ultrasound (EUS) rather than ERCP should be used to along with antibacterial agents (used for prophylaxis or screen for choledocholithiasis. treatment) are not recommended. Also, ERCP on one hand, it can be a therapeutic modality for biliary pancreatitis, while on the other hand, Nutrition in AP it can be an important and preventable etiology of AP. Traditionally patients having AP were kept nil per mouth The risk of post-ERCP pancreatitis is around 5%. Three (NPO) to theoretically provide rest to the organ. Multiple methods to reduce the risk of post-ERCP pancreatitis, experimental and clinical studies have subsequently especially severe AP include: shown that bowel rest causes mucosal atrophy and „„ Pancreatic duct stents increases infectious complications due to bacterial „„ Use of guidewire for cannulation translocation from the gut. Also, studies have shown that „„ Rectal NSAIDs (diclofenac suppository) pre-procedure. early enteral feeding in the course of AP reduces hospital stay, and hence decreased morbidity. In mild AP, if there is Infected Pancreatic Necrosis absence of vomiting, and if abdominal pain has improved, oral feeds should be started as soon as possible. Oral The step-up approach is recommended with conservative st feeds in mild AP are introduced as a low-fat, low-residue, treatment in ICU 1 followed by percutaneous drainage, 7,8 light diet as the patient improves clinically. Polymeric which is followed by minimally invasive necrosectomy. feeds (feeds containing all major nutrients) are preferred Primarily conservative management results in mortality consisting of 25–30 kcal/kg with 1.2–2 gm/kg protein. In comparable to surgery in patients with infected pancreatic 9 mild as well as severe AP, total parenteral nutrition ideally necrosis. If necrosectomy is required, endoscopic step-up 10,11 should be avoided as it increases chances of infectious approach should be preferred. complications and other peripheral or central line-related complications. Conclusion Use of nasogastric tube for enteral nutrition appears to be safe; however, the use of nasojejunal tube is typically The diagnosis and optimal management of AP requires preferred to avoid gastric phase of pancreatic stimulation. a systematic approach and multidisciplinary decision- Nasogastric tube placement is far easier compared to making. Regardless of pancreatitis severity, recommended the nasojejunal tube (requires fluoroscopic guidance for medical management includes goal-directed intravenous placement and is expensive), which is advantageous for fluid resuscitation, early enteral feeding, avoidance of patients in intensive care unit (ICU) treatment. In patients antibiotics as prophylaxis and urgent ERCP for patients presenting as severe AP, on initial assessment, should with acute biliary pancreatitis complicated by cholangitis. be started on enteral tube feeding as a part of primary Hence to conclude the first 24–48 hours are critical, and hence triaging of these patients on first presentation to therapy. In the late phase of AP (2nd–3rd week) maintaining hospital is an important approach to enable appropriate level nutrition is critical, the target should be to provide 1500– of care. 2000 kcal diet.

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References 6. Haydock MD, Mittal A, Wilms HR, et al. Fluid therapy in acute pancreatitis: anybody’s guess. Ann Surg. 2013;257(2):182-8. 1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute 7. Jiang K, Huang W, Yang X-N, et al. Present and future of prophylactic pancreatitis-2012: revision of the Atlanta classification and antibiotics for severe acute pancreatitis. World J Gastroenterol WJG. definitions by international consensus. Gut. 2013;62(1):102-11. 2012;18(3):279-84. 2. Tenner S, Baillie J, DeWitt J, et al. American College of 8. IAP/APA evidence-based guidelines for the management of acute Gastroenterology. American College of Gastroenterology pancreatitis. Pancreatology. 2013;13(4.2):1-15. guideline: management of acute pancreatitis. Am J Gastroenterol. 9. Garg PK, Sharma M, Madan K, et al. Primary conservative treatment 2013;108(9):1400-15. results in mortality comparable to surgery in patients with infected 3. Mahapatra SJ, Jain S, Bopanna S, et al. Pentazocine, a Kappa-Opioid pancreatic necrosis. Clin Gastroenterol Hepatol. 2010;8(12):1089-94. 10. Lakhtakia S, Basha J, Talukdar R, et al. Endoscopic “step-up approach” agonist, is better than diclofenac for analgesia in acute pancreatitis: using a dedicated biflanged metal stent reduces the need for direct a randomized controlled trial. Am J Gastroenterol. 2019;114(5): necrosectomy in walled-off necrosis (with videos). Gastrointest 813-21. Endosc. 2017;85(6):1243-52. 4. de-Madaria E, Banks PA, Moya-Hoyo N, et al. Early factors associated 11. Bang JY, Arnoletti JP, Holt BA, et al. An endoscopic transluminal with fluid sequestration and outcomes of patients with acute approach, compared with minimally invasive surgery, reduces pancreatitis. Clin Gastroenterol Hepatol. 2014;12(6):997-1002. complications and costs for patients with necrotizing pancreatitis. 5. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution Gastroenterology. 2019;156(4):1027-40. reduces systemic inflammation compared with saline in patients 12. Feldman M, Friedman L, Brandt L. Sleisenger and Fordtran’s with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-7. Gastrointestinal and Liver Disease, 10th edition. Saunders; 2015.

MU-126.indd 804 29-01-2021 14:59:52 CHAPTER

Functional Gastrointestinal 127 Disorders

Uday C Ghoshal

Abstract Functional gastrointestinal disorders (FGIDs), common problems in GI practice, are diagnosed by symptom-based criteria, such as the most recent iteration by the Rome Foundation, called Rome IV criteria and limited laboratory investigations. However, in presence of alarm symptoms, which may suggest presence of organic diseases, more thorough investigations may be needed. Different FGIDs may overlap in a single patient. The two common subtypes of FGIDs, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), are elaborated in this chapter. Treatment of FGIDs would depend on its subtypes, such as diarrhea- or constipation-predominant IBS or epigastric pain and postprandial distress syndrome subtypes of FD. The treatment also depends on severity of the condition, presence of psychological comorbidity, biological factors, etc.

Introduction released its fourth iteration of Rome criteria in April 2016.3 Experts of Rome Foundation correctly decided to Physicians and Gastroenterologists often encounter underscore term “functional” and consider the gut to be patients with functional gastrointestinal disorders more important than brain in the pathogenesis; hence, the (FGIDs) in their clinical practice. Patients with FGIDs new name for these disorders has been “Disorders of Gut- are diagnosed based on the symptom-based criteria. brain Interaction (DGBI).”3 FGIDs are characterized by the presence of chronic FGIDs are chronic disorders that are not fatal but gastrointestinal (GI) symptoms (at least during the last cause considerable impairment of quality of life, work 3 months with onset at least 6 months previously) in the absenteeism, burden to the society, health care, economy, absence of identifiable structural lesions explaining these and family. Considering the high frequency of these 1 symptoms on investigations including GI endoscopy. disorders in the global population, the magnitude of the It is, however, noteworthy that though the routine problem of FGIDs cannot be underestimated. Hence, investigations, including GI endoscopy, do not pick-up knowledge about the diagnosis and management of these organic lesions in patients with FGIDs, more sensitive disorders at primary and secondary care settings are tests may pick-up subtle structural abnormalities and essential issues that need to be deliberated. Accordingly, molecular aberrations that may explain their symptoms. this chapter will briefly discuss the current classification Hence, in the recent time, it has been considered that of FGIDs, and the diagnostic criteria, and management many of these disorders may be “micro-organic” in nature, of common forms of FGIDs, for example, irritable bowel challenging the concept that these disorders are entirely syndrome (IBS) and functional dyspepsia (FD). The functional or psychogenic.1,2 Rome Foundation, which current classification of FGIDs (Rome IV) is presented in formulates diagnostic and treatment algorithm for FGIDs, Table 1.1,3

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Different categories of functional gastrointestinal disorders according to the most recent iteration of Rome Foundation TABLE 1 (Rome IV classification)

Esophageal disorders zz Functional chest pain zz Globus zz Functional heartburn zz Functional dysphagia zz Reflux hypersensitivity

Gastroduodenal disorders zz Functional dyspepsia zz Nausea and vomiting disorders —— Postprandial distress syndrome (PDS) —— Chronic nausea vomiting syndrome (CNVS) —— Epigastric pain syndrome —— Cyclic vomiting syndrome (CVS) zz Belching disorders —— Cannabinoid hyperemesis syndrome (CHS) —— Excessive supragastric belching zz Rumination syndrome —— Excessive gastric belching Bowel disorders zz Irritable bowel syndrome (IBS) zz Functional constipation —— IBS with predominant constipation (IBS-C) zz Functional diarrhea —— IBS with predominant diarrhea (IBS-D) zz Functional abdominal bloating/distension —— IBS with mixed bowel habits (IBS-M) zz Unspecified functional bowel disorder —— IBS unclassified (IBS-U) zz Opioid-induced constipation zz Centrally mediated disorders of gastrointestinal pain zz Centrally mediated abdominal pain syndrome (CAPS) zz Narcotic bowel syndrome (NBS)/opioid-induced GI hyperalgesia

Gallbladder and sphincter of oddi (SO) disorders zz Biliary pain zz Functional pancreatic SO disorder —— Functional gallbladder disorder —— Functional biliary SO disorder Anorectal disorders zz Fecal incontinence zz Functional defecation disorders zz Functional anorectal pain —— Inadequate defecatory propulsion —— Levator ani syndrome —— Dyssynergic defecation —— Unspecified functional anorectal pain —— Proctalgia fugax Childhood functional GI disorders: Neonate/Toddler zz Infant regurgitation zz Functional diarrhea zz Rumination syndrome zz Infant dyschezia zz Cyclic vomiting syndrome (CVS) zz Functional constipation zz Infant colic Childhood functional GI disorders: Child/Adolescent zz Functional nausea and vomitting disorders zz Functional abdominal pain disorders —— Cyclic vomiting syndrome (CVS) —— Functional dyspepsia —— Functional nausea and functional vomiting Postparandial distress syndrome Functional nausea Epigastic pain syndrome Functional vimiting —— Irritable bowel syndrome (IBS) —— Rumination syndrome —— Abdominal migraine —— Aerophagia —— Functional abdominal pain - NOS zz Functional defecation disorders —— Functional constipation —— Nonretentive fecal incontinence

MU-127.indd 806 29-01-2021 14:59:32 Functional Gastrointestinal Disorders CHAPTER 127 807

A B

Figs. 1A and B: (A) Overlap between common functional gastrointestinal disorders (Source: Reproduced from Reference 4). (B) Summary of results from in Indian rural community study showing overlap between IBS, dyspepsia and different subtypes of dyspepsia (For the data in details, see Reference 5) C, constipation-predominant; D, diarrhea-predominant; EPS, epigastric pain syndrome; FC, functional constipation; FD, functional dyspepsia; FDr, functional diarrhea; IBS, irritable bowel syndrome; PDS, postprandial distress syndrome

In the above classification, the different FGIDs are prokinetic drug such as prucalopride along with fundic considered as pure disorders. However, in practice, more relaxant such as acotiamide. than two-thirds of patients present overlapping symptoms of multiple FGIDs. The various categories of bowel Functional Dyspepsia disorders such as IBS, functional diarrhea, and functional “Dyspepsia” is a Greek word that refers to “bad digestion.” As constipation often overlap with upper GI disorders such per Rome IV criteria, FD is diagnosed using the symptom- 4 as FD and gastroesophageal reflux disease (Fig. 1A). In an based criteria that are listed in Table 2.7 However, if a patient earlier study on 3,426 adult population of rural northern fulfills the symptom-based criteria, he should be considered India, overlap of FD-IBS was commoner (4.1%) than IBS as having uninvestigated dyspepsia. Subsequently, a few alone (2.7%) though FD was the most common form investigations, including upper GI endoscopy, are required of FGID (15%; Fig. 1B).5 Overlap disorders often have a before a diagnosis of FD is made. However, in the absence more severe illness, may require combination treatment, of alarm features discussed later in this chapter, even an and may have a worse prognosis.6 In this chapter, the empirical trial of drug-treatment may be instituted after diagnosis and treatment of two common FGIDs (FD and due consideration by the physician on a case-to-case IBS) are briefly discussed. It is important to note that basis. A firm diagnosis of FD, however, requires an upper several management principles of pure FGIDs, such as GI endoscopy. Though currently, most international those of FD and IBS, would apply to overlap disorders. recommendation warrant tests for Helicobacter pylori and For example, a patient with constipation-predominant its eradication, if present, its universal acceptability in the IBS and postprandial distress syndrome subtype of FD Indian scenario is subject to debate based on the limited is expected to benefit from treatment with a pan-GI available data (Flowcharts 1A and B).7

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subtype is treated with proton pump inhibitors and Rome IV criteria for the diagnosis of functional TABLE 2 dyspepsia (FD)7 when unresponsive, antidepressants, PDS is treated with prokinetics, fundic relaxants, and psychotropic agents. Functional dyspepsia Overlap syndrome is treated with combined therapeutic Diagnostic criteria agents. Table 4 lists the drugs available currently in the 1. One or more of the following: 7 a. Bothersome postprandial fullness Indian market for the treatment of two subtypes of FD. b. Bothersome early satiation c. Bothersome epigastic pain d. Bothersome epigastic burning Irritable Bowel Syndrome No evidence of structural disese (including at upper endoscopy) Diagnosis of IBS that is likely to explain the symptoms IBS is one of the common FGIDs seen in clinical practice  Must fulfill criteira for PDS and/or EPS. both by the Gastroenterologists and the Physicians. IBS was Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. variously called earlier, albeit inappropriately, as spastic colitis, chronic amebiasis, etc. In the past, the diagnosis of IBS could only be made once extensive investigations Epigastric pain syndrome (EPS) and postprandial failed to find a cause for the chronic lower GI symptoms. distress syndrome (PDS) are the two subtypes of FD. In Manning and Thompson, for the first time, introduced the practice, however, patients rarely present with pure EPS criteria-based diagnosis of IBS in 1978.8 Since then, the or PDS, but most patients have overlapping symptoms. Rome Foundation brought in several iterations of Rome The criteria, as suggested by the Rome IV Committee for criteria for the diagnosis of IBS. Manning’s criteria (Box 1) diagnosis of EPS and PDS, are presented in Table 3.7 encourage a positive diagnosis of IBS without the need for multiple unnecessary investigations to exclude organic Management of FD diseases before diagnosing IBS.8 Management of the patients with dyspepsia as per the However, it is essential to note that in the study by Rome IV system is presented in Flowcharts 1A and B. One Manning and Thompson, organic disorders excluded must not forget to look for alarm features (age >45 years, were peptic ulcer disease, inflammatory bowel disease, history of GI bleeding, weight loss, family history of gastric gastroesophageal reflux disease, gallstones, and cancer, anemia, etc.). Patients with a history of alarm carcinoma of the colon and not the conditions which features must undergo thorough investigations including closely mimic IBS such as lactose intolerance, celiac upper GI endoscopy and CT scan of the abdomen (in disease, microscopic colitis, small intestinal bacterial patients with a family history of gastric cancer and overgrowth, fecal evacuation disorder, collagenous colitis a high degree of clinical suspicion of gastric cancer) and microscopic, etc.2,8 Hence, over-reliance on such before considering dyspepsia to be functional.7 It is also symptom-based criteria to exclude every organic disorder important to note that the age cut off of 45 years may vary (some of which are rather micro-organic) may result in depending on the local epidemiology of gastric cancer. overlooking such conditions. Another limitation of the International societies, including experts in the Rome IV Manning criteria is the lack of due consideration for the committee, suggested that H. pylori infection, if present on duration of symptoms. As some of the organic disorders appropriate testing, should preclude the diagnosis of FD. If are expected to have a short duration of symptoms, the eradication of infection improves dyspeptic symptoms, the importance of time of illness cannot be overestimated. condition should instead be called H. pylori-associated However, despite these limitations, Manning’s criteria dyspepsia.7 The applicability of this international guideline remain quite useful and popular in practice not only in India, however, may be viewed with skepticism. Though among Gastroenterologists but also among Physicians. Indian literature on this issue is scanty, yet considering In addition to the higher sensitivity of Manning’s criteria the high frequency of H. pylori infection in Indian adults, as compared to the various iteration of Rome criteria in this strategy may not be practicable. Treatment of FD India,4 the simplicity of the former is a significant reason depends on its subtype. Whereas EPS, an uncommon for its popularity.

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Flowcharts 1A and B: Rome IV algorithm for management of functional dyspepsia

A

B Bx, biopsy; Hp, helicobacter pylori; UGI, upper gastrointestinal

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Rome IV criteria for the diagnosis of epigastric pain Drugs available currently in Indian market for TABLE 3 TABLE 4 and postprandial distress syndromes7 treatment of two subtypes of FD

Postprandial distress syndrome Epigastric pain syndrome Postprandial distress syndrome zz Diagnostic criteria: Must include one or both of the following at zz Omeprazole Fundic relaxants least 3 days per week: zz Pantoprazole zz Acotiamide zz zz —— Bothersome postprandial fullness (i.e., severe enought to Lansoprazole Buspirone impact on usual activities) zz Dexlansoprazole zz Mirtazapine zz Esomeprazole Prokinetics —— Bothersome early satiation (i.e., severe enough to prevent zz Ilaprazole zz Metoclopramide finishing a regular-size meal) zz Rabeprazole zz Domperidone zz No evidence of organic, systemic, or metabolic disease that zz Dexrabeprazole zz Mosapride is likely to explain the symptoms on routine investigations zz Potassium competitive zz Itopride (including at upper endoscopy) acid blocker zz Levosulpiride aCriteria fulfilled for the last 3 months with symptom onset at least zz Cinitapride 6 months before diagnosis zz Prucalopride zz Supportive remarks Visceral neuromodulators —— Postprandial epigastic pain or burning, epigastric bloating excessive belching, and nausea can also be present —— Vomiting warrants consideration of another diorder TABLE 5 Rome IV criteria for IBS9 —— Heartburn is not a dyspeptic symptom but may often coexist —— Symptoms that are relieved by evacuation of feces or gas Recurrent abdominal pain, on average, at least 1 day per week in should generally not be considered as part of dyspepsia the last 3 months, associated with two or more of the following criteria: zz Other individual digestive symptoms or gourps of symptoms, e.g. from gastroesophageal reflux disease and the irritable bowel zz Related to defecation syndrome may coexist with PDS zz Associated with a change in frequency of stool Epigastric pain syndrome zz Associated with a change in form (appearance) of stool zz Diagnositc criteria:a Must include at least 1 of the following Criteria fulfilled for the last 3 months with symptom onset at least symptoms at least 1 day a week: 6 months before diagnosis —— Bothersome epigastric pain (i.e., severe enough to impact on usual activities) AND/OR The Manning criteria that suggest a positive —— Bothersome epigastic burning (i.e., severe enought to impact BOX 1 diagnosis of irritable bowel syndrome if any four of on usual activities) the listed six symptoms are present8 zz No evidence of organic systemic, or metabolic disease that is likely to explain the symptoms on routine investigations zz Onset of pain associated with more frequent bowel movements (including at upper endoscopy). zz Onset of pain associated with more loose bowel movements a Criteria fulfilled for the last 3 months with symptom onset at least 6 zz Relief of pain with defecation months before diagnosis zz Abdominal distension zz Supportive remarks zz Sense of incomplete evacuation — — Pain may be induced by ingestion of a meal, relieved by zz Passage of mucus ingestion of a meal, or may occur while fasting —— Postprandial epigastric bloating, belching, and nausea can also be present —— Persistent vomiting likely suggests another disorder Currently, Rome IV criteria (Table 5), developed after —— Heartburn is not a dyspeptic symptom but may often coexist several iterations through Rome I, II, and III criteria, are —— The pain does not fulfill biliary pain criteria used to diagnose IBS. —— Symptoms that are relieved by evacuation of feces or gas generally should not be considered as part of dyspepsis Alarm Features zz Other digestive symptoms (such as from gastroesophageal refuls disease and the irritable bowel syndrome) may coexist Alarm features also called “red flags,” suggest the possible with EPS presence of an organic disease warranting investigations

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before the diagnosis of IBS is made. Alarm features include Multidimensional clinical profile in functional BOX 2 the age of onset at or more than 45 years, anemia, blood in gastrointestinal disorders10 the stools, unintended weight loss, nocturnal symptoms, fever, abdominal mass, and a family history of colorectal zz Categorical diagnosis (symptom-based criteria) cancer. As mentioned earlier, the age cut off of 45 years zz Clinical modifier (e.g., IBS-C, D, M, post-infectious, FODMAP sensitive) may vary depending on the local epidemiology of gastric cancer. zz Impact (mild, moderate, severe) For clinical trials, all patients should have at least full zz Psychosocial modifier blood counts, erythrocyte sedimentation rate, C-reactive zz Physiological dysfunction and biomarker protein, and limited colonoscopic examination, and other IBS: irritable bowel syndrome, FODMAP: fermentable oligo- di- investigations, if indicated.9 monosaccharides and polyols.

Multidimensional Clinical Profile and improving the quality of life. To address these issues, There has been a significant paradigm shift in the dieticians and psychologists are essential members of the management of FGIDs after the introduction of a team to manage these patients. Treatment would depend multidimensional clinical profile (MDCP) in the Rome IV on the predominant symptoms: diarrhea, constipation, or 4 algorithm in 2016. Currently, experts, including the author, pain/gas/bloat (Figure 3, Table 7). are in the process of generating a plausibility consensus Initial treatment for patients with IBS should include in relation to organic issues on FGIDs. According to various combinations of antispasmodic, laxative, and MDCP, in addition to assigning the patients to a diagnostic antidiarrheal agents as they are quite safe and relatively 12 category, it is essential to evaluate the patients as a whole inexpensive. Antispasmodics, which reduce abdominal rather than only a diagnostic label. Sir William Osler wrote pain by reducing muscle spasm, include antimuscarinics, 12 that it is better to treat the patient who has the disease smooth-muscle relaxants, and anticholinergics. rather than treating the disease. MDCP necessitate the Common adverse effects include dry mouth, dizziness, physician to assess several critical issues in addition to the blurred vision, confusion, urinary retention, and categorical diagnosis of FGIDs such as IBS (Box 2).10 constipation, which are associated with anticholinergics. A component of MDCP includes subtyping Bulking agents are commonly prescribed drugs, especially for IBS-C.12 However, bulking agents may even aggravate (Fig. 2) of FGIDs; for example, constipation-predominant 12 or diarrhea-predominant IBS (IBS-C, and IBS-D, abdominal pain and bloating. For the control of diarrhea, loperamide has the best quality of evidence but has not respectively), EPS or PDS subtypes of FDF, etc. As described been shown to improve abdominal pain or distension. in the treatment of these disorders, such subtyping is the Several visceral neuromodulators, which also cornerstone for the choice of appropriate drugs to treat have central nervous system effect, such as tricyclic these disorders.9 Moreover, those with alternating (change antidepressants, serotonin reuptake inhibitors (SSRI), in symptoms over weeks to months) and mixed type is and serotonin-norepinephrine reuptake inhibitors more difficult to treat and may require pathophysiology (SNRI), relieve abdominal pain, diarrhea, insomnia, and modifying measures such as an attempt at manipulating depression. These drugs are useful in the treatment of gut microbiota. IBS even in the absence of psychiatric illness.12 Another Table 6 and Figure 3 list the biological factors that approach to treating IBS is psychotherapy.12 Aims of may contribute to two subtypes of IBS, namely diarrhea- psychotherapy include reframing maladaptive beliefs, predominant and constipation-predominant IBS.4 reduction of over-responsiveness to stress, reduction of maladaptive psychological responsiveness, and Treatment modification of maladaptive behaviors. Hypnotherapy is In addition to pharmacological treatment, dietary one of the essential tools in psychotherapy. The essence modification (low FODMAP diet) and management of of hypnotherapy is to create a relaxing and calming psychological issues may help in relieving symptoms environment and allowing the patient to refocus away

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Fig. 2: 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 (I and II) or 25% of the stools are diarrheal types (VI or VII) determine IBS subtypes according to Rome IV criteria

Another novel approach to the treatment of IBS is Different physiological factors that may cause or TABLE 6 exacerbate symptoms of patients with two subtypes targeting the gut microbiota dysbiosis and small intestinal of irritable bowel syndrome4 bacterial overgrowth (SIBO). Rifaximin, a broad-spectrum poorly absorbed antibiotic, has been found useful in the Types of IBS Contributing physiological dysfunctions treatment of non-constipating IBS.13 Rifaximin works Constipation- zz Fecal evacuation disorder against Gram-negative bacteria, Gram-positive bacteria, predominant IBS zz Slow transit and anaerobes and also has anti-inflammatory activity. Diarrhea- zz FODMAP sensitivity including lactose or predominant IBS fructose intolerance In the famous TARGET study, a 2-week treatment with zz Bile acid malabsorption rifaximin (550 mg thrice daily) resulted in 41% non- zz Non-celiac wheat sensitivity constipating IBS patients reporting improvement as zz Small intestinal bacterial overgrowth compared to 30% placebo-treated patients.13 However, zz Post-infectious symptoms recur in most patients within 2–3 months. This IBS: irritable bowel syndrome, FODMAP: fermentable oligo- di- study is essential as it brings a novel concept of treating a monosaccharides and polyols. “functional disorder,” which is now believed to result from altered gut microbiota, with an antibiotic. from uncomfortable symptoms and toward a more Dietary modification is an essential component of the pleasant perception of his or her current state. There is treatment of patients with IBS. Symptoms exacerbation little evidence for the efficacy of such an approach in IBS. due to intolerance to different nutritional ingredients is The major drawback of hypnotherapy is the requirement not uncommon among patients with FGIDs, including of well-trained mental health professional. IBS. Worsening of symptoms following intake of curry and

MU-127.indd 812 29-01-2021 14:59:35 Functional Gastrointestinal Disorders CHAPTER 127 813 Reproduced from Reference 4) Reference from Reproduced ( Source: Pathophysiological mechanisms of constipation and diarrhea-predominant irritable bowel syndrome (IBS-C and D) and possible therapeutic agents to target target (IBS-C to agents syndrome and possible therapeutic irritableand D) and diarrhea-predominant bowel mechanisms of constipation Pathophysiological Figure 3: Figure these abnormalities. It in functionalthese abnormalities. and IBS-C work agents is important constipation the therapeutic that and functional note to diarrhea and IBS-D comparably

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TABLE 7 Current symptom-based management of irritable bowel syndrome11

Symptom First line Second line Future Constipation zz Fiber zz Bisacodyl Elobixibat (ileal bile acid zz Osmotic laxative, including polyethylene glycol zz Sodium picosulfate transporter inhibitor) zz Lactulose/Lactitol zz Tegaserod (withdrawn) zz Stool softener, e.g., docusate zz Lubiprostone zz Linaclotide zz Prucalopride (5-HT4 agonist) Diarrhea zz Loperamide zz Alosetron zz Diphenoxylate zz Ramosetron zz Ondansetron zz Bile acid sequestrant (cholestyramine, colestipol) zz Rifaximin zz Clonidine Bloating Treat constipation zz Probiotic zz Antibiotic (rifaximin) Pain zz Antispasmodics zz Anticholinergics zz Mebeverine zz Pinaverium zz Otilonium bromide zz Antidepressant —— Tricyclic antidepressants —— SSRI —— RI SSRI: serotonin re-uptake inhibitor, RI: reuptake inhibitor

chili is not unusual in Asia.14,15 Though malabsorption of References lactose is as common among patients with IBS as healthy . 1 Drossman DA. Functional Gastrointestinal Disorders: History, subjects, the patients reported symptoms following the Pathophysiology, Clinical Features and Rome IV. Gastroenterology. ingestion of this disaccharide than the controls, possibly 2016;150(6):1262-79. due to visceral hypersensitivity. Lactose is a component . 2 Barbara G, Feinle-Bisset C, Ghoshal UC, et al. The intestinal of Fermentable Oligo-, Di-, Monosaccharide, and Polyol microenvironment and functional gastrointestinal disorders. (FODMAP) foods. All the high FODMAP foods lead Gastroenterology. 2016;150:1305-18. to pathophysiological effects, such as production of . 3 Drossman DA, Hasler WL. Rome IV-Functional GI Disorders: osmotically active substances, and gas causing flatulence, Disorders of Gut-Brain Interaction. Gastroenterology. 2016; 150(6):1257-61. distension, and pain, somewhat similar to lactose, among . 4 Ghoshal UC. Pros and cons while looking through an Asian the patients with IBS. Hence, avoidance of high FODMAP window on the Rome IV criteria for irritable bowel syndrome. Pros J 16 foods improves symptoms of IBS. FODMAP diet chart Neurogastroenterol Motil. 2017;23(3):334-40. is available from http://spreadhealth.in/New%20Folder/ 5. Ghoshal UC, Singh R. Frequency and risk factors of functional gastro- High%20&%20low%20FODMAP%20foods.pdf. intestinal disorders in a rural Indian population. J Gastroenterol Hepatol. 2017;32(2):378-87. . 6 Ghoshal UC. Marshall and Warren Lecture 2019: A paradigm shift Conclusion in pathophysiological basis of irritable bowel syndrome and its FGIDs, including IBS and FD, are common in medical practice. implication on treatment. J Gastroenterol Hepatol. 2020;35(5): These disorders have multiple pathophysiological basis. Multi- 712-21. modality treatment directed to the subtypes and underlying 7. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. pathophysiological factors is often successful in managing Gastroenterology. 2016;150:1380-92. . 8 Manning AP, Thompson WG, Heaton KW, et al. Towards positive these patients. diagnosis of the irritable bowel. Br Med J. 1978;2(6138):653-4.

MU-127.indd 814 29-01-2021 14:59:39 Functional Gastrointestinal Disorders CHAPTER 127 815

9. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology. 13. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients 2016;150:1393-407. with irritable bowel syndrome without constipation. N Engl J Med. 10. Drossman DA, Chang L, Chey WD, et al. Multidimensional Clinical 2011;364:22-32. Profile for Functional Gastrointestinal Disorders, 2nd edition. North 14. Gonlachanvit S, Mahayosnond A, Kullavanijaya P, et al. Effects Carolina: Rome Foundation, Raleigh; 2016. pp. 6-14. of chili on postprandial gastrointestinal symptoms in diarrhoea 11. Schmulson M, Corazziari E, Ghoshal UC, et al. A four-country predominant irritable bowel syndrome: evidence for capsaicin- comparison of healthcare systems, implementation of diagnostic sensitive visceral nociception hypersensitivity. Neurogastroenterol criteria, and treatment availability for functional gastrointestinal Motil. 2009;21(1):23-32. disorders: a report of the Rome Foundation Working Team on 15. Gupta D, Ghoshal UC, Misra A, et al. Lactose intolerance in patients cross-cultural, multinational research. Neurogastroenterol Motil. with irritable bowel syndrome from northern India: a case-control 2014;26(10):1368-85. study. J Gastroenterol Hepatol. 2007;22(12):2261-5. 12. Gwee KA, Bak YT, Ghoshal UC, et al. Asian consensus on 16. Gibson PR, Shepherd SJ. Evidence-based dietary management of irritable bowel syndrome. J Gastroenterol Hepatol. 2010;25(7): functional gastrointestinal symptoms: The FODMAP approach. J 1189-205. Gastroenterol Hepatol. 2010;25(2):252-8.

MU-127.indd 815 29-01-2021 14:59:39 CHAPTER

128 Variceal Bleed Management

Srikanth Gopi, Deepak Gunjan

Abstract Variceal bleed is a clinically significant event in the natural history of cirrhosis, and provides opportunity to treat and correct the underlying cause in the first decompensation. With advancement in critical care, endoscopic variceal band ligation and use of vasoactive agents had improved the management of acute variceal bleed in last few decades. However, refractory variceal bleed is difficult to manage, requires specialized care, and has poorer prognosis. Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for patients with high risk for treatment failure and refractory variceal bleed. Primary and secondary prophylaxis by non-selective beta blocker is another important development in the medical management of esophageal varices and variceal bleed.

Introduction bleed in cirrhosis is 12–22%.3 The following sections will be the overview of the management of the esophageal Upper gastrointestinal bleed (UGIB), one of the common variceal bleed in accordance with the recent guidelines.4-6 medical emergencies, can be broadly divided into variceal We will not discuss the management of gastric and ectopic and non-variceal UGIB. Varices are the abnormally varices. dilated submucosal veins in gastrointestinal tract usually developed as a complication of portal hypertension to decompress the portal system. The collaterals gradually Risk Stratification (Fig. 1) increase in size due to various factors and the most Cirrhosis can be stratified according to Child-Pugh- important factor is progressive rise in portal pressure and Turcotte (CTP) stage or MELD. Higher the score, more consequent increase in flow through these collaterals. severe is the disease. For clinical point of view, it is broadly Approximately half of the patients with cirrhosis have classified into compensated and decompensated cirrhosis, esophageal varices and one-third of all the patients with and later is characterized by variceal bleed, ascites, or varices will bleed in their natural course of the disease. hepatic encephalopathy. The higher the number of the In India, the proportion of patients with variceal bleed decompensation events, the worse is the prognosis. among all the cases of UGIB presenting to emergency Hepatic venous pressure gradient (HVPG) ≥10 mm Hg varies widely between 12% and 55% based on region of is associated with clinically significant portal hypertension study.1 The esophageal varices are the most common (CSPH), where esophageal varices start to appear; and source of variceal bleed followed by gastric varices. HVPG >12 mm Hg is associated with bleeding risk. HVPG Cirrhosis is the most common cause of the variceal bleed responders (reduction in HVPG by ≥20% of the baseline in >90% of the cases. The overall 6-week rebleeding rate at value or absolute HVPG <12 mm Hg by NSBBs) are 6 weeks is 24–30%,2 whereas 6-week mortality of variceal associated with lower risk of rebleed; however, in routine

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Fig. 1: Stages of cirrhosis, clinical events, and underlying hemodynamics in portal system (modified and adapted from AASLD 2016 Practice Guidance4) (CSPH, clinically significant portal hypertension; HE, hepatic encephalopathy; HVPG, hepatic venous pressure gradient; kPa, kilo Pascal; PH, portal hypertension)

clinical practice HVPG measurement is not feasible due to with massive hematemesis with high-risk of aspiration. its cost and invasiveness.4 Intravenous access with two large-bore cannula should be secured for careful volume resuscitation. Blood samples Management of Acute Variceal should be sent for complete blood counts, liver function test, blood urea and creatinine, and for cross-matching. Hemorrhage (Flowchart 1) The volume resuscitation is done by the crystalloids; Acute variceal hemorrhage (AVH) is to be suspected and and a “restrictive” packed red blood cell (PRBC) treatment should be started immediately in all cases transfusion strategy (i.e., target range for the post- of UGI bleed in known cirrhotics or patient with high- transfusion hemoglobin level of 7–9 g/dL), which is risk of cirrhosis without waiting for the confirmation associated with significant lower early rebleeding and by endoscopy. The main cause of death in AVH mortality rates in patients with cirrhosis compared is not uncontrolled bleeding, but due to additional to liberal transfusion strategy.7 However, cases with decompensation and complications resulting from acute cardiovascular comorbidities, ongoing bleeding, and bleed. The management of AVH will be discussed here. hemodynamic instability require higher hemoglobin target and it should be individualized considering the Immediate Management patient conditions. Assessment of the airway and circulatory function In a recent randomized control trial, thromboelasto­ should be done first and orotracheal intubation should graphy-guided blood-product transfusion strategy was be considered in any obtunded patient or in patients associated with reduced blood-product transfusion to

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Flowchart 1: Algorithm for acute variceal bleed management (adapted and modified from AASLD 2016 Practice Guidance4)

(CTP, Child-Pugh-Turcotte; EGD, esophagogastroduodenoscopy; SEMS, self-expandable metallic stent; TIPS, transjugular intrahepatic portosystemic shunt) *Baveno VI consensus and American Association for the Study of Liver Diseases guidelines also consider Child B cirrhosis with active bleed on endoscopy despite vasoactive drugs as high-risk patient.

correct coagulopathy without compromising hemostasis nasogastric tube placement is usually not recommended in cirrhotic patients.2 There is no recommendation for and prokinetic administration can enhance the gastric use of platelet transfusion, intravenous vitamin K, or mucosa visualization during endoscopy (erythromycin tranexamic acid to halt the acute ongoing variceal bleed. 250 mg IV 30–120 minutes before endoscopy, if no QT Transfusion of fresh frozen plasma or factor VIIa to correct prolongation on electrocardiography). INR is not recommended.8 Any one of the vasoactive drugs (Table 1) and Endoscopic Treatment antibiotic prophylaxis should be initiated at the earliest There is no need to hurry for EGD to achieve hemostasis. prior to esophagogastroduodenoscopy (EGD).4 These While the first and foremost step is hemodynamic vasoactive drugs cause splanchnic vasoconstriction resuscitation and stabilization before sending the patients and reduce the portal pressure. Even in patients on for endoscopic hemostasis. EGD can be safely performed noradrenaline infusion for hypotension, one of the between 6–24 hours after presentation to the emergency, vasoactive drugs should be continued.9 Intravenous but it should be individualized if there is evidence of active antibiotic prophylaxis (ceftriaxone 1 g/24 hourly) prevent ongoing bleed despite vasoactive drugs, hemodynamic the infectious complications and reduce mortality. A instability due to blood loss despite resuscitation, actively

MU-128.indd 818 29-01-2021 14:59:29 Variceal Bleed Management CHAPTER 128 819

TABLE 1 Vasoactive drugs used in acute variceal hemorrhage (adapted from AASLD 2016 Practice Guidance4)

Drug Recommended dose Predominant mechanism Significant adverse effects and of action contraindications Somatostatin Initial IV bolus 250 µg (can be repeated Splanchnic vasoconstriction Major adverse events are rare in the first hour if ongoing bleeding) due to inhibition of followed by continuous IV infusion of vasodilatory hormones 250–500 µg/hr Duration: 2–5 days Octreotide Initial IV bolus of 50 µg (can be repeated Similar to somatostatin Major adverse events are rare. (somatostatin analogue) in first hour if ongoing bleeding) Category B drug in pregnancy followed by continuous IV infusion of 50 µg/hr Duration: 2–5 days Terlipressin Initial 48 hours: 2 mg IV every 4 hours Mesenteric arteriolar Common adverse events: abdominal (vasopressin analogue) until control of bleeding followed vasoconstriction pain, hypertension, and hyponatremia by 1 mg IV every 4 hours to prevent Contraindications: history of rebleeding ischemic disease of heart, brain, gut or Duration: 2–5 days peripheral limb; and in pregnancy Use with caution in elderly and hypertension

vomiting fresh blood, or persistent fresh blood from Post-endoscopic Hemostasis Management 10 nasogastric tube. Vasoactive drugs should be continued for 3–5 days and Endoscopic variceal obliterative techniques commonly antibiotic prophylaxis should be given for 5–7 days. used are endoscopic variceal band ligation (EVL), Assessment for any other decompensation should be the preferred technique; and the endoscopic variceal done and treated accordingly. Non-selective beta blockers sclerotherapy (EST). Once EVL is done, next session will (NSBBs) (Table 2) should be started before hospital be planned after 2–4 weeks till complete eradication of discharge after the discontinuation of vasoactive agents varices. Once eradicated, next screening endoscopy will unless the patient undergoes TIPS. be after 3–6 months and then every 6–12 months. At our center, in hemodynamically stable patient, we keep the patient fasting for 4–6 hours after endoscopic Role of TIPS hemostasis followed by liquid diet for 24–48 hours and then the solid food is allowed. There are some concerns for Monitor for rebleed (recurrence of hematemesis/drop in increase in splanchnic blood flow and increase in portal hemoglobin/hypotension due to bleed after endoscopic pressure after enteral nutrition. Some guidelines advocate hemostasis) and assessment for high-risk factors for withholding of enteral nutrition for at least 48–72 hours treatment failure should be done. In patients with high- after an episode of AVH.12 Avoid placing a nasogastric tube risk of treatment failure [Child C (with CTP score ≤13) after EVL for first few days to avoid the risk of dislodging or Child B with active bleeding on endoscopy despite the newly placed bands. However, if there is indication for vasoactive drug therapy], evidence showed that the nasogastric tube placement, a tube can be gently placed by early transjugular intrahepatic portosystemic shunt an experienced clinician. (TIPS) done within 24–72 hours of presentation after first endoscopy was associated with lower treatment failure and mortality rates compared to standard therapy.11 So, Management of Refractory guidelines recommend “early or pre-emptive TIPS” in Bleed or Treatment Failure acute variceal bleed at high-risk of treatment failure after Treatment failure occurs in 10–15% of the patients combined vasoactive drugs and endoscopic therapy. with AVH despite treatment and associated with high

MU-128.indd 819 29-01-2021 14:59:29 820 SECTION 10 Gastroenterology <130 meq/L) and hepatorenal <130 meq/L) and hepatorenal + ) 4 Significant adverse effects adverse Significant and contraindications lightheadedness, fatigue, events: adverse Common and shortness of breath heart decompensated failure, Contraindications: aortic heartadvanced sinus bradycardia, block, severe arterial peripheral advanced disease, disease, valve obstructive pulmonary insulin-dependent disease, diabetes -In refractory bacterial spontaneous peritonitis, circulatory dysfunction like and severe ascites, (Na hyponatremia orthostatic hypotension, events: adverse Common dizziness and fatigue heart decompensated failure, Contraindications: heartadvanced block, obstructive airway and disease, bradycardia severe cirrhosis as it can in decompensated be avoided To dysfunction and renal ascites worsen syndrome, the dose of NSBB should be reduced or the dose of NSBB should be reduced syndrome, till circulatory dysfunctionwithheld temporarily or sepsis improves -adrenergic action (reduce action (reduce -adrenergic 1 Predominant mechanism of action portalReduce by inflow venous splanchnic vasoconstriction (by β2-bloc kade and unopposed activity) α-adrenergic and decrease β1-blockade) output (by cardiac intrahepatic resistance) intrahepatic Non-selective beta-blocker (reduce Non-selective beta-blocker (reduce portal with additional blood flow) anti-α (adapted from AASLD 2016 Practice Guidance AASLD 2016 from (adapted Recommended dose Recommended propranolol dose: 20–40 mg BD for Initiation nadolol and 10–20 mg OD for every to Adjust 2–3 days Dose titration: dose or therapy maximally tolerated achieve goal achieved Maximal daily dose: and if no ascites 320 mg/day propranolol: For present if ascites 160 mg/day and 80 if no ascites nadolol: 160 mg/day For present if ascites mg/day goal : Resting heart of 55–60 rate Therapy blood pressure and systolic beats/minute should not be < 90 mm Hg Initiation dose: 3.125 mg OD Initiation 6.25 every to Adjust 3 days Dose titration: mg BD in (except Maximal daily dose: 12.5 mg/day arterial with persistent patients hypertension) should blood pressure goal: Systolic Therapy not be <90 mm Hg Drugs used in prophylaxis of esophageal variceal bleed of esophageal variceal Drugs used in prophylaxis TABLE 2 TABLE Drug non-selective beta Oral blockers (Propranolol or Nadolol) Carvedilol

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mortality.4 Patient should be referred to higher center for NSBBs to EVL, while the addition of EVL to NSBBs has no adequate and prompt management. If rebleed is mild (no survival benefit.17 NSBBs can be used as monotherapy if hemodynamic instability), a re-look endoscopy should be patients are unable or unwilling to undergo EVL.5 Currently attempted by experienced endoscopists. neither HVPG-guided therapy nor TIPS is recommended for secondary prophylaxis. Unless contraindicated, TIPS Tamponade as Bridge Therapy is the recommended treatment in patients with recurrent If the rebleeding is persisting despite first endoscopy bleed despite combination therapy and also in patients or the rebleed is massive (hemodynamic instability, who are intolerant to NSBBs (EVL alone cannot be used blood transfusion or 3 g/dL drop in hemoglobin) or the as secondary prophylaxis) and especially if patient has second endoscopic attempt fails, balloon tamponade ascites also. (Sengstaken–Blakemore tube) or self-expandable metal stent (SEMS) can be used as bridge therapy till definite Screening and Primary portal decompressive therapies is available. The balloon Prophylaxis for Varices tamponade can achieve hemostasis in ~80% cases All cirrhotics should undergo variceal screening by and should be used for maximum of 24 hours, but it is endoscopy. However, EGD can be avoided in patients associated with severe complications such as aspiration whose liver stiffness on transient elastography (TE) is <20 and esophageal rupture.5,13 SEMS is effective and safer kPa with platelet count >1,50,000/µL (TE-based criteria); alternative than balloon tamponade for control of bleeding or serum albumin >3.6 g/dL and platelets >1,20,000/mm3 and can be left in place for up to 7 days.14 (platelet-albumin criteria).6,18 Rescue or Salvage TIPS There is no role of prophylaxis in cirrhosis with no varices or low-risk varices. Primary prophylaxis must be This can effectively control bleeding in more than 90% initiated in all cirrhosis with varices at high-risk of rupture. of refractory esophageal variceal bleeding cases, but High-risk varices are small varices with red color signs, the mortality rate remains high (30–50%) as well as the small varices in CTP C cirrhosis and medium or large risk of encephalopathy.15 So, the patients with high-risk varices irrespective of CTP class. The choice between of rebleed are to be identified and offered aggressive NSBBs (Table 2) and EVL depends on variceal size, patient strategies (like early TIPS) to prevent treatment failure. preference, and local resources. A recent network meta- Surgical shunts are rarely performed nowadays, may be analysis showed that NSBBs are associated with lower done in good surgical candidate (child A cirrhosis), when 19 mortality compared to EVL. TIPS is not technically feasible. Patients who Recovered from Recent Conclusion Variceal Bleed and Secondary Prophylaxis Acute variceal bleed is an important prognostic event in the natural history of cirrhosis. It is a medical emergency with high Untreated patients who recover from first episode of mortality and must be managed with resuscitation, vasoactive bleed are at high-risk of rebleed (55–67% in first year) drugs, prophylactic antibiotics, and endoscopic treatment. 16 and mortality (25–50%). So, initiation of secondary Non-selective beta blocker plays a crucial role in the primary prophylaxis against rebleed is essential before hospital and secondary prophylaxis. TIPS has role in refractory bleed discharge. Patients with indication for liver transplantation and prevention of rebleed in high-risk patients. should be referred for the same. The patients who underwent TIPS as a part of AVH management do not require additional therapy for rebleed prevention. References All guidelines recommend combination of NSBB 1. Singh SP, Panigrahi MK. Spectrum of upper gastrointestinal (propranolol or nadolol) with EVL as first-line management hemorrhage in coastal Odisha. Trop Gastroenterol. 2013;34:14-7. 2. Rout G, Shalimar, Gunjan D, et al. Thromboelastography-guided for secondary prophylaxis. NSBBs (Table 2) form the blood product transfusion in cirrhosis patients with variceal cornerstone of combination therapy; meta-analysis bleeding: a randomized controlled trial. J Clin Gastroenterol. showed an improvement in survival with the addition of 2020;54(3):255-62.

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3. Rout G, Sharma S, Gunjan D, et al. Development and validation of 12. Merli M, Berzigotti A, Zelber-Sagi S, et al. EASL Clinical Practice a novel model for outcomes in patients with cirrhosis and acute Guidelines on nutrition in chronic liver disease. J Hepatol. variceal bleeding. Dig Dis Sci. 2019;64(8):2327-37. 2019;70(1):172-93. 4. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive 13. Sarin SK, Nundy S. Balloon tamponade in the management of bleeding in cirrhosis: risk stratification, diagnosis, and management: bleeding oesophageal varices. Ann R Coll Surg Engl. 1984;66(1): 2016 practice guidance by the American Association for the study 30-2. of liver diseases. Hepatology. 2017;65(1):310-35. 14. Rodrigues SG, Cárdenas A, Escorsell À, et al. Balloon tamponade 5. Angeli P, Bernardi M, Villanueva C, et al. EASL Clinical Practice and esophageal stenting for esophageal variceal bleeding in Guidelines for the management of patients with decompensated cirrhosis: a systematic review and meta-analysis. Semin Liver Dis. cirrhosis. J Hepatol. 2018;69(2):406-60. 2019;39(2):178-94. 6. de Franchis R, Faculty BV. Expanding consensus in portal 15. Vangeli M, Patch D, Burroughs AK, et al. Salvage tips for uncontrolled hypertension: report of the Baveno VI Consensus Workshop: variceal bleeding. J Hepatol. 2002;37(5):703-4. stratifying risk and individualizing care for portal hypertension. J 16. Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet. Hepatol. 2015;63(3):743-52. 2003;361:952-4. 7. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute 17. Albillos A, Zamora J, Martínez J, et al. Stratifying risk in upper gastrointestinal bleeding. N Engl J Med. 2013;368(14):1362-3. the prevention of recurrent variceal hemorrhage: results of 8. Bosch J, Thabut D, Albillos A, et al. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomized, an individual patient meta-analysis. Hepatology. 2017;66(4): controlled trial. Hepatology. 2008;47(5):1604-14. 1219-31. 9. Osman D, Djibré M, da Silva D, et al. Management by the intensivist 18. Sharma S, Agarwal S, Gunjan D, et al. Deciding among noninvasive of gastrointestinal bleeding in adults and children. Ann Intensive tools for predicting varices needing treatment in chronic Care. 2012;2(1):46. liver disease: an analysis of Asian Cohort. Am J Gastroenterol. 10. Lau JYW, Yu Y, Tang RSY, et al. Timing of endoscopy for acute upper 2020;115(10):1650-6. gastrointestinal bleeding. N Engl J Med. 2020;382(14):1299-308. 19. Sharma M, Singh S, Desai V, et al. Comparison of therapies 11. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in for primary prevention of esophageal variceal bleeding: a patients with cirrhosis and variceal bleeding. N Engl J Med. systematic review and network meta-analysis. Hepatology. 2019; 2010;362(25):2370-9. 69(4):1657-75.

MU-128.indd 822 29-01-2021 14:59:29 CHAPTER

Hepatorenal Syndrome: Current 129 Diagnosis and Management

Shri Krishna Gautam

Abstract HRS is a life threatening complication of advanced liver disease. It is considered as development of renal failure in patients with pre-existing liver disease but without any underlying renal dysfunction. The term HRS first emerged in the year 1932 in a group of postoperative patients of billiary tract surgery. The Pathophysiology of HRS is poorly understood, three essential components play vital role in Pathophysiology of HRS: • Arterial vasodilatation in the splanchnic and systemic circulation, • Renal vasoconstriction, and • Cardiac dysfunction. Spontaneous bacterial peritonitis is an important risk factor for development of HRS. About one third of patient of spontaneous bacterial peritonitis develop HRS. Most common presentation of HRS is asymptomatic followed by decrease in urine output. Due to acute kidney injury (AKI), glomerular filtration rate decreases (GFR) and the blood urea nitrogen (BUN) level increases which may result in hepatic encephalopathy as the initial clinical presentation of HRS. Based on clinical features and prognosis HRS is of two types: Type 1 HRS and Type 2 HRS. HRS requires a very aggressive management considering its poor prognosis. There are three treatment options available for management of HRS: • Medical therapies are the mainstay of treatment of HRS consisting of vasoconstrictor agents like: Terlipressin, Noradrenaline, and Midodrine plus Octreotide. • Transjugular intrahepatic portosystemic shunt (TIPS) placement, and • Liver transplantation. Therefore, HRS is a life threatening complication of liver cirrhosis. In addition to increased knowledge regarding liver cirrhosis, portal hypertension, ascites as well as HRS, new pharmacological treatments like administration of terlipressin and albumin have proven vital role in improving the short-term outcome of HRS. The other medical treatments using different pharmacological principles such as endothelin antagonists, adenosine-receptor antagonists, and N-acetylcysteine may also help in minimizing renal vasoconstriction and improving renal function, but liver transplant remains to be the mainstay of the treatment.

Introduction The term HRS first emerged in the year 1932 in a group of postoperative patients of biliary tract surgery.2 Hepatorenal syndrome (HRS) is a life-threatening International ascites club has formulated diagnostic complication of advanced liver disease. It is considered guidelines for HRS in 1994, which were modified in 2007.3 as development of renal failure in patients with pre- existing liver disease but without any underlying renal Diagnostic Criteria for HRS dysfunction.1 See Box 1.

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These hemodynamic changes in renal microvasculature BOX 1 Diagnostic criteria of HRS (EASL) and splanchnic vasodilation compromises renal blood 5 zz Cirrhosis with ascites flow leading to fall in glomerular filtration rate. zz Serum creatinine 1.5 mg/dL (133 lmol/L) So, HRS is initially a functional renal syndrome, which zz Absence of shock later progresses to an organic disease. zz Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to 133 lmol/L) following at least 2 days of diuretic withdrawal (if on Cardiac Dysfunction diuretics), and volume expansion with albumin at 1 g/kg/day up The development of cirrhotic cardiomyopathy leads to to a maximum of 100 g/day impairment of cardiac function, which may further lead zz No current or recent treatment with nephrotoxic drugs to a relative impairment of the compensatory increase in zz Absence of parenchymal renal disease as defined by proteinuria cardiac output secondary to vasodilatation. 0.5 g/day, no micro hematuria (50 rbc/high powered field), and normal renal ultrasonography Risk Factors of HRS Spontaneous bacterial peritonitis is an important risk Pathophysiology factor for development of HRS.12-14 The pathophysiology of HRS is poorly understood, three About one third of patient of SBP develops HRS.12 The essential components are: outcome of HRS is very poor. Median survival time of all 15 „„ Arterial vasodilatation in the splanchnic and systemic patients with HRS is approximately 3 months only. High circulation, MELD scores and type 1 HRS further worsen the prognosis. „„ Renal vasoconstriction, and Type 1 HRS patients if not treated have very poor outcome 16 „„ Cardiac dysfunction. with median survival of approximately 1 month. Several cytokines are involved which alter the renal blood flow and glomerular microvasculature. Important Clinical Features and Classification of HRS among them are cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1. Knowledge about Most common presentation of HRS is asymptomatic these vasoactive compounds is also important from followed by decrease in urine output. Due to acute kidney therapeutic and preventive point of view. injury (AKI), glomerular filtration rate (GFR) decreases and the blood urea nitrogen (BUN) level increases which Arterial Vasodilatation in the Splanchnic and may result in HE as the initial clinical presentation of HRS. Systemic Circulation Based on clinical features and prognosis, HRS is of two types (type 1 and type 2).3 Splanchnic vasodilatation is the hallmark of portal hypertension seen in chronic liver disease. Several vasodilators like nitric oxide, glucagon, carbon mono Type 1 HRS oxide, prostacyclin are released which are responsible Type 1 HRS has worse prognosis than type 2 HRS. There for these vasodilatory response.4-7 In the initial stages, is very rapid deterioration in renal function in type 1 HRS. cardiac compensatory mechanism tends to counter the Typically, the leve[0l] of serum creatinine rises to a value vasodilation.8 higher than 2.5 mg/dL within 2 weeks or less. Most of time type 1 HRS has a triggering event. These triggers interfere Renal Vasoconstriction with the renal blood flow.17 Some of the common triggers Due to splanchnic vasodilatation and renal vasoconstriction are bacterial infections,18 GI bleeding, surgery, and acute there is activation of the renin-angiotensin-aldosterone hepatic injury3,19 system (RAAS). The clear pathway is not known but Among bacterial infections, SBP is the most important cytokines like endothelins, prostaglandins, kallikreins, trigger event to develop HRS.20,21 There are certain and F2 isoprostanes are considered to cause renal vaso­ predisposing factors like high levels of inflammatory constriction.9-11 markers, severe circulatory depression prior to the onset

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of infection, and adrenal insufficiency, which have more —— Infection control: prophylactic antibiotic therapy chances of development of HRS. should be given if indicated for prevention of SBP. Sepsis should be identified early using culture of Type 2 HRS blood, urine, and ascetic fluid. There is no role of Type 2 HRS is more slowly progress[0i]ve than type 1 HRS, antibiotic without proven infection. but still carries a median survival of only approximately —— Diuretic has to be stopped to prevent depletion of 6 months. Typically patient presents with pre-existing intravascular volume. resistant ascites with mild renal dysfunction (serum „„ Specific therapies: creatinine < 2.5 mg/dL). Type 2 HRS patient can progress Vasoconstrictors: Aim is to reverse the splanchnic into type 1 HRS after a triggering event. vasodilatation to maintain the renal blood flow vasopressin analogues are most commonly used for vasoconstriction. Terlipressin has been studied Prevention of HRS extensively in HRS patients.15,22 HRS has a very poor prognosis and very high mortality Terlipressin improves renal function in about rate. So prevention of HRS is an important aspect in 40–50% patients of HRS15,23 The dose of terlipressin is management of patients of chronic liver disease. Most 1 mg every 4–6 hours. It can be increased up to 2 mg important strategy is to prevent depletion of intravascular every 4–6 hours after 3 days if there is no improvement volume. Important causes of volume depletion are over in renal function (fall in serum creatinine by at least diuresis, diarrhea due to lactulose, variceal bleed, and 25% of baseline). Terlipressin is discontinued if serum large volume paracentesis. creatinine comes below 1.5 mg/dL22 with improvement Use of nephrotoxic drugs should be avoided. Beside in renal function there is increase in urine volume, these prevention of infection and its prompt treatment is blood pressure, and serum sodium concentration. 18 also very important for prevention of HRS. Improvement is slow and can take up to 14 days for renal function to become normal. Duration is shorter Treatment of HRS with lower serum creatinine at the time of starting terlipressin.24 HRS requires a very aggressive management considering Better response is observed in patients with baseline its poor prognosis. There are three treatment options 24 serum bilirubin less than 10 mg/dL. Also patients available for management of HRS: who show reduction in mean arterial pressure of more „„ M2 4ed]ical therapies, than 5 mm Hg after 3 days of medical therapy have „„ Transjugular intrahep[0a] tic portosystemic shunt favorable response to medical therapy.24 Reoccurrence (TIPS) placement, after stopping terlipressin is rare. Terlipressin is effective „„ Liver transplantation. in reoccurrence. Aim of medical therapy is to maintain intravascular Common side effects of terlipressin include volume. Vasoconstrictors are used to counter splanchnic cardiovascular and ischemic complications. So terlipressin vasodilatation. Colloid infusion is done for volume is avoided in patients with known cardiovascular and expansion. Aim of the medical therapy is to act as a bridge ischemic conditions. Patients of HRS are given albumin until definitive treatment of liver disease is done or until along with terlipressin to maintain intravascular volume. the triggering event (SBP, UGI bleed) has subsided. Albumin is given in a dose of 1 g/kg body weight. Terlipressin shows improvement in renal function in Medical Therapy patients of type 2 HRS also,25 but there are limited studies „„ Non-specific medical therapy: in patients of type 2 HRS. —— Vitals monitoring and maintaining fluid balance There are other vasopressors that are used in type 1 is very important. Monitoring of blood pressure, HRS: central venous pressure, urine output helps in „„ Midodrine plus octreotide maintaining fluid balance. „„ Noradrenaline

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Midodrine is an alpha adrenergic receptor agonist. Conclusion It is an oral drug started at a dose of 2.5 mg tds and can be increased up to 12.5 mg. Octreotide is started with a Therefore, HRS is a life-threatening complication of liver dose of 100 microgram tds and can be increased up to 200 cirrhosis. In addition to increased knowledge regarding liver cirrhosis, portal hypertension, ascites as well as HRS, new microgram tds. There are only few studies with midodrine 26 pharmacological treatments like administration of terlipressin and octreotide. and albumin have proven vital role in improving the short-term Noradrenaline (0.5–3 mg/h) is a vasopressor drug. outcome of HRS. The other medical treatments using different Increased arterial pressure helps to maintain adequate pharmacological principles such as endothelin antagonists, 27 blood flow to kidneys. comparative studies between adenosine-receptor antagonists and N-acetylcysteine may noradrenaline and other vasoconstrictors drugs are the also help in minimizing renal vasoconstriction and improving area of research. Noradrenaline is given as continuous renal function,32,33 but liver transplant remains to be the infusion with an aim to keep systolic blood pressure above mainstay of the treatment. The multiple aspects in the 110 mm Hg. pathophysiological process will likely be targeted by the future There have been few studies on prevention of HRS. treatment of HRS. Short-term treatment (4 week) with pentoxifylline (400 mg three times a day) in a randomized double-blind st[u8]dy References was shown to prevent the development of HRS in patients . 1 Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic with severe alcoholic hepatitis. In a recent study, long- criteria of refractory ascites and hepatorenal syndrome in cirrhosis. term treatment with pentoxifylline was not associated with Hepatology. 1996;23(1):164-76. an improved survival but with reduced frequency of some 2. Helvig F, Schutz C. A liver and kidney syndrome: clinical, pathological, complications of cirrhosis, including renal failure, yet and experimental studies. Surg Gynecol Obstet. 1932;55:570-82. this 7w as not the primary endpoint of the study. Finally, 3. Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56(9):1310-8. norfloxacin (400 mg/day) reduced the incidence of HRS in 4. Angeli P, Merkel C. Pathogenesis and management of hepatorenal advanced cirrhosis. syndrome in patients with cirrhosis. J Hepatol. 2008;48(1):S93-103. . 5 Arroyo V, Fernandez J, Ginès P. Pathogenesis and treatment of Transjugular Intrahepatic Portosystemic Shunt hepatorenal syndrome. Semin Liver Dis. 2008;28(1):81-95. (TIPS) 6. Bolognesi M, Sacerdoti D, Piva A, et al. Carbon monoxidemediated activation of large conductance calcium-activated potassium TIPS has been used for treatment of portal hypertension channel contributes to mesenteric vasodilation in cirrhotic rats. J associated with cirrhosis.28 TIPS helps to control ascites Pharmacol Exp Ther. 2007;321(1):187-94. along with improvement in renal function in patients of . 7 Ro J, Claria J, To-Figueras J, et al. Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in HRS. experimental cirrhosis in the rat. Gastroenterology. 2002;122(1): Renal replacement therapy: Hemodialysis is used in 85-93. patients of HRS. Indication of hemodialysis is similar to 8. Fernandez-Seara J, Prieto J, Quiroga J, et al. Systemic and regional 29,30 hemodynamics in patients with liver cirrhosis and ascites with any cause of acute renal failure. There are no separate and without functional renal failure. Gastroenterology. 1989;97(5): studies to see results of hemodialysis in HRS patients. 1304-12. Comparison of renal replacement therapy and medical . 9 Munoz S. The hepatorenal syndrome. Med Clin N Am. therapy for HRS is an area of further evaluation. 2008;92(4):813-37. 10. Salerno F, Gerbes A, Ginès P, et al. Authors’ response. Gut. 2008;57:139-40. Liver Transplantation 11. Neuhoffer W, Pittrow D. Role of endothelin receptor antagonists in Treatment of choice for both types of HRS is liver renal disease. Eur J Clin Invest. 2006;36(3):78-88. transplantation.31 Liver transplantation success rate 12. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin is about 65% in patients of type 1 HRS.31 Renal failure on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341(6):403-9. subsides after liver transplantation. Patients who remain 13. Fasolato S, Angeli P, Dallagnese L, et al. Renal failure and bacterial on renal support therapy for more than 12 weeks should infections in patients with cirrhosis: epidemiology and clinical be considered for combined liver kidney transplantation. features. Hepatology. 2007;45(1):223-9.

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14. Thabut D, Massard J, Gangloff A, et al. Model for end-stage liver 25. Alessandria C, Venon WD, Marzano A, et al. Renal failure in cirrhotic disease score and systemic inflammatory response are major patients: role of terlipressin in clinical approach to hepatorenal prognostic factors in patients with cirrhosis and acute functional syndrome type 2. Eur J Gastroenterol Hepatol. 2002;14(12):1363-8. renal failure. Hepatology. 2007;46(6):1872-82. 26. Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal 15. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. syndrome with the administration of midodrine and octreotide. 2009;361(13):1279-90. Hepatology. 1999;29(6):1690-7. 16. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical 27. Duvoux C, Zanditenas D, Hézode C, et al. Effects of noradrenalin and type predict prognosis in hepatorenal syndrome: relevance to liver albumin in patients with type I hepatorenal syndrome: a pilot study. transplantation. Hepatology. 2005;41(6):1282-9. Hepatology. 2002;36(2):374-80. 17. Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis: 28. Brensing KA, Textor J, Perz J, et al. Longterm outcome after perspective in the age of MELD. Hepatology. 2003;37(2):233-43. transjugular intrahepatic portosystemic-stent shunt in non- 18. Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and transplant cirrhotics with hepatorenal syndrome: a phase II study. treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol. Gut. 2000;47(2):288-95. 2007;46(5):935-46. 29. Keller F, Heinze H, Jochimson F, et al. Risk factors and outcome of 19. Cardenas A, Ginès P, Uriz J, et al. Renal failure after gastrointestinal 107 patients with decompensated liver disease and acute renal bleeding in cirrhosis: incidence, clinical course, predictive factors, failure (including 26 patients with hepatorenal syndrome): the role and short term prognosis. Hepatology. 2001;34(4 Pt 1):671-6. of hemodialysis. Ren Fail. 1995;17(12):135-46. 20. Terra C, Guevara M, Torre A, et al. Renal failure in patients with 30. Capling RK, Bastani B. The clinical course of patients with type cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: 1 hepatorenal syndrome maintained on hemodialysis. Ren Fail. value of MELD score. Gastroenterology. 2005;129(6):1944-53. 2004;26(5):563-8. 21. Arroyo V, Fernandez J, Ginès P. Pathogenesis and treatment of 31. Gonwa TA, Morris CA, Goldstein RM, et al. Long-term survival and hepatorenal syndrome. Semin Liver Dis. 2008;28(1):81-95. renal function following liver transplantation in patients with and 22. Kew MC, Varma RR, Sampson DJ, et al. The effect of octapressin without hepatorenal syndrome—experience in 300 patients. on renal and intrarenal blood flow in cirrhosis of the liver. Gut. Transplantation. 1991;51(2):428-30. 1972;13(4):293-6. 32. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal 23. Moreau R, Lebrec D. The use of vasoconstrictors in patients with syndrome with selective endothelin-A antagonist. Lancet. cirrhosis: type 1 HRS and beyond. Hepatology. 2006;43(3):385-94. 1996;347(918):1842-3. 24. Nazar A, Pereira GH, Guevara M, et al. Predictors of response to 33. Stanley AJ, Forrest EH, Dabos K, et al. Natriuretic effect of an therapy to terlipressin and albumin in patients with cirrhosis and adenosine-1 receptor antagonist in cirrhotic patients with ascites. type 1 hepatorenal syndrome. Hepatology. 2010;51(1):219-26. Gastroenterology. 1998;115(2):406-11.

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Hepatic Encephalopathy: 130 Management

Sudhir Maharshi, Barjesh Chander Sharma

Abstract Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting; its clinical manifestations include spectrum of neurological or psychiatric dysfunction ranging from subclinical alterations to deep coma. The development of hepatic encephalopathy correlates with the severity of liver disease. Hepatic encephalopathy is classified into overt hepatic encephalopathy, which is characterized by neurologic and neuropsychiatric dysfunctions detected by clinical examination and bedside tests or minimal hepatic encephalopathy, characterized by normal mental status and normal neurologic examination but abnormalities on psychometric testing. Early detection and rectification of precipitating factors is most important in the management. The first-line therapy is still lactulose which is effective in minimal, overt and recurrent hepatic encephalopathy. Rifaximin is equally effective to lactulose and is better tolerated. Branch chain amino acids have a beneficial effect on hepatic encephalopathy in protein intolerant patients. Probiotics and L-ornithine L-aspartate are also useful in the management of hepatic encephalopathy. Combinations of rifaximin and lactulose have shown promising results in the treatment of overt and recurrent hepatic encephalopathy. Embolization of large portosystemic shunts and liver transplantation are effective treatment in few and highly selected patients. Nutritional therapy and fecal microbiota transplantation are emerging treatment options but data is limited.

Introduction (MHE), overt neuropsychiatric features characterized as Hepatic encephalopathy (HE) is identified by indis­ overt hepatic encephalopathy (OHE) to comatose state. criminate neurological and psychiatric manifestations, Overt HE is observed in 10–14% of cirrhotic patients which adversely impacts the life of patients and their at the time of diagnosis. Forty percent of patients with family members. The requirement of multiple hospital cirrhosis encounter at least one outbreak and many admissions due to HE is a matter of great concern for the encounter frequent outbreaks of HE. In cirrhotic patients 3-5 health-care sector. HE has been categorized based on the prevalence of MHE is 20–80%. In patients with preexisting liver disorder, gravity of the clinical features, cirrhosis HE is a marker of poor prognosis, with up to 85% 4 the trends over time, and triggering/precipitating factors 1-year mortality. The available literature on pathogenesis (Table 1).1,2 Type A HE is a consequence of acute liver suggest that an increase in ammonia concentration is failure, type B of large portosystemic shunts (PSS), and implicated and a role for inhibitory neurotransmission type C of liver cirrhosis.3 Type C is the most common. through gamma aminobutyric acid (GABA) receptors in The scope of HE scales from not easily observable clinical the central nervous system along with changes in central features characterized as minimal hepatic encephalopathy neurotransmitters and circulating amino acids.

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TABLE 1 Classification of hepatic encephalopathy

According to WHC severity According to ISHEN Based on underlying disease Based on time course Based on precipitating factors

MHE Covert A Episodic Spontaneous

Grade I

Grade II Overt B Recurrent Precipitated

Grade III

Grade IV C Persistent ISHEN, International Society for Hepatic Encephalopathy and Nitrogen Metabolism; WHC, West Haven Criteria

TABLE 2 West Haven Criteria for severity of hepatic encephalopathy

Grade of HE Minimal Grade I Grade II Grade III Grade IV

Clinical No clinical Short attention span, Altered Lethargy, Disorientation for Gross disorientation, Confusion, Coma features manifestations sleep rhythm, Impairment of time, Personality changes, Somnolence to semi stupor, addition or subtraction, Minimal Inappropriate behavior, Bizarre behavior, Involuntary lack of awareness, Anxiety Flapping tremors passage of urine and feces HE, hepatic encephalopathy

Overt Hepatic Encephalopathy cirrhosis and HE are vulnerable to over sedation with drugs. If at all medications are required, haloperidol is a better Management 6 and safe option than benzodiazepine. Nutritional support Management of OHE includes finding and resolving any includes 35–40 kcal/kg energy with 1.2–1.5 g/kg protein triggering factor, to reduce blood ammonia level with per day. Cirrhotic patients are usually malnourished and lactulose or rifaximin and the proper setup for its treatment. restriction of protein can increase mortality, so patients The severity of OHE is graded from I to IV, based on the with HE should not restrict their protein intake.7,8 Grades clinical features (Table 2). The treatment depends on the I and II HE patients can take their diet orally, but patients severity of OHE. Patients with grade I HE may be managed with severe HE are usually unable to receive oral nutrition. on outpatient basis, if caregivers are available to look for These patients should be fed through Ryle’s tube along signs of worsening and to bring the patient to the hospital with necessary medications. All HE patients are advised if required. Hospital admission of a patient with grade II to take small portions at regular intervals with a late- HE depends on the degree of lethargy and confusion. If the patient is not able to take the treatment or if caregivers night snack of complex carbohydrates, as fasting further are not available for monitoring the patient, the patient promotes the production of glucose from amino acids, 9 needs to be admitted to the hospital. Patients with more which leads to ammonia production. Vegetable proteins severe HE (grades III and IV) require hospital admission are preferred as they improve nitrogen balance and mental for management, ideally in the intensive care unit and status. Addition of branched-chain amino acids (BCAA) intubation should be considered for airway protection. to a low-protein diet should be considered for patients All patients with HE should receive supportive care, intolerant to protein. Usually patients with transjugular which includes balanced nutrition, avoiding dehydration intrahepatic portosystemic shunt (TIPS) or surgical PSS and electrolyte abnormalities, and providing a safe have severe HE and use of vegetable protein or protein environment. Disoriented and agitated patients need restriction with BCAA supplementation is beneficial in extra care to prevent falls. Judicious use of restraints is a these patients. The algorithm for management of HE has safe option than sedative drugs, as patients with advanced been shown in Flowchart 1.

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Flowchart 1: Algorithm for management of hepatic encephalopathy

BCCA, branch-chain amino acids; BRTO, balloon occluded retrograde transvenous obliteration; FMT, fecal microbiota transplantation; HE, hepatic encephalopathy; LOLA, L-ornithine L-aspartate; MHE, minimal hepatic encephalopathy; PSS, portosystemic shunts.

Acute Episode of Overt Hepatic lactulose, lactitol, rifaximin, and other ammonia lowering agents. Lactulose is administered in the dose of 30–45 mL Encephalopathy Management (20–30 gm) two to four times per day and it should be The treatment of acute HE starts with finding and adjusted so that it results in two to three soft stools per management of triggering factors and the reduction of day. Lactitol powder of 67–100 gm diluted in 100 mL of blood ammonia level. Treatment of precipitating factors water represents an equivalent dose. It is recommended combined with standard ammonia lowering therapy to administer lactulose or lactitol enemas (1–3 L of a is associated with a rapid reversal of HE. Common 20% solution) in patients who cannot take it orally. For precipitating factors are constipation, gastrointestinal patients who have not improved within 48 hours or who bleeding, infections (including spontaneous bacterial are unable to take lactulose or lactitol, rifaximin is the next peritonitis, urinary tract infection, and respiratory option. The recommended dose of rifaximin is 400 mg tract infection), renal failure, hypokalemia, metabolic orally thrice daily or 550 mg twice daily. Both the doses are alkalosis, hypovolemia, hypoxia, hypoglycemia, and use of equally effective. The safety and tolerability of rifaximin sedatives. Blood ammonia concentration is reduced with has been proved for up to 2 years. As a rule, antibiotics

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are added rather than substituted to nonabsorbable Management of Minimal disaccharides. In a study, complete reversal of HE was observed more with combination of lactulose and Hepatic Encephalopathy rifaximin compared to lactulose alone (76% vs. 50.8%, Patients with MHE have poor quality of life, increased risk p=0.004) along with decreased mortality (23.8% vs. 49.1%, of OHE, require frequent hospitalization, and have high P < 0.05).10 Hence, combination therapy is recommended mortality. The available treatment options for MHE are in the management of HE. If the precipitating factor disaccharides (lactulose, lactitol), rifaximin, probiotics, 24-28 has been resolved and there is no recurrence of HE and nutritional support. In a study that compared a for next 3 months, the rifaximin can be discontinued. nutritional therapy of 30–35 kcal/kg and 1.0–1.5 g vegetable Neomycin, vancomycin, and metronidazole are other protein/kg with no dietary intervention in 120 cirrhotic alternatives of rifaximin but rifaximin is preferred as patients with MHE, the rate of reversal of MHE was higher it has less side effects. L-ornithine L-aspartate (LOLA) in those receiving nutritional therapy (71.1% vs. 28.8%, and branch-chain amino acids (BCCA) are the next p=0.001). Prevention of OHE and improvement in quality 28 in consideration for patients who do not respond to of life was also observed with nutritional therapy. conventional therapy.11,12 Drugs Used in Management of Hepatic Encephalopathy—Primary and Hepatic Encephalopathy Secondary Prophylaxis Nonabsorbable Disaccharides Lactulose and rifaximin are proved to be equally effective in Lactulose and lactitol are nonabsorbable disaccharides patients with acute variceal bleed for primary prophylaxis used as first-line treatment for HE. Lactulose reduces of HE. In a study, HE developed in a smaller number of formation and absorption of ammonia from the gut by cirrhotic patients with variceal bleed in lactulose group altering the microbiota, increases nitrogen excretion in compared to placebo group (14% vs. 40%, p=0.03).13 the feces and reduces production of toxic short chain In another study, lactulose and rifaximin were equally 14 fatty acids. It works as an osmotic purgative, prebiotic, effective. Secondary prophylaxis of HE is defined as 29 and also leads to gut acidification. A Cochrane data base preventing another episode of HE in patients who had review proved the efficacy of lactulose in HE management a previous episode of HE. In secondary prophylaxis compared to placebo or no intervention. Efficacy of chronic therapy with lactulose or lactitol is indicated lactulose has been seen in the management of MHE, OHE, and if HE recurs on lactulose therapy, combination and recurrent HE. It is also effective in reducing the risk therapy including lactulose and rifaximin should be of variceal bleeding, spontaneous bacterial peritonitis, considered.10,15,16 A published study revealed the efficacy hepatorenal syndrome, liver failure, and mortality.30 of lactulose in prevention of HE recurrence compared Lactulose is well tolerated, and the main side effects to placebo (19.6% vs. 46.8%, p=0.001).16 Recurrence of include abdominal cramps, diarrhea, and flatulence. HE can also be prevented with the help of probiotics, About 70–80% patients of HE responds to lactulose.31 glycerol phenylbutyrate (PB), BCAA, and LOLA.15-20 Lactitol is as effective as lactulose, is more palatable, and Patients with refractory HE may have large spontaneous have less side effects.32,33 PSS. Refractory HE in these patients can be prevented by PSS embolization and balloon occluded retrograde transvenous obliteration (BRTO) of large spontaneous Nonabsorbable Antibiotics splenorenal shunts.21,22 Fecal microbiota transplantation Ammonia lowering effect has been observed with use of (FMT) also prevents recurrence of HE, improve cognition antibiotics such as metronidazole, vancomycin, neomycin, and dysbiosis without major side effects in patients with paromomycin, and rifaximin as they have activity against cirrhosis.23 Liver transplant is the last resort in patients urease -producing gut bacteria. As rifaximin has minimal with decompensated cirrhosis who present with recurrent systemic absorption, broad spectrum, and less adverse HE despite of being on above therapy. events, it is most commonly used. Rifaximin effectively

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prevented the recurrence of HE when used as an add- preparations.42 Prophylactic LOLA infusion proved to be on therapy for refractory HE, despite on appropriate effective in decreasing venous ammonia concentration lactulose therapy.11 Rifaximin is effective in recovery in patients who underwent TIPS placement.43 LOLA is from HE, secondary prophylaxis, and in reducing the ineffective in patients acute liver failure. mortality as shown in a meta-analysis.34 It also enhances the performance and health-related quality of life in Probiotics 35,36 patients with MHE. Rifaximin had similar efficacy to Prebiotics and probiotics reduce blood ammonia nonabsorbable disaccharides for acute and chronic HE, concentrations by promoting colonization of acid- and somewhat better tolerated. Although neomycin and resistant, non-urease producing bacteria. The most metronidazole have been used for the management of HE, efficacious species for HE appears to be Lactobacilli and 37-39 data are very old and inadequate. These antibiotics Bifidobacterium. Use of probiotics improves recovery also have serious adverse events, like neomycin can in HE, but when compared with lactulose they failed cause nephrotoxicity, ototoxicity, malabsorption, and to show a benefit in significant outcomes as shown in a metronidazole can lead to peripheral neurotoxicity. meta-analysis.44 Probiotics are effective in MHE, OHE, and prevention of recurrent HE.27 Branch Chain Amino Acids Cirrhotic patients show reduce blood level of BCCA Other Therapies (leucine, isoleucine, valine). The BCCA have a role in skeletal muscle protein synthesis and detoxification of Large Spontaneous Portosystemic ammonia. High ammonia level decreases protein synthesis Shunts Embolization by diminishing the mTOR signaling in cirrhotic patients, Improvement in OHE and recurrence of HE has been this effect is prevented by BCAAs. A Cochrane data base observed with embolization of these shunts and BRTO of review showed that BCAAs have a favorable effect on HE in splenorenal shunt without deteriorating ascites, variceal cirrhotic patients.40 Both oral and intravenous preparations bleed, and portal hypertensive gastropathy.21,22 are effective. The BCCA helps in muscle building in all cirrhotic patients with sarcopenia along with favorable Polyethylene Glycol effects on HE which lead to improvement in quality of Polyethylene glycol (PEG) solution results in increase life. There is no benefit of BCAA supplementation in excretion of ammonia in the stool by its purgative action protein-tolerant patients. A recent randomized trial on thus it helps in HE management. Although the efficacy 116 patients who had an episode of HE in the past, found of PEG has been proved in a study, more such studies are no benefit of BCAA on the prevention of recurrent HE, 45 required for the same. although supplementation appeared to improve MHE and muscle mass.20 Based on these results, dietary BCAA supplementation is indicated only in severely protein- Acarbose intolerant patients. Acarbose enhances the growth of gut saccharolytic bacterial flora and diminishes proteolytic flora that L-Ornithine L-Aspartate produces ammonia, mercaptans, and benzodiazepine- like substances. Improvement in HE and reduction in LOLA promotes ammonia detoxification as it works as ammonia level has been observed with use of acarbose.46 metabolic substrates for urea cycle in liver and glutamine synthesis in skeletal muscle thus reduces blood ammonia levels. There was improvement in HE, reduction in venous Ammonia Lowering Agents ammonia level, recovery time and duration of hospital Ammonia lowering agents like PB, ornithine phenylacetate stay with use of intravenous LOLA along with lactulose.17 (OPA), and benzoate binds to ammonia and leads to A Cochrane data base review revealed favorable effect of excretion of nitrogen by urinary non-urea excretion. To LOLA on HE in cirrhotic patients and reduced mortality.41 date there is no definite evidence for OPA and PB for the This effect was observed with both oral and intravenous management of HE. Sodium benzoate had similar efficacy

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to lactulose in the management of HE in a small study.47 treatment of HE with less side effects. In protein intolerant Further studies are required to prove their efficacy. patients, BCCA have a favorable effect on HE. Probiotics and LOLA also have favorable effects in the treatment of HE. Flumazenil Nutritional therapy and FMT are emerging therapies for HE Use of flumazenil shows reduction in the GABA/ treatment but the data are limited. Combination of rifaximin benzodiazepine receptor complex activity thus reversing and lactulose is more effective in the management of overt and the neurological inhibition in HE. The short-term recurrent HE. Liver transplant, embolization of large PSS, and (minutes) favorable effect of flumazenil on HE has been BRTO of splenorenal shunts are effective management options in highly selected patients. proved in a meta-analysis but it does not have any effect on recovery, mortality, and quality of life.48 Flumazenil may be useful, in patients who received benzodiazepines. References . 1 Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose Zinc and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. Zinc has a role in few patients with recurrent HE, but more 1977;72(4pt 1):573-83. studies are required to prove its efficacy. . 2 Bajaj JS, Cordoba J, Mullen KD, et al. International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Review article: the design of clinical trials in hepatic encephalopathy—an Newer Therapies International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. Fecal Microbiota Transplant 2011;33(7):739-47. In cirrhotic patients there is reduced level of favorable 3. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic bacterial families like Lachnospiraceae and Rumino­ liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the coccaceae and rise of the pathogenic Enterobacteriaceae, Study of the Liver. Hepatology. 2014;60(2):715-35. Streptococcaceae. Fecal microbiota transplant prevents 4. Jepsen P, Ott P, Andersen PK, et al. Clinical course of alcoholic liver HE recurrence, improves cognitive function, and decreases cirrhosis: a Danish population-based cohort study. Hepatology. 2010;51(5):1675-82. frequent hospitalization as shown in a randomized pilot . 5 Sharma P, Sharma BC, Puri V, et al. Critical flicker frequency: 23 trial. diagnostic tool for minimal hepatic encephalopathy. J Hepatol. 2007;47(1):67-73. Albumin . 6 Prabhakar S, Bhatia R. Management of agitation and convulsions in hepatic encephalopathy. Indian J Gastroenterol. 2003;22(Suppl Albumin has anti-inflammatory properties; it binds and 2):S54-8. clears many toxic substances, which accumulate in liver . 7 Bajaj JS. Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther. 2010;31(5):537-47. failure. Lactulose with albumin has been proved to be . 8 Maharshi S, Sharma BC, Srivastava S. Malnutrition in cirrhosis more effective than lactulose alone in treatment of HE increases morbidity and mortality. J Gastroenterol Hepatol. (75% vs. 53.3%, p=0.03).49 2015;30(10):1507-13. . 9 Amodio P, Bemeur C, Butterworth R, et al. The nutritional management of hepatic encephalopathy in patients with cirrhosis: Other Experimental Therapy International Society for Hepatic Encephalopathy and Nitrogen Glutamine synthetase replacement, Liposome supported Metabolism Consensus. Hepatology. 2013;58(1):325-36. 10. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double- peritoneal dialysis, Melatonin, L-carnitine, Glutamatergic blind, controlled trial comparing rifaximin plus lactulose with antagonist, serotonin antagonist, opioid antagonist, and lactulose alone in treatment of overt hepatic encephalopathy. Am spherical carbon (AST-120). J Gastroenterol. 2013;108(9):1458-63. 11. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-81. Conclusion 12. Hudson M, Schuchmann M. Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the Early detection and correction of precipitating factors is utmost evidence. Eur J Gastroenterol Hepatol. 2019;31(4):434-50. important in the management of HE. The most commonly used 13. Sharma P, Agrawal A, Sharma BC, et al. Prophylaxis of hepatic therapy is still lactulose, which is effective in MHE, OHE, and encephalopathy in acute variceal bleed: a randomized controlled recurrent HE. Efficacy of rifaximin is similar to lactulose in the trial of lactulose versus no lactulose. J Gastroenterol Hepatol. 2011;26(6):996-1003.

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14. Maharshi S, Sharma BC, Srivastava S, et al. Randomised controlled 31. Sharma P, Sharma BC. Disaccharides in the treatment of hepatic trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy. Metab Brain Dis. 2013;28(2):313-20. encephalopathy in patients with acute variceal bleed. Gut. 32. Blanc P, Daures JP, Rouillon JM, et al. Lactitol or lactulose in 2015;64(8):1341-2. the treatment of chronic hepatic encephalopathy: results of a 15. Agrawal A, Sharma BC, Sharma P, et al. Secondary prophylaxis of metaanalysis. Hepatology. 1992;15(2):222-8. hepatic encephalopathy in cirrhosis: an open label, randomized 33. Camma C, Fiorello F, Tine F, et al. Lactitol in treatment of controlled trial of lactulose, probiotics and no therapy. Am J chronic hepatic encephalopathy. A meta-analysis. Dig Dis Sci. Gastroenterol. 2012;107(7):1043-50. 1993;38(5):916-22. 16. Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of 34. Kimer N, Krag A, Moller S, et al. Systematic review with meta- hepatic encephalopathy: an open-label randomized controlled trial analysis: the effects of rifaximin in hepatic encephalopathy. Aliment of lactulose versus placebo. Gastroenterology. 2009;137(3):885-91. Pharmacol Ther. 2014;40(2):123-32. 17. Sidhu SS, Sharma BC, Goyal O, et al. L-ornithine L-aspartate in bouts 35. Rahimi RS, Rockey DC. Hepatic encephalopathy: pharmacological of overt hepatic encephalopathy. Hepatology. 2018;67(2):700-10. therapies targeting ammonia. Semin Liver Dis. 2016;36(1):48-55. 18. Sharma BC, Maharshi S. Prevention of hepatic encephalopathy 36. De Las Heras J, Aldamiz-Echevarria L, Martinez-Chantar ML, et al. An recurrence. Clin Liver Dis. 2015;5(3):64-7. update on the use of benzoate, phenylacetate and phenylbutyrate 19. Rocky DC, Vierling JM, Mantry P, et al. Randomized, double- ammonia scavengers for interrogating and modifying liver nitrogen blind, controlled study of glycerol phenylbutyrate in hepatic metabolism and its implications in urea cycle disorders and liver encephalopathy. Hepatology. 2014;59(3):1073-83. disease. Expert Opin Drug Metab Toxicol. 2017;13(4):439-48. 20. Les L, Doval E, Martinez RG, et al. Effects of branched-chain amino 37. Fichet J, Mercier E, Genee O, et al. Prognosis and 1-year mortality of acids supplementation in patients with cirrhosis and a previous intensive care unit patients with severe hepatic encephalopathy. J episode of hepatic encephalopathy: a randomized study. Am J Crit Care. 2009;24(3):364-70. Gastroenterol. 2011;106:1081-8. 38. Gluud LL, Dam G, BorreM, et al. Lactulose, rifaximin or branched 21. Laleman W, Talero SM, Maleux G, et al. Embolization of large chain amino acids for hepatic encephalopathy: what is the spontaneous portosystemic shunts for refractory hepatic evidence? Metab Brain Dis. 2013;28(2):221-5. 39. Oettl K, Stadlbauer V, Petter F, et al. Oxidative damage of albumin encephalopathy: a multicenter survey on safety and efficacy. in advanced liver disease. Biochim Biophys Acta Mol Basis Dis. Hepatology. 2013;57(6):2448-57. 2008;1782(7-8):469-73. 22. Mukund A, Rajesh S, Arora A, et al. Efficacy of balloon-occluded 40. Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for retrograde transvenous obliteration of large spontaneous people with hepatic encephalopathy. Cochrane Database Syst Rev. lienorenal shunt in patients with severe recurrent hepatic 2015;2017(5):CD001939. encephalopathy with foam sclerotherapy: initial experience. J Vasc 41. Goh ET, Stokes CS, Sidhu SS, et al. L-ornithine L-aspartate for Interv Radiol. 2012;23(9):1200-6. prevention and treatment of hepatic encephalopathy in people 23. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant with cirrhosis. Cochrane Database Syst Rev. 2018;5(5):CD012410. from a rational stool donor improves hepatic encephalopathy: a 42. Bajaj JS, Lauridsen M, Tapper EB, et al. Important unresolved randomized clinical trial. Hepatology. 2017;66(6):1727-38. questions in the management of hepatic encephalopathy: an 24. Sharma P, Sharma BC, Puri V, et al. An open-label randomized ISHEN consensus. Am J Gastroenterol. 2020. controlled trial of lactulose and probiotics in the treatment of 43. Bai M, He C, Yin Z, et al. Randomised clinical trial: L-ornithine-L- minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol. aspartate reduces significantly the increase of venous ammonia 2008;20(6):506-11. concentration after TIPSS. Aliment Pharmacol Ther. 2014;40(1):63-71. 25. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy 44. Dalal R, McGee RG, Riordan SM, et al. Probiotics for people is independently associated with poor survival and increased risk of with hepatic encephalopathy. Cochrane Database Syst Rev. hospitalization. Am J Gastroenterol. 2014;109(11):1757-63. 2017;2(2):CD008716. 26. Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive 45. Rahimi RS, Singal AG, Cuthbert JA, et al. Lactulose vs polyethylene functions and health-related quality of life in patients with glycol 3350—electrolyte solution for treatment of overt hepatic cirrhosis who have minimal hepatic encephalopathy. Hepatology. encephalopathy: the HELP randomized clinical trial. JAMA Intern 2007;45(3):549-59. Med. 2014;174(11):1727-33. 27. Bajaj JS, Heuman DM, Sanyal AJ, et al. Modulation of the metabiome 46. Gentile S, Guarino G, Romano M, et al. A randomized controlled trial by rifaximin in patients with cirrhosis and minimal hepatic of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol. encephalopathy. PLoS One. 2013;8(4):e60042. 2005;3(2):184-91. 28. Maharshi S, Sharma BC, Sachdeva S, et al. Efficacy of nutritional 47. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in therapy for patients with cirrhosis and minimal hepatic the treatment of acute hepatic encephalopathy: a double-blind encephalopathy in a randomized trial. Clin Gastroenterol Hepatol. randomized trial. Hepatology. 1992;16(1):138-44. 2016;14(3):454-60. 48. Goh ET, Andersen ML, Morgan MY, et al. Flumazenil versus 29. Krnerup LS, Gluud LL, Vilstrup H, et al. Update on the therapeutic placebo or no intervention for people with cirrhosis and hepatic management of hepatic encephalopathy. Curr Gastroenterol Rep. encephalopathy. Cochrane Database Syst Rev. 2017;2017:1-78. 2018;20(5):21. 49. Sharma BC, Singh J, Srivastava S, et al. Randomized controlled 30. Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for trial comparing lactulose plus albumin versus lactulose alone for hepatic encephalopathy: a systematic review and meta-analysis. treatment of hepatic encephalopathy. J Gastroenterol Hepatol. Hepatology. 2016;64(3):908-22. 2017;32(6):1234-9.

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The Healthy Indian 131 Gut Microbiota

Rupjyoti Talukdar

Abstract This chapter discusses the current understanding of the gut microbiome in Indian population. It also highlights the differences of the Indian gut microbiome from other populations. Most of the earlier studies involved small to relative moderate sample size from specific geographic locations of India. An ideal study to evaluate the core gut microbiota of healthy Indians should involve a large homogeneous population across the country and use the same technology and data analytics tools. The LogMPIE (Landscape of gut microbiome-Pan India Exploration) is such a study. This study confirmed the most predominant organisms in the Indian gut are Prevotella copri and Faecalibacterium prausnitzii.

Introduction The Indian subcontinent, which has a rich biodiversity, is undergoing a transition in the sociodemographic The microbial ecosystem within the human body has profile.8 Therefore, the India gut microbiota has evolved established a symbiotic relationship that results in to be an interesting area to be studied. In this chapter, we mutually beneficial metabolic and protective functions. review the published data on the gut microbiota in healthy Depending on the mode of delivery, the human gut gets Indian individuals. colonized earliest from the maternal vaginal or skin flora.1 Even though organisms had been demonstrated in amniotic fluid, studies have even raised the possibility Indian Gut Microbiota and Its Determinants of colonization even before birth as organisms have been demonstrated in the first meconium. However, Mode of Delivery and Early Diet this observation is currently under scrutiny.2-4 Recent It was shown by Pandey et al. that the fecal microbiota of studies have also reported similarity between the ancient vaginally born infants was dominated by Acinetobacter microbiome to the modern human gut microbiome, sp., Bifidobacterium sp., and Staphylococcus sp.9 On especially with modern rural population.5 It is now known the contrary, the infants born by cesarean delivery that the gut microbiome is shaped throughout life in a conspicuously lacked Bifidobacterium, which is a crucial dynamic manner by factors such as mode of delivery, organism required for milk digestion. In a subsequent diet patterns (vegan, fiber-rich, or meat-based), use study, Kabeerdoss et al.10 reported a dynamic evolution of of food preservatives and emulsifiers, environmental organisms in the infant gut, with the most dominant being antimicrobial peptides, lifestyle behavior, such as alcohol Lactobacilli and Enterobacteriaceae. This was significantly intake, use of antibiotics and probiotics1,6,7 host genetics, higher than in infants born by cesarean delivery on the and surrounding biodiversity. first day of life but equaled thereafter. After 3 months

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of birth, an abundance of Bifidobacterium was higher Vibrio, Eggerthella, and Pseudomonas were high in both in stools of the vaginally born infants while there was a the Ballabgarh cohorts. progressive increase in abundance of the Bacteroides- The region-specific variation in the gut microbiota Prevotella group in these infants from birth to 3 months of in this study was also associated with enrichment of life. Meanwhile, exclusively breast-fed infants had a higher xenobiotic metabolizing pathways in the Ballabgarh rural abundance of Enterobacteriaceae compared to those who and urban cohorts compared to the Ladakh population, were additionally fed with supplemental cow’s milk.10 implying higher exposure to industrial chemical and drugs in the Ballabgarh populations. Age Another recent study15 that evaluated the gut Balamurugan et al. reported the first Indian study on 130 microbiota in Bhopal (Central India) and Kerala (South children and adolescents that demonstrated a dynamic India) identified two distinct clusters of organisms. change in the gut bacterial composition.11 The study cohort Cluster 1 was enriched in organisms from the genera was fairly homogeneous and predominantly consumed Prevotella while Cluster 2 was enriched with species from a lactovegetarian diet with infrequent meat intake. the genus Bifidobacterium, Ruminococcus, Clostridium, Bifidobacterium longum showed predominance from and Faecalibacterium. Location-wise distribution revealed the age of 2–3 years but declined rapidly after reaching Prevotella and Megasphaera to be predominant in Central adulthood. Similarly, Lactobacillus acidophilus was Indian cohort while the others including Bacteroides were predominant in the 2–3 years age group but progressively more abundant in the South Indian cohort. Moreover, declined as age progressed toward adulthood. On the the authors also reported three characteristics fecal other hand, the Bacteroides-Prevotella-Porphyromonas metabolomic clusters among the study cohorts. The group which was low in early childhood constituted the Central Indian cohort abounded in metabolites such as major organisms in later childhood and adolescence. The palmitic acid, stearic acid, and valeric acid, while in the study by Marathe et al. also suggested a change in the gut South Indian cohort, there was a significant enrichment microbiota with progressing age.12 of BCAAs (especially isoleucine), cadaverine, propionate, and lauric acid. Habitat and Geography A multicenter study13 from urban and adjacent rural Ethnicity Delhi and Pune reported Prevotella, Megasphaera, Since tribal populations are closely attached to nature Faecalibacterium, Lactobacillus, Ruminococcus, and and their lifestyle is largely determined by agriculture, Roseburia as the most dominant organisms. Interestingly, fishing, hunting, tribe specific dietary patterns, culture, the gut microbiota in these individuals could be divided and traditions, they are likely to harbor an evolutionarily into two groups on the basis of the absolute counts of conserved gut microbiota. India harbors the largest tribal Prevotella and Megasphaera. The microbial diversity was population in the world and thus constitutes the ideal for significantly higher among the urban individuals. evaluation of the “normal” gut microbiota. In the first and Another subsequent study14 that evaluated the gut so far, the largest study on the Indian tribal gut microbiota,16 microbiota in rural and urban Ballabgarh (sea level) and we evaluated healthy tribal volunteers belonging to 15 Ladakh (11,500 ft above sea level) demonstrated region- tribes of Mongoloid or Proto-Australoid decent dispersed specific differences in bacterial diversity. The genus and over different geographic locations across Northeast species level diversity were least in the rural Ladakh region and Southern India. The genus Prevotella contributed to while in individuals from urban Ballabgarh had high 40% of the genus across all tribes. The other genera that alpha and beta diversity, while individuals from the rural constituted the core microbiota irrespective of geography region had high alpha but low beta diversity.14 The genus and ethnicity included Faecalibacterium, Eubacterium, Parabacteroides, Blautia, Brevundimonas, Pelomonas, and Clostridium, Blautia, Collinsella, Ruminococcus, and Megamonas were significantly higher in the Ballabgarh Roseburia. In addition to these genera, Bacteroides, Dialster, rural cohort. On the other hand, while Lactobacillus was and Veillonella were found to abound the tribes from abundant in the Ballabgarh urban cohort, Bacteroides, Manipur while Bacteroides, Dialster, Bifidobacterium, and

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Lactobacillus abounded in the tribes from Sikkim. Tribes pork meat, and non-intake of milk, and milk products due from Manipur had the least abundance of Bifidobacterium. to their religious beliefs.17 Correlational analyses within the core microbiota revealed that Prevotella had a negative correlation with Bacteroides, Comparison of Indian Gut Microbiota Faecalibacterium, and Clostridium in the Telangana with Worldwide Data tribes, with Faecalibacterium, Bacteroides, and Roseburia in the Manipur tribes, and with Bacteroides, Clostridium, It has now been consistently shown that the Indian gut Ruminococcus, and Blautia in the tribes from Sikkim. microbiota differs significantly from that of other regions of 16 Tribes from Sikkim had a significantly lower abundance of the world. In our study, we observed two distinct clusters, Enterobacter compared to tribes from Assam, Telangana, the first involving the Hadza, Italian, and Americans and Manipur. individuals that abounded in Faecalibacterium. The rest of the tribal groups, including Indians, constituted the other Dietary Factors group with a higher abundance of Prevotella. Interestingly, within this group there was close similarity of the Indian Diet has been established as a major factor that shapes tribal microbiome to the Mongolian tribal microbiota. Of the human gut microbiota. In the foregoing sections of note, the origins of the Nepali and Tai-Phake tribes from this review, even though there were variations in the India can be mapped to Mongolians. gut microbiota according to geography and habitat, a 13 In the study by Bhute et al., comparison of gut closer look actually converges these variations to dietary microbiota of Western and North Indian cohorts with patterns. Overall, Prevotella, which is responsible for Americans revealed 76 OTUs, out of which six, including complex plant-derived polysaccharide degradation, Prevotella, Lactobacillus, Lachnococcus, and Roseburia, was dominant in a majority of the study populations specifically belonged to the Indians. In this study, it was also implicating this as a signature genus in Indians.13,15-17 observed that Indians shared 25 OTUs with the Bangladeshi The study from Ballabgarh and Ladakh14 also suggested cohort (majority belonging to families Lachnospiraceae, that cooking oil and ghee could impact the Indian gut Ruminococcaceae, and Enterobacteriaceae, and genus microbial composition. For instance, individuals from Prevotella). Other than differences at the overall genera Ladakh consumed predominantly sunflower oil, which and species level OTUs, differences were also noticed has a high concentration of linoleic acid that is known to between Indian and European cohorts even within the be degraded by Roseburia. Similarly, Sporobacter was also same genus.13 abundant in individuals consuming sunflower oil; while Finally, a metagenome wide meta-analyses (MGWAS) Collinsella was specifically predominant in individuals by Dhakan et al., which included datasets from India, who consumed clarified butter (ghee). 16 China, USA, and Denmark demonstrated completely In the tribal study by Dehingya et al., the gut microbiota separate species level clustering of the Indian gut was similar between tribes from Assam and Telangana microbiome compared to the American, Danish, and despite the geographic and ethnic differences. Therefore, Chinese microbiome.15 Prevotellaceae emerged as the it appears likely that the carbohydrate and dietary fiber- most highly abundant bacterial family in the Indian rich diet (including rice, whole grain, vegetables, fruits, individuals. In addition, the Indian gut microbiota was legumes, tubers) determines the core microbiota, which found to be enriched in functions that corroborate with a is predominant in Prevotellaceae, Ruminococcaceae, carbohydrate-rich diet. Lachnospiraceae, and Eubacteriaceae, which are enriched in carbohydrate metabolizing enzymes. In the Lepcha, Conclusion Nepali, and Bhutia tribes from Sikkim the abundance of Bifidobacterium and Lactobacillus can be explained by Results of gut microbiota studies can be influenced by several the higher consumption of milk products and fermented technical factors such as sample size, sample collection and food. Among the Malayali tribes from Tamil Nadu, the storage, sequencing technique, reference database, and depth higher abundance of Bacteroidetes and Clostridium could of statistical and bioinformatics analyses. be explained by their daily intake of a moderate amount of Contd...

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Contd... 6. Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic In this review, we discussed the gut microbiota in healthy syndrome. Nature. 2015;519(7541):92-6. Indians based on the individual studies that involved small to . 7 Tasnim N, Abulizi N, Pither J, et al. Linking the gut microbial medium sample size and different techniques to evaluate the ecosystem with the environment: does gut health depend on microbiome. The ideal way to evaluate the true core Indian where we live? Front Microbiol. 2017;8:1935. gut microbiota would be to include a large homogeneous . 8 Biodiversity in India. Available from https://indiabiodiversity.org/ page/4246006 [Accessed October, 2019]. population across the entire country and use the same . 9 Pandey PK, Verma P, Kumar H, et al. Comparative analysis of fecal methods of sample processing, sequencing, and data analyses. microflora of healthy full-term Indian infants born with different The LogMPIE (Landscape of gut microbiome-Pan India methods of delivery (vaginal vs cesarean): Acinetobacter sp. Exploration) is such a study that was recently published.18 This prevalence in vaginally born infants. J Biosci. 2012;37(6):989-98. study evaluated 1,004 individuals from 14 centers across India 10. Kabeerdoss J, Ferdous S, Balamurugan R, et al. Development of the (4 from north, 3 from east, 4 from west, and 3 from south) and gut microbiota in southern Indian infants from birth to 6 months: a molecular analysis. J Nutr Sci. 2013;2:e18. bacterial metagenomic sequencing was performed in the Ion 11. Balamurugan R, Janardhan HP, George S, et al. Bacterial succession oneTouch 2 system. There were 390 microorganisms that were in the colon during childhood and adolescence: molecular studies common in all the geographic locations, while 36 were unique in a southern Indian village. Am J Clin Nutr. 2008;88(6):1643-7. to north, 149 to south, 95 to west, and 62 to east India. The most 12. Marathe N, Shetty S, Lanjekar V, et al. Changes in human gut flora predominant organisms emerged to be Prevotella copri and with age: an Indian familial study. BMC Microbiology. 2012:12:22. Faecalibacterium prausnitzii, thereby qualifying Prevotella and 13. Bhute S, Pande P, Shetty SA, et al. Molecular characterization and Faecalibacterium. meta-analysis of gut microbial communities illustrate enrichment of prevotella and megasphere in Indian subjects. Front Microbiol. 2016;7:660. 14. Das B, Ghosh TS, Saxena S, et al. Analysis of the gut microbiome of References rural and urban healthy indians living in sea level and high-altitude 1. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal areas. Sci Rep. 2018;8(1):10104. gut microbiota. World J Gastroenterol. 2015;21(29):8787-803. 15. Dhakan DB, Maji A, Sharma AK, et al. The unique composition . 2 Collado MC, Rautava S, Aakko J, et al. Human gut colonisation of Indian gut microbiome, gene catalogue, and associated fecal metabolome deciphered using multi-omics approaches. may be initiated in utero by distinct microbial communities in the Gigascience. 2019;8(3):1-20. placenta and amniotic fluid. Sci Rep. 2016;22;6:23129. 16. Dehingia M, Devi KT, Talukdar NC, et al. Gut bacterial diversity of the . 3 Stinson LF, Boyce MC, Payne MS, et al. The not-so sterile womb: tribes of India and comparison with the worldwide data. Sci Rep. evidence that the human fetus is exposed to bacteria prior to birth. 2015;5:18563. Front Microbiol. 2019;10:1124. 17. Ramadass B, Rani BS, Pugazhendhi S, et al. Faecal microbiota . 4 Lim ES, Rodriguez C, Holtz LR. Amniotic fluid from healthy term of healthy adults in south India: comparison of a tribal & a rural pregnancies does not harbor a detectable microbial community. population. Indian J Med Res. 2017;145(2):237-46. Microbiome. 2018;6(1):87. 18. Dubey AK, Uppadhyaya N, Nilawe P, et al. LogMPIE, pan-India . 5 Tito RY, Knights D, Metcalf J, et al. Insights from characterizing profiling of the human gut microbiome using 16S rRNA sequencing. extinct human gut microbiomes. PLoS One. 2012;7(12):e51146. Sci Data. 2018;5:180232.

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Celiac Disease: Who to Screen 132 and How to Screen?

Ashish Agarwal, Archita Makharia, Govind K Makharia

Abstract Traditionally celiac disease (CeD) has been defined as a disease involving the proximal small intestine with a presentation with diarrhea, loose stools, malabsorption, weight loss, failure to thrive, and growth retardation in children. This presentation which has long been portrayed as “classical” for CeD, allows us to diagnose only the patients with most severe gastrointestinal involvement and thus miss out those with milder or no GI manifestations. However, it is being increasingly recognized that celiac disease is a multisystem disease with a myriad of presentation including asymptomatic. Even though studies have indicated around 1% population prevalence of celiac disease, most of these patients however remain undiagnosed and hence untreated. There is thus a need for increased awareness of these varied presentations of celiac disease so that the patients can be diagnosed and treated with gluten-free diet thus preventing complications. In this chapter we have discussed the indications for screening for celiac disease and the strategy for screening these individuals.

Introduction abnormalities on duodenal biopsies) is 0.7% (means 1 in 140 individuals globally has CeD).1 With a global Celiac disease (CeD) is a chronic immune-mediated population of 7.2 billion people, approximately 40–60 enteropathy which is triggered on consumption of gluten million people around the world are likely to have CeD. protein present in cereals like wheat, barley, and rye in genetically predisposed individuals. Although initially believed to be an uncommon disease and Burden of CeD in India limited to the western countries, CeD has now become a Although reported since 1960s in India, an increase in global disease and it is now reported from almost all the number of patients with CeD in the last 2 decades has been continents. reported from many states, predominantly Northern and Western States of India. Two population-based studies from Northern part of India have shown that the population Global Burden of CeD prevalence of CeD is 1.04% (1 in 96) and 0.33% (1 in 330), In a systematic review and meta-analysis, we have respectively.2,3 Because of predominance of reporting of recently shown that the global pooled seroprevalence CeD from the Northern states, people believe that CeD (proportion of people having a positive celiac specific is seen only in the Northern part of India. To explore the serological test in a population) is 1.4% (that means, 1 question “is there a regional variation in the prevalence of in 70 people is seropositive for CeD) and the prevalence CeD in India,” we conducted a multi-site population-based of biopsy-confirmed CeD (proportion of patients having study recruiting 23,331 healthy individuals from three a combination of positive serological tests and villous different regions of India including Northern (Haryana),

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Southern (Vellore), and Northeastern (Guwahati) regions „„ While CeD is thought to be mainly a disease of of India. The combined pan-India prevalence of CeD is the intestine and recognized in those having 0.67% (1 in 140). Indeed, there is a regional variation in gastrointestinal symptoms, only half of the patients the prevalence of CeD at this point of time, the highest however present with predominant gastrointestinal being in Northern India (1.23%), lowest in Southern India manifestations. The GI symptoms (Classical CeD) (0.1%) and in between in the Northeastern region of India include chronic diarrhea, malabsorption, failure to (0.87%).4 This difference is likely related to the different thrive, abdominal distension, and weight loss (Fig. 1). eating patterns, with rice being staple diet in Southern „„ Approximately half of all the patients with CeD India and wheat in Northern India. However, with increase present to a clinician with predominant non-GI in the consumption of products made from wheat in rice symptoms such as short stature, liver abnormalities, eating regions, it is very likely that CeD will emerge in such infertility, endocrinopathies, etc. in the absence of populations also. With the Indian population of 120 crores, or with minimal GI symptoms. The diagnosis of CeD it is estimated that approximately 60–80 lakhs of Indians is often not suspected in such patients, since most have CeD. Of this large estimated numbers of people physicians believe that patients with CeD should have having CeD, only a minority have been diagnosed and a GI manifestations (Fig. 1). large proportion of them (85–95%) exists in the population Therefore, patients with CeD can present to an but currently remain undiagnosed. internist/gastroenterologists with symptoms of chronic diarrhea, anemia, fatigability, to a pediatrician with Where are They? irritability, diarrhea, failure to thrive and anemia, to a hematologist with anemia refractory or unresponsive If there are so many patients with CeD both worldwide and to iron supplementation, to an endocrinologist with in India, then where are they? Why are we not able to pick type 1 diabetes, hypothyroidism, or growth failure, to them up? There are multiple reasons: a dermatologist with dermatitis herpetiformis, to a „„ The lack of awareness amongst physicians about neurologist with ataxia, peripheral neuropathy, and to a changing epidemiology of this disease is the most gynecologist with menstrual abnormalities or infertility. important reason. We do not think about this diagnosis Thus, there is an increased need for increasing in appropriate clinical setting. awareness amongst primary care physicians, internists, „„ It was believed that CeD affects only children, but now gastroenterologists, hematologists, endocrinologists, it is known that CeD can affect people of all age groups. and neurologists about a wide and varied spectrum of Although not well established, it is however believed manifestations of CeD so that these patients are diagnosed that the pathophysiological changes in CeD starts early. An early diagnosis and initiation of gluten- since early part of life. The clinical manifestations may free diet in them can control and the symptoms, and appear at different ages of life depending upon the prevent consequences of malabsorption and nutritional severity of the disease. 5 deficiencies and prevent adverse health consequences. „„ While some patients have fully expressed disease with Therefore, CeD should be suspected in the patients even obvious symptoms and manifests in childhood or in the absence of typical gastrointestinal manifestations. during adolescence, in others, the disease is expressed We have summarized below the diseases or symptoms in milder form, and hence may not come to clinical where screening for CeD should be done. attention till late. CeD is diagnosed nowadays more often in adulthood and even in the elderly. Who should be Screened for CeD (Table 1) „„ The classical manifestations, as portrayed in the older textbooks, draw our attention to mainly the Patients having Diseases and Symptoms more classical form of disease (emaciated child with Secondary to CeD diarrhea and anemia), which are present in those having a more advanced disease. In early stages of the Chronic Diarrhea with Features of Malabsorption disease, patients may not have any symptoms or have Patients having intermittent or chronic diarrhea with only mild symptoms. features of malabsorption, such as anemia, growth

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Fig. 1: Clinical manifestations of celiac disease

TABLE 1 Indications for screening for celiac disease

Gastrointestinal manifestations Extraintestinal manifestations Associated conditions Chronic diarrhea Cryptogenic hypertransaminasemia First-degree relatives Malabsorption Cryptogenic cirrhosis Type I diabetes Growth retardation/Short stature Infertility Hypothyroidism Failure to thrive Idiopathic cerebellar ataxia Other autoimmune diseases Iron deficiency anemia Dermatitis herpetiformis Down’s syndrome IBS (IBS-D, IBS-M)

retardation, poor weight gain, easy fatigability, should be pain/discomfort, and bloating. With such a symptom screened for CeD. CeD is now the most common cause of complex, they are likely to be diagnosed as having malabsorption syndrome, unlike tropical sprue being the functional gastrointestinal diseases including irritable most common cause some times back. bowel syndrome. In fact, in a meta-analysis of 7 studies including 3,383 patients with CeD, it was shown that 38% Functional Gastrointestinal Disorders patients with CeD had IBS-like symptoms.6 In yet another Some of the patients with CeD may have mild GI meta-analysis of 22 eligible studies including 6,991 manifestations such as altered bowel activity, abdominal patients with irritable bowel syndrome, it was found that

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3.3% of them had CeD more so in those having mainly IBS- Infertility 7 diarrhea predominant and IBS-mixed subtypes. Menstrual abnormalities including delayed menarche and secondary amenorrhea are quite frequent in patients Iron Deficiency Anemia with CeD. Furthermore, patients with CeD have been Between 50–80% of patients with CeD have anemia and found to have a low rate of fertility. Patients with CeD are that occurs most commonly because of iron deficiency. at three-times higher risk for infertility than the general Anemia secondary to B12 and folate deficiency in addition population. On the other hand, 2.3% of patients with to iron deficiency has also been described. infertility have been found to have CeD.9 As CeD is one of On the other hand, it has been observed that 3.2% the few treatable causes of infertility, all women patients (95% CI 2.6–3.9%) of all patients with iron deficiency with infertility should be screened for CeD. anemia, when screened for CeD, are found to have CeD.8 That would mean than 1 of every 31 patients with iron Liver Abnormalities deficiency anemia has CeD. In a study from India, almost 1 in 10 with iron deficiency anemia had CeD. Thus, all Almost one-fourth patients with CeD have asymptomatic patients with iron deficiency anemia should be screened elevation of serum transaminases at the time of diagnosis for CeD. which normalize within 1 year of GFD in majority. If this liver injury is not recognized and remains untreated, Short Stature/Growth Failure it can lead to cirrhosis of the liver. In fact, CeD has been found to be one of the causes of cryptogenic Almost one third of the adult patients and half of the cirrhosis. Furthermore, approximately 7% of all those adolescent patients with CeD have short stature. Since who have hypertransaminasemia and 5% of those having height can increase only till 18 years of age, it is really cryptogenic liver disease have been found to have CeD.10,11 important to make a diagnosis of CeD much before that Treatment of CeD in these patients has been shown to age. A timely treatment of CeD can lead to catch up growth lead to an improvement in the liver disease. Therefore, and attainment of a normal height. all patients with cryptogenic hypertransaminasemia On that other hand, of the patients presenting for the and cryptogenic cirrhosis of liver should be screened for evaluation of short stature, 6.6% (approximately 1 in 15) CeD. As discussed below, as anti-tissue transglutaminase have been found to have CeD. The proportion of patients antibody may be falsely positive in those with cirrhosis; having CeD is still higher (13.4%; 1 in 8) in those having therefore, a more reliable screening test in this setting is idiopathic short stature, when all known causes have been anti-endomysial antibody. excluded. The prediction of having CeD in these patients is higher if they also have associated GI manifestations or anemia. Nevertheless, all patients with short stature at any Neurological Disorders age, with or even without associated GI manifestations, Some of the patients with cerebellar ataxia, especially should be screened for CeD. those having idiopathic ataxia, have been found to have gluten-related disorders and CeD. The treatment of Dermatitis Herpetiformis CeD has also been shown to lead to some improvement in ataxia. Therefore, patients with idiopathic ataxia Dermatitis herpetiformis (DH) is characterized by clusters should be screened for gluten-related disorders. In of papules and vesicles associated with intense pruritus. such patients both anti-gliadin antibody and anti-tissue The typical sites for DH lesions include extensor surfaces transglutaminase antibodies should be used for screening. of upper and lower extremities, elbows, knees, scalp, and buttocks. The extent of skin lesions may vary from small area to more diffuse involving multiple sites at one time. First-degree Relatives of Patients with CeD DH shows an excellent response to GFD with complete As we know, genes play a major role in the pathogenesis resolution of skin lesions. Thus, all patients with DH must of CeD. The first-degree relatives of index patients with be screened for CeD. CeD are at much higher risk of developing CeD. A recent

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meta-analysis including 10,252 FDRs of patients with CeD How do we Screen for CeD? has shown that 7.5% of first-degree relatives of CeD have Once we suspect a patient to have CeD, the first- CeD.12 Furthermore, the sisters (1 in 7) and daughters (1 line screening tests are the CeD specific serological in 8) of the index patients with CeD are at the highest risks. tests. Immunoglobulin subclass A (IgA) anti-tissue Thus, all the first-degree relatives of index patients with transglutaminase, (IgA anti-tTG Ab), anti-endomysial CeD should be screened for CeD. antibody (IgA EMA), and deamidated glutamine dipeptide (IgA anti-DGP Ab) are the currently available assays for Type I Diabetes screening for CeD. Of these, IgA anti-tTG is the most CeD has been found to be strongly associated with type I commonly used test for the screening and diagnosis of diabetes and a recent meta-analysis has shown that 6% of CeD because of the ease of detection and a high accuracy all patients with type I diabetes have CeD.13 It means that with a sensitivity of 92.8% and specificity of 97.9%16 of 16 patients with type I diabetes, one will have associated (Table 2). While IgA EMA testing has a high specificity CeD. Many of them may have symptoms because of CeD, of 99%, recent systematic review has reported a lower but these symptoms are often considered to be due to sensitivity of 73%. Detection of anti-EMA requires indirect diabetes, and hence they are not specifically investigated immunofluorescence and it is not widely available. IgA for CeD. Therefore, all patients with type I diabetes should anti-DGP assay have a pooled sensitivity of 87.8% (95% CI, be screened for CeD. 85.6–89.9%), and specificity 94.1% (95% CI, 92.5–95.5%) and thus have an inferior performance than anti-tTG Autoimmune Thyroid Disease Ab (Table 2). Since all these antibodies are IgA based, hence they may be falsely negative in patients having IgA An association has been shown between CeD and deficiency. In such situations, IgG based tests such as IgG autoimmune thyroid disorders. Between 10–15% patients anti-DGP or IgG anti-tTG Ab should be done.17 with CeD have coexistent clinical hypo/hyperthyroidism. ELISA kits for anti-tTG antibody are manufactured In fact, a recent study showed that of 6,024 patients with by many companies and their performance varies autoimmune thyroid disorders screened for CeD, 1.4% significantly. Furthermore, there are differences in the 14 patients had CeD. Thus, all patients with autoimmune cut-off values of the anti-tTG antibody amongst ethnically thyroid disorders should be screened for CeD. different population. Hence, a clinician should be aware about these limitations.18 Down’s Syndrome Approximately 1%–19% patients with Down’s syndrome Diagnosis of Celiac Disease (Flowchart 1) have been reported to have CeD. A recent meta-analysis If a patient screened for CeD is detected to have a positive of 31 studies and including 4,383 patients with Down’s celiac specific serological assays, the diagnosis needs to syndrome has reported that 5.8% of them have CeD, which be confirmed by demonstration of villous abnormalities is much higher than that in the general population.15 in the intestinal mucosa, which is still the gold standard Therefore, all patients with Down’s syndrome should be screened for CeD. Diagnostic performance of various serological TABLE 2 Other Conditions assays for the diagnosis of celiac disease A higher prevalence of CeD has also been observed in Sensitivity Specificity certain other conditions including patients having dental IgA anti-tTG 92.8% 97.9% enamel defects, other autoimmune disorders like systemic (95% CI, 90.3–94.8) (95% CI, 96.4–98.8) lupus erythematosus, juvenile rheumatoid arthritis, and EMA 73.0% 99.0% (95% CI, 61.0–83.0) (95% CI, 98.0–99.0) autoimmune liver diseases, etc.; however, there is a lack of robust data suggesting the utility of routine screening for IgA anti-DGP 87.8% 94.1% (95% CI, 85.6–89.9) (95% CI, 92.5–95.5) CeD in these patients.

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Flowchart 1: Algorithm for the diagnosis of celiac disease

for the diagnosis of CeD. Multiple biopsy specimens from crypt hyperplasia, and villous atrophy. A diagnosis of CeD the second part of duodenum and at least one biopsy is made in patients with villous abnormalities of modified specimen from the first part of the duodenum should Marsh grade II or more. be taken for adequate histopathological assessment.19-21 The gold standard diagnostic criteria of CeD is based Modified Marsh classification system is currently used on a combination of clinical manifestations, a positive to grade the severity of villous abnormalities based on celiac specific serology and demonstration of villous identification of increased intraepithelial lymphocytes, abnormalities of modified Marsh grade II or more. The

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European Society of Gastroenterology, Hepatology and 5. Green PHR, Cellier C. Celiac Disease. N Engl J Med. 2007;357(17): Nutrition (ESPGHAN 2019) has suggested a Non-Biopsy 1731-43. Approach for making of a diagnosis of CeD.20 This is based 6. Sainsbury A, Sanders DS, Ford AC, et al. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta- on the evidences that suggest a high degree of prediction analysis. Clin Gastroenterol Hepatol. 2013;11(4):359-65. of presence of villous abnormalities if anti-tTG Ab titers 7. Irvine AJ, Chey WD, Ford AC, et al. Screening for celiac disease in are more than tenfolds higher above the cut-off value. irritable bowel syndrome: an updated systematic review and meta- The ESPGHAN 2019 guidelines suggest that a non-biopsy analysis. Am J Gastroenterol. 2017;112(1):65-76. approach may be considered in children if their anti- 8. Mahadev S, Laszkowska M, Sundström J, et al. Prevalence of celiac disease in patients with iron deficiency anemia—a systematic tTG Ab titer is more than tenfolds and there is a positive review with meta-analysis. Gastroenterology. 2018;155(2):374-82. anti-endomysial antibody in a second blood samples. 9. Singh P, Arora S, Lal S, et al. Celiac disease in women with infertility: Otherwise, duodenal biopsies should be performed, if a meta-analysis. J Clin Gastroenterol. 2016;50(1):33-9. anti-tTG titer is less than tenfolds. For adults patients, 10. Annasamy C, Narayanasamy K, Karthick R, et al. Prevalence of Elevated most of the guidelines, including Indian, recommend a Serum Aminotransferases Among Asymptomatic Population of Tamil Nadu, India. Biomed Pharmacol J. 2017;10:1249-57. confirmation of diagnosis of CeD with small intestinal 11. Sainsbury A, Sanders DS, Ford AC, et al. Meta-analysis: coeliac 19,21,22 biopsy in patients having a positive serological test. disease and hypertransaminasaemia. Aliment Pharmacol Ther. More often around the world, the ESPGHAN guidelines 2011;34:33-40. are misinterpreted and the diagnosis of CeD is made even 12. Singh P, Arora S, Lal S, et al. Risk of celiac disease in the first- and when anti-tTG Ab titer is less than tenfolds. A hurried diagnosis second-degree relatives of patients with celiac disease: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110(11):1539-48. based on incomplete evidence leads to problems during 13. Elfström P, Sundström J, Ludvigsson JF, et al. Systematic review with follow-up. All efforts should be made for the confirmation of meta-analysis: associations between coeliac disease and type 1 the diagnosis before advising GFD. One should realize that diabetes. Aliment Pharmacol Ther. 2014;40(10):1123-32. anti-tTG Ab, especially at low titer could be falsely positive 14. Roy A, Laszkowska M, Sundström J, et al. Prevalence of celiac and the enteropathic changes are not specific for CeD and disease in patients with autoimmune thyroid disease: a meta- they could be caused by many other conditions. analysis. Thyroid. 2016;26(7):880-90. 15. Du Y, Shan L-F, Cao Z-Z, et al. Prevalence of celiac disease in patients with Down syndrome: a meta-analysis. Oncotarget. 2017;9(4):5387-96. Conclusion 16. Chou R, Bougatsos C, Blazina I, et al. Screening for celiac disease: evidence report and systematic review for the US Preventive CeD has now become a global public health problem and Services Task Force. JAMA. 2017;317(12):1258-68. it affects approximately 1% of the world’s population. The 17. Villalta D, Tonutti E, Prause C, et al. IgG antibodies against spectrum of clinical manifestations of CeD is wide include deamidated gliadin peptides for diagnosis of celiac disease in both gastrointestinal and extra-intestinal manifestations. Many patients with IgA deficiency. Clin Chem. 2010;56(3):464-8. patients with CeD do not have GI manifestations but present 18. Singh P, Singh A, Silvester JA, et al. Inter- and Intra-assay solely with non-gastrointestinal manifestations. All patients with Variation in the Diagnostic Performance of Assays for Anti-tissue high-risk of CeD should be screened using IgA anti-tTG antibody. Transglutaminase in 2 Populations. Clin Gastroenterol Hepatol. 2020;18(11):2628-30. References 19. Husby S, Murray JA, Katzka DA, et al. AGA Clinical practice update on diagnosis and monitoring of celiac disease-changing utility of 1. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: serology and histologic measures: expert review. Gastroenterology. Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019;156:885-9. 2018;16:823-36.e2. 20. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society 2. Sood A, Midha V, Sood N, et al. Prevalence of celiac disease among Paediatric Gastroenterology, Hepatology and Nutrition Guidelines school children in Punjab, North India. J Gastroenterol Hepatol. for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2006;21(10):1622-5. 2020;70(1):141-56. 3. Makharia GK, Verma AK, Amarchand R, et al. Prevalence of celiac 21. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management disease in the northern part of India: a community based study. J of adult coeliac disease: guidelines from the British Society of Gastroenterol Hepatol. 2011;26:894-900. Gastroenterology. Gut. 2014;63:1210-28. 4. Ramakrishna BS, Makharia GK, Chetri K, et al. Prevalence of Adult 22. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: Celiac Disease in India: Regional Variations and Associations. Am J diagnosis and management of celiac disease. Am J Gastroenterol. Gastroenterol. 2016;111(1):115-23. 2013;108:656-76.

MU-132.indd 845 29-01-2021 14:58:28 CHAPTER Differentiating Crohn’s Disease from Intestinal Tuberculosis: 133 A Diagnostic Challenge

Pabitra Sahu, Saurabh Kedia, Vineet Ahuja

Abstract Diagnosing intestinal tuberculosis (ITB) and Crohn’s disease (CD) has always been a challenge in countries like India where TB is endemic and incidence of inflammatory bowel disease (IBD) is increasing rapidly. Definitive diagnosis of tuberculosis requires demonstrating AFB in smear or culture, caseation necrosis in biopsy or necrotic lymph node in cross sectional imaging. But all these are limited by poor sensitivity. There are certain clinical (diarrhea, hematochezia, perianal disease common in CD; fever, night sweats common in ITB), endoscopic (longitudinal, aphthous ulcers common in CD; transverse ulcers/patulous ileocecal valve common in ITB), histologic (caseating confluent large granuloma common in ITB; microgranuloma common in CD) and radiologic (long segment involvement, comb sign, skip lesions common in CD; necrotic lymph node, contiguous ileocecal involvement common in ITB) differences between CD and ITB. Despite all these differentiating features, in more than 1/3rd of cases a definitive diagnosis cannot be made without a therapeutic ATT trial. Recent advances in this field like newer biomarkers (enumeration of peripheral blood T-regulatory cells) and CT based predictive models (quantification of visceral and subcutaneous fat) can help in difficult cases. As a clinician we need to assess all these clinical and investigational parameters meticulously to solve this diagnostic conundrum.

Introduction toxicity of anti-tubercular therapy (ATT), delay in CD- specific therapy leading to disease progression along Intestinal tuberculosis (ITB) and Crohn’s disease (CD), with impaired quality-of-life, and flare up of TB on a sub-type of inflammatory bowel disease (IBD), are 6,7 both chronic granulomatous disorders of the intestine immunosuppressive therapy for CD. For definitive with different etiologies, but similar presentations.1,2 diagnosis of ITB, we need to demonstrate mycobacterium Due to globalization and industrialization Southeast tuberculosis (MTB) in smear or culture, or caseating Asian countries like India, which are endemic for TB, granuloma in biopsy or a complete symptomatic and are in a state of socio-epidemiologic transition with a endoscopic response to ATT; but all these methods have 8,9 rising incidence of CD and other non-communicable unsatisfactorily low sensitivity. So in clinical practice, disorders (Crohn’s disease and the “white plague” most often we gather diagnostic clues from conglomerate 10 hypothesis).3,4 Despite growing number of literature, of laboratory tests and investigations. In this review, we conclusive diagnosis of ITB and CD still remains a clinical will discuss the overlapping and discriminative features of conundrum. There have been reports of misdiagnosing both the diseases and try to elucidate a proper approach ITB as CD for as long as 7 years before the correct to solve the diagnostic dilemma. Evaluation of any patient diagnosis was reached.5 Misdiagnosing these two clinical suspected of ITB or CD runs through the following steps conditions can have disastrous implications like drug (Flowchart 1):

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Flowchart 1: Diagnostic algorithm TABLE 1 Features differentiating CD and ITB

Favoring Crohn’s Favoring ITB disease Clinical features zz Chronic diarrhea zz Ascites zz Hematochezia zz Perianal disease zz Longer duration of symptoms EIM zz Peripheral arthropathy zz Aphthous ulcers zz Any/multiple EIMs Endoscopic zz Left as well as zz Transverse ulcers features right colonic zz Ileocecal valve involvement involvement zz Longitudinal ulcers zz Aphthous ulcers zz Cobblestoning Histology zz Microgranuloma zz Large caseating (minimum 6–8 confluent biopsies from the granuloma ulcerated and inflamed area) Radiology zz Long segment zz Ileocecal involvement involvement zz ≥3 segments zz Lymph node >1 cm involvement zz Necrotic lymph zz Comb sign node Clinical Features zz VF/SF >0.63 zz <3 segment zz Pseudosacculation involvement Both the diseases present with some common clinical zz Short segment features like abdominal pain, diarrhea, partial bowel involvement obstruction, fever, weight loss and extra intestinal manifestation (EIM) like arthralgia, skin rash, or ocular symptoms. But some of the symptoms are more frequently cobblestoning, and skip lesions are more common in seen in either of two diseases. Despite some heterogeneity CD whereas presence of transverse ulcers and patulous most studies reported diarrhea, hematochezia, perianal ileocecal valve are more common in ITB (Table 1 and disease, and EIMs as being more common in CD whereas Figs. 1A to D).10,11,13,14 Lee et al. described a predictive partial bowel obstruction, night sweat, and ascites model based on four common endoscopic findings in 10-13 predominate in ITB (Table 1). Longer disease duration CD (anorectal lesion, longitudinal ulcers, aphthous also supports the diagnosis of CD over ITB, but a specific ulcers, and cobblestone appearance) and ITB (less than 4 12 cut off for duration is not available. A recent meta-analysis segment involvement, patulous IC valve, transverse ulcers, reported that diarrhea, hematochezia, perianal disease, and and pseudopolyps). A score of +1 and –1 was assigned for EIMs favored the diagnosis of CD, while fever, night sweats, each parameter of CD and ITB respectively. Total score 14 lung involvement, and ascites favored the diagnosis of ITB. >0 indicated the diagnosis of CD with a PPV of 94.9% and score <0 indicated diagnosis of ITB with a PPV of 88.9%.15 Endoscopic Appearance Endoscopic features in CD and ITB have been well Histopathology described. Albeit some overlap, left colonic involvement, Both these diseases are chronic granulomatous disease presence of longitudinal ulcers, aphthous ulcers, of the GI tract and share many histopathological features

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A B

C D Figs. 1A to D: Endoscopic images. (A) Deep longitudinal jejunal ulcer in a patient with Crohn’s disease. (B) Cobblestoning in a patient with Crohn’s disease. (C) Ulcerated stricture in a patient with ITB. (D) Strictured IC valve with gaping in a patient with healed ITB

like architectural abnormalities (crypt distortion, CD. A recent meta-analysis also echoed similar findings.19 crypt branching, or crypt loss), chronic inflammation One of the major limitations of HPE is that more often we (chronic inflammatory infiltrate, increased IEL, basal do not find granuloma in biopsy specimens to characterize plasmacytosis) and granulomas.10,16,17 But there are subtle it. Minimum 6–8 biopsies must be taken from the ulcerated differences which can be helpful to discriminate these two and inflamed area to mitigate this problem. pathologies. As reported by Pulimood et al., granulomas are more common in tuberculosis than CD and tubercular granulomas are usually multiple (>5–10/HPF), large (>200 Microbiology μm), confluent, located more in submucosa and with One of the major challenges of diagnosing ITB is the poor central caseation which is almost pathognomic for ITB sensitivity of microbiological tests to detect the bacilli while the granulomas in CD are sparse, small and poorly (Table 2). ITB is a paucibacillary disease, so demonstrating organized (microgranuloma).17,18 Apart from granuloma, the organism is difficult. Acid fast bacillus (AFB) staining ulcers lined by epitheloid histiocytes and disproportionate in a biopsy specimen has a sensitivity of 2.7–37.5% as submucosal inflammation favors the diagnosis of ITB, on reported in different studies.20-22 Although culture of the other hand focally enhanced colitis is characteristic of intestinal biopsy in Lowenstein Jensen medium is the

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Patients with ITB may also have evidence of TABLE 2 Sensitivity of different microbiological tests for ITB concomitant pulmonary involvement. 3–25% of ITB Diagnostic tests Sensitivity patients show evidence of healed or active pulmonary AFB smear20-22 (2.7–37.5)% TB on chest X-ray.29 Data from our centre (not published) Culture (LJ/BACTEC)21-23 (19–50)% indicates addition of CT chest (in place of chest X-ray) with TB-PCR24 47% CT enterography can significantly increase the sensitivity Gene-Xpert MTB/RIF20,25 (8.1–32)% of diagnosing ITB.

Adjunct Tests gold standard, it has been replaced largely by BACTEC Both interferon gamma release assays (IGRA) and culture which is less time consuming. Most of the studies Mantoux are predictive of latent TB rather than active TB; have reported less than 50% culture positivity rate in hence, a positive or a negative IGRA will neither rule in nor biopsy from ITB patients.8,21-23 Polymerase chain reaction rule out the diagnosis of ITB. Positive Mantoux has been targeted against IS6110 (TB-PCR) as a stand-alone test is reported in 50–100% patients with ITB patients whereas not diagnostic for ITB but can help in diagnosis. Jin et al. in meta-analysis on IGRA reported a pooled sensitivity of his meta-analysis reported a pooled sensitivity of 47% and 24 74% and specificity of 87% in differentiating ITB from specificity of 95% for TB-PCR in intestinal biopsy. Gene- 30,31 Xpert MTB/RIF in the intestinal biopsies has not been well CD. Both these tests provide supporting evidence but studied in patients with ITB. In a study of 37 ITB patients are not diagnostic. it showed sensitivity of 8.1% and specificity of 100%.20 Another serological test, anti-saccharomyces cerevisiae Another study by Bellam et al. reported sensitivity of 32% antibody (ASCA), has been investigated for this purpose and specificity of 100%.25 but one study from India and a recent meta-analysis denied any significant role.32,33 Radiology Therapeutic ATT Trial CT/MR enterography are the preferred imaging modalities for evaluating and differentiating between patients with As we have discussed above, all these investigations have ITB and CD. Along with access to whole of the GI tract, limited diagnostic accuracies and despite all these tests, in cross sectional imaging has additional advantage as it some cases it is nearly impossible to conclusively diagnose can detect other significant findings like peritoneal or ITB or CD. Treating with steroid in such cases can be omental involvement and mesenteric or intra-abdominal disastrous if the patient has underlying ITB, so trial of lymphadenopathy. CT findings commonly seen in ATT is almost imperative for further management of such patients with CD are left colonic involvement, multifocal a case. A recent retrospective study from Korea reported (>3 segments) or long-segment involvement, comb sign, that 17.9% CD patients were misdiagnosed as ITB and and pseudosacculation. On the other hand, involvement 10.8% patients of ITB were misdiagnosed as CD before of ileocecal area, short segment involvement (<3 cm), the correct diagnosis being made. Forty-eight percent of and presence of lymph nodes larger than 1 cm are more ITB patients required therapeutic ATT trial for the final 34 common in ITB.26,27 A predictive model based on three diagnosis. Asia-Pacific consensus statements for CD characteristics [long segment (>3 cm) involvement, >1 have also advocated ATT trial in a patient with CD/ITB cm lymph node, ileocecal involvement] had a specificity dilemma, and the diagnosis of CD should be considered in of 90% in differentiating CD from ITB.27 A meta-analysis a patient who does not respond to ATT, and subsequently involving six studies concluded that necrotic lymph responds to CD-specific therapy.35 But the big question nodes had the highest diagnostic accuracy (sensitivity is the timeline of ATT trial, when to say a patient as non- 23%, specificity 100%) for ITB diagnosis, and comb responder and how to assess response. A recent study from sign (sensitivity 82%, specificity 81%) followed by skip our centre compared the response between two groups lesions (sensitivity 86%, specificity 74%) had the highest (CD patients who received ATT as therapeutic trial and diagnostic accuracy for CD diagnosis28 (Figs. 2A to D). ITB patients). By 3 months more than 90% of patients with

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A B

C D Figs. 2A to D: Radiologic images (CT enterography). (A) Stricture with comb sign in a patient with CD. (B) Pseudosacculation in a patient with CD. (C) Thickening of terminal ileum with IC valve involvement in a patient with ITB. (D) Long segment stricture with enhancement and proximal dilatation in a patient with CD

ITB, and up to 1/3rd patients with CD responded to ATT much data on prevalence of MDR-TB in gastrointestinal but response was ill-sustained in patients with CD, and up tuberculosis. Lin et al. reported MDR-TB rate of 13% to 80% of them worsened on follow-up. Moreover, repeat among patients with lower gastrointestinal TB.37 But an colonoscopy at 6 months of treatment showed mucosal Indian study reported a prevalence of only 5.4% among healing in 100% patients with ITB, whereas less than 5% of patients with abdominal TB and another study from our patients with CD had an endoscopic response.36 Based on center found no cases of MDR-TB among patients with this study following algorithm has been proposed which is ITB.20,38 Moreover ITB being a paucibacillary disease is now a routine practice (Flowchart 2). expected to have a low rate of drug resistance. Although most ITB patients respond well to ATT, study from our centre showed that only one-fourth of patients Pitfalls of the Strategy with ITB related stricture had resolution of stricture after One of the major concerns is that should we consider ATT and majority had symptoms pertaining to stricture possibility of MDR-TB while designating a case as CD even after ATT.39 This observation should also be kept in on the basis of non response to ATT trial. There is not mind during assessment of response to ATT.

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Flowchart 2: Algorithm for follow-up of a patient with CD/ITB with an AUC of 0.92.40 But most of these predictive models dilemma who has been initiated on a therapeutic ATT trial have their own limitations in terms of application in clinical practice and these have not been widely validated across other population.

Recent Advances in this Field There have been many recent advances in the field regarding newer biomarker or other investigational parameters to differentiate these two diseases. Mesenteric fat proliferation and creeping fat have long been associated with active CD.41,42 A Korean study described increased visceral fat (VF) in patients with CD and ratio of VF and subcutaneous fat (SF) can help in differentiating CD from ITB.41 Yadav et al. in his study established a cut off value for VF and SF ratio. At a cut off value of 0.63, VF/SF ratio was found to have a sensitivity of 82% and specificity of 81% in differentiating CD from ITB. It showed equally good diagnostic accuracy when applied to the validation cohort.42 Another study from our centre combined VF/SF ratio with other features on CT scan and showed that combination of VF/SF >0.63 and long segment involvement was almost exclusive for diagnosing CD.43 T-regulatory cells (CD4+CD25+FOXP3+) are regulators of inflammation and these are increased in peripheral blood and at the site of infection in patients with pulmonary TB. In a preliminary study, it was shown that FOXP3 mRNA expression was upregulated in the colonic mucosa of patients with ITB as compared to CD.44 We further showed higher frequency of FOXP3+ T regulatory cells in peripheral blood of patients with ITB compared Predictive Models with CD. A value of more than 32.5% for FOXP3+ cells Due to limitation in accuracy and sensitivity of any single in peripheral blood could differentiate ITB and CD with characteristic, several multiparametric predictive models 75% sensitivity and 90.6% specificity.45 This has also been incorporating more than one feature across single or validated in a separate cohort of 73 patients.46 VF/SF ratio multiple diagnostic modalities have been described. A and circulating FOXP3+ cells in peripheral blood are multicentre study from India described hematochezia, specially helpful where differentiation between CD and weight loss, sigmoid colon involvement, and focal ITB is not possible on the basis of routine radiological, enhanced colitis as independent predictors for diagnosis histological, and microbiological evidence. of CD/ITB, and a score based on these variables had an One recent study reported that immune-histochemistry AUC of 0.91 in differentiating CD from ITB.10 Another (IHC) for CD-73 in biopsies could differentiate granulomas Korean study included age, gender, diarrhea, transverse of CD and ITB with high diagnostic specificity but it has ulcer, longitudinal ulcer, sigmoid colon involvement, and not been replicated in other studies.47 suspicion of pulmonary TB in their predictive models. He et al. developed a nomogram based on seven The AUC for differentiating CD and ITB was 0.98, and on parameters that were significant on regression analysis validation in a separate cohort, the accuracy was similar including age, transverse ulcer, rectum involvement,

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skipped small bowel involvement, target sign, comb sign, tools and biomarkers, we have made significant progress in and IGRA (for model 1) or Mantoux test (for model 2), solving the clinical dilemma. But it needs careful interpretation respectively. Nomogram 1 showed a sensitivity of 86.8% of all diagnostic evidence and clinical judgment on case to and specificity of 90.9% while nomogram 2 showed 84.2% case basis. And with newer challenges like “TB on CD” or ATT sensitivity and 100% specificity for differentiating CD from complicating disease course of CD patients, we need to be ITB in the validation cohort.48 more accurate, more precise, and more vigilant in diagnosing One of the most significant findings was described and managing patients with ITB and CD. recently from our centre. It described that patients who received ATT before an eventual diagnosis of CD have higher chance of progressing to stricturing or fistulizing References disease compared to patients who are ATT naive (OR: . 1 Almadi MA, Ghosh S, Aljebreen AM. Differentiating intestinal 11.05; 95% CI 3.17–38.56, p <0.001) and they also have tuberculosis from Crohn’s disease: a diagnostic challenge. Am J Gastroenterol. 2009;104(4):1003-12. higher risk of surgery than ATT naive patients (HR: 3.22; . 2 Marshall JB. Tuberculosis of the gastrointestinal tract and 49 95% CI, 1.46–7.12, p = 0.004) on long-term follow-up. peritoneum. Am J Gastroenterol 1993;88(7):989-99. This finding can challenge our practice of therapeutic ATT 3. Kedia S, Ahuja V. Is the emergence of inflammatory bowel disease trial in cases with diagnostic dilemma. This also highlights a prime example of “the third epidemiological transition?” Indian J the importance of accurate discrimination between these Gastroenterol. 2018;37(3):183-5. . 4 Das K. Crohn’s disease and the ‘white plague’: a hypothesis. Gut. two diseases right at the outset and the importance of 2014;63(6):1030-1. close follow-up and early assessment in suspected cases. . 5 Riedel L, Segal I, Mohamed AE, et al. The prolonged course of gastrointestinal tuberculosis. J Clin Gastroenterol. 1989;11(6):671-4. 6. Amarapurkar DN, Patel ND, Rane PS. Diagnosis of Crohn’s disease in TB on CD: The New Challenge India where tuberculosis is widely prevalent. World J Gastroenterol. As more and more patients of CD are now being treated 2008;14(5):741-6. with anti-TNF therapy in developing countries like India, . 7 Longobardi T, Jacobs P, Bernstein CN. Work losses related to a new challenge is setting in. Agarwal et al. reported that inflammatory bowel disease in the United States: results from the National Health Interview Survey. Am J Gastroenterol. 2003; 11.6% IBD patients on infliximab therapy developed 98(5):1064-72. reactivation of tuberculosis despite that all these patients . 8 Patel N, Amarapurkar D, Agal S, et al. Gastrointestinal luminal were screened for latent TB before the initiation of therapy tuberculosis: establishing the diagnosis. J Gastroenterol Hepatol. and most of them developed it within 1st year of therapy.50 2004;19(11):1240-6. Similar findings have also been reported in other studies.51 9. Kirsch R, Pentecost M, Hall PM, et al. Role of colonoscopic biopsy in distinguishing between Crohn’s disease and intestinal tuberculosis. A recent meta-analysis compiled 128 studies (130,114 IBD J Clin Pathol. 2006;59(8):840-4. patients) and reported a pooled prevalence of 0.08% for 10. Makharia GK, Srivastava S, Das P, et al. Clinical, endoscopic, and developing TB on anti-TNF therapy. The risk increased histological differentiations between Crohn’s disease and intestinal with increasing TB burden, pooled prevalence being tuberculosis. Am J Gastroenterol. 2010;105(3):642-51. 0.02%, 0.21%, and 1.59% for low, intermediate, and high 11. Li X, Liu X, Zou Y, et al. Predictors of clinical and endoscopic findings in differentiating Crohn’s disease from intestinal tuberculosis. Dig TB burden countries, respectively. Seventy-three percent Dis Sci. 2011;56(1):188-96. of patients who developed TB had no evidence of latent 12. Singh B, Kedia S, Konijeti G, et al. Extra intestinal manifestation of TB on screening. Apart from therapeutic challenge, this inflammatory bowel disease and intestinal tuberculosis: frequency tubercular reactivation poses a new set of diagnostic and relation with disease phenotype. Indian J Gastroenterol. 2015;34(1):43-50. dilemma, as to decide whether it was ITB to start with or it 52 13. Yu H, Liu Y, Wang Y, et al. Clinical, endoscopic and histological is only tubercular reactivation on immunosuppression. differentiations between Crohn’s disease and intestinal tuberculosis. Digestion. 2012;85(3):202-9. Conclusion 14. Limsrivilai J, Shreiner AB, Pongpaibul A, et al. Meta-analytic bayesian model for differentiating intestinal tuberculosis from Crohn’s Since time long the deceptive similarities between CD and disease. Am J Gastroenterol. 2017;112(3):415-42. ITB has been a matter of debate among clinical practitioners. 15. Lee YJ, Yang SK, Byeon JS, et al. Analysis of colonoscopic findings With scientific advances and availability of newer radiological in the differential diagnosis between intestinal tuberculosis and Crohn’s disease. Endoscopy. 2006;38(6):592-7.

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16. Kleer CG, Appelman HD. Surgical pathology of Crohn’s disease. Surg disease and intestinal tuberculosis in India. J Postgrad Med. Clin North Am. 2001;81(1):13-30. 2007;53(3):166-70. 17. Pulimood AB, Peter S, Ramakrishna B, et al. Segmental colonoscopic 33. Ng SC, Hirai HW, Tsoi KK, et al. Systematic review with meta- biopsies in the differentiation of ileocolic tuberculosis from Crohn’s analysis: accuracy of interferon-gamma releasing assay and anti- disease. J Gastroenterol Hepatol. 2005;20(5):688-96. Saccharomyces cerevisiae antibody in differentiating intestinal 18. Pulimood AB, Ramakrishna BS, Kurian G, et al. Endoscopic mucosal tuberculosis from Crohn’s disease in Asians. J Gastroenterol biopsies are useful in distinguishing granulomatous colitis due to Hepatol. 2014;29(9):1664-70. Crohn’s disease from tuberculosis. Gut. 1999;45(4):537-41. 34. Seo H, Lee S, So H, et al. Temporal trends in the misdiagnosis 19. Du J, Ma YY, Xiang H, et al. Confluent granulomas and ulcers lined rates between Crohn’s disease and intestinal tuberculosis. World J by epithelioid histiocytes: new ideal method for differentiation of Gastroenterol. 2017;23(34):6306-14. ITB and CD? A meta analysis. PLoS One. 2014;9(10):e103303. 35. Ooi CJ, Makharia GK, Hilmi I, et al. Asia Pacific Association of 20. Kumar S, Bopanna S, Kedia S, et al. Evaluation of Xpert MTB/RIF Gastroenterology (APAGE) Working Group on Inflammatory Bowel assay performance in the diagnosis of abdominal tuberculosis. Disease. Asia Pacific Consensus Statements on Crohn’s disease. Intest Res. 2017;15(2):187-94. Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific 21. Sekine K, Nagata N, Shindo T, et al. Combined identifying Crohn’s Disease Consensus—Part 1). J Gastroenterol Hepatol. granuloma and biopsy culture is useful for diagnosing intestinal 2016;31(1):45-55. tuberculosis. Int J Colorectal Dis. 2015;30(7):939-45. 36. Pratap Mouli V, Munot K, Ananthakrishnan A, et al. Endoscopic 22. Dutta AK, Sahu MK, Gangadharan SK, et al. Distinguishing Crohn’s and clinical responses to anti-tubercular therapy can differentiate disease from intestinal tuberculosis-a prospective study. Trop intestinal tuberculosis from Crohn’s disease. Aliment Pharmacol Gastroenterol. 2011;32(3):204-9. Ther. 2017;45(1):27-36. 23. Ye BD, Yang SK, Kim D, et al. Diagnostic sensitivity of culture 37. Lin PY, Wang JY, Hsueh PR, et al. Lower gastrointestinal tract and drug resistance patterns in Korean patients with intestinal tuberculosis: an important but neglected disease. Int J Colorectal tuberculosis. Int J Tuberc Lung Dis. 2012;16(6):799-804. Dis. 2009;24(10):1175-80. 24. Jin T, Fei B, Zhang Y, et al. The diagnostic value of polymerase 38. Samant H, Desai D, Abraham P, et al. Acid-fast bacilli culture chain reaction for Mycobacterium tuberculosis to distinguish positivity and drug resistance in abdominal tuberculosis in intestinal tuberculosis from Crohn’s disease: a meta-analysis. Saudi J Mumbai, India. Indian J Gastroenterol. 2014;33(5):414-9. Gastroenterol. 2017;23(1):3-10. 39. Aggarwal P, Kedia S, Sharma R, et al. Tubercular intestinal strictures 25. Bellam BL, Mandavdhare HS, Sharma K, et al. Utility of tissue Xpert- show a poor response to anti-tuberculous therapy. Dig Dis Sci. Mtb/Rif for the diagnosis of intestinal tuberculosis in patients with 2017;62(10):2847-56. ileocolonic ulcers. Ther Adv Infect Dis. 2019;6:2049936119863939. 40. Jung Y, Hwangbo Y, Yoon SM, et al. Predictive factors for 26. Sharma R, Madhusudhan KS, Ahuja V. Intestinal tuberculosis versus differentiating between Crohn’s disease and intestinal tuberculosis Crohn’s disease: clinical and radiological recommendations. Indian in Koreans. Am J Gastroenterol. 2016;111(8):1156-64. J Radiol Imaging, 2016;26(2):161-72. 41. Ko JK, Lee HL, Kim JO, et al. Visceral fat as a useful parameter in the 27. Kedia S, Sharma R, Bopanna S, et al. Predictive model for differential diagnosis of Crohn’s disease and intestinal tuberculosis. differentiating Crohn’s disease and intestinal tuberculosis: Intest Res. 2014;12(1):42-7. the story is incomplete without imaging. Am J Gastroenterol. 42. Yadav DP, Madhusudhan KS, Kedia S, et al. Development and 2017;112(1):188-9. validation of visceral fat quantification as a surrogate marker for 28. Kedia S, Sharma R, Sreenivas V, et al. Accuracy of computed differentiation of Crohn’s disease and intestinal tuberculosis. J tomographic features in differentiating intestinal tuberculosis from Gastroenterol Hepatol. 2017;32(2):420-6. Crohn’s disease: a systematic review with meta-analysis. Intest Res. 43. Kedia S, Madhusudhan KS, Sharma R, et al. Combination of 2017;15(2):149-59. increased visceral fat and long segment involvement: development 29. Kedia S, Das P, Madhusudhan KS, et al. Differentiating Crohn’s and validation of an updated imaging marker for differentiating disease from intestinal tuberculosis. World J Gastroenterol. Crohn’s disease from intestinal tuberculosis. J Gastroenterol 2019;25(4):418-32. Hepatol. 2018;33(6):1234-41. 30. Hallur V, Sharma M, Sethi S, et al. Development and evaluation of 44. Ahuja V, Subodh S, Tuteja A, et al. Genome-wide gene expression multiplex PCR in rapid diagnosis of abdominal tuberculosis. Diagn analysis for target genes to differentiate patients with intestinal Microbiol Infect Dis. 2013;76(1):51-5. tuberculosis and Crohn’s disease and discriminative value of FOXP3 31. Chen W, Fan JH, Luo W, et al. Effectiveness of interferon-gamma mRNA expression. Gastroenterol Rep (Oxf) 2016;4:59-67. release assays for differentiating intestinal tuberculosis from 45. Tiwari V, Kedia S, Garg SK, et al. CD4+ CD25+ FOXP3+ T cell frequency Crohn’s disease: a meta-analysis. World J Gastroenterol. 2013;19(44): in the peripheral blood is a biomarker that distinguishes intestinal 8133-40. tuberculosis from Crohn’s disease. PLoS One. 2018;13:e0193433. 32. Ghoshal UC, Ghoshal U, Singh H, et al. Anti-Saccharomyces 46. Rampal R, Kedia S, Wari MN, et al. Prospective validation of CD4+ cerevisiae antibody is not useful to differentiate between Crohn’s CD25+ FOXP3+ T-regulatory cells as an immunological marker to

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differentiate intestinal tuberculosis from Crohn’s disease. Intest Res 50. Agarwal A, Kedia S, Jain S, et al. Very high rate of tuberculosis 2020. doi: 10.5217/ir.2019.09181. complicating infliximab therapy for inflammatory bowel disease 47. Banerjee R, Balaji M, Sasikala M, et al. Granulomas of intestinal despite tuberculosis screening in India. Intest Res. 2018;16(4): tuberculosis and Crohn’s disease can be differentiated by CD73 588-98. cell surface marker expression: a pilot study. Dig Dis Sci. 2013;58(8): 51. Puri AS, Desai D, Sood A, et al. Infliximab-induced tuberculosis in 2301-7. patients with UC: experience from India—a country with high 48. He Y, Zhu Z, Chen Y, et al. Development and validation of a prevalence of tuberculosis: infliximab-induced tuberculosis: India. J novel diagnostic nomogram to differentiate between intestinal Gastroenterol Hepatol. 2017;32(6):1191-4. tuberculosis and Crohn’s disease: a 6-year prospective multicenter 52. Kedia S, Mouli VP, Kamat N, et al. Risk of tuberculosis in patients study. Am J Gastroenterol. 2019;114(3):490-9. with inflammatory bowel disease on infliximab or adalimumab 49. Gupta A, Mouli VP, Mohta S, et al. Antitubercular therapy given is dependent on the local disease burden of tuberculosis: a to differentiate Crohn’s disease from intestinal tuberculosis systematic review and meta-analysis. Am J Gastroenterol. 2020; predisposes to stricture formation. J Crohn’s Colitis. 2020;jjaa091. 115(3):340-9.

MU-133.indd 854 29-01-2021 14:58:23 CHAPTER Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They 134 Are Different from West?

Subrat Kumar Acharya

Abstract Acute liver failure (ALF) and acute-on-chronic-liver failure (ACLF) are severest forms of liver failure with high short-term mortality. Their definition and diagnosis depend upon the clinical phenotypic presentation and global consensus on each of these entities are lacking due to differences in regional etiologies of liver injury which is considered to be important determinants of the natural course and clinical manifestations of such liver failures. These differences have been discussed in the present chapter. While hepatitis virus(es) are the major causes of ALF and to some extent in ACLF India, etiologies of ALF in West is heterogenous with Paracetamol overdose as the major causes. Pregnant females in India are more prone to contact hepatitis virus(es), particularly hepatitis E virus and develop more severe hepatitis leading to more frequent ALF than similar patients in males and non-pregnant females. Such events in west is infrequent. Cerebral edema and infections are major complications in ALF leading to high mortality. Prognostic models in ALF are important to identify patients for liver transplant which is associated with significant improved survival in those who are likely to die with expectant therapy. The prognostic models in ALF described from west have been found to perform less efficiently than the recently described ALF-Early Dynamic model (ALF-ED) from India. The differences and controversies in definition of ACLF in Asia Pacific region including India and West (EASL-AASLD) have been discussed in the present chapter. At present Alcohol has emerged as a major cause of ACLF globally. Hepatitis virus(es), drugs, complementary alternative medicines induced acute hepatic insult over pre-existing chronic liver disease are other major causes of ACLF in India while infection, variceal bleed, and alcohol are the major causes of ACLF in west. Occurrence of sever systemic inflammatory response in such patients leading to multiorgan dysfunction results in high short-term mortality. Within 3–7 days of onset of ACLF the prognostic models described both from Asian Pacific region and west predicts mortality assisting in providing to liver transplant to such patients.

Introduction contrast to the above sequential events in cirrhosis, some In health, the liver has multiple functions, and liver failure of them do present with rapid and sudden deterioration usually denotes loss of these functions, often threatening in their liver function and liver reserve resulting in life.1 The concept of liver failure is getting clarified over features of acute decompensation (AD) (sudden and time and have several phenotypes. The most frequent rapid development of ascites, encephalopathy, variceal form of liver failure encountered in clinical practice is bleed), often with occurrence of jaundice, prolonged the chronic liver failure as in cirrhosis of the liver. In such International Normalized Ratio (INR) with or without patients, development of varices, ascites, variceal bleed, kidney failure and infrequently with involvement of other encephalopathy, renal failure, and infections gradually extrahepatic organ dysfunction or failure over few days or sets in over a long period, in many months to many year.2 In weeks. Such rapid AD usually ensues subsequent to an

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Fig. 1: Five phenotypes of liver failure. In (a), (b), and (c), there is no previous known liver disease. However, it unclear if presence of a subclinical mild liver disease will change presentation, course and outcome, e.g., in patients with non-alcoholic fatty liver, silent autoimmune hepatitis, Wilson’s disease, or inactive hepatitis B carrier state. Since classification is based on clinical presentation, phenotype concept helps to classify patient for planning management

acute precipitating event like acute hepatic insult (drugs, in individuals with naïve liver. Patients with acute super infection of another hepatitis virus or reactivation hepatitis may also have variable degree of liver injury with of underlying etiology of existing chronic liver disease), variable clinical manifestation and natural course such or a sequel of cirrhosis like a variceal bleed, infection thus as: conventional acute hepatitis with high spontaneous causing, rapid loss of hepatocyte reserve in an already recovery, severe acute liver injury (sALI), acute liver failure compromised liver. (ALF), or subacute hepatic failure (SHF).6 The later two These later patients die quickly and a 28 days mortality forms are associated with high short-term mortality. So of around 50% (high short-term mortality) have been the presentations of liver failure in a naïve liver could be documented in many reports.3-5 This is in contrast to those acute or subacute. Figure 1 depicts various forms of Liver patients with cirrhosis who gradually decompensate over Failure.7 years in whom the annual mortality depending upon the Patients with acute hepatitis having persistent or decompensating event is much lower.2 Therefore, the progressive jaundice for several weeks with coagulopathy former patients are identified as a distinct group with liver (INR >1.5), but without encephalopathy, are recognized failure and named as “Acute-on-Chronic Liver Failure as sALI.6 Appearance of encephalopathy in such a patient (ACLF),” albeit, there is no universally accepted consensus with in few hours to days or weeks is termed as ALF definition of this entity.3-5 (Fig. 2).7 Whereas, some with acute hepatitis, in whom However, various hepatotoxic agents like drugs, the jaundice is prolonged or increases for over a month hepatitis viruses, and ischemia may cause acute hepatitis followed by appearance of ascites (as the manifestation

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Fig. 2: Clinical course of acute liver failure as seen in Indian subcontinent after infection with a hepatitis virus or drugs or Complementary Alternative Medicine (CAM). As liver dysfunction proceeds rapidly, patient may slide from stage of acute hepatitis to severe acute liver injury and then to (or often directly to) acute liver failure. Deterioration may be seen over a few hours, days, or less often weeks

of liver failure), are identified as patients with SHF.7 These liver disease.” However, over the ensuing time, regional entities of ALF, SHF, and ACLF are associated with high difference in etiology, natural course, complication, short-term mortality but the former two occur over a naïve and some demographic features in ALF were reported, liver, whereas the later ensues over a pre-existing chronic resulting in variable definition of ALF.8 Each definition liver diseases either known or diagnosed previously included encephalopathy as an essential criteria but or unknown carrying a silent underlying chronic liver some centers additionally included prolonged INR (>1.5) disease3-5,7 Their diagnosis is based on their characteristic or prothrombin time (PT) prolongation by more than phenotypic presentation with absence of any evidence of 15 seconds over control or prothrombin activity (<40%) presence of chronic liver disease in the former two and as an additional criteria to define ALF.8 The essential with direct or indirect evidence of clinical/endoscopic/ difference in various definitions of ALF was “the interval imaging or histologic evidence of chronic liver disease between onset of acute hepatitis illness and subsequent in the later. The characteristic differences between these encephalopathy and varied from 2 to 26 weeks.9 In India, three forms of liver failure have been depicted in Table 1. hepatitis virus(es) are the most frequent cause of ALF and The present chapter is not intended to include the encephalopathy occurred in all patients within 4 weeks management of ALF and ACLF or any other form of liver of onset of jaundice.10,11 The American Association for failure and they need a complete chapter by themselves. the Study of Liver Diseases (AASLD), however defines ALF if encephalopathy ensues within 26 weeks of onset of Acute Liver Failure acute hepatitis symptoms.9 Indian National Association for the Study of Liver (INASL) consensus statement Definition on ALF published recently defines ALF “A clinical Trey and Davidson in 1969 first defined ALF “as appearance syndrome characterized by encephalopathy, jaundice, of encephalopathy within 8 weeks of the onset of acute and prolonged PT (INR >1.5) developing in a patient hepatitic illness, in an individual without pre-existing without pre-existing liver disease within 4 weeks of the

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Clinical differentiation between acute liver failure (ALF), subacute hepatic failure (SHF), and acute on chronic liver failure TABLE 1 (ACLF)7

Criteria ALF SHF ACLF Previous liver status Naïve – No h/o of previous liver Naïve-No history of previos Presence of underlying liver disease either disease liver disease in history or by evidences accrued at presentation Clinical Presentation:

zz Encephalopathy Present (Definition) Absent at presentation Usually absent at presentation

zz Jaundice Usually present Always present Always present

zz Overt features of In 50–80% Usually absent Usually absent—occurs as terminal event Cerebral edema

zz Ascites Invariably absent Always present Always present

zz Liver size Small—not palapable—Liver span Usually not small—Liver Not small—may be palpable, span is not reduced markedly span normal or increased reduced in most

zz Precipitting factors Not identified—primay cause of Not identified—Primary Usally present—Sepsis, variceal bleed, super liver damage causes liver failure cause with impaired infection, Superadded DILI, alcoholic binge, regeneration cause liver flare of underlying cause of chronic liver failure disease, idiopathic Laboratory Parameter Transaminases Markedly raised 15–30 times ULN Moderately raised—5–10 Minimally or moderately raised depending times ULN upon Precipitating factors—3–5 times ULN

INR >1.5 Usualy prolonged variably Prolonged (>1.5 as per APASL definition) Bilirubin Markedly raised Markedly raised Moderately raised Albumin Usually normal—may be Initially normal—reduces Usually low than normal decreased in Pregnant females over time Arterial Ammonia Markedly raised (100 micromoles/L Not raised or moderately Mildly raised—may be raised in flares or raised super added liver injury (usually less than 100 micromoles) Natural Course Duration of disease Usually 2–7 days Months—4 week to 6 4 weeks to 1 year course months Imaging Naïve small liver Regenerating nodules— Evidence of chronic liver disease with or resulting in humps on liver without porto-systemic collaterals surface Endoscopy No varices (but not usually done) In 30% small varices may More than half ususlly have varices present Histology Features of acute hepatitis with Acute hepatitis with Features of Chronic liver disease with or sub massive necrosis of liver bridging necrosis without super added acute liver damage Etiology Mostly hepatitis viruses, ATT drug Hepatitis viruses, drugs Alcohol, hepatitis virus, NAFLD, other cause of CLD, Precipitating factors in preexisting CLD APASL, Asian Pacific Association for the Study of Liver; CLD, chronic liver disease; INR, international normalized ratio; NAFLD, non-alcoholic fatty liver disease; ULN, upper limit of normal

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onset of symptoms. A few patients presenting with sALI „„ Subacute hepatic failure (SHF) (encephalopathy mostly due to DILI may develop encephalopathy later within 5–24 weeks of onset of jaundice).11 than 4 weeks up to 8 weeks.”7 Further, because the etiology These regions noticed that those presenting with of ALF is heterogenous in the West, all patients clinically hyperacute or fulminant liver failure had better survival do not have similar natural course and subclassification of than the other ones and therefore subcategorized them ALF depending upon the interval between onset of acute and such events do influence on deciding high risk patients hepatitic illness and encephalopathy has been suggested for liver transplantation. However, in India, large series by British and French.7-9 The French subclassification have reported that rapidity of onset of encephalopathy categorizes ALF in to: (hyperacute) and the others had similar outcome probably due to homogeneous etiology. Therefore, in India, most „„ Fulminant Liver failure (encephalopathy occurring within 2 weeks of onset of jaundice) and patients are either hyperacute or acute without any difference in outcome and practically do not need any „„ Subfulminant (encephalopathy occurring between 2 subcategorization.11 and 12 weeks of jaundice). The British subcategorizes them to three groups: Etiology „„ Hyperacute liver failure (encephalopathy within 7 days The differences in etiology of ALF among the adults of onset of jaundice across the world are striking (Tables 2 and 3).7,9 In India, „„ ALF (encephalopathy between 7 days and 4 week) viral etiology predominates, which is responsible for

TABLE 2 Etiological profile in ALF across various centers in India7,9,11

Center/Year Number HAV HBV HEV Cryptogenic/ Drugs Miscellaneous Non-A-Non-E Delhi, 1986–2015 1462 2% 8.8% 28.7% 36.0% ATT- 7.0% Dual infection (4%), (AIIMS) chronic markers (9%), No serology report (4%) Delhi (ILBS), 2011–2016 109 39.4% 0 1.8% 14.6% 11%, n=12 Metabolic liver Pediatric Population ATT- 4, antibiotics 3, disease 13.2% CAM 2, Parvovirus-2.7%, acetaminophen 2, EBV 0.9%, VZV 0.9%, valproate 1 Others-15.5% Assam, 2207–15 255 29.8% 3.1% 13.3% 43.9% 0 Amatoxin 6.2%, AIH 0.7%, combined viruses 2.7% Bangalore, 1997–2017 128 - - - - ATT-72.4%, anti- - Only drug induced ALF epileptic 10%, dapsone 5.5%, other drugs 13% Kashmir, 1989–1996 180 2.2% 13.9% 43.9% 31.1% 1 HDV 1.1%, HCV 7.2%

Kolkata, 2005–2007 45 20% 8.8% 13.3% 22.2% 2.2% Wilsons 2.2%, malaria 2.2%, dual viral 15.5% Lucknow, 2003–2010 52 23% 12% 23% 15% 15% Dual infections 48%, All ATT no serology 4% New Delhi (ILBS) 61 13.1% 11.4% 13.1% 27.8% 14.7% Others 19.6% 2011–2018 All ATT Chandigarh, 1998 204 Viral hepatitis 7.4% Others 1.5% 91.1% All ATT

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TABLE 3 Etiologies of ALF in other countries7,9,11

UK (1999–2008) 422 2% 5% 1% 17% Paracetamol 57%, 7% Other drugs 11% USA 1696 2% 7% 13% Paracetamol 46%, Antimicrobial Autoimmune 6.5% agents: ATT, antibiotics, antifungals, Ischemic 5%, Wilsons 1% antiepileptics, NSAIDs and Budd-Chiari 1% antimetabolites 12% Pregnancy 1% Other causes 5%. France (1986–2006) 363 5% 28% 18% Paracetamol 7%, 21% Other drugs 21% Germany (2008–2009) 109 4% 10% 4% 24% 32% (most importantly Autoimmune 3% Phenprocoumon: 23% of non Wilsons 3% acetaminophen cases) Budd-Chiari 2% Valproate, NSAIDs, sertraline, Malignancy 3% clindamycin Pregnancy 3% Amanita 2% Others 4% Australia (1988–2001) 80 4% 10% 34% Paracetamol 36%, Wilsons 7% (Non-A Other drugs 6% Budd-Chiari 3% Non-B) (Nitrofurantoin Sodium valproate Isoflurane and ketorolac) Japan (1998–2006) 856 6% 42% 1% 3% 10% (ATT, Acetaminophen), anti- Autoimmune 7% cancer agents, allopurinol and Unknown 30% Acarbose

90% of ALF cases. The various viral etiologies in order of nephrotoxicity and therefore renal failure have been frequencies those reported in published studies include, reported in about 10% of the patients.7,9,11 The other non-A to non-E in about 40%, HEV in approximately causes associated with increased incidence of renal one third, whereas HBV and HAV causing ALF is less failure include amanita poisoning and trimethoprim- frequent.7,10,11 Among other causes of ALF, drugs— sulfamethoxazole toxicity. especially antituberculosis drugs—account for 6% of the „„ GI bleed: Gastrointestinal bleed has been reported cases of ALF. Whereas in the West, where safe drinking less frequently from all the part of the world, despite water is available, feco-orally transmitted viruses (HEV associated coagulation abnormality in these patients. and HAV) are not seen; drugs and toxins are major causes The usual reported frequency of gastrointestinal bleed of ALF and acetaminophen overdose is the most common in most series varied between 7% and 20%.9 factor responsible. Tables 2 and 3 highlight the different „„ Cerebral edema: Frequency of overt cerebral edema 7,9 etiologies of ALF across the world. in ALF have been reported to be present in 58% of the Indian patients at hospitalization.12 Eighty-two Complications of ALF percent patients of these with cerebral edema died in Patients with ALF may develop various life-threatening comparison to 44% mortality in those without it.11,12 complication but their magnitude varies regionally. Cerebral edema irrespective of the region was reported „„ Renal failure: In the western reports renal failure in to be one of the main causes of death in ALF. Both from ALF was documented in 40–80% of ALF. NSAIDs and the east as well from the West, cerebral edema has acetaminophen are the dominant cause of ALF in the been reported more frequently as the encephalopathy West and these agents are well-known nephrotoxic grade worsens.7,9,11,12 Intracranial pressure estimation agents. In contrast, hepatitis virus(es) being the most assesses the intracranial hypertension subsequent common cause of ALF in India do not cause direct to cerebral edema. With the wide availability of such

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methods, presence of intracranial hypertension due to develop severe liver diseases than similar male and cerebral edema has been documented in all patients nonpregnant females patients.7,9 Further, it is believed that with ALF irrespective of the grades of encephalopathy.9 pregnant women with ALF than the ALF in nonpregnant However, in the West, over the years, improvement women and males are more sick with higher complication in awareness about ALF, early referral to tertiary care rates and mortality. However, the later conjecture was center and improved intensive unit care, frequency of not evidence based and a large study on pregnant ALF cerebral edema in the West is being reported to be less due to viral hepatitis from India disproved this conjecture frequent than in former years.9 indicating that in India pregnant females with ALF (except „„ Sepsis: Infection in ALF is frequent and reported from in Acute Fatty Liver of Pregnancy or severe pre-eclamptic both West and India.9 ALF is a condition associated toxemia induce ALF) do not benefit from the termination with innate immune system compromise occurring of pregnancy.14 A summary of studies reporting pregnancy rapidly.7 Therefore infection in them occur very and ALF is shown in Table 4.7,9 early in the course of the disease.9,12 The incidence The number of pregnant patients developing ALF is of infection in the authors’ experience, from a single relatively small in the West and therefore do not constitute center in India is around 55%, the most common site a major problem in management. In India, about 60% of of infection is respiratory tract and the commonest the females with ALF in the child bearing age are pregnant organisms are Gram-negative bacilli.9,11 Quarter of the whereas, the fertility rate among similar population patient in the series reported by the author had also in general is 2.9%.9,14 It is believed that pregnancy is a fungal infections.11 From the UK, the report on ALF in immunocompromised state with predilection to contact early series, identified that about 90% of their patients various infections and manifest usually in more severe develop infection, which included bacterial sepsis in form. Multiple epidemics of HEV infection have been 80% and 32% had fungal infection.9 In more recent documented in India.7 During such epidemics, pregnant reports the predominant organisms reported from the females had more frequent infection (12–20%) than West are Gram-negative but the initial reports from the the men and nonpregnant women (2–4%) for unclear UK the gram positive organisms were isolated more reasons.9,15 The frequency of ALF among the pregnant frequently.13 females was also higher (10–22%) than similar men and nonpregnant women (1–2%).7,9 This observation indicate Key points: Complications zz Renal failure in ALF is frequent in the West, because the bulk of that pregnant females are more prone as well develop the patients are due to drugs (Acetaminophen is associated with more severe liver disease subsequent to HEV infection, direct nephrotoxicity) which is the major cause of viral hepatitis as well as zz Renal failure in ALF is infrequent in India because of predominant ALF in India. Therefore, the mortality was significantly viral etiology higher among pregnant women with epidemic hepatitis zz Sepsis is frequent in ALF. In the West and the bacterial species are mixed between Gram-positive and Gram-negative whereas (10–39%) than in the general population affected with Gram-negative organisms are common in India. In about quarter similar hepatitis (0.06–12%).9,11 In the sporadic setting, of Indian patients’ fungal infection has also been documented HEV is one of the most important etiology of ALF in India accounting for about 30–45% of patients hospitalized with Gender, Pregnancy, and Acute Liver Failure ALF (Table 2). However, the mortality in pregnant females All over the globe, in ALF females predominates except in has been found to be similar to that of nonpregnant Japan where the sex distribution is even between the two females and males and is independent of the cause genders. Despite the fact that the etiology across the region or trimester.14 The reason for predilection of pregnant are distinct, the predilection of female sex to develop ALF females to contact HEV and severe liver disease remains remains unclear. In India as described earlier, hepatitis unclear. To elucidate this, viral and host factors in HEV- virus(es) are the major etiological agent particularly HEV. ALF were evaluated in one study.15 The study reported Various epidemiological as well as sporadic studies reveal more frequent progesterone receptor (PR) gene mutations that pregnant females are more prone than nonpregnant (PROGINS) associated with reduced expression of PR females and males to contact HEV infection and also and progesterone induced blocking factor (PIBF), a

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TABLE 4 Studies reporting female predominance and role of pregnancy in ALF7,9

Country No. of cases (N) Number of females Pregnancy Percentage of female Etiology of Overall mortality overall (%) patients with pregnancy ALF (pregnant females) associated liver failure USA 1696 1173 (69%) 16 1.5% UK 422 257 (61%) Germany 109 69 (63%) 3 33% Australia 80 64 (80%) - India 1015 590 (58%) 249 38.5% 59.4% (HEV) 54% India 180 111 (62%) 49/83 59% 96% (HEV) 66% France 363 2% Japan 856 423 (49%) -

higher IL-12/IL-10 ratio, and a high viral load. The author zoonotic transmission is considered to be the cause of associated these changes to the poor outcome in HEV-ALF infection of human beings, leading to autochthonous in pregnant females. Pregnancy as a predisposition to ALF acute HEV. Genotypes 3 and 4 have not been reported to in India could be due to: (1) large number of pregnant be associated with severe liver disease and the majority of population (3%); (2) unavailability of clean drinking cases appear to represent subclinical infection.19 water; (3) predilection of pregnant females to contact Key Points: ALF in Pregnancy HEV infection. Hepatitis E virus has been identified as zz West and Europe: Pregnant females account for 1–3% of cases a very important cause of severe liver disease in areas zz India: 40–60% of females of child-bearing age with ALF are of world where more than 70% of the global population pregnant and HEV is the most frequent cause in them resides. The Global Disease Burden study by World Health zz Mortality is not increased in pregnant ALF than the others Organization identified that, approximately 3.7 million zz Termination of pregnancy not indicated in such patients zz people are infected by HEV annually and 70,000 of them AFLP: Genetic predisposition, termination of pregnancy improves prognosis die due to HEV induced severe liver disease of whom a large proportion are pregnant.16 Outcome Acute fatty liver of pregnancy (AFLP) on the other hand is more frequent in the West than in India.7 Termination The etiology of ALF, which is regionally varied, influences of pregnancy is required for improving prognosis in outcome, particularly in the West where the etiology AFLP. However, termination of pregnancy may not be is heterogeneous. Paracetamol is the major cause of appropriate in pregnant females with HEV-ALF, because: ALF in the West. Paracetamol induced ALF presents „„ ALF-HEV, in comparison to other causes of ALF, has rapidly (hyperacute) with a spontaneous survival rate of lowest mortality,17 64% which is significantly higher than similar outcome „„ the mortality in ALF-HEV with pregnancy, ALF-HEV due to other causes such as ALF due to idiosyncratic 9,11 in females without pregnancy and males with ALF- drug toxicity (spontaneous survival in 20% cases). HEV are similar and not higher, indicating that in the However, paracetamol induced ALF may progress very pregnancy once ALF develops does not influence the rapidly in some. The paracetamol being the frequent natural course.14 etiology in the West constitutes the bulk of all ALF Genotypes 1 and 2 of hepatitis E virus are prevalent patients in these regions and therefore the total number in hyperendemic regions where the reservoir for HEV of deaths due to paracetamol toxicity exceeds all other seems to be human, and cause outbreaks, sporadic diagnoses. Nearly one third of these patients who develop acute hepatitis, ALF, and ACLF.18 Genotypes 3 and 4 are encephalopathy die. Paracetamol overdose whether more prevalent in the USA, Europe, and Japan, where suicidal or unintentional presenting with ALF has similar the reservoir seems to be represented by pigs, and the outcomes.20

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In the India, acetaminophen overdose induced criteria are specific, they are not very sensitive in predicting ALF is infrequent. The drug induced ALF are due to cases that will need transplantation. Unfortunately, antituberculosis therapy (ATT).21 The mortality in ATT- none of the currently available models have consistently ALF has been reported to be 70%.21 In India, about demonstrated reliable accuracy in predicting outcome.23 90–95% of ALF are due to hepatitis viruses (homogeneous Multiple prognostic models have been reported from etiology).7,9,11,12 ATT induced ALF constitutes about 6–7% India.7,9,12 A report from North India, the following variables of all ALFs.21 Therefore, etiology could not be identified present at admission were identified as independent as an independent predictor of mortality.9,12,21 However, predictors for poor outcome: when HEV as a separate group was compared with „„ age 40 years or more; each individual other etiologies, such as ATT induced „„ bilirubin 15 mg/dL or more; ALF and non-A non-E–ALF, etc. the survival frequency „„ PT prolongation 25 seconds or more; and 21 among HEV was reported to be significantly superior to „„ clinical features of overt cerebral edema. With other etiologies.18,21 These survival frequencies reported increasing number of above risk factors, mortality are transplant-free survivals. Liver transplantation is increased; with three or more factors it was 93%.11,12,24 established therapy in all end stage liver disease and with In another study from India, clinical prognostic transplantation, overall survival exceeds 75%.7,9 indicators (CPI) included age 50 years or more, jaundice encephalopathy interval (JEI) more than Key points: Outcome zz West: Etiology affects the outcome, because etiology is 7 days, grade 3 or 4 encephalopathy, presence of heterogeneous cerebral edema, PT ≥35 seconds, and creatinine ≥1.5 zz India: Etiology in general does not influence the outcome, mg/dL. Presence of any 3 of 6 CPIs was superior to because etiology is almost due to hepatitis virus(es) zz Among hepatitis virus induced ALF, HEV has a better prognosis model for end stage liver disease (MELD) or King’s zz Commonest cause of drug induced ALF in India is antitubercular College hospital (KCH) criteria in identifying survivors drugs and have high mortality and nonsurvivors.9 ALF is a dynamic process in which variables 7,9,12 Prognostic Models determining prognosis at admission change over time, Liver transplantation has been well established as and thus the clinical course varies accordingly. A new a curative option in ALF.9,11 Prognostic models are prognostic model, ALF early dynamic (ALFED) model was therefore necessary to identify patients who will need reported which included four variables: arterial ammonia, transplantation or should continue on medical therapy. serum bilirubin, INR, and hepatic encephalopathy more Many prognostic models from all around the globe than grade II, which were identified as the independent have been described.7,9 Each of the prognostic models predictor of outcome at admission.7,24 This model in summary have highlighted the following important evaluated the dynamicity of these four variables over 3 facts. Age and etiology in most reports are important days and documented that the prediction of outcome variables influencing survival. HAV, HEV, acetaminophen using these variables on day 3 was markedly superior to toxicity, and acute fatty liver of pregnancy induced the prediction based on admission parameters. Recently, ALF, survive more frequently.7,9,12 Patients with drug the INASL recommended the ALFED prognostic model to induced, autoimmune, HBV, and cryptogenic ALF all have be more appropriate for the Indian subcontinent because spontaneous survival of less than 30%.7,9,18,21,22 Wilson’s it was derived from the cohort of Indian patients who had disease with ALF survive rarely.7 Among the dynamic predominantly viral etiology unlike in the West where viral variables, the degree of encephalopathy was documented etiology as a cause of ALF is infrequent.7 to influence survival—Patients with encephalopathy This is one of the first dynamic models to assess and grade of III or more in comparison to less advanced stratify ALF patients dynamically over a period of 3 days encephalopathy (I & II) die more frequently.7,9,21,22 rather than considering variables at baseline. ALFED Among the prognostic models, King’s College Hospital model study identified four prognostically significant Criteria (KCC) for liver transplantation were proposed by variables: arterial ammonia, serum bilirubin, INR, and O’Grady, and have been widely used.22 Although these hepatic encephalopathy more than grade II. This ALFED

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TABLE 5 ALFED Score7,24 TABLE 6 Principles in the management of ALF

Variables over 3 days Score assigned Aggressive supportive therapy: Hepatic encephalopathy 2 Intensive care unit, organ support system, nutrition, electrolyte (Persistent or progressed to grade >2) correction, hypoglycemia prevention, monitoring, hydration INR 1 Identification and removal of precipitating factors: (Persistent or increased to ≥5) Control of GI bleed, sepsis, hyponatremia, renal failure, Arterial ammonia 2 constipation, psycho-active drugs. (Persistent or increased to ≥123 μmol/L) Reduction of nitrogenous load from the Gut: Serum bilirubin 1 Lactulose (not used), antibiotics, enema (Persistent or increased to ≥15 mg/dL) Manipulation of neurotransmitters: Each of the variables above on the day 3 of hospitalization carries Flumazenil, branched chain amino acids (not used) a score determined on the strength of the beta integer of the odd’s Cerebral edema: ratio identified in multivariate analysis to predict mortality. Each of the above variables were independent predictors of mortality. On IV Mannitol, thiopentone, hypertonic saline, hypothermia (not day 3 a score of 4 is associated with 90% mortality where as score 1 is used), IV phenytoin (not used) associated with about 5% mortality. With increasing score mortality Ammonia lowering therapy: increases L-ornithine L-aspartate (LOLA- not used), L-ornithine phenyl acetate (LOPA), sodium benzoate, hypothermia (not used), CRRT, plasma exchange model had an AUROC of 0.91 in the derivation cohort and of 0.92 in the validation cohort. The model showed similar Novel therapies: increase in mortality with increasing risk scores from 0 to Molecular adsorption various bioartificial support system, recirculating system (MARS, promethus), probiotics with increased 6 (Table 5). The performance of the ALFED model was capacity to consume ammonia (not found beneficial) found to be superior to the KCH and the MELD score, Liver even when their 3-day serial values were considered. An Transplantation: LDLT (living donor liver transplant), DDLT ALFED score of ≥4 had a high PPV (85%) and NPV (87%) (deceased donor liver transplant), auxiliary LT, split LT in the validation cohort. Further, in each patient the model could stratify the risk of dying or surviving on day 3 (score 1 through 6) of hospitalization. Those with score of 1–3 had a are different. In India, the etiology is homogenous in survival frequency of about 80% or more and those with ≥4 contrast to the West where it is heterogeneous had a mortality risk of more than 80%.7,24 These parameters „„ In the West: Drug induced ALF and in the East: Viral at baseline were also independent predictors of mortality, etiology is the most common but the dynamic assessment made these parameter as also „„ Outcome of viral (HAV, HEV) and Drug (paracetamol) model for survival. In India ALF etiology is hepatitis virus are better than other etiologies, but antitubercular and usually individuals without any underlying chronic drug-ALF has high mortality liver pathology develop ALF. In ALF along with hepatic „„ In India, pregnant females are more prone for ALF but necrosis, the liver regeneration simultaneously kicks not so in the West off. Therefore, with liver regeneration, these predictive „„ Prognostic models described across the world; parameters change, and hence dynamic assessment are dynamic models have been described recently from important to identify the outcome more accurately. The India and are appropriate for Indian patients management and pathogenesis in ALF need another „„ Management: conservative, organ support and liver chapter and particularly the therapeutic approach against transplantation in select group specific drivers of pathogenesis need special mention (Table 6). Acute-on-Chronic-Liver Failure Summary Introduction „„ ALF in India and the West have different etiology and In the early sections of the present chapter the concept of natural course, and therefore the prognostic models liver failure in general and ALF, ACLF, and chronic liver

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failure as well as SHF in particular has been highlighted. (European Association for the Study of Liver-American Table 1 depicts the essential phenotypic difference Association for the Study of Liver) defined ACLF as between ALF, SHF, and ACLF. “Acute deterioration of pre-existing, chronic liver disease, Patients with decompensated cirrhosis clinically usually related to a precipitating event and associated presents with heterogeneity with variable prognosis. with increased mortality at 28 days due to multisystem AD in cirrhosis usually denotes appearance of ascites, organ failure.” Some report suggested and documented encephalopathy, variceal bleeding or combination of any that severity of OF assessed by sequential organ failure 4,5 later three. Since liver transplantation in such patients assessment (SOFA) scores could differentiate patients with is probably is the only curative option, there short-term various prognosis (58% with OF vs. 8% without OF).31 survival prediction (usually in 2 years) has been used 2 The first prospective, observational, multicentric at many centers. Three states with increasing risk of European study known as CANONIC study documented death have been proposed for decompensated cirrhosis the distinction between AD without OF and AD with OF defined by the occurrence of a first variceal bleeding alone (which according to Western concept was ACLF). Among (without other decompensating events—mortality 20%), patients with known cirrhosis admitted with AD (ascites, any first non-bleeding decompensating event alone (80% variceal bleed, encephalopathy, infection; n=1,343), the ascites—mortality 24%), or any second decompensating 28 days and 90 days mortality in those with OF versus event (mortality—50–78%).25 However, recent reports those without OF were 34% and 51% versus 5% and 14%, indicate that, a more advanced rapid AD state do occur with a very high short-term 28 days mortality of around respectively. Thus, this study provided the documentation 20–90% depending upon degree and extent of associated that patients with AD who were hospitalized with or extrahepatic organ failure.25 These are patients, who developed OF after hospitalization were distinct and developed systemic inflammatory response through were named as—ACLF and justified their definition proinflammatory precipitating factors (sepsis, excessive (EASL-CLIF—European Association for the Study of 28 alcohol consumption, sudden reactivation of previous Liver-Chronic Liver Failure definition). North American chronic liver disease inducing further acute hepatic Consortium for the Study of End-Stage Liver Disease necrosis) who are usually jaundiced with prolonged INR (NACSELD) defined ACLF by the presence of at least two and develop various organ failures (OF) probably because very severe extrahepatic OFs (shock, grade III/IV HE, of cytokine storm effecting extrahepatic organs resulting renal replacement therapy, or mechanical ventilation), from the proinflammatory precipitating events. These are which are much more stringent criteria than those of the patients with ACLF. EASL-CLIF consortium or the APASL. The NACSELD- defined ACLF is associated with a 30-day mortality Definitions and Concept rate of 41% compared to 7% for patients without ACLF. The term ACLF was first introduced to identify the above Accordingly, by definition, the main difference between mentioned often observed but not categorized entity traditional AD and ACLF is the short- and medium-term in 2002.26 The first consensus definition on ACLF was prognosis. To unify the definition on ACLF the WGO provided by APASL (Asian Pacific Association for the (World Gastroenterology Association) suggested that Study of Liver) as “an acute hepatic insult manifesting “ACLF is a syndrome in patients with chronic liver disease as jaundice (total bilirubin ≥5 mg/dL) and coagulopathy with or without previously diagnosed cirrhosis, which is (INR ≥1.5), complicated within 4 weeks by ascites and/or characterized by acute hepatic decompensation resulting encephalopathy in a patient with chronic liver disease.”3 in liver failure (jaundice and prolongation of the INR) and However, it was slightly modified in 2014 in which chronic one or more extrahepatic organ failures that is associated liver disease was modified to “with previously diagnosed with increased mortality within a period of 28 days and up or undiagnosed chronic liver disease/cirrhosis” and a to 3 months from onset”(Fig. 3).4 “high 28 days mortality” was added.27 With this APASL criteria, 28 days mortality was reported by the APASL Components of ACLF between 25–34%.27 However, certain patients with AD All the above definitions and concept irrespective in their having above criteria with OF had markedly higher disagreement and region of origin elucidated that there mortality than those without. Therefore, the EASL-AASLD should be five components in ACLF:

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Fig. 3: World Gastroenterology Definition of ACLF4 AD, acute decompensation; ACLF, acute on chronic liver failure; CLD-A, chronic liver disease (non-cirrhotics) CLD-B (cirrhosis compensated), CLD-C (cirrhosis with previous history of decompensation)

„„ There should be pre-existing chronic liver disease quantifying the severity of the hepatic insult resulting (APASL excluded known decompensated liver in AD). disease and emphasized that only non-cirrhotics „„ The above-mentioned acute deteriorations should or compensated cirrhosis of any etiology should be occur within a short period of time (APASL defined it included as underlying silent liver disease, which to be within 4 weeks). may have been diagnosed or undiagnosed previously; „„ The presence or development of hepatic failure however, the EASL-CANONIC study as described should be associated with extrahepatic organ failure earlier did not exclude patients with chronic liver like encephalopathy, respiratory failure, renal failure, disease with previous history of decompensation and coagulation abnormality, circulatory compromise in WGO in an effort to unify these categorized underlying form of hemodynamic instability as per the EASL- AASLD and NASCLED definition but APASL did not Chronic liver Disease to A-CLD without cirrhosis, include it and suggested that only with liver failure B-compensated Cirrhosis and C-Cirrhosis with the mortality exceeded 30% and should be enough previous history of decompensation—Fig. 3). to define ACLF and extrahepatic organ failures are „„ There should be a precipitating factor causing acute the sequels of ACLF. However, the INASL consortium hepatic insult with systemic inflammatory response experiences documented that indeed occurrence of which were different regionally (described below) the extrahepatic organ failure imparts high short-term which should result in overt acute deterioration of mortality.29-31 hepatic function as well as reserve, resulting in features „„ As has been elucidated earlier, these patients with overt liver failure (CANONIC study defined them as AD CLD are distinct from AD and should be categorized and included both hepatic and extrahepatic insult but as another form of liver failure and to be termed as APASL excluded extrahepatic insults like variceal bleed ACLF. By now both APASL and Western group agree and sepsis and emphasized on only acute hepatic that they have high 28 days mortality (various reports insult to be further qualified by presence of conjugated from different region describe it to a tune of around hyperbilirubinemia of more than 5 mg/dL with INR 50%).1,5 The mortality, however, linearly increases with more than 1.5 accompanied with development AD in increases in number of extrahepatic OF (20% with one the form of ascites and/or encephalopathy; there by OF to 90% with >4 extrahepatic OF) (Table 7).28,31

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European Association for the Study of Liver Consortium for Liver Failure Sequential Organ Failure Assessment Score TABLE 7 (EASL-CLIF-SOFA Score- Panel A) and ACLF Grades (Panel B)28,31

Panel A Panel B Parameter for organs Score 1 Score 2 Score 3 AD group Mortality ACLF grade Liver—Serum Bilirubin (mg/dL) < 6 6-11.9 >12 No OF 4% NO ACLF Kidney—Serum Creatinine (mg/dL) <2 2-3.4 >3.5 One OF + No BD/KD 6.3% Brain—Encephalopathy Grade 0 Grade 1–2 Grade 3–4 Single KF 18.6% (West-Haven Criteria) ACLF Single non kidney OF + 27.6% Grade 1 Coagulation (INR) <2 2-2.4 >2.5 KD/BD Circulation (MAP in mm Hg) >70 <70 Vaso pressure Two 32% ACLF requirement OF Grade 2

Respiration (PaO2/Fio2) or >300 ≤300–>200 ≤200 Three 68% SPO2/FiO2 >357 ≤357–>214 ≤214 OF ACLF Score 1: Absence of OD or OF. Score 2: Organ Dysfunction (OD). Score 3: 4-6 89% Grade 3 Organ Failure (OF) OF INR: International Normalized Ratio; MAP: mean arterial pressure

TABLE 8 Precipitating factors causing ACLF27-32

Acute hepatic Insult Acute Extra hepatic Insult Idiopathic Other non-identifiable cause of hepatic insult like Complementary and Alternative medicines (CAM) Environmental Non-environmental zz HBV Reactivation zz Bacterial infection Variceal bleeding In various series on ACLF 30–50% zz HAV super infection zz Alcohol excessive patients with ACLF did not have zz HEV Super infection continuous consumption identifiable precipitating factors and zz Hepatotoxic drug injury within last 3 months in India CAM may be a possibility of zz Autoimmune hepatitis flare hepatic insult zz Wilson’s disease flare zz Surgery/liver resection/Transarterial chemoembolization for liver cancer

Precipitating Factors Causing ACLF the major cause of ACLF has been reported because of Varieties of acute insults causing rapid deterioration in liver continuous excess alcohol consumption, which causes functions (clinical, biochemical, coagulation parameters) chronic liver disease as well as acute insult on the liver resulting in rapid AD (severe alcoholic hepatitis) and needing hospitalization have been documented and they 29,30 vary regionally. In brief they can be categorized as follows ACL F. in Table 8.4,5,26,28-32 Acute hepatic insult as mentioned in the above table Categorization/Types of ACLF and Prediction/ are more often documented as the cause of ACLF in Asian Prognostic Models in ACLF Countries whereas they are less frequent in Europe and Depending upon the pre-existing hepatic reserve due to America. The hepatitis virus(es) are endemic in Asia as underlying CLD and further loss of hepatic functional well as antitubercular therapy.30,31 In the West the common capacity due to acute hepatic insult and its regenerative causes were variceal bleed, infection, and idiopathic.31 capacity, severity of the systemic inflammatory response However, in recent time Asian region as well as in India due to the cytokine storm and their effect on extrahepatic

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organs, the course in ACLF is dynamic and usually unfolds (Table 7). Since OF were not included in APASL definition, over subsequent few days usually between 3–7 days.33,34 the ACLF was not categorized or typed in APASL cohorts collated subsequently. However, in APASL cohort and Types/Categorization of ACLF many other reports on ACLF which included large cohorts The canonic study first tried to identify and qualify the of patients with ACLF reported that occurrence of OF was 32 extrahepatic organ failure by quantifying the change in the major determinant of outcome and prognosis. Further sequential organ failure assessment (SOFA).28,31 The study the admission grading or status of organs were dynamic included six organs to be evaluated for SOFA score (Liver, and the outcome prediction based on the OF on day 3–7 Kidney, Brain, Coagulation, Circulation, and Respiration) were more accurate predictors of outcome. Both EASL- and graded their dysfunction based on values of serum CLIF (CLIF-C-ACLF) score and APASL groups have defined bilirubin, creatinine, INR, mean arterial pressure (MAP), their dynamic prognostic scores, which simply reflect the dynamic changes of variable organ parameters.3,33 and ratio between PaO2/FiO2 or SpO2/FiO2, respectively and allocated 1–3 point scores to these values. Patients 26,31 with score 2 for each parameter were considered as organ Pathogenesis (Flowchart 1) dysfunction (OD) like liver dysfunction (LD), kidney Pathogenesis in ACLF is unclear. However, the severe dysfunction (KD), brain dysfunction (BD), circulatory cytokine storm in ACLF has been documented to be more dysfunction (CD), coagulation dysfunction or respiratory pronounced (documented by enhanced C-reactive protein dysfunction (RD) and patients with score 3 were defined response, neutrophilic leukocytosis, tumor necrosis as individual organ failure. This score was named as α, IL18) than in patient with AD as well as in patients EASL, CLIF, SOFA score and depending on these scores as with compensated cirrhosis without AD.31 The ammonia mentioned above. No OD and OF were defined for each levels also have been recently identified to be markedly of the six organs and then the ACLF in patients with AD increased in such patients than in the other groups.32 The were graded as No ACLF, ACLF grade 1–3 depending upon Cause of Cytokine Storm has been briefly explained in the presence or subsequent development of number of OD/ Flowchart 1. The DAMP (damage associated molecular OF. With increasing grade, the 28 days mortality increased pathogen) due to liver cell damage in diseases causing

Flowchart 1: Pathogenesis in ACLF

BD, brain dysfunction; BF, brain failure; DAMP, damage associated molecular pattern; KD, kidney dysfunction; KF, kidney failure; NLRs, nod like receptors; NO, nitric oxide; PAMP, pathogen associated molecular pattern; RLRs, rig like receptors; TLR, toll like receptors

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The Model for End Stage Liver Disease (MELD) score TABLE 9 Principles in management of ACLF and addition of sodium value (MELD-Na) score in addition zz Intensive care unit, organ support system, nutrition, electrolyte to the scores of failing organs have been the principles to zz Treatment of infection with appropriate antibiotics with prognosticate and transplant such patients to improve monitoring of renal function and maintenance of serum albumin 32-34 values with albumin replacement preventing volume overload survival. Table 9 briefly provides the components of zz Treatment of precipitating factors: management in ACLF. —— antivirals in HBV reactivation —— steroid in alcoholic ACLF after ruling out infection —— specific management for acute variceal bleeding if occurs, d) Conclusion withdrawal of hepatotoxic drug, CAM zz Specific organ failure management: ACLF is a syndromic condition that occurs in patients with —— For RF/RD—CRRT underlying chronic liver disease (CLD) irrespective of the cause —— Noradrenaline if needed to maintain MAP>70 mm Hg of CLD. These patients develop intense systemic inflammation, —— Treatment for encephalopathy if occurs organ failure, and high short-term mortality and ensue in —— Adrenal insufficiency (may occurs in some)-IV hydrocortisone close temporal relationship with a precipitating event, which zz Treating systemic inflammatory response: is regionally variable. Whether extrahepatic organ failure is an —— Molecular Adsorbtion Recirculating System(MARS)—till date no evidence that it improves survival integral part of the syndrome or consequence is the difference —— plasma exchange—experimental in defining the syndrome in the West and Asia. Bacterial zz Immunomodulatory/Regenerative therapy: G-CSF has been infection is frequent in these patients and in the West it is tried in small studies, but needs to be validated in large considered as a precipitating event, but in Asia it is considered multicentric studies as a frequent association in ACLF. However, irrespective the zz Fecal microbial transplantation: has been tried in alcoholic ACLF differences between the West and Asia the syndrome is seen in small studies with promising results zz Liver transplantation if needed across the world and about half of them need liver transplant.

super added injury to liver or sepsis or bleeding causing References ischemia to liver are recognized by the innate immune . 1 Olson JC. Acute-on-chronic and decompensated chronic liver systems presence in liver cells such as TLRs and other failure: definitions, epidemiology, and prognostication. Crit Care Innate immune PRR (pathogen recognizing receptors) Clin. 2016;32(3):301-9. sensors and produce various cytokines which cause . 2 D’Amico G, Morabito A, D’Amico M, et al. New concepts on the clinical course and stratification of compensated and neutrophilic recruitment and also attracts the immune decompensated cirrhosis. Hepatol Int. 2018;12(Suppl 1):34-43. cells of adaptive immune system resulting in release of 3. Sarin SK, Kumar A, Almeida JA, et al. Acute-on chronic liver failure: various proinflammatory cytokines which may spill over consensus recommendations of the Asian Pacific Association for to systemic circulation effecting various extrahepatic the study of the liver (APASL). Hepatol Int. 2009;3(1):269-82. organs. Perpetuating the events by the transmigration 4. Jalan R, Yurdaydin C, Bajaj JS, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;147(1):4-10. of gut microbes due to a leaky gut documented in such 5. Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure patients further enhance such response and also induces in cirrhosis. Nat Rev Dis Primer. 2016;2:16041. endothelial nitric oxide by upregulating the nitric oxide 6. Koch DG, Speiser JL, Durkalski V, et al. The natural history of severe synthase enzyme.32 These events result in various organ acute liver injury. Am J Gastroenterol. 2017;112(9):1389-96. dysfunction or OF depending upon the severity of the . 7 Anand AC, Nandi B, Acharya SK, et al. Indian National Association cytokine storm and the degree of liver injury resulting in For the Study of Liver Consensus Statement on Acute Liver Failure(Part 1): Epidemiology, Pathogenesis, Presentation. J Clin Exp ACL F. Hepatol. 2020;10(4)339-76. . 8 Wlodzimirow KA, Eslami S, Abu-Hanna A, et al. Systemic review: Management acute liver failure—one disease, more than 40 definitions. Aliment The management principles comprise of: Pharmacol Ther. 2012;35(11):1245-56. . 9 Shalimar, Acharya SK, Lee W. World wide differences in acute „„ Treating the precipitating factors liver failure. Future Medicine. 2013. Available from https://www. „„ Support to the failing organ futuremedicine.com/doi/abs/10.2217/ebo.12.326. „„ Continuous assessment and by day 3–7 decision for 10. Tandon BN, Bernauau J, O’Grady J, et al. Recommendations of the liver transplant. international association for the study of the liver subcommittee on

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nomenclature of acute and subacute liver failure. J Gastroenterol 23. Shalimar, Sonila U, Kaur H, et al. Comparison of dynamic changes Hepatol. 1999;14(5):403-4. among various prognostic scores in viral hepatitis-related acute 11. Acharya SK, Panda SK, Saxena A, et al. Acute hepatic failure in India: liver failure. Ann Hepatol. 2018;17(3):403-12. a perspective from the East. J Gastroenterol Hepatol. 2000;15(5): 24. Kumar R, Shalimar, Sharma H, et al. Prospective derivation and 473-9. validation of early dynamic model for predicting outcome in 12. Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in a patients with acute liver failure. Gut. 2012;61(7):1068-75. tropical population: clinical course, cause, and early predictors of 25. Gustot T, Richard M. Acute-on-chronic liver failure Vs traditional outcome. Hepatology. 1996;23(6):1448-55. decompensation of cirrhosis. J Hepatol. 2018;69(6):1384-93. 13. Karvellas CJ, Pink F, McPhail M, et al. Predictors of bacteraemia and 26. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological mortality in patients with acute liver failure. Intensive Care Med. basis of therapeutic options. Blood Purif. 2002;20(3):252-61. 2009;35(8):1390-6. 27. Sarin SK, Kedarisetty CK, Zaigham, et al. Acute-on-chronic 14. Bhatia V, Singhal A, Panda SK, et al. A 20-year single-center liver failure: consensus recommendations of the Asian Pacific experience with acute liver failure during pregnancy: is the Association for the Study of the Liver (APASL) 2014. Hepatol Int. prognosis really worse? Hepatology. 2008;48(5):1577-85. 2014;8(4):453-71. 15. Bose PD, Das BC, Kumar A, et al. High viral load and deregulation 28. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure of the progesterone receptor signaling pathway: association is a distinct syndrome that develops in patients with acute with hepatitis E-related poor pregnancy outcome. J Hepatol. decompensation of cirrhosis. Gastroenterology. 2013;144(7): 2011;54(6):1107-13. 1426-37. 16. Rein DB, Stevens GA, Theaker J, et al. The global burden of hepatitis 29. Shalimar, Kumar D, Vadiraja PK, et al. Acute-on-chronic liver failure E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55(4):988-97. because of acute hepatic insults: etiologies, course, extrahepatic 17. Shalimar, Kedia S, Gunjan D, et al. Acute liver failure due to hepatitis organ failure and predictors of mortality. J Gastroenterol Hepatol. E virus infection is associated with better survival than other 2016;31(4):856-64. etiologies in Indian Patients. Dig Dis Sci. 2017;62(4);1058-66. 30. Shalimar, Saraswat V, Singh SP, et al. Acute-on-chronic liver failure 18. Aggarwal R. Hepatitis E. Historical, contemporary and future in India: The Indian National Association for the Study of Liver perspectives. J Gastroenterol Hepatol. 2011;26(Suppl 1):72-82. consortium experiences. J Gastroenterol Hepatol. 2016;31(10):1742-9. 19. Acharya SK, Panda SK. Hepatitis E. Water, water everywhere—now a 31. Arroyo V, Moreau R, Jalan R. Acute-on-chronic-liver failure. New Eng global disease. J Hepatol. 2011;54(1):9-11. J Med. 2020;380:2137-45. 20. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced 32. Shalimar, Sheikh ML, Mookerjee RP, et al. Prognostic role of acute liver failure: results of a United States multicenter, prospective ammonia in patients with cirrhosis. Hepatology. 2019;70(3):980-94. study. Hepatology. 2005;42(6):1364-72. 33. Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic 21. Kumar R, Shalimar, Bhatia V, et al. Antituberculosis therapy-induced liver failure: consensus recommendation of the Asian Pacific acute liver failure: magnitude, profile, prognosis, and predictors of Association For the Study for Liver(APASSL);An update. Hepatol Int. outcome. Hepatology. 2010;51(5):1665-74. 2019;13(4):353-90. 22. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators 34. Jalan R, Saliba F, Paveshi M, et al. Development and validation of of prognosis in acute liver failure liver. Gastroenterology. a prognostic score to predict mortality in patients with acute-on- 1989;97(2):439-45. chronic liver failure. Hepatol. 2014;61(5):1038-47.

MU-134.indd 870 29-01-2021 14:58:16 CHAPTER

Proton Pump Inhibitors— 135 Long-term Use: Boon or Bane?

Manish Manrai, Rohit Upreti

Abstract Proton Pump Inhibitors (PPIs) have been an important part of the physicians’ arsenal in the fight against acid peptic disorders. PPIs are among the drugs which are most frequently prescribed both to outpatients and those admitted in the hospital including critically ill patients. The approved indications for PPI therapy include erosive esophagitis, peptic ulcer, NSAID-induced ulcer, Gastroesophageal Reflux Disease, Helicobacter pylori infection and management of pathologic hypersecretory conditions like Zollinger-Ellison syndrome. However, long-term use of PPIs has also been associated with multiple side effects including small intestinal bacterial overgrowth, pneumonia, increased bone fractures, Vit B12 deficiency among others. A sensible strategy for PPI prescription should be as per indications, avoiding broad off-label use and following deprescription strategies.

Introduction They are taken around 1 hour before a meal, so that the The pharmacologic use of Proton Pump Inhibitors (PPIs) maximal activity of proton pump secretion is at the same started in the late 1980s and since then they have been an time as the peak serum concentration of the PPI. They important part of the armamentarium of physicians and have a short half-life of approximately one and a half gastroenterologists for treating acid peptic disorders. hour, but since they irreversibly inhibit the proton pump PPIs are substituted benzimidazoles, which are similar the secretion of acid remains inhibited up to 24 hours. In to the H2 receptor antagonists (H2RAs) in structure but optimal doses PPIs inhibit around 90–98% of 24-hour acid have a different mechanism of action. PPIs are given as secretion. When intravenous preparations are used, only prodrugs. Oral formulations are prepared as acid resistant the actively secreting pumps are inactivated. Therefore, delayed release enteric coated capsules or tablets so that during the first 24–48 hours of treatment, the intravenous they do not undergo destruction due to the acid in the formulations must be given as infusion or as repeated 1 stomach. PPIs easily diffuse across lipid membranes into bolus injections. acidified compartments like parietal cell canaliculus PPIs are the cornerstone of treatment regimens of where the protonation of the prodrug takes place and a number of acid peptic disorders and other related gets converted to its active form, a thiophilic sulfenamide conditions. The various definitions of long-term use of cation.1 This cation irreversibly inactivates the H/K- PPI that have been used in different studies vary from ATPase (Figure 1) by forming a covalent disulfide bond one repeated prescription over 12 months to continuous with it.1,2 therapy for periods ranging from 4 to >12 months.3 PPIs should be taken empty stomach because food Prolonged use of PPI, however, is a two-edged sword and decreases the bioavailability of all agents by around 50%. has been related with an excess of systemic adverse effects,

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Fig. 1: Mechanism of action of proton pump inhibitor: PPIs irreversibly inactivates the H/K-ATPase by forming a covalent disulfide bond with it and thus inhibit the common pathway involved in the acid release from the cell

which lead to the subject that whether long-term use of TABLE 1 Indications of long-term use of PPIs PPI is a boon or a bane? Indication Study Inference Long-term PPI Use: Is It a Boon? NSAID ulcer Sugano et al., 201210 Decreased incidence prophylaxis PPIs have statistically proven benefit over placebo/H2RAs 11 in management of diseases associated with increased GERD Pace et al., 2005 Decreased recurrence acid production. The indications for PPI therapy, which

are approved by FDA include Gastroesophageal Reflux 11,12 patients without any maintenance therapy. Long-term Disease (GERD), erosive esophagitis, peptic ulcer, NSAID- administration of PPIs may also prevent transformation induced ulcer (treatment and prophylaxis), Helicobacter 13 of Barrett’s esophagus to a neoplastic lesion. Common pylori infection (along with antibiotics) and management indications of long-term PPI use along with the studies of pathologic hypersecretory conditions (including establishing their role have been summarized in Table 1. Zollinger-Ellison syndrome).4 The other common indication of long-term PPI use is However apart from the above-mentioned indications, for prevention of NSAID-induced gastroduodenal ulcers the existing evidence suggests overuse of PPIs with almost recurrence by decreasing it to approximately one-tenth 25–70% of prescriptions lacking appropriate indication.5 on comparison with patients treated with placebo.10 Thus, In fact, the “off-label” use of PPIs is among the highest they are the drug of choice for the prevention of aspirin/ (55% prevalence) in intensive care units.6 NSAID induced ulcers. In patients of GERD, who present with reflux symptoms after meals, long-term inhibition of acid secretion is achieved by use of PPIs.5-10 Since the effect of acid Long-term Use of PPI: Is It a Bane? suppression remains for almost 24 hours, a single dose of Increased usage of PPI for past many years now has led PPI empty stomach in the morning is effective. There is to the conundrum of their long-term effects. Prolonged evidence that PPIs can be used in prevention of recurrent PPI use has been implicated in adverse effect of several reflux symptoms as well as esophageal erosions/ulcers.7-9 body functions and has been associated with increased The regular use of PPIs as maintenance therapy of GERD incidence of various diseases. Common adverse effects of decreases the recurrence rates to less than 15% for 1 long-term PPI usage along with the studies establishing year compared to recurrence rates of more than 50% for their role have been summarized in Table 2.

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Gastric neuroendocrine tumor—Prolonged PPI TABLE 2 Adverse effects of long-term use of PPIs use leads to increased intra-gastric pH thereby causing Side effect Study Inference increased plasma gastrin concentration, thus stimulating SIBO Lo WK et al., 201322 Increased risk enterochromaffin like (ECL) cells proliferation.19 There Gall bladder Cahan et al., 200626 Increased risk are only isolated case reports of PPI administration- dysfunction related gastric neuroendocrine tumors in humans and Pneumonia Wongtrakul et al., 202029 Increased risk presently to ascertain a pathogenic role, the data is 20 Acute interstitial Xie et al., 201631 Increased risk scarce. Therefore, at present there is insignificant clinical nephritis relevance of the risk of carcinoid tumor after long-term Chronic kidney Wijarnpreecha et al., 201732 Increased risk PPI use. Although periodic endoscopic screening may be disease considered during the period of use. 33 Hypomagnesemia Park CH et al., 2014 Decreased Gut microbiome changes and Small Intestinal Bacterial magnesium levels Overgrowth (SIBO)—The resultant decrease in the acid secretion and the bactericidal effect of the gastric juice Dementia M A Khan et al., 202035 No definite risk due to PPIs leads to an increase in the microbial density Bone fracture Nassar et al., 201837 Increased risk of bone fracture of the gut especially with Streptococcus which colonize the oral cavity.21 Lo et al. in a meta-analysis done in 2013 found that as compared to non-users, there was 7.5 times increased risk of SIBO in PPI users. Therefore, prolonged Adverse effects of PPI based on their property of TABLE 3 acid inhibition or unrelated to it PPI administration is considered a risk factor for SIBO (Defined as presence of 100,000 bacterial colonies/ Due to acid Pneumonia, GI infection, Carcinoid tumor, GI mL in small intestinal contents).22 However, the clinical inhibition mucosal hypertrophy, Fractures, SIBO, Vit B12 deficiency, Gastric cancer, SBP importance of this altered microbiome in patients treated Collagenous colitis, Acute interstitial nephritis, with PPIs is elusive at present. Unrelated to acid Dementia Spontaneous bacterial peritonitis (SBP)—PPI inhibition administration is useful in few cases of cirrhosis as they reduce the risk of variceal rupture and ulcer occurrence.23 Long-term PPI use leads to hypochlorhydria promoting These side effects can be separated either as per the bacterial translocation, colonic transmigration and mechanism or as per the involved site. may lead to Gram-negative organisms related SBP in cirrhotics.24 Although, the available evidence at present As Per the Mechanism does not recommend withholding PPIs whenever Adverse effects of PPIs occur either due to the fact that they indicated in patients with liver disease; the evidence does cause acid inhibition or else they are unrelated to their suggest that PPI use is associated with augmented risk of property of acid inhibition.14 These adverse effects have SBP in cirrhotics. been shown in Table 3. Gastric cancer—In patients with H. pylori infection, long-term PPI usage increases mucosal inflammation, As Per the Site Involved hastens mucosal atrophy, which might be a potential risk factor for gastric malignancy.25 However, more data is Gastrointestinal System required to establish causality between long-term PPI use Increased risk of gastrointestinal infection—Use of PPIs and gastric malignancy in H. pylori patients. has an association with increased risk of Clostridium Gall bladder dysfunction—Cahan et al. in 2006 difficile (C. difficile) infection.15,16 Possible mechanism is found that PPI therapy reduces gallbladder motility in that long-term PPI use alters the colonic microbiome and healthy volunteers.26 Chronic PPI therapy may pose a hampers the normal barriers against C. difficile, which risk for long-term gallbladder dysfunction and biliary proliferates using the available amino acids.17,18 complications.

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Atrophic gastritis—PPIs can alter the gastric mucosal Vitamin B12—The acidic environment of the stomach architecture and Li et al. found in a meta-analysis in 2017 assists in the release of Vit. B12 bound with food and that there was a higher presence of gastric atrophy in PPI subsequently helps its binding to intrinsic factor. Lam et al. group compared to the control group.27 in 2013 found a 65% increased risk of B12 deficiency in PPI users more than 2 years.34 Respiratory Pneumonia—PPIs increase gastric pH by suppressing Neurological gastric acid release, promoting bacterial overgrowth which Dementia—Long-term PPI use inhibits beta and gamma in turn leads to colonization of trachea and pneumonia. secretase, which may lead to an increase in the amyloid There is evidence to suggest that immune cell function beta peptide levels in the brain. Khan et al. in their may also be impaired by PPIs, thereby augmenting the systematic review found lack of evidence pertaining to the risk of infectious complications.28 Wongtrakul et al. in their proposed suggestion of PPI use and an increased risk of recent meta-analysis concluded a significantly higher risk dementia.35 They recommended that PPI use should not of development of pneumonia in cirrhotic patients with be curtailed because of concerns about dementia risk. a history of PPI use than those without. Thus, prudent use of PPIs in patients with definite indication may be Drug Interactions suggested.29 Anti-platelets—There is competitive inhibition of CYP2C19 to variable grades by PPIs, thus affecting the metabolism of Renal clopidogrel. Omeprazole is the most noteworthy inhibitor Acute interstitial nephritis—In patients on PPI treatment, of CYP2C19. The two meta-analyses done in this regard an allergic reaction to the drug may cause interstitial found an increased rate of adverse cardiovascular events 30 nephritis. As many as 70% of acute interstitial nephritis in patients on simultaneous PPI-clopidogrel therapy.36 was reportedly related to drugs, of which 14% were caused While the pharmacological interaction between these two 31 by PPIs in biopsy-proven cases. drugs is established beyond doubt, more data is required Chronic kidney disease—The mechanism by which to ascertain the clinical significance of this interaction. PPI use can lead to CKD is not well understood. One of the mechanisms proposed is the acute interstitial nephritis Endocrine caused by PPI. Other postulated mechanisms include lysosomal acidification hydrogen/potassium adenosine Alteration in bone density—The bone health and increased triphosphatase enzyme system abnormalities, reduced fracture susceptibility due to PPIs may be linked to renal tubular cells regeneration, altered gene expression, impaired calcium absorption (acid suppression leads and elevated oxidative stress.32 Although, there is a need of to decreased release of ionized calcium from insoluble more data to ascertain this association, it is suggested that calcium salts) and hypergastrinemia. In a meta-analysis the indication of initiation as well as continuation of PPIs conducted by Nassar et al. published in JBM in 2018 it was should be carefully assessed in patients with pre-existing found that long-term PPI use might increase the fracture risk factors for CKD development. risk but has no significant alteration of bone mineral density (BMD).37 Presently there is insufficient evidence to Nutrient Absorption recommend regular BMD monitoring of patients on PPIs. Hypomagnesemia—One of the postulated mechanism for hypomagnesemia related to PPI use is a reduction in the Hematological affinity of magnesium to its transport receptors caused PPIs have their anti-inflammatory properties as they by the pH change thereby decreasing the active transport can bind to neutrophils and can inhibit neutrophil of magnesium across the intestinal lumen. Park et al., in accumulation and release of ROS. However, long-term their meta-analysis, showed an increased incidence of use can also lead to neutropenia and thrombocytopenia.38 hypomagnesemia in PPI users.33 In general, the recognized theories are the immune-

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Flowchart 1: The algorithm for deprescribing PPIs

mediated and the toxic mechanism. Drug-induced long-term PPI use, a lot of research is going on to formulate antibodies against circulating hemocytes form the basis of a well-structured model to deprescribe PPIs. immune mediated mechanism whereas the toxic mechanism is due to direct toxicity of the drug to Deprescribing PPIs hematopoietic cells. Patients on PPIs should be monitored for symptom recurrence and symptoms should gradually be managed All-cause Mortality with on-demand PPIs, stepping down to H2RA therapy, Xie et al., in their cohort study, demonstrated an increased other over-the-counter agents (e.g., calcium carbonate) 39 risk of all-cause mortality in association with PPI use. or nonpharmacologic approaches (weight loss, avoid The speculated mechanism for this association was the meals 2–3 hours before bed time, head end elevation, probable role of oxidative stress, heme oxygenase-1 and avoid dietary triggers). Stepping down to H2RA involves accelerated senescence of human endothelial cells. discontinuation or tapering of the PPI followed by prescription of an H2RA. Any H2RA at any approved dose The Road Ahead and dosing interval can be used.40 Implementation of Presently, PPIs are among the most frequently prescribed deprescription guidelines (Flowchart 1) will encourage class of drugs and are often continued for duration way clinicians to carefully evaluate the ongoing use of beyond the indication. In view of this and with many medications and potentially reduce the negative effects of recent studies suggestive of systemic adverse effects of polypharmacy.

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Conclusion oesophagitis, followed by a maintenance open-label, low-dose therapy with rabeprazole. Digest Liver Dis. 2005;37(10):741-50. PPIs have a robust helpful impact when used correctly for 12. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment the standard indications. However, PPIs have also been of oesophagitis: clinical and functional correlates and further incriminated with multiple systemic side effects. Although validation of the Los Angeles classification. Gut. 1999;45(2):172-80. 13. Singh S, Garg SK, Singh PP, et al. Acid-suppressive medications the evidence is limited for causality at present and this is an and risk of oesophageal adenocarcinoma in patients with area of active research, there is enough evidence to indicate Barrett’s oesophagus: a systematic review and meta-analysis. Gut. a tendency to develop adverse effects with long-term use of 2014;63(8):1229-37. PPIs. Optimal strategy at this time for PPI prescription is to 14. Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages advise it to patients with clear indications, following of clear of long-term proton pump inhibitor use. J Neurogastroenterol deprescription strategies and avoidance of broad off-label Motil. 2018;24(2):182-96. usage. 15. Clooney AG, Bernstein CN, Leslie WD, et al. A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors. Aliment Pharmacol Ther. 2016;43(9):974-84. References 16. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta- . 1 Katzung BG, Trevor AJ (Eds). Basic & Clinical Pharmacology. New analysis. Am J Gastroenterol. 2012;107(7):1011-9. York: McGraw-Hill Education; 2015. 17. Freedberg DE, Salmasian H, Friedman C, et al. Proton pump . 2 Aronson JK. Inhibiting the proton pump: mechanisms, benefits, inhibitors and risk for recurrent Clostridium difficile infection harms, and questions. BMC Med. 2016;14(1):172. among inpatients. Am J Gastroenterol. 2013;108(11):1794-801. . 3 Raghunath AS, O’Morain C, McLoughlin RC. Review article: the 18. Seto CT, Jeraldo P, Orenstein R, et al. Prolonged use of a proton long-term use of proton-pump inhibitors. Aliment Pharmacol Ther. pump inhibitor reduces microbial diversity: implications for 2005;22(Suppl 1):55-63. Clostridium difficile susceptibility. Microbiome. 2014;2(1):42. . 4 Nehra AK, Alexander JA, Loftus CG, et al. Proton pump inhibitors: 19. Lundell L, Vieth M, Gibson F, et al. Systematic review: the effects of review of emerging concerns. Mayo Clin Proc. 2018;93(2):240-6. long-term proton pump inhibitor use on serum gastrin levels and . 5 Batuwitage BT, Kingham JG, Morgan NE, et al. Inappropriate gastric histology. Aliment Pharmacol Ther. 2015;42(6):649-63. prescribing of proton pump inhibitors in primary care. Postgrad 20. Olbe L, Carlsson E, Lindberg P. A proton-pump inhibitor expedition: Med J. 2007;83(975):66-8. the case histories of omeprazole and esomeprazole. Nat Rev Drug . 6 Barletta JF, Lat I, Micek ST, et al. Critical Care Pharmacotherapy Discov. 2003;2(2):132-9. Trials Network. Off-label use of gastrointestinal medications in the 21. Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors intensive care unit. J Intensive Care Med. 2015;30(4):217-25. alter the composition of the gut microbiota. Gut. 2016;65(5):749-56. . 7 Hongo M, Fujimoto K. Gastric Polyps Study Group. Incidence and 22. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small risk factor of fundic gland polyp and hyperplastic polyp in long- intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol term proton pump inhibitor therapy: a prospective study in Japan. Hepatol. 2013;11(5):483-90. J Gastroenterol. 2010;45(6):618-24. 23. Hidaka H, Nakazawa T, Wang G, et al. Long-term administration . 8 Labenz J, Armstrong D, Zetterstrand S, et al. Clinical trial: factors of PPI reduces treatment failures after esophageal variceal band ligation: a randomized, controlled trial. J Gastroenterol. associated with resolution of heartburn in patients with reflux 2012;47(2):118-26. oesophagitis—results from the EXPO study. Aliment Pharmacol 24. Khan MA, Kamal S, Khan S, et al. Systematic review and meta- Ther. 2009;29(9):959-66. analysis of the possible association between pharmacological . 9 Kinoshita Y, Kato M, Fujishiro M, et al. Efficacy and safety of gastric acid suppression and spontaneous bacterial peritonitis. Eur twice-daily rabeprazole maintenance therapy for patients with J Gastroenterol Hepatol. 2015;27(11):1327-36. reflux esophagitis refractory to standard once-daily proton 25. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis pump inhibitor: the Japan-based EXTEND study. J Gastroenterol. and Helicobacter pylori infection in patients with reflux esophagitis 2018;53(7):834-44. treated with omeprazole or fundoplication. N Engl J Med. 10. Sugano K, Kinoshita Y, Miwa H, et al. Esomeprazole NSAID 1996;334(16):1018-22. Preventive Study Group. Randomised clinical trial: esomeprazole 26. Cahan MA, Balduf L, Colton K, et al. Proton pump inhibitors reduce for the prevention of nonsteroidal anti-inflammatory drug-related gallbladder function. Surg Endosc. 2006;20(9):1364-7. peptic ulcers in Japanese patients. Aliment Pharmacol Ther. 27. Li Z, Wu C, Li L, et al. Effect of long-term proton pump inhibitor 2012;36(2):115-25. administration on gastric mucosal atrophy: a meta-analysis. Saudi J 11. Pace F, Annese V, Prada A, et al. Rabeprazole is equivalent to Gastreneterol. 2017;23(4):222-8. omeprazole in the treatment of erosive gastro-oesophageal 28. Bateman BT, Bykov K, Choudhry NK, et al. Type of stress ulcer reflux disease: a randomised, double-blind, comparative study of prophylaxis and risk of nosocomial pneumonia in cardiac surgical rabeprazole and omeprazole 20 mg in acute treatment of reflux patients: cohort study. Version 2. BMJ. 2013;347:f5416.

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29. Wongtrakul W, Charoenngnam N, Ungprasert P. Use of proton 35. Khan MA, Yuan Y, Iqbal U, et al. No Association Linking Short- pump inhibitors is associated with a higher risk of pneumonia Term Proton Pump Inhibitor Use to Dementia: Systematic Review in cirrhotic patients: a systematic review and meta-analysis. Ann and Meta-analysis of Observational Studies. Am J Gastroenterol. Gastroenterol. 2020;33(3):277-84. 2020;115(5):671-8. 30. Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial 36. Niu Q, Wang Z, Zhang Y, et al. Combination use of clopidogrel and nephritis secondary to proton pump inhibitors: experience from a proton pump inhibitors increases major adverse cardiovascular single UK renal unit. Nephrol Dial Transplant. 2004;19(6):1441-6. events in patients with coronary artery disease: a meta-analysis. J 31. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute Cardiovasc Pharmacol Ther. 2017;22(2):142-52. 37. Nassar Y, Richter S. Proton-pump inhibitor use and fracture risk: interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. an updated systematic review and meta-analysis. J Bone Metab. 2014;64(4):558-66. 2018;25(3):141-51. 32. Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users 38. Yu Z, Hu J, Hu Y. Neutropenia and thrombocytopenia induced of proton pump inhibitors without intervening acute kidney injury. by proton pump inhibitors: a case report. Drug Saf Case Rep. Kidney Int. 2017;91(6):1482-94. 2018;5(1):28. 33. Park CH, Kim EH, Roh YH, et al. The association between the use 39. Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump of proton pump inhibitors and the risk of hypomagnesemia: a inhibitors: a longitudinal observational cohort study of United systematic review and meta-analysis. PLoS One. 2014;9(11):e112558. States veterans. BMJ Open. 2017;7(6):e015735. 34. Lam JR, Schneider JL, Zhao W, et al. Proton pump inhibitor and 40. Farrell B, Pottie K, Thompson W, et al. Deprescribing proton pump histamine 2 receptor antagonist use and vitamin B12 deficiency. inhibitors: evidence-based clinical practice guideline. Can Fam JAMA. 2013;310(22):2435-42. Physician. 2017;63(5):354-64.

MU-135.indd 877 29-01-2021 14:58:07 CHAPTER

Eosinophilic Esophagitis— 136 An Underdiagnosed Entity

Goundappa Loganathan, H Leena Shree

Abstract Eosinophilic oesophagitis (EOE) is a locally immune mediated chronic oesophageal disease occurring as a consequence of allergen exposure. It is a male predominant widely prevalent but less well recognized disease with genetic preponderance and often associated with atopy. EoE has a progressive course from mucosal disease to subepithelial disease over decades resulting in fibro stenotic esophageal disease. The diagnosis is based on the constellation of symptoms, endoscopic and histological findings with >15 eosinophils/HPF confirming the diagnosis. The new genetic, molecular, cellular, animal, and translational studies show the cascade of coordinated type 2 inflammatory response. The newer classification based on histologic, endoscopic, and molecular features defines three endotypes each with distinct genetic, clinical, endoscopic, and histological features. Treatment principles include elimination of possible food allergen, mast cell stabilizer, proton pump inhibitor which has a cause and effect relationship, steroids, and biologicals. Earlier diagnosis with newer tools and biopsy help to diagnose EoE early in disease thus preventing progression to fibro stenotic disease thereby reducing morbidity. (Eosinophilic oesophagitis; Food allergens; esophageal eosinophilia; proton pump inhibitors; Allergy)

Introduction Definition Eosinophilic esophagitis (EoE) is a part of spectrum EoE is defined as locally immune mediated chronic of eosinophilic disorders of the gastrointestinal tract esophageal disease with clinical symptoms of esophageal histologically characterized by eosinophilic infiltration dysfunction and histological eosinophil predominant and inflammation consequent to exposure to an allergen, inflammation with a progressive natural course.1-5 It often food, resulting in esophageal dysfunction and is IgG 4 mediated disease associated with atopy (20– progressive serious complications, though a definite cause 80%), urticaria and anaphylaxis; positive family history eludes. This diagnosis from esophageal eosinophilia (50%), asthma (30–50%) and allergic rhinitis (50–75%) in (1968) has progressed from initial association with reflux children.6 disorders to EoE in 1993. A male predominant disease, is associated with various allergic disorders including atopy Natural History and seen to increase progressively over these two decades. „„ Epidemiology: It is a disease with global presence Etiopathobiology includes genetic and IgG 4 association including America, Europe, Australia, and Asia, male and as a cause with familial susceptibility. Care of these predominant [3:1], ethnically variable (more common patients involves primary care providers to multi-specialty in Caucasians) with overall pooled prevalence of departments. 22.7/100,000, 0.5–1 per thousand, 2–7% of gastroscopy,

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12–23% of gastroscopy for dysphagia, and is seen to be unprimed host living in virtual hygienic environment increasing over time.7 initiate Th2 response over Th1 which is mild and „„ Course: EoE is a chronic and progressive disease. protective. Earlier symptoms in children are due to inflammation „„ Helicobacter pylori (H. pylori)/Proton Pump Inhibitor and later in life due to subepithelial collagen deposition (PPI) Hypothesis—Harmful or protective: Presence of resulting in fibro stenotic EoE. Presence of strictures H. pylori polarizes the immune system toward a Th1 was observed in 17% and 71% with less than 2 years response and the lack of it leads to Th2 response. EoE and 20 years of symptoms thus emphasizing the need has a strong inverse relationship with H. pylori and for early diagnosis. atopic disorders.9 „„ Temporal trends: From 9 to 12.8/100,000 over 3 years —— PPI is hypothesized to increase upper gastro­ in Ohio, USA, 0.35 to 9.5/100,000 in Minnesota, intestinal tract (GIT) permeability facilitating new USA, over 15 years, 1.2 to 7.4/100,000 in Switzerland route of antigen entry; over 20 years indicating that there is an increasing —— use of PPI is associated with food specific IgE incidence. The reasons for increase will be discussed antibodies. in etiopathobiology in addition to awareness and —— PPI has shown anti-inflammatory/anti- increasing mucosal biopsies. eosinophilic effects. Use of PPI has resulted in histological resolution of Etiopathobiology (Fig. 1) inflammation and eosinophils in 30–40% making use 8 „„ Allergen and Hygiene Hypothesis: The strength of of PPI as a candidate trial drug. PPI thus can cause evidence stems from increased prevalence and EoE indirectly by removing the protective barrier incidence in developed countries which have better and eliminating H. pylori; paradoxically PPI heals hygiene and association with most of the allergic EoE by its anti-inflammatory and anti-eosinophilic disorders in a significant proportion. Aero-allergen activity; conclusive evidence is required to say if PPI is exposure gains support by the increased incidence causative or curative.10-17 in summer or fall. Increased prevalence is noted in „„ Early Life Exposure Hypothesis/Environmental arid region, cold weather lacking vegetation, rural Factor:18-23 EoE is associated with use of antibiotics in low density populated regions. This requires further children delivered by caesarean, less than 1 year of age, research. Food elimination results in improvement of premature babies, non-exclusively breast fed babies. EOE, and hence is considered a risk. Various reasons Establishment of esophageal microbiome would help mentioned stay unproven. Allergen/infection in an in understanding microbial dysbiosis as the cause.

Fig. 1: Etiopathobiology shows the mechanism due to acid reflux, genetic, cytokine induced mechanisms

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„„ Familial/Genetic Susceptibility: EoE is associated with like edema, rings, exudates, furrows, and strictures connective tissue and auto-immune disorders.24,25 graded separately at upper, middle, and lower third of EoE has racial and gender bias, predominance in esophagus. The inflammatory signs edema, exudates, white ancestry, inherited in non-Mendelian manner, and furrows had a sensitivity of 89%, 96%, 89%, and a sibling risk ratio of 80%; parents had history of specificity of 88%, 76%. and 90%, respectively and esophageal stricture and eosinophilic infiltrate in 10% correlated with eosinophilia. Composite inflammatory and 8% respectively. score, the sum of maximum of inflammatory variables The new genetic, molecular, cellular, animal, and namely edema, rings, and exudate excluding furrows translational studies help to postulate a detailed pathway. and stricture showed a superior correlation amongst This shows how, exposure to allergens results in a complex the diagnostic and post-treatment cohorts.31,32 and coordinated type 2 inflammatory cascade. Delayed Schatzki’s ring is one of the endoscopic manifestations intervention can result in odynophagia, esophageal of EoE. 26 strictures, and food impaction. „„ Histologic: Biopsy is mandatory in patients clinically The genetics, epigenetics, and transcriptional analysis, suspected to have EoE even if the esophageal mucosa the role of cytokines, chemokines, and other molecules, looks normal. Endosonography guided deeper pathological and protective cells including commensal biopsies would provide more information. A meta- bacteria are vividly described.26-28 analysis of EoE endoscopic findings in isolation have poor sensitivity, specificity, and predictive value33 and Diagnosis the sensitivity increases to 100% when 6–9 esophageal 34,35 The diagnosis of EoE is made on the constellation of mucosal biopsies are taken. Presence of >15 clinical manifestations, endoscopic and histological eosinophils/hpf confirms the diagnosis of EoE. findings. Newer principles36 (Fig. 2): „„ Clinical: There is a distinct phenotypic variability „„ Removal of age cut-off in symptomatology amongst people in early and „„ Removing PPI from list of diagnostic criteria advanced disease. Esophageal dysfunction symptoms „„ Evaluate for condition causing esophageal eosinophilia include esophageal dysphagia in 60–100%, food rather than excluding them impaction in 25%, heart burn in 30–60%, atypical chest „„ Criteria should be clinically operational pain in 8–44% and 1–8% of those with refractory reflux „„ Should be utilizable in patients in whom diagnosis was 29 symptoms. Dysphagia, refractory heart burn, and made using earlier criteria, applicable clinically widely mucosal disruption on intubation are the predominant and for future research symptom/sign in advanced disease. Vomiting, food rejection and growth retardation are also observed.30 Newer tools: 37 Association of symptoms of atopy adds to the diagnosis. „„ Tetsuo Shoda et al. using EoE diagnostic panel (EDP) „„ Endoscopic: Endoscopic Reference Scoring (EREFS) and Consortium of Eosinophilic Disease Researchers (Table 1) classification as given by Hirano et al. has (CEGIR), Endoscopic Reference Scoring (EREFS) scoring for visually observed endoscopy findings and histologic scoring system (HSS) analyzed the

TABLE 1 Endoscopic reference scoring

Variable Grade 0 Grade 1 Grade 2 Grade 3 Edema Distinct Vascularity Decreased Vascularity Absent Vascularity Rings None Mild ridges Moderate/Distinct rings Severe—Cannot pass scope Exudate None Mild <10% of surface area Severe > 10% of surface area Furrows None Mild Severe Stricture Absent Present

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Fig. 2: Antigens presenting cells (APC) present the antigen to the adaptive response sites. Imbalance between pathological and protective cells result in inflammatory cascade

association of histologic, endoscopic, and molecular measurements.38 Absolute eosinophil count (AEC) is features. This study characterized three endotypes the single biomarker of relevance as on this date.27 namely EoEe1, EoEe2, and EoEe3 each with distinct genetic, clinical, endoscopic and histological features Treatment providing effective therapeutic intervention (Table 2). Treatment principles include elimination of potential Diagnostic criteria: antigen, attenuation or elimination of antigen induced „„ Symptoms suggestive of esophageal dysfunction allergic/immunogenic pathway induced inflammation „„ Presence of eosinophilic infiltrate (>15 e/hpf) on early in the disease using PPI and steroids and esophageal biopsy to treat fibrostenotic complications of like strictures „„ Exclusion of other disease like Gastro Esophageal endoscopically in advanced disease. 3D acronym for Diet, Reflux Disease (GERD) and Proton Pump Inhibitor Drugs, and Dilatation forms the basis of treatment of EoE. Responsive Esophageal Eosinophilia (PPI-REE) after 8 Diet: Elimination diet: Elemental diet still is the most weeks PPI trial. effective strategy but associated with poor compliance. A AGREE Conference36 2018 includes the following: meta-analysis by Arias et al. observed efficacy of elemental „„ Symptoms of esophageal dysfunction. diet in 90.8%, six food elimination diet (SFED—cow milk, „„ Esophageal mucosal biopsies with eosinophils >15/ wheat, egg, soy, peanut, and seafood) in 72.1% and allergy hpf (60 eosinophils/smm). testing directed elimination diet in 45.5% of cases.39 A „„ Presence of exudates, grooves, rings, stenosis, luminal novel 2-4-6 step up elimination diet strategy with each narrowing, and crepe’ mucosa. elimination diet step lasting for 6 weeks observed 43% „„ Concomitant atopic conditions. remission in Two Food Elimination Diet (TFED Milk and „„ Esophageal eosinophilic infiltration in isolation. gluten containing diet), 60% in those receiving TFED „„ Evaluation of potential contributors of esophageal and four food elimination with addition of eggs and eosinophilia. legumes (FFED) and 79% with six food elimination diet

36 by additionally excluding nuts and seafood. This method „„ Updated diagnostic algorithm (Fig. 3) helped to identify possible food antigen and avoided „„ Emerging diagnostic tools: Transnasal endoscopy, unnecessary food elimination.40 Endoscopic functional lumen imaging probe (FLIP), Cytosponge to obtain biopsy have sensitivity and Drugs: specificity of 75% and 86%, respectively, esophageal „„ Steroids: Dampening of EoE associated inflammation, string test and real time mucosal impedance improving mucosal barrier function and histologic

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TABLE 2 EoE Endotypes

Variable EoEe1 EoEe2 EoEe3 % of subjects 35% 29% 36% Inflammation Pauci -Inflammatory High type 2 immune mechanism Higher frequency of narrow caliber esophagus Near normal esophagus with steroid refractoriness Fibrostenotic Inflammatory Epithelial Small changes Low expression differentiation genes Onset Pediatric Adult Adult Allergy Atopic Atopic Non-Atopic Steroid sensitivity Sensitive Refractory Refractory Genetic Low expression of ALOX 15 Inflammatory cytokines IL-4, TSLP Enriched for epithelial genes that lose Mild phenotype are expressed expression, of ACPP, CITED2, CTNNAL1, EML1, Expression in ACTG2 gene FLG, GRPEL2, MT1MPNLIPPR3, TSPAN12

Treatment response Anti-Type 2 immune therapy (anti IL-4 Ralpha) Anti TSLP Biologicals Learning zz Adult and pediatric EoE have comparable pathogenesis zz Adult and pediatric EoE are amenable to similar therapeutic interventions zz Eosinophils levels may not indicate severity or help to subtype EoE zz Endotyping offers useful subtyping of EoE zz Biomarkers need to be developed zz EoE exists in three disease endotypes with characteristic/unique clinical, endoscopic and molecular features zz Endotyping could transcend eosinophil levels as gold standard

Fig. 3: Showing the updated EoE algorithm and the principles in newer diagnostic criteria

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TABLE 3 Follow up and monitoring response

Variable Non-response Response Complete remission Symptom Less than 30% symptom 90% decrease in symptom metric. Greater than 90 % response in symptom metric persistence in a symptom metric Eosinophilia decrease by 30% EEsAI score < 20 Endoscopy Persistent endoscopic finding Improved endoscopic findings Normal esophagus < 30% decrease in EREFS EREFS > 2 but less than baseline EREFS < 2 Histology Persistent eosinophilia Reduced eosinophilia 7–14 eos/ Normal biopsy < 1 eos/HPF >15 eos/HPF HPF to 1–6 eos/HPF EEsAI, eosinophilic esophagitis symptom activity index; eos/hpf, eosinophils/high power field; EREFS, eosinophilic esophagitis endoscopic reference score

remodeling; improved esophageal diameter and Reduction in esophageal subepithelial activity (ESEA) dispensability.41-44 Induction regimen of oral 1 mg could evolve as a relevant objective endpoint of treatment. budesonide twice daily for 2–4 weeks to reach clinical ESEA can be known by deeper biopsies guided by response followed by maintenance regimen of 0.25 endosonography. Presently available instruments— mg twice daily for not less than 6 months after which biomarkers and clinical techniques—are limited or not steroid can be discontinued if remission is maintained. fully utilized. This remains as a need to meet.48,49 Deep remission was achieved at 89 weeks in 9.4% of Treatment Response and Monitoring: spectrum includes adult EoE patients with corticosteroid discontinuation non-response, response, and complete remission at 104.7 weeks and relapse at 22.4 weeks. Relapse is managed with induction regimen for 1–2 weeks. (Table 3). All biomarkers now on use are investigational Esophageal candidiasis in 20% and herpetic infection, and include IL-3, IL-5, IL-6, IL-13, transforming growth adrenal insufficiency were reported following steroid factor alpha, and beta, TNF alpha, eotaxin 1, 2, and 3 use. Oral and aerosolized fluticasone is also used. thymic stromal lymphoprotein (TSLP) and major basic „„ PPI: The ability of PPI to reduce inflammation—PPI protein and neurotoxin derived from eosinophils. responsive esophageal eosinophilia (PPI-REE) has made it a first-line therapeutic modality. Use of PPI (8 Future Directions weeks) by a meta-analysis showed clinical response Aimed at identifying the antigens responsible for the in 60.8%, histological remission in 50.5%, sustained inflammatory cascade, early detection of EoE, noninvasive 45,46 remission in 73–86%. biomarkers for detection and monitoring, target directed „„ Leukotriene B4 inhibitor: Use of Montelukast a therapies and prevention of relapse after achieving leukotriene B4 inhibitor results in mast cell inhibition remission. thereby reducing cytokine release retarding or preventing inflammatory cascade. Conclusion „„ Biologicals: These include monoclonal antibodies against IL-13, IL-5, IL-4, anti-tumor necrosis factor EoE is a chronic antigen induced immune mediated progressive alpha (TNF alpha) and antibodies against immuno­ disease of the esophagus characterized by eosinophilic infiltration. This progresses from inflammation to fibrostenotic globin E. Studies indicate a promise for dupilumab, disease. Earlier diagnosis by liberal biopsies in symptomatic but monoclonal antibody acting on IL-4 receptor by a with normal esophageal mucosa can identify more patients. negative regulation of Th2 response causing inhibition Endosonography guided deeper biopsies will give more of IL-4/IL-13 signaling.47 information on subepithelial activity, which results in fibrostenotic disease. Earlier intervention improve the quality and quantity of Dilatation therapy: Advanced disease with fibro-stenotic life with less morbid and mortality indices. Increasing awareness manifestation need endoscopic dilatation, incising of amongst family physicians and patients with allergic disorders coupled with esophageal biopsies is desirable. Schatzki’s ring.

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Eosinophilic upper gastrointestinal tract transmucosal permeability increase. esophagitis: current concepts in diagnosis and treatment. World J Aliment Pharmacol Ther. 2008;28(11-12):1317-25. Gastroenterol. 2019;25(32):4598-613. 13. Untersmayr E, Bakos N, Schöll I, et al. Anti-ulcer drugs promote 31. Wechsler JB, Bolton SM, Amsden K, et al. Eosinophilic esophagitis IgE formation toward dietary antigens in adult patients. FASEB J. reference score accurately identifies disease activity and treatment 2005;19(6):656-8. effects in children. Clin Gastroenterol Hepatol. 2018;16(7):1056-63. 14. Untersmayr E, Schöll I, Swoboda I, et al. Antacid medication inhibits 32. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the digestion of dietary proteins and causes food allergy: a fish allergy oesophageal features of eosinophilic oesophagitis: validation of a model in BALB/c mice. J Allergy Clin Immunol. 2003;112(3):616-23. novel classification and grading system. 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Histopathologic features of eosinophilic esophagitis. evidenced based approach to the diagnosis and management of Gastrointest Endosc Clin N Am. 2008;18(1):59-71. esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J 36. Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated International Gastroenterol. 2013;108(5):679-92. Consensus Diagnostic Criteria for Eosinophilic Esophagitis:

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Proceedings of the AGREE Conference. Gastroenterology. 43. Simon D, Page B, Vogel M, et al. Evidence of an abnormal epithelial 2018;155(4):1022-33. barrier in active, untreated and corticosteroid-treated eosinophilic 37. Shoda T, Wen T, Aceves SS, et al. Eosinophilic oesophagitis esophagitis. Allergy. 2018;73(1):239-47. endotype classification by molecular, clinical, and histopathological 44. Andreae DA, Hanna MG, Magid MS, et al. Swallowed fluticasone analyses: a cross-sectional study. Lancet Gastroenterol Hepatol. propionate is an effective long-term maintenance therapy for 2018;3(7):477-88. children with eosinophilic esophagitis. Am J Gastroenterol. 38. Nhu QM, Moawad FJ. New developments in the diagnosis 2016;111(8):1187-97. and treatment of eosinophilic esophagitis. Curr Treat Options 45. Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of proton pump Gastroenterol. 2019;17(1):48-62. inhibitor drugs for inducing clinical and histologic remission in 39. Arias A, González-Cervera J, Tenias JM, et al. Efficacy of dietary patients with symptomatic esophageal eosinophilia: a systematic interventions for inducing histologic remission in patients with review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14(1): eosinophilic esophagitis: a systematic review and meta-analysis. 13-22. Gastroenterology. 2014;146(7):1639-48. 46. Molina-Infante J, Prados-Manzano R, Gonzalez-Cordero PL. The 40. Molina-Infante J, Arias Á, Alcedo J, Garcia-Romero R, et al. role of proton pump inhibitor therapy in the management of Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis. Expert Rev Clin Immunol. 2016;12(9): eosinophilic esophagitis: the 2-4-6 study. J Allergy Clin Immunol. 945-52. 2018;141(4):1365-72. 47. Sastre J, Dávila I. Dupilumab: a new paradigm for the treatment 41. Blanchard C, Mingler MK, Vicario M, et al. IL-13 involvement in of allergic diseases. J Investig Allergol Clin Immunol. 2018;28(3): eosinophilic esophagitis: transcriptome analysis and reversibility 139-50. with glucocorticoids. J Allergy Clin Immunol. 2007;120(6):1292-300. 48. Hirano I. Clinical relevance of esophageal subepithelial activity in 42. Katzka DA, Tadi R, Smyrk TC, et al. Effects of topical steroids on eosinophilic esophagitis. J Gastroenterol. 2020;55(3):249-60. tight junction proteins and spongiosis in esophageal epithelia of 49. Dellon ES, Gupta SK. A conceptual approach to understanding patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. treatment response in eosinophilic esophagitis. Clin Gastroenterol 2014;12(11):1824-9. Hepatol. 2019;17(11):2149-60.

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Non-Cirrhotic Portal 137 Hypertension in India

Srikant Mohta, Anoop Saraya

Abstract Non-cirrhotic portal hypertension is an entity with a normal hepatic venous pressure gradient (HVPG) but significant portal hypertension. It could be due to pre-hepatic, hepatic, or post-hepatic causes. The most notable etiologies are extrahepatic portal vein obstruction (EHPVO) and non-cirrhotic portal fibrosis (NCPF) while other causes include schistosomiasis, congenital hepatic fibrosis, and regenerative nodular hyperplasia. The pathogenesis for NCPF and EHPVO is multifactorial and not very clear. However, there is evidence to suggest the role of a prothrombotic state and infection. EHPVO presents 10–20 years before NCPF and they both predominantly present with gastrointestinal bleed without other decompenstations. In severe cases, they may have ascites and encephalopathy as well. They differ in their association of portal biliopathy, associated autoimmune conditions, histology, and diagnostic modalities needed. Diagnosis is established easily for EHPVO by Doppler ultrasonography; however, NCPF requires exclusion of cirrhosis and may necessitate a liver biopsy. Treatment options include variceal ligation and beta-blocker for secondary prophylaxis of bleeding. A major complication of EHPVO is portal biliopathy which needs endoscopic therapy if cholangitis occurs. Shunt surgeries remain important in the long term; however, their role for bleeding has reduced due to better endotherapy and availability of newer modalities like TIPSS. With advent of better therapy, the prognosis of these conditions has improved and most patients live a healthy life.

Introduction Non-Cirrhotic Portal Fibrosis Portal hypertension (PHT) is usually defined by araised NCPF is a disease without a specific known cause, because hepatic venous pressure gradient (HVPG) more than of which it is also termed as idiopathic PHT. Hallmark 5 mm Hg. HVPG is the difference in pressure between features include massive splenomegaly, often with portal vein (PV) and inferior vena cava. The most common hypersplenism with no liver cell failure.1 The disease is cause of PHT is cirrhosis in which case the HVPG is raised commoner in developing countries. The disease accounts due to sinusoidal resistance. However, there is another for 10–30% of cases of variceal bleed in several parts of the group of diseases with PHT, but a normal HVPG, which world including India.2 However, a recent review compiling are grouped under non-cirrhotic PHT (NCPH). Causes the studies from India showed a declining prevalence in of NCPH are primarily vascular and may be prehepatic, prospective studies.3 It is seen most commonly in the age hepatic, and posthepatic (Table 1). group of 30–40 and has a male preponderance. Non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are two common Etiopathogenesis causes of NCPH and will be discussed in detail while The accurate etiopathogenesis is unknown; infections others will be discussed briefly in the chapter. and prothrombotic states are the factors which have been

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TABLE 1 Important causes of non-cirrhotic portal hypertension

Prehepatic Hepatic Posthepatic EHPVO zz Presinusoidal—PBC, PSC, schistosomiasis, NCPF, zz Posthepatic Budd Chiari syndrome (IVC web, RA Splenic vein thrombosis congenital hepatic fibrosis thrombosis) Massive splenomegaly zz Sinusoidal—Alcoholic hepatitis, drug induced fibrosis zz Restrictive cardiomyopathy zz Postsinusoidal—Budd Chiari syndrome, sarcoidosis, zz Severe tricuspid regurgitation tuberculosis, veno-occlusive disease

EHPVO, extrahepatic portal vein obstruction; IVC, inferior vena cava; NCPF, non-cirrhotic portal fibrosis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; RA, right atrium.

incriminated most commonly. Although data is limited, may also occur due to inflammation in the local milieu or better obstetric hygiene and neonatal care are likely the paraneoplastic thrombosis. In spite of all evaluation, up to reason behind to bring down the incidence of NCPF. This 70% cases may remain idiopathic. has been shown in Western countries and supports the role of hygiene in pathogenesis of disease.1 India is more Etiopathogenesis predisposed as populations have lack of clean drinking Perinatal history is important as sepsis and manipulation water, inadequate sewage facilities, and continuous gut of the umbilical vein have been implicated as inciting inflammation due to antigenic exposure. Autopsy series factors.6 At the time of diagnosis, most of the times a from western countries showing high prevalence of PV cavernoma is seen as the initial thrombosis is often missed thrombosis lend support to the role of prothrombotic as it is asymptomatic and there is formation of collaterals factors. An imbalance of low ADAMTS13 and von within 1–2 weeks followed by cavernoma in another Willebrand factor levels could be linked to promotion week. These collaterals are able to compensate partially of PV radicals. This was first established from relation and overcome the prehepatic obstruction, but their between therapeutic arsenic exposure (Fowler’s solution) insufficiency leads to formation of varices. and NCPF in Europe. It has been shown to be associated with autoimmune diseases like inflammatory bowel disease (IBD) and celiac disease. Patients with HIV have Diagnosis shown a higher prevalence of NCPF.4 Possible contributory The typical scenario when one should suspect NCPF and factors could include opportunistic gastrointestinal (GI) EHPVO is presentation with GI bleed with relatively well infections, antiretroviral therapy or the effect of the viral preserved liver function tests. Ultrasound of the abdomen by itself. provides a further clue since massive splenomegaly is seen in both conditions, which is larger than cirrhosis. Doppler Extrahepatic Portal Venous Obstruction shows a thrombosed PV with surrounding collaterals EHPVO is a cause of PHT seen predominantly in children. (cavernoma) in case of EHPVO and normal flow in NCPF. The central pathophysiology involves a chronically blocked PV supplying blood via collaterals to a normally Clinical Features functional liver. EHPVO is the commonest cause of PHT EHPVO presents in the first decade with peaks at 3 and 8 (up to 80%) and uppergastrointestinal bleeding (up to years of age.7 NCPF on the other hand is seen more in young 60%) in children in developing nations.5 and middle aged adults median age of onset in Indian In children, specific prothrombotic states are identified series being 30–32 years.8 Patients often give a history of less commonly and methylene tetrahydrofolate reductase long standing dull aching pain in the left upper abdomen (MTHFR) deficiency is the commonest. Amongst adults due to massive splenomegaly; however, it requires medical and in western nations, primary myeloproliferative attention infrequently. Unlike cirrhosis, the episodes disorders (MPD) are common. Overall, prothrombotic of variceal bleed are often not life threatening and well states are found in one third to half the cases. Thrombosis tolerated. Being a childhood chronic disorder affecting the

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TABLE 2 Differences between NCPF and EHPVO

NCPF EHPVO Nature of precipitating event Mild, recurring Severe, progressive Affected age Childhood and adolescence Early childhood Associated autoimmune diseases Yes No Growth retardation Not seen Seen Portal biliopathy Not seen Seen Encephalopathy Usually absent Minimal HE usually occurs in natural history HVPG Normal or elevated Normal Investigation of choice for diagnosis Liver biopsy Ultrasound Doppler Hallmark on liver biopsy Obliterative portal venopathy Normal liver architecture unless secondary biliary cirrhosis occurs EHPVO, extrahepatic portal vein obstruction; HVPG, hepatic venous pressure gradient; NCPF, non-cirrhotic portal fibrosis.

liver blood supply, EHPVO is often complicated by anemia seen in both conditions and along with raised nitric oxide and growth retardation (Table 2). has been proposed to lead to autonomic dysfunction. Cell Incidences of variceal bleed are frequently precipitated mediated immunity may be hampered. by infections and recurrences tend to decrease after puberty. Hypersplenism is present in both the disorders. Findings on Esophagogastroduodenoscopy Although liver cell failure is rare, ascites may occur in up to Esophageal varices are seen in more than 80% of patients. one third of the patients. This usually occurs after a bleed Compared to cirrhotics, esophageal varices are larger and and is related to low serum albumin levels or in cases of gastroesophageal varices are commoner.10 Ectopic varices secondary biliary cirrhosis. The left upper abdomen pain in the rectum and colon may lead to lower GI bleed in may be exacerbated and acute at times of perisplenitis or EHPVO. splenic infarction. On clinical examination, liver span is normal or slightly Radiological Features reduced. Peripheral clinical stigmata of cirrhosis are At clinical suspicion, ultrasound of the abdomen with absent. Icterus may be seen in EHPVO in those with portal Doppler for splenoportal axis is the initial investigation biliopathy. of choice. In NCPF, liver is normal in size and spleen is enlarged with a dilated and patent splenoportal axis. Laboratory Parameters PV is thickened (>3 mm) and intrahepatic branches Hypersplenism with anemia is the commonest finding. show a withered tree appearance. The etiological Liver function tests are usually normal; however, albumin workup for cirrhosis is negative. NCPF may mimic early levels in serum may be reduced at the time of bleed stage cirrhosis very often and only HVPG can reliably further creating a diagnostic dilemma with cirrhosis. differentiate between them. The diagnosis of EHPVO in Elevated conjugated bilirubin and cholestatic pattern children is usually much simpler as the finding of a portal (raised alkaline phosphatase) may be a harbinger of portal cavernoma replacing the PV has a very high sensitivity and biliopathy in long standing cases.7 Prolonged prothrombin specificity. In adults, with cirrhosis, it becomes difficult time, reduced fibrinogen is seen in most patients. The as cirrhosis may also lead to bland PV thrombosis. There shunted blood flow leads to impaired production of is cavernomatous transformation of PV. CT and MR coagulation factors and lead to a low grade of disseminated venography have better sensitivity and also provide a intravascular coagulopathy.9 Hyperdynamic circulation is roadmap to surgery.11

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Pathology as poor synthetic function, jaundice, and decompensation EHPVO can be reliably diagnosed by USG; however, a in the form of ascites. liver biopsy may be needed to differentiate early cirrhosis and NCPF. The characteristic pathological findings for Treatment NCPF by phlebosclerosis, periportal, and perisinusoidal The event that can change the natural history of a patient fibrosis, aberrant vessels in portal tract, preserved lobular with NCPH is massive upper GI bleed. Control of the index architecture, and “obliterative portal venopathy.”12 In cases bleed and prevention of further bleed is the focus in most of EHPVO, the PV is replaced by cluster of varying sized cases. Another aspect of the treatment is symptomatic vessels more so around the hilum. Nodular arrangement splenomegaly and hypersplenism. Rest of the treatment and fibrosis, which are characteristic of cirrhosis are revolves around complications like MHE, portal biliopathy, absent. and growth failure.

Natural History Control and Prophylaxis of Variceal Bleed Variceal bleed is an important complication in NCPH. The natural course of NCPF is usually much more In view of limited data as compared to variceal bleed, predictable as compared to the complexity seen in EHPVO guidelines recommend the principles of management to sometimes. A likely reason for this is the early insult in remain same.16 The patient should be resuscitated with life, which leads to a long time available for the disease fluids and be taken up for endoscopy within 24 hours. to progress insidiously. It may lead to short stature, Endotherapy in the form of endovascular ligation is parenchymal destruction, poor quality of life, hepatic the mainstay of therapy in terms of intervention. Older encephalopathy, and portal biliopathy. studies used more of sclerotherapy. These techniques are Once GI bleed is controlled after variceal eradication, successful in more than 80% patients. Vasoactive agents long-term prognosis in NCPF is excellent. Liver cell failure should be started prior to endotherapy to reduce the and decompensation is usually absent but may occur severity of bleed and possibly control it. The goal should at times of GI bleed or in nodular NCPF.13 Uncontrolled be variceal eradication as role of beta blockers is not very upper GI bleeding from varices may lead to mortality. clear although they are widely used. Non-selective beta While the general outcome of EHPVO is good, certain blockers should be used for secondary prophylaxis. complications need to be monitored and treated carefully. Growth retardation occurs in up to half of the children. Transjugular Intrahepatic Portosystemic The postulated mechanism behind this is deprivation of hepatotropic factors and malabsorption due to portal Shunt (TIPS) hypertensive enteropathy.14 They also have a poor health- TIPS is an option for treatment for complicated NCPH, related quality of life. especially those with recurrent or refractory bleed. Portal biliopathy is defined as cholangiographic However, it is best avoided in cases of renal dysfunction, abnormalities, which occur in patients with portal malignancy, or prothrombotic conditions. cavernoma. This may be intrahepatic or extrahepatic. Long standing portal cavernoma in the biliary region causes Surgery compressive and ischemic changes on the biliary tree. The most common indication for surgical management Portal biliopathy usually remains asymptomatic may lead is recurrent bleed or bleed refractory to endotherapy. to jaundice, biliary colic, abdominal pain, and recurrent Other indications are symptomatic hypersplenism, cholangitis. Another dreaded complication is minimal hepatopulmonary syndrome, or portopulmonary hepatic encephalopathy (MHE). It is understandably hypertension.17 Surgery has now mainly been replaced by more after shunt surgery but it may occur even prior to TIPS. The types of surgeries performed are: 15 surgery. Usage of lactulose improves MHE. Prolonged „„ Shunt procedures: They bypass blood from the portal biliopathy leads to extinction of liver parenchyma portal system to systemic circulation removing gradually and may mimic cirrhosis later. It may manifest the carvernoma from the pathway. Shunts may be

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physiological or non-physiological depending on is characterized by hepatomegaly with features of PHT. whether they preserve the hepatic portal blood flow Diagnosis is based on detection of eggs in stool or rectal or not (maintained in physiological). As is expected, biopsy or ELISA test for antigen. On ultrasound, PV surgery reduces complications of PHT like varix radicles show echogenic thickening giving the appearance size and spleen size; however, adverse effects from of a mesh of fish scales. There may be complete reversal portosystemic shunting include risk of MHE and shunt of periportal thickening with use of antihelminthic like 18 nephropathy. Selective shunts like distal splenorenal praziquantel. shunt are associated with less complication than proximal, non-selective shunts. Shunt surgery is Congenital Hepatic Fibrosis undertaken only after a particular age (generally 8 years) and with a favorable anatomy (adequate Congenital hepatic fibrosis (CHF) is a developmental shuntable vein diameter).19 disorder of the portobiliary system characterized „„ Ablative procedures: These surgeries are very morbid histologically by defective remodeling of the ductal and include visceral devascularization with or without plate and progressive fibrosis of the portal tracts.22 It is splenectomy. It has gone out of vogue due to advances usually autosomal recessive in inheritance and presents in endotherapy and is reserved for emergency in the first or second decade of life. Autosomal recessive scenarios. polycystic kidney disease and ciliopathies are commonly associated disorders.23 Clinical findings include an Salvage Emergency Therapy enlarged, abnormally shaped liver and splenomegaly with preserved liver functions. Biliary complications In spite of newer endoscopic modalities, in 10% of the cases endotherapy fails. Options then include ablative include cholangitis and an increased predisposition to procedures, TIPS, or balloon occluded retrograde cholangiocarcinoma. Imaging reveals dilatation of biliary transvenous obliteration.16,17 system and enlarged caudate lobe and splenomegaly. Routine anticoagulation is not recommended in Since no specific therapies are available, treatment of EHPVO or NCPF according to the current available complications and eventually liver transplant may be data. The management for portal biliopathy is generally needed. supportive and not curative. Biliary stenting is done using ERCP for biliary strictures.20 Nodular Regenerative Hyperplasia Nodular regenerative hyperplasia (NRH) is a characte­ Miscellaneous Causes of NCPH rized by widespread benign transformation of hepatic Although infrequently seen in clinical practice, a few parenchyma into small regenerative nodules. It is important causes of NCPH that merit discussion have common in Europe and Japan with preponderance 24 been described here. amongst octogenarians. There is a limitation of population based studies on NRH. It can be caused by Schistosomiasis various drugs (commonly chemotherapeutic agents and Schistosomiasis is one of the most common causes of immunosuppressants), hematological, autoimmune, NCPH in the world but rarely seen in India. Schistosoma inflammatory, and neoplastic disorders. Pathogenesis mansoni and Schistosoma japonicum are the two main appears to be related to adaptive hyperplastic reaction species of Schistosoma that are known to cause liver of hepatocytes in response to mechanical or functional disease. S. japonicum is distributed throughout the abnormalities of portal hepatic blood flow. Pathologically, world and S. mansoni is endemic to Africa and Middle it is differentiated from cirrhosis by absence of perinuclear East. Both are however not found in India. The eggs are collagen and fibrous septa. Most patients remain stuck in the portal venules and lead to granulomatous asymptomatic, but some present with NCPH. Treatment inflammation. Over a period, fibrosis occurs and portal is aimed at removal of inciting factor and management of pressures increase.21 Chronic hepatic schistosomiasis primary disease.25

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Conclusion 12. Hillaire S, Bonte E, Denninger M-H, et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 NCPH are important causes of PHT in developing countries patients. Gut. 2002;51(2):275-80. like India. The most important disorders are NCPF in adults and 13. Sawada S, Sato Y, Aoyama H, et al. Pathological study of idiopathic EHPVO in children. The complications if managed well, patients portal hypertension with an emphasis on cause of death based can have a good prognosis and leave a healthy life. on records of annuals of pathological autopsy cases in Japan. J Gastroenterol Hepatol. 2007;22(2):204-9. 14. Sarin SK, Bansal A, Sasan S, et al. Portal-vein obstruction in children References leads to growth retardation. Hepatology. 1992;15(2):229-33. 15. Chandra R, Kapoor D, Tharakan A, et al. Portal biliopathy. J 1. Sarin SK, Kumar A. Noncirrhotic portal hypertension. Clin Liver Dis. Gastroenterol Hepatol. 2001;16(10):1086-92. 2006;10(3):627-51. 16. de Franchis R, Baveno VF. Revising consensus in portal hypertension: 2. Sarin SK, Kumar A, Chawla YK, et al. Non-cirrhotic portal fibrosis/ report of the Baveno V consensus workshop on methodology idiopathic portal hypertension: APASL recommendations for of diagnosis and therapy in portal hypertension. J Hepatol. diagnosis and treatment. Hepatol Int. 2007;1(3):398-413. 2010;53(4):762-8. 3. Goel A, Ramakrishna B, Zachariah U, et al. What makes non-cirrhotic 17. Sarin SK, Sollano JD, Chawla YK, et al. Consensus on extra-hepatic portal hypertension a common disease in India? Analysis for portal vein obstruction. Liver Int. 2006;26(5):512-9. environmental factors. Indian J Med Res. 2019;149(4):468-78. 18. Pal S, Radhakrishna P, Sahni P, et al. Prophylactic surgery in non- 4. Khanna R, Sarin SK. Non-cirrhotic portal hypertension—diagnosis cirrhotic portal fibrosis: is it worthwhile? Indian J Gastroenterol. and management. J Hepatol. 2014;60(2):421-41. 2005;24(6):239-42. 5. Poddar U, Thapa BR, Rao KN, et al. Etiological spectrum of 19. Mack CL, Zelko FA, Lokar J, et al. Surgically restoring portal blood esophageal varices due to portal hypertension in Indian children: flow to the liver in children with primary extrahepatic portal is it different from the West? J Gastroenterol Hepatol. 2008;23(9): vein thrombosis improves fluid neurocognitive ability. Pediatrics. 1354-7. 2006;117(3):405-12. 6. Yadav S, Dutta AK, Sarin SK, et al. Do umbilical vein catheterization 20. Dhiman RK, Puri P, Chawla Y, et al. Biliary changes in extrahepatic and sepsis lead to portal vein thrombosis? A prospective, clinical, and sonographic evaluation. J Pediatr Gastroenterol Nutr. portal venous obstruction: compression by collaterals or ischemic? 1993;17(4):392-6. Gastrointest Endosc. 1999;50(5):646-52. 7. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin 21. Ross AGP, Bartley PB, Sleigh AC, et al. Schistosomiasis. N Engl J Med. Liver Dis. 2002;22(1):43-58. 2002;346(16):1212-20. 8. Madhu K, Avinash B, Ramakrishna B, et al. Idiopathic non-cirrhotic 22. Shorbagi A, Bayraktar Y. Experience of a single center with intrahepatic portal hypertension: common cause of cryptogenic congenital hepatic fibrosis: a review of the literature. World J intrahepatic portal hypertension in a Southern Indian tertiary Gastroenterol. 2010;16(6):683-90. hospital. Indian J Gastroenterol. 2009;28(3):83-7. 23. Srinath A, Shneider BL. Congenital hepatic fibrosis and autosomal 9. Bajaj JS, Bhattacharjee J, Sarin S-K, et al. Coagulation profile recessive polycystic kidney disease. J Pediatr Gastroenterol Nutr. and platelet function in patients with extrahepatic portal vein 2012;54(5):580-7. obstruction and non-cirrhotic portal fibrosis. J Gastroenterol 24. Wanless IR. Micronodular transformation (nodular regenerative Hepatol. 2001;16(6):641-6. hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies 10. Sarin SK, Shahi HM, Jain M, et al. The natural history of portal and a new classification of benign hepatocellular nodules. hypertensive gastropathy: influence of variceal eradication. Am J Hepatology. 1990;11(5):787-97. Gastroenterol. 2000;95(10):2888-93. 25. Hartleb M, Gutkowski K, Milkiewicz P, et al. Nodular regenerative 11. Glatard A-S, Hillaire S, d’Assignies G, et al. Obliterative portal hyperplasia: evolving concepts on underdiagnosed cause of portal venopathy: findings at CT imaging. Radiology. 2012;263(3):741-50. hypertension. World J Gastroenterol. 2011;17(11):1400-9.

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138 Drug-induced Liver Injury

Harshad Devarbhavi

Abstract Drug-induced liver injury is an under-diagnosed cause of liver disease. It mimics all forms of liver disease. The three patterns of DILI are hepatocellular, cholestatic, and mixed. Presence of hepatocellular jaundice in DILI is associated with a mortality of >10%; this is also known as “Hy’s law”. Combination anti-TB drugs, i.e., isoniazid, rifampicin, and pyrazinamide are the most common cause of DILI and drug-induced acute liver failure (ALF) in India followed by traditional and complementary medicines. Prompt recognition and cessation of the “culprit” drug is the key to managing patients with DILI followed by supportive therapy. Few antidotes include N-acetyl cysteine for paracetamol toxicity and drug-induced ALF, cholestyramine for leflunomide DILI, and steroids for drugs associated with hypersensitivity features or drugs causing autoimmune like hepatitis.

Introduction most patients experience DILI within the first 2–3 months of therapy, in some instances (e.g. amoxicillin-clavulanate Drug-induced liver injury (DILI) is underdiagnosed related DILI) symptoms can present with up to a month and underappreciated as a cause or contributor to liver delay after treatment cessation or arise after months of injury. Drugs and toxins should be considered in the exposure to a drug such as nitrofurantoin, minocycline, differential diagnosis of all types of liver injury across all and alpha methyldopa.1 ages, although the risks are higher in older individuals and in women. It is not clear why older individuals or women have an increased risk; this may be due to increased Causality Assessment intrinsic risk or because older people take more drugs and Since DILI is a diagnosis of exclusion there are no therefore have more opportunities to experience adverse established diagnostic markers. Causality assessment drug reactions (ADRs). This review will focus on recent methods are used to determine likelihood of a drug concepts on DILI with particular emphasis on DILI from causing liver injury and the best known is the Roussel India. Uclaf causality assessment method (RUCAM).2 DILI is a diagnosis of exclusion. A high degree of Information on time to onset (latency), course of suspicion and consequently a careful history of reaction upon medication discontinuation, time to prescription medication and over the counter drugs resolution, risk factors, concomitant drugs exclusion of (pain killers) exposure as well as exposure to herbal and other causes, prior knowledge on DILI potential, and traditional medicines or dietary supplements (often response to readministration are variables required to overlooked by the physician) should be obtained. While establish a compatible relationship with the suspected

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causative agent. The degree of causality is assessed including any of the following: fever, nausea, vomiting, as definite (highly probable), probable, possible, and jaundice, dark urine, right upper quadrant pain, skin unlikely in descending order of strength.2 rashes, and itching.1 The level of elevation of liver enzymes alone does not Case Definitions and Severity reflect liver function severity. Liver enzyme elevation is a reflection of liver injury not function, whereas bilirubin Transient asymptomatic minor elevation of aspartate elevation (liver excretory function), or increased INR or transaminase (AST) or alanine transaminase (ALT) decreased albumin (liver synthetic function) are more is common during routine evaluation. In one study accurate indices of liver function.6 The presence of incidence of baseline liver chemistry abnormalities in a jaundice, or development of ascites, coagulopathy, and/ population of over 18,000 patients (without underlying or encephalopathy indicates severe disease1 and connotes liver disease), the baseline prevalence of any ALT elevation poor prognosis.7 above the upper limit of normal (ULN) was 6% while the overall prevalence of ALT values of more than 3 × ULN was 0.076% (<1 in 1,000).3 Hy’s Law Transient elevation of AST or ALT may occur following Hyman Zimmerman observed the presence jaundice exposure to medication and may resolve on its own or in the setting of DILI suggested severe hepatocellular with continuation of drugs or following decrease in dose. functional impairment with potential for liver failure and This phenomenon (called adaptation) is characteristic 10–50% mortality.6,8 Thus, “Hy’s law” is used clinically of antituberculosis (anti-TB) drug or statin therapy and during drug evaluation to indicate highly significant and depends on the frequency of liver biochemistry and severe hepatotoxic potential of a drug when patients estimation. Awareness of this condition will prevent fulfill the following criteria, that is, AST or ALT more than inappropriate withdrawal of medications such as in 3 × ULN + bilirubin >2 × ULN (in absence of biliary tract the treatment of tuberculosis where even a temporary disease).8 Presence of jaundice during anti-TB therapy cessation of treatment may have adverse disease outcome results in a mortality of 16–26% in India.7,9 Patients with 4 including risk of drug resistance. Transient elevation of anti-TB DILI who fulfill Hy’s law criteria have a mortality transaminases in patients with elevated liver enzymes of 17%. Furthermore, development of acute liver failure while on statin therapy (e.g. in patients with coronary during treatment of anti-TB drugs results in a mortality in 5 heart disease or diabetes) is not an indication to stop two-thirds of patients.10 Paradoxically in the Indian setting therapy. a substantial proportion of individuals who develop anti- DILI is defined as an adverse hepatic reaction that is TB DILI, never required the drugs in the first place, having unexpected on the basis of the pharmacological action received anti-TB drugs empirically on a presumptive 1 of the drug administered. International expert panel basis.10,11 Therefore, great caution should be exercised recommended DILI to be considered when any one of while administering anti-TB drugs empirically, especially the following thresholds are met even in the absence of in women, the elderly, and those with comorbidities.12 symptoms: „„ ALT or AST ≥ 5 × ULN „„ ALP ≥ 2 × ULN in the absence of extrahepatic source Patterns of Liver Injury driving the rise in ALP level Most patients with DILI in clinical practice are „„ Total bilirubin concentration exceeding 2 × ULN characterized based on their liver biochemistry, these associated with any elevation of the aminotransferases are categorized as hepatocellular, cholestatic, or mixed or alkaline phosphatase.1 pattern of DILI.1 Pattern of liver disease is based on In the presence of symptoms including extrahepatic Ratio (R value) of ALT (or AST) activity expressed as fold symptoms of hypersensitivity such as skin rashes or elevation over its ULN laboratory range to ALP activity. eosinophilia, ALT or AST ≥ 3 × ULN is deemed to be DILI. Pattern of DILI is hepatocellular when R is ≥5, cholestatic The symptoms related to DILI are often similar to that when R is ≤2 and mixed when R is 2–5.1 The pattern of of acute liver injury or cholestasis due to other etiology liver injury has implications for prioritizing immediate

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investigations essential to exclude alternative causes of the paracetamol hepatotoxicity in western countries. In a event as well as prognosticate outcome. prospective India nationwide study,9 drugs causing DILI in Examples of drugs associated with above patterns and the descending order of frequency were as follows: 13 other additional patterns are listed below: „„ Combination anti-TB drugs (46.4%) „„ Hepatocellular: Isoniazid, rifampicin, pyrazinamide, „„ Complementary and alternative medicines (13.9%) diclofenac, lamotrigine, minocycline, nitrofurantoin, „„ Antiepileptic drugs (AED) (8.1%) nevirapine, efavirenz, sulfonamides, disulfiram. „„ Non-anti-TB antimicrobials (6.5%) „„ Cholestatic: Chlorpromazine, erythromycin, peni­ „„ Antimetabolites (3.8%) cillins, amoxicillin-clavulanate, sulfonamide, terbina­ „„ Antiretroviral drugs (3.5%) fine, androgens, oral contraceptives. „„ NSAIDs (2.6%) „„ Mixed pattern: Phenytoin, carbamazepine, lamotrigine, „„ Hormones (2.5%) sulfonamides. „„ Statins (1.4%) „„ Drug reaction with eosinophilia and systemic symptoms „„ Others (11.3%) (DRESS): Carbamazepine, phenytoin, phenobarbitone, Although patients with pre-existing liver disease are allopurinol, lamotrigine, cephalosporins, dapsone, not more likely than others to experience hepatic injury sulfonamide, nevirapine. on exposure to drug, recovery from DILI in patients with „„ Autoimmune like hepatitis: Nitrofurantoin, α-methyl- chronic liver disease is generally poor.20 Complementary dopa, minocycline, diclofenac, statins, adalimumab, and alternative medicines (73%) and anti-TB drugs (22%) infliximab, herbals and complimentary medicines. are responsible for 99% of cases of drug-induced acute „„ Nonalcoholic fatty liver disease (NAFLD): Amiodarone, on chronic liver failure (ACLF) in India and Asia and is methotrexate, tamoxifen, 5-fluorouracil, amiodarone, associated with 46% mortality, much more than other didanosine, stavudine. causes of ACLF.21 „„ Vanishing bile duct (ductopenic) syndrome: Azathioprine, amoxicillin-clavulanate, carbamazepine, chlorpromazine, erythromycin, phenytoin, terbinafine Mechanism of Liver Injury and cotrimoxazole. Simplistically, the mechanism of DILI may be divided into two broad groups, that is, direct hepatotoxicity as Causes exemplified by paracetamol overdose or idiosyncratic injury wherein the characteristics of the individual Antibiotics are the most common cause of idiosyncratic patient/subject plays a major role in causing DILI.20 In DILI and drug-induced acute liver failure worldwide and idiosyncratic reaction, the dose of a drug does not play 7,9,13-16 also in India. In India, first-line combination anti- a role although most DILIs are encountered following TB drugs, isoniazid, rifampicin, and pyrazinamide are exposure to drugs used in daily dose of 50 gm or higher.22 the commonest agents causing DILI accounting for 46% Table 1 summarizes the characteristics of mechanism of of all cases followed by complementary and alternative injury. A recently described third category is the indirect 9 medicines at 14%. Combination anti-TB drugs accounts hepatotoxicity, wherein hepatotoxicity is secondary to for 67–72% of cases of drug-induced acute liver failure the indirect action of agent on liver or immune system followed by anti-epileptic drugs (10%), and dapsone (Table 1).23 (5.5%) in a single center series.9,17,18 DILI from anti-TB drugs appears disproportionately more severe than other drugs causing liver injury.7 Almost three-fourths of anti- Management TB DILI occur within the first 2 months of administration The first consideration in the management of DILI is to of drugs although the risk of DILI persists throughout harbor a high index of suspicion regarding the role of the course of treatment.19 Paradoxically paracetamol- medications in causing liver injury. The drugs implicated induced DILI and liver failure is very uncommon in India should be stopped immediately and alternate causes and accounts for less than 1% of DILI or drug-induced including viral hepatitis especially hepatitis E (which AL F. 9,18 This is in stark contrast to the high incidence of is common in Northern India)24 and biliary causes

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TABLE 1 Mechanism of drug-induced liver injury and associated features

Basis for injury Dose Incidence in Latent period Implicated agents dependence humans

Direct (intrinsic) Yes Common Often short Paracetamol, ferrous sulfate, i.v. amiodarone, hepatotoxicity (1–100%) IV methotrexate, aspirin, cancer chemotherapy

Idiosyncratic No Rare Often long INH, rifampicin, pyrazinamide amox-clavulinate, (unpredictable reaction) (1:10000) and variable sulfonamides, cephalosporins

Indirect hepatotoxicity No Intermediate Delayed Steroids, anti-TNF, Anti-CD20, checkpoint inhibitors, (months) protein kinase inhibitors

(by ultrasonography) should be excluded. Most References episodes of DILI resolve with discontinuance of the . 1 Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and culprit drug and with supportive treatment. There are phenotype standardization in drug-induced liver injury. Clin very few antidotes for specific drugs producing DILI. Pharmacol Ther. 2011;89(6):806-15. These include N-acetylcysteine for paracetamol toxicity,25 . 2 Danan G, Benichou C. Causality assessment of adverse reactions desferrioxamine for ferrous sulfate toxicity, L-carnitine to drugs—I. A novel method based on the conclusions of for valproate DILI, and cholestyramine for leflunomide international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323-30. DILI. Patients who develop hypersensitivity skin rashes . 3 Weil JG, Bains C, Linke A, et al. Background incidence of liver and eosinophilia or DRESS should be considered for chemistry abnormalities in a clinical trial population without steroid treatment, which should be continued for 4–8 underlying liver disease. Regul Toxicol Pharmacol. 2008;52(2):85-8. weeks, although steroids have not been evaluated in a 4. Devarbhavi H. Adaptation and antituberculosis drug-induced liver randomized fashion.26 injury. Am J Respir Crit Care Med. 2012;186(4):387-8. . 5 Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated Reintroduction of anti-TB drugs after an episode liver enzymes are not at higher risk for statin hepatotoxicity. of anti-TB DILI needs special mention. The American Gastroenterology. 2004;126(5):1287-92. Thoracic Society guidelines are the most up to date and . 6 Senior JR. Alanine aminotransferase: a clinical and regulatory tool elaborate.27,28 Ethambutol has no hepatotoxic potential and for detecting liver injury-past, present, and future. Clin Pharmacol needs to be continued during and after DILI. Rifampicin is Ther. 2012;92(3):332-9. . 7 Devarbhavi H, Dierkhising R, Kremers WK, et al. Single-center the least hepatotoxic drug and needs to be considered experience with drug-induced liver injury from India: causes, first followed by isoniazid and pyrazinamide. These drugs outcome, prognosis, and predictors of mortality. Am J Gastroenterol. may be administered sequentially with staggered doses. In 2010;105(11):2396-404. case of a severe DILI at index presentation, pyrazinamide 8. Senior JR. How can ‘Hy’s law’ help the clinician? Pharmacoepidemiol should be omitted during rechallenge.27 Drug Saf. 2006;15(4):235-9. . 9 Devarbhavi H, Joseph T, Kumar NS, et al. The Indian network of drug-induced liver injury: etiology, clinical features, outcome and Conclusion prognostic markers in 1288 patients. J Clin Exp Hepatol. 2021. DOI 10.1016/j.jceh.2020.11.002. Anti-tuberculosis drugs are the most common cause of DILI 10. Devarbhavi H, Dierkhising R, Kremers WK. Antituberculosis therapy and drug-induced acute liver failure in India. DILI is a diagnosis drug-induced liver injury and acute liver failure. Hepatology. of exclusion. Awareness of the fact that drugs can mimic all 2010;52(2):798-9. forms of liver disease is crucial in diagnosing DILI. Occurrence 11. Kumar R, Bhatia V, Khanal S, et al. Antituberculosis therapy-induced of hepatocellular jaundice entails a mortality of >10%, and acute liver failure: magnitude, profile, prognosis, and predictors of hence the implicated drug should be stopped immediately. outcome. Hepatology. 2010;51(5):1665-74. There is emerging evidence of the increasing role of traditional 12. Devarbhavi H. Gender enigma: increased occurence of anti- and complimentary medicines in causing DILI all over the world tuberculosis drug-induced liver injury and acute liver failure including India. in women despite tuberculosis being more common in men. Hepatology. 2017;66:6A.

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13. Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver 21. Devarbhavi H, Choudhury AK, Sharma MK, et al. Drug-induced injury. Nat Rev Dis Primers. 2019;5(1):58. acute-on-chronic liver failure in Asian patients. Am J Gastroenterol. 14. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and 2019;114(9):929-37. outcomes of 899 patients with drug-induced liver injury: the DILIN 22. Lammert C, Einarsson S, Saha C, et al. Relationship between daily prospective study. Gastroenterology. 2015;148(7):1340-52. dose of oral medications and idiosyncratic drug-induced liver 15. Rathi C, Pipaliya N, Patel R, et al. Drug induced liver injury at a injury: search for signals. Hepatology. 2008;47(6):2003-9. tertiary hospital in India: etiology, clinical features and predictors of 23. Hoofnagle JH, Bjornsson ES. Drug-induced liver injury—types and mortality. Ann Hepatol. 2017;16(3):442-50. phenotypes. N Engl J Med. 2019;381(3):264-73. 16. Devarbhavi H. Acute liver failure induced by anti-infectious 24. Sarda P, Sharma SK, Mohan A, et al. Role of acute viral hepatitis drugs: causes and management. Current Hepatology Reports. as a confounding factor in antituberculosis treatment induced 2017;16:276-85. hepatotoxicity. Indian J Med Res. 2009;129(1):64-7. 17. Devarbhavi H, Patil M, Reddy VV, et al. Drug-induced acute liver 25. Tujios SR, Lee WM. Acute liver failure induced by idiosyncratic failure in children and adults: results of a single-centre study of 128 reaction to drugs: challenges in diagnosis and therapy. Liver Int. patients. Liver Int. 2018;38(7):1322-9. 2018;38(1):6-14. 18. Devarbhavi H, Joseph T, Kumar NS, et al. Causes, clinical features, 26. Devarbhavi H, Raj S. Drug-induced liver injury with skin reactions: and outcome of patients with drug-induced acute liver failure drugs and host risk factors, clinical phenotypes and prognosis. Liver from a nationwide prospective study of drug-induced liver injury. Int. 2018;4:14004. Hepatology. 2019;70(s1):513-4. 27. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: 19. Devarbhavi H, Singh R, Patil M, et al. Outcome and determinants of hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care mortality in 269 patients with combination anti-tuberculosis drug- Med. 2006;174(8):935-52. induced liver injury. J Gastroenterol Hepatol. 2013;28(1):161-7. 28. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic 20. Zimmerman HJ. Hepatotoxicity: the Adverse Effects of Drugs and Society/Centers for Disease Control and Prevention/Infectious Other Chemicals on the Liver, 2nd edition. Philadelphia: Lippincott; Diseases Society of America Clinical Practice Guidelines: Treatment 1999. of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):147-95.

MU-138.indd 896 29-01-2021 14:57:44 CHAPTER

Achalasia Cardia—Diagnosis 139 and Endoscopic Treatment

Mohan Ramchandani, Partha Pal

Abstract Achalasia cardia is a primary esophageal motility disorder due to autoimmune neurodegeneration of esophageal myenteric plexus resulting in impaired relaxation of lower esophageal sphincter (LES) on swallowing and failure of peristalsis in distal smooth muscle segment of the esophagus. High resolution manometry (HRM) has greatly improved the sensitivity of diagnosing achalasia in the early stages of disease when endoscopy and barium esophagogram can be normal or equivocal. Manometrically achalasia cardia can be divided into three subtypes, which help in deciding treatment, and hence have prognostic significance. The primary distinction from other motility disorders (e.g., Jackhammer esophagus and distal esophageal spasm) is failure of LES relaxation in achalasia. So, most of the therapies are directed toward reduction in LES pressures. Treatment modalities in AC acts by causing either mechanical disruption of LES by per oral endoscopic myotomy (POEM), laparoscopic Heller’s myotomy (LHM) and pneumatic dilatation (PD) or biochemical reduction in LES pressure (pharmacological therapy, e.g., nitrates and botulinum toxin). There is renewed interest in this motility disorder in the past few years as with the advent of third space endoscopy (i.e., POEM), the endoscopic management of achalasia has been revolutionized.

Introduction LES. Mainstay of management of AC is by pneumatic Achalasia cardia (AC) is rare yet most common and best dilatation (PD), per oral endoscopic myotomy (POEM) characterized esophageal motility disorder.1 It is equally and laparoscopic Heller’s myotomy (LHM) in surgical fit common in both sexes and most frequently observed candidates. Biochemical reduction of LES by botulinum in 40–60 years age.2 AC is characterized by progressive toxin (BT)/pharmacotherapy (nitrates, calcium channel degeneration of ganglion cells in the esophageal myenteric blockers) are reserved for surgical unfit patients or patients plexus resulting in impaired relaxation of lower esophageal with limited life expectancy due to short lasting efficacy. sphincter (LES) on swallowing and failure of peristalsis Esophagectomy is reserved for surgically fit patients with in distal smooth muscle segment of the esophagus.1 long standing symptoms who failed multiple therapies 2,5 Presenting symptoms are dysphagia to both liquids and repeatedly. In this chapter we shall focus on diagnosis solids, regurgitation of undigested food, retrosternal and endoscopic treatment (BT, POEM, and PD) of AC. chest pain, heartburn, weight loss, and symptoms due to aspiration pneumonia.3 Upper GI endoscopy and timed Diagnosis barium esophagogram are the initial investigations and high resolution manometry (HRM) is diagnostic.4 Therapy History and Clinical Examination in AC is directed toward reduction in LES pressures either Dysphagia to both solids and liquids (85–91%), regurgitation by biochemical reduction or mechanical disruption of of undigested food (75–91%), substernal chest pain and

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TABLE 1 Clinical features favoring esophageal motility disorder over mechanical dysphagia

Esophageal motility disorder Mechanical dysphagia Duration Long standing Short in malignant Course Intermittent Progressively increasing Relation with food and posture Relation with type of food Both liquids and solids from the onset Soilds then liquids later on Relation with posture Decreased with raising arms and erect position No such Relation with temperature of food More in extreme temperatures (hot and cold) None Associated symptoms Regurgitation Common Unusual Chest pain Episodic pain highly suggestive Usually painless Weight loss No or minimal Profound

TABLE 2 Eckardt score

Score Dysphagia Regurgitation Retrosternal pain Weight loss (kg) 0 None None None None 1 Occasional Occasional Occasional <5 2 Daily Daily Daily 5-10 3 Each meal Each meal Each meal >10

heartburn (40–60%), weight loss and aspiration pneumonia a rare but noteworthy symptom in achalasia.8 Eckardt (8–10%) are the various symptoms of achalasia.3,6,7 score is a system for evaluation of achalasia symptoms Appropriate history taking help to differentiate esophageal and treatment efficacy which is based on degree of motility disorders from mechanical dysphagia (Table 1). dysphagia, regurgitation, chest pain, and weight loss Liquids require better neuromuscular coordination than (Table 2).9 Clinical examination is usually unremarkable solids for esophageal emptying so dysphagia to both solids except emaciation and oral cavity ulcerations in some and liquids are present from the onset. Compression of patients. Examination of the respiratory system may show the esophagus between spine and manubrium sterni diminished breath sounds, dull note on percussion, and in specific postures like raising arms in erect position crepitations over area of consolidation due to aspiration increase the intraesophageal pressure and propel food in pneumonia.6 aperistaltic esophagus. Achalasia is often misdiagnosed as gastroesophageal Diagnostic Tools reflux disease (GERD) as retrosternal chest pain and Primary Diagnostic Tools heartburn are common. Reflux or lactate production by fermentation of undigested carbohydrates lead to Upper GI endoscopy and timed barium esophagogram are heartburn. Chest pain is least responsive to treatment the initial investigations in any case of dysphagia. Once, compared to other symptoms but can spontaneously mechanical obstruction is ruled out on endoscopy/barium 10 disappear over time.7 Weight loss is not as profound as in swallow, HRM is diagnostic and helps subclassification. mechanical dysphagia. Aspiration pneumonia can occur due to regurgitation into bronchopulmonary tree can lead Upper GI Endoscopy to cough and fever. Impaired belching due to compression Normal upper GI endoscopy rules out mechanical causes of membranous trachea by dilated esophagus and of dysphagia. Upper GI endoscopy in AC shows dilated inadequate relaxation of upper esophageal sphincter is and often tortuous esophagus with food/liquid residue.

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The contracted LES in AC does not open spontaneously contractions and bird-beak appearance (Figs. 1A and B). and is usually traversed with a gentle pressure with the It is done in both pre- and post-treatment states in AC to endoscope unlike neoplastic/fibrotic strictures.6 The evaluate response to therapy. Hugely dilated esophagus or esophageal mucosa is usually normal in AC but can megaesophagus (>7 cm) can be seen in late/long standing develop erythema and ulceration due to food stasis (stasis cases of AC. Dilated, tortuous esophagus in late stage AC esophagitis). Stasis predisposes to esophageal candidiasis. is termed as sigmoid esophagus. Both mega-esophagus Tertiary contractions may be noticed during endoscopy and sigmoid esophagus denote decompensated disease, due to spontaneous, simultaneous contractions of which implies poor response to therapy. Esophageal esophageal smooth muscles. An esophageal epiphrenic epiphanic diverticulum (EED) can rarely be found in diverticulum (EED) (pulsion type pseudodiverticulum) association with AC.12 can be associated with AC, which makes endoscopic 11 Other imaging: Chest X-ray may be required in AC therapy challenging but yet feasible. to evaluate for aspiration pneumonia. Computed Laboratory Work Up tomography (CT) of chest could be helpful to rule out pseudoachalasia. Endoscopic ultrasound (EUS) findings Complete blood count, serum creatinine, serum electro­ of marked (>10 mm)/asymmetric lower esophageal wall lytes, liver function tests, and thyroid profile can be done thickening suggest underlying malignancy.13 as a part of work up for endoscopic/surgical myotomy, which requires general anesthesia. High resolution manometry (HRM) (Table 3): HRM is superior to conventional esophageal manometry for Imaging diagnosis and classification of AC with higher sensitivity Timed barium esophagogram: Timed barium and reproducibility. AC can be classified into three subtypes esophagogram is the imaging of choice in AC. 100–250 according to Chicago classification 3.0 (Table 3) (Fig. 2A).4 mL of barium (45% weight/volume) is swallowed by Type I AC represents later stage disease leading to dilated the patient over 15–20 seconds and X-ray done at 1, 2, atonic esophagus due to minimal esophageal muscle and 5 minutes.12 The height and width of the barium activity. Type II AC is characterized by panesophageal column in esophagus is measured at 1, 2, and 5 minutes pressurization indicating simultaneous contraction which denotes the esophageal emptying. In AC, there is of esophageal muscles between upper and LES due delayed emptying of barium from the esophagus, tertiary to disorganized neuromuscular activity of esophagus

A B Figs. 1A and B: Timed barium esophagogram (TBE) in achalasia cardia. (A) Preprocedure TBE after 1 minute showing tertiary contractions and dilated esophagus and no esophageal emptying. (B) Preprocedure TBE after 2 minutes showing dilated esophagus with minimal esophageal emptying

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(Fig. 2B). Panesophageal pressurization indicates that contraction of the distal esophagus (Fig. 2C). Type III AC esophageal smooth muscle tone is still intact, and hence is least common and least responsive to both endoscopic type II AC represents early stage of disease. Type II AC is and surgical therapy.2 the most common subtype of AC and most responsive to PD. Type III AC is characterized by premature, spastic Differential Diagnosis (Table 4) The differential diagnoses of AC are GERD, pseudo­ achalasia, esophageal motility disorders, and mechanical High resolution manometry diagnostic criteria of TABLE 3 dysphagia. achalasia cardia27 Integrated relaxation pressure (IRP) > upper limit of normal with Management 100% failed peristalsis The goal of management of AC is symptomatic relief zz Type I: No contractility, no esophageal pressurization, IRP >10 mm Hg of dysphagia and associated complications. Treatment zz Type II : Panesophageal pressurization in ≥20% swallows, directed at underlying pathology is not available as IRP> 15 mm Hg pathophysiology is poorly understood. Treatment of AC is zz Type III: Premature contractions (distal latency <4.5 s) in ≥20% directed by AC subtypes and surgical risk of the patient.2 swallows, Segmental esophageal pressurization, IRP>15 mm Hg Mechanical disruptions of LES by PD, LHM, or POEM

A B

Figs. 2A to C: (A) High resolution manometry picture of Type I achalasia showing absent esophageal body contractility and integrated relaxation pressure of 17 mm Hg (more than upper limit of normal). (B) High resolution manometry picture of Type II achalasia showing panesophageal pressurisation and high integrated relaxation pressure (>15 mm Hg). (C) High resolution manometry picture of Type III achalasia showing premature contractions (distal latency <4.5 sec), segmental distal esophageal C pressurization and high integrated relaxation pressure (>15 mm Hg)

MU-139.indd 900 29-01-2021 14:57:19 Achalasia Cardia—Diagnosis and Endoscopic Treatment CHAPTER 139 901

TABLE 4 Differential diagnosis of achalasia cardia

Suspected diagnosis Clinical clues Diagnostic testing GERD Normal clinical zz History of reflux, regurgitation and heartburn examination zz Endoscopic findings of esophagitis, Lax LES, or hiatus hernia zz 24 Hour pH monitoring Pseudoachalasia Hepatomegaly (may zz Symptoms of dysphagia suggest liver metastasis) zz Endoscopic finding of mechanical resistance at GE junction and may show GE and supraclavicular lymph junction tumor nodes zz EUS may show asymmetric, thickening of GEJ (>10 mm) zz CT chest may show extrinsic compression by tumor or lung malignancy Other motility disorders Hot and cold food zz On high resolution manometry (Distal esophageal spasm, sensitivity and zz Normal IRP Jackhammer esophagus) disproportionate chest zz Distal esophageal spasm (DES) (>20% premature contractions: distal latency pain relative to dysphagia <4.5 sec) could be a diagnostic clue zz Jackhammer esophagus (>20% swallows with distal contractile integral -DCI >8000 mm Hg.s.cm) Mechanical dysphagia Duration and course zz Endoscopy usually shows mechanical obstruction (malignancy, web, strictures, of dysphagia, relation etc.) to food/posture and zz Biopsy can be taken if any growth is noted in endoscopy associated symptoms can zz Barium swallow findings show asymmetric, long segment strictures with differentiate (See Table 1) shouldering *Chicago Classification v.3.027

are the mainstays of AC treatment. However, in patients safe.16 Repeat injections can be done for patients in whom with high surgical risk and/or limited life expectancy, surgical risk remains high even on follow-up but it can biochemical reduction of LES pressure can be attempted lead to fibrosis precluding continued BT injections/other (botulinum toxin ± pharmacotherapy). In this review we endoscopic therapy. Hence, repeated BT injections should shall discuss endoscopic treatment of AC (botulinum be used in patients with high surgical risk and poor life toxin, PD, and POEM). expectancy.17

Botulinum Toxin Pneumatic Dilatation BT blocks release of acetylcholine (ACh) from the PD is a recommended initial treatment for AC.2 PD is done presynaptic cholinergic nerve terminals. Selective loss of with Rigiflex balloon dilator (Microvasive, Milliford, MA, inhibitory nitrinergic (NO producing) ganglion cells with USA) available in three sizes (outer diameter: 30 mm, 35 partial preservation of cholinergic neurons is responsible mm, and 40 mm). Initially 30 mm balloon is used followed for such therapeutic benefit.14 Hundred units of vacuum by progressively larger size balloon (graded approach) dried BT powder is dissolved in sterile saline solution (4 except in case of young male in whom 35 mm can be used mL) and 1 mL (25 U) each is then injected into all four initially due to poor response rate with 30 mm.18,19 Graded quadrants via sclerotherapy needle under endoscopic dilatation is performed for index dilatation. Repeated guidance at 1 cm above the Z line (squamocolumnar dilatation on follow-up when required for recurrent junction). Doses >100 U do not have increased efficacy. symptoms is known as “on demand approach.” Patient BT decreases LES pressure in one third of patients and is kept on overnight fast. Conventionally the procedure improves dysphagia in two-thirds of patients of AC for is done under fluoroscopic guidance with conscious up to 6 months. Up to 50% patients require reinjection by sedation although a novel technique without fluoroscopy 612 months.15 The short lasting effect is due to growth of under endoscopic guidance has been described.20 Initially new cholinergic neurons leading to loss of efficacy. Side a guide wire (preferably 0.038 inch diameter) is passed effects like esophageal perforation, mediastinitis, and into the stomach under endoscopic guidance and scope is heartburn/chest pain can occur post BT, but BT is usually withdrawn to the GE junction (GEJ). The length between

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the incisors and GEJ is noted along length of endoscope. not be subjected to PD.21 Age less than 40 years, chest pain, Endoscope is then withdrawn maintaining position of the type III achalasia, and pretreatment esophageal diameter catheter. Rigiflex balloon is passed over the guide wire into less than 4 cm are poor predictors of treatment success the stomach marking a tape in the dilating ballon catheter with PD. Response rate for chest pain is around 50%.22 corresponding to distance from incisors to GEJ (balloon Based on available evidence (meta-analysis of three RCTs catheter working length 90 cm and diameter is 14 Fr). and one large RCT), clinical efficacy of PD is comparable Alternatively small amount of radiographic contrast can with LHM although long-term durability (especially in be injected at the GEJ prior to placing catheter to mark young males) was higher in LHM compared to PD as higher the GEJ. Balloon (length 10 cm) is then placed across the proportion (24%) of patients had recurrent symptoms after GEJ under fluoroscopic guidance (by help of radiopaque PD requiring redilatation compared to LHM (14%).23,24 PD marks in the balloon catheter). Small volume of dilute was compared with POEM in a recent RCT which showed contrast can be used for radiographic visualization of significantly higher success rate at 2 years follow-up with balloon. As the placement of balloon waist is confirmed POEM compared to PD (92% vs. 54%). This low response across GEJ, the balloon is gradually inflated with air to 10– rate in PD could be due to dilatation with only 30–35 mm 15 psi until the balloon waist disappears and maintained balloon and inclusion of 40 mm balloon would increase 25 for 1 minute (Fig. 3). Adequacy of dilatation confirmed by response rate to 76% (Table 5). waist obliteration, blood smearing of the balloon, chest pain, and mucosal tear/widening of GEJ. Adverse events Per Oral Endoscopic Myotomy are esophageal perforation (3–5%), hematoma formation, POEM is a form of natural orifice transluminal endoscopic 21 diverticula formation. Incidence of GERD post PD is surgery (NOTES), which uses submucosal endoscopy to

around 2–4%. Tachycardia, persistent chest pain more perform myotomy and is efficacious for both treatment than 4 hours should alert the endoscopist for possible naive and treatment failure cases. The procedure is done perforation. Contrast esophagogram should be done if under general anesthesia with endotracheal intubation perforation is suspected based. Small perforations can be and carbon dioxide insufflation.26 There are four steps managed conservatively with antibiotics and parenteral of POEM: mucosal incision, creation of submucosal nutrition whereas large perforations with free flow of tunnel, myotomy, and closure of mucosal incision barium into mediastinum warrant urgent thoracotomy (Fig. 4). Normal saline (10 mL) mixed with 0.3% indigo- and repair. Hence, patients with high surgical risk should carmine is injected approximately 13 cm proximal to GEJ and 2-cm longitudinal incision is made anteriorly or posteriorly with the use of triangular tip (TT knife) (Fig. 4A). Endoscope with transparent cap inserted into submucosal tunnel and tunnel is extended by injection and cautery (Fig. 4B). Attention should be given not to injure the mucosal layer by keeping the scope close to circular muscle layer. The tunnel should be one third of the esophageal circumference and should extend 3 cm distal to the GEJ. GEJ is identified by palisade vessel visualization/narrowing of tunnel/visualization of aberrant longitudinal muscle bundle/by transillumination of ultra-slim gastroscope in the submucosal tunnel. Myotomy should begin at 2–3 cm distal to mucosal entry and initially circular muscle is cut with TT knife until longitudinal muscles are visible (Fig. 4C). Then myotomy should continue in the plane between circular Fig. 3: Pneumatic dilatation in achalasia by Rigiflex balloon dilator. The waist of the balloon is seen between the two crus of diaphragm and longitudinal muscle fibers. Prior to closure, 20 mL and radiopaque marks can be seen in the balloon catheter saline with 80 mg gentamicin is injected into the tunnel

MU-139.indd 902 29-01-2021 14:57:19 Achalasia Cardia—Diagnosis and Endoscopic Treatment CHAPTER 139 903

TABLE 5 Landmark randomized controlled trials comparing outcome of various treatment modalities for achalasia cardia

Name/year Comparison n Success Follow-up Adverse GERD Drawbacks events Moonen et al., PD vs. LHM + Dor n-96 82% 5 years 5% 12% Re-dilatation required in 25% of PD 201622 Fundoplication n-105 84% 11% 34% patients—considered as treatment success Boeckxstaens PD vs. LHM + Dor n-96 86% (2 years) 43 months 4% 15% zz Follow-up short as effect may et al., 201624 Fundoplication n-105 90% (2 years) 12% 23% decrease over time p=0.46 zz Rigorous PD protocol over 2 years—only 3rd series of PD within 2 years of 2nd series considered as failure Ponds et al., POEM vs. PD n-67 92% 2 years 0% 41% zz Only allowed PD up to 35 mm 201925 n-66 54% 3.03 % 7% zz Considered re-dilatation as treatment failure Werner et al., POEM vs. n-112 83% 2 years 2.7% 44% zz Length of myotomy was not 201938 LHM + Dor n-109 81.7% 7.3% 29% standardized fundoplication (p=0.007 zz POEM was not accompanied by any non-inferiority) anti-reflux procedure where LHM was done with for fundoplication

and then mouse incision is closed by application of 5–10 tackled by reentering the tunnel and coagulating the clips at a distance of 5 mm applying first clip at the distal culprit vessel.34 Mucosal perforation can be closed with end of the longitudinal incision (Fig. 4D). A water soluble clips ± endoloops, fibrin glue, suturing by overstitch device contrast esophagogram is done at postoperative day 1 or fully covered metal stent. The prevalence of increased (POD1) to exclude leak and ascertain smooth passage esophageal acid exposure, reflux esophagitis, and GERD of contrast into stomach. Routine CT most procedure is symptoms after POEM ranges from 13% to 58%, 18% to not warranted. Patients, who tolerate oral diet and timed 65%, and 17% to 40%, respectively.35 Novel modifications barium esophagogram has shown no leak, can be started of POEM by addition of fundoplication (POEM-F) like in on liquid diet on POD1, pureed diet on POD2 and regular LHM have been shown to reduce reflux in pilot studies.36 diet from POD4. Initial clinical success with POEM is Anterior gastric wall is retracted at GEJ to form endoscopic 82–100% and intermediate term efficacy at 2 years is fundoplication wrap. Increased procedure time, cost, 78–91% at 2 years follow-up.27-29 The choice of anterior (1 and uncertain durability are the drawbacks of this novel o’clock) or posterior myotomy (5–6 o’clock) is operator procedure. Preservation of sling fibers by identifying dependent and based on clinical scenario as there is equal two penetrating vessels at distal end of myotomy can efficacy of both the approaches with shorter procedure reduce degree of esophagitis.37 A short course of proton time in posterior approach.30,31Adverse events can be pump inhibitor (PPI) for 1 month is recommended for all insufflation related (pneumoperitoneum: 16–30%, 8% patients and further continuation of therapy should be require decompression, pneumomediastinum: 8.7–11%, based on pH metry, symptoms, and endoscopic finding of 2.7% require decompression, mediastinal emphysema: esophagitis.2 4.9%, and subcutaneous emphysema: 21–36%), bleeding POEM has been shown to be superior to PD and non- (early or delayed) an mucosal perforation (2.6%).32 inferior to LHM in two recent RCTs. It is emerging as one 25,38 Low/extra low flow CO2 can reduce the incidence of of the first-line options to treat AC (Table 5). Results of pneumoperitoneum (up to 10%). Tense capnoperitoneum POEM are better than LHM, especially in type III achalasia

manifested by high end tidal CO2 can be treated with due to ability to perform long myotomy based on length of Veress needle.33 Minor bleeding during dissection can spastic distal segment of esophagus.2 POEM is also better be controlled with coagrasper or electrocautery knife. than LHM in case of sigmoid esophagus and other spastic Significant delayed bleeding is rare (0.7%) and can be motility disorders.39

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A B

C D Figs. 4A to D: Steps of per oral endoscopic myotomy. (A) Mucosal incision, (B) Submucosal tunneling, (C) Myotomy, (D) Closure of mucosal incision

TABLE 6 Comparison of treatment efficacy of various treatment modalities in achalasia cardia

PD LHM POEM

Type I AC 63.3–85% 81% 91.3%

Type II AC 90–93% 93–100% 96.3%

Type III AC 33.3–40% 80–86% 87.5–98%

Overall efficacy 44–84% 57–89.3% 75–97%

Follow-up (yrs) ≥5 years ≥5 years 1–3 years

GERD 2–4% 2–33% 20–54% AC, achalasia Cardia; GERD, gastroesophageal reflux disease; LHM, laparoscopic Heller’s myotomy, POEM, per oral endoscopic myotomy; PD, pneumatic dilatation

MU-139.indd 904 29-01-2021 14:57:21 Achalasia Cardia—Diagnosis and Endoscopic Treatment CHAPTER 139 905

Flowchart 1: Diagnosis and management algorithm for achalasia cardia

Conclusion References

Diagnosis of achalasia is based on clinical history and 1. Reynolds JC, Parkman HP. Achalasia. Gastroenterol Clin North Am. 1989;18(2):223-55. investigations like endoscopy, timed barium esophagogram, . 2 Jung HK, Hong SJ, Lee OY, et al. 2019 Seoul Consensus on and HRM. Treatment of achalasia should be individualized Esophageal Achalasia Guidelines. J Neurogastroenterol Motil. (Table 6) (Flowchart 1). Patients with high surgical risk should 2020;26(2):180-203. undergo BT/pharmacotherapy. For patients with low surgical . 3 Boeckxstaens GE, Zaninotto G, Richter JE, et al. Achalasia. Lancet. risk options are PD, LHM with fundoplication, and POEM. In 2014;383:83-93. young (<40 years), type I achalasia POEM/LHM should be the 4. Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classification first option of treatment as response rates to PD is low. In of esophageal motility disorders, v3.0. Neurogastroenterol Motil. type II AC, PD can be used as initial option along with POEM/ 2015;27(2):160-74. LHM as results to PD is best in type II AC. For type III AC, POEM . 5 Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to with extended myotomy is recommended. On failure of laparoscope. JAMA. 1998;280(7):638-42. therapy, any of the three modalities can be used as salvage . 6 Fisichella PM, Raz D, Palazzo F, et al. Clinical, radiological, and therapy but POEM is preferred in both prior endoscopic failure. manometric profile in 145 patients with untreated achalasia. World Esophagectomy should be reserved for end stage AC that is J Surg. 2008;32(9):1974-9. surgically fit with leg standing symptoms after repeated failure 7. Eckardt VF, Stauf B, Bernhard G, et al. Chest pain in achalasia: patient of different therapies. characteristics and clinical course. Gastroenterol. 1999;116(6): 1300-4.

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. 8 Massey BT, Hogan WJ, Dodds WJ, et al. Alteration of the upper 24. Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic esophageal sphincter belch reflex in patients with achalasia. dilation versus laparoscopic Heller’s myotomy for idiopathic Gastroenterol. 1992;103(5):1574-9. achalasia. N Engl J Med. 2011;364(19):1807-16. 9. Gockel I, Junginger T. The value of scoring achalasia a comparison 25. Ponds FA, Fockens P, Lei A, et al. Effect of peroral endoscopic of current systems and the impact on treatment—the surgeon’s myotomy vs pneumatic dilation on symptom severity and viewpoint. Am Surg. 2007;73(4):327-31. treatment outcomes among treatment-naive patients with 10. Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new achalasia: a randomized clinical trial. JAMA. 2019;322(2):134-44. clinically relevant classification by high-resolution manometry. 26. Darisetty S, Nabi Z, Ramchandani M, et al. Anesthesia in per-oral Gastroenterol. 2008;135:1526-33. endoscopic myotomy: a large tertiary care centre experience. 11. Fisichella PM, Jalilvand A, Dobrowolsky A, et al. Achalasia and Indian J Gastroenterol. 2017;36(4):305-12. epiphrenic diverticulum. World J Surg. 2015;39(7):1614-9. 27. NOSCAR POEM White Paper Committee; Stavropoulos SN, Desilets 12. Neyaz Z, Gupta M, Ghoshal UC, et al. How to perform and interpret DJ, et al. Per-oral endoscopic myotomy white paper summary. timed barium esophagogram. J Neurogastroenterol Motil. Gastrointest Endosc. 2014;80(1):1-15. 2013;19(2):251-6. 28. Inoue H, Sato H, Ikeda H, et al. Per-oral endoscopic myotomy: a 13. Agrusa A, Romano G, Frazzetta G, et al. Achalasia Secondary to series of 500 patients. J Am Coll Surg. 2015;221(2):256-64. Submucosal Invasion by Poorly Differentiated Adenocarcinoma of 29. Werner YB, Costamagna G, Swanström LL, et al. Clinical response to the Cardia, Siewert II: Consideration on Preoperative Workup. Case peroral endoscopic myotomy in patients with idiopathic achalasia Rep Surg. 2014;2014:654917. at a minimum follow-up of 2 years. Gut. 2016; 65:899. 14. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric botulinum 30. Ramchandani M, Nabi Z, Reddy DN, et al. Outcomes of anterior toxin for the treatment of achalasia. N Engl J Med. 1995;332(12): myotomy versus posterior myotomy during POEM: a randomized pilot study. Endosc Int Open. 2018;6(2):190-8. 774-8. 31. Mohan BP, Ofosu A, Chandan S, et al. Anterior versus posterior 15. Vela MF, Richter JE, Wachsberger D, et al. Complexities of managing approach in peroral endoscopic myotomy (POEM): a systematic achalasia at a tertiary referral center: use of pneumatic dilatation, review and meta-analysis. Endoscopy. 2020;52(4):251-8. heller myotomy, and botulinum toxin injection. Am J Gastroenterol. 32. Haito-Chavez Y, Inoue H, Beard KW, et al. Comprehensive analysis 2004;99(6):1029-36. of adverse events associated with per oral endoscopic myotomy 16. van Hoeij FB, Tack JF, Pandolfino JE, et al. Complications of in 1826 patients: an International Multicenter Study. Am J botulinum toxin injections for treatment of esophageal motility Gastroenterol. 2017;112(8):1267-76. disorders. Dis Esophagus. 2017;30(3):1-5. 33. Ramchandani M, Reddy DN, Darisetty S, et al. Peroral endoscopic 17. Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus myotomy for achalasia cardia: treatment analysis and follow up pneumatic dilatation in the treatment of achalasia: a randomised of over 200 consecutive patients at a single center. Dig Endosc. trial. Gut. 1999;44(2):231-9. 2016;28(1):19-26. 18. Kadakia SC, Wong RK. Graded pneumatic dilation using Rigiflex 34. Li QL, Zhou PH, Yao LQ, et al. Early diagnosis and management achalasia dilators in patients with primary esophageal achalasia. of delayed bleeding in the submucosal tunnel after peroral Am J Gastroenterol. 1993;88(1):34-8. endoscopic myotomy for achalasia (with video). Gastrointest 19. Farhoomand K, Connor JT, Richter JE, et al. Predictors of outcome Endosc. 2013;78(2):370-4. of pneumatic dilation in achalasia. Clin Gastroenterol Hepatol. 35. Repici A, Fuccio L, Maselli R, et al. GERD after per-oral endoscopic 2004;2(5):389-94. myotomy as compared with Heller’s myotomy with fundoplication: 20. Ghoshal UC, Chaudhuri S, Pal BB, et al. Randomized controlled a systematic review with meta-analysis. Gastrointest Endosc. trial of intrasphincteric botulinum toxin A injection versus 2018;87(4):934-43. balloon dilatation in treatment of achalasia cardia. Dis Esophagus. 36. Inoue H, Ueno A, Shimamura Y, et al. Peroral endoscopic myotomy 2001;14(3-4):227-31. and fundoplication: a novel NOTES procedure. Endoscopy. 21. Eckardt VF, Kanzler G, Westermeier T, et al. Complications and their 2019;51(2):161-4. impact after pneumatic dilation for achalasia: prospective long- 37. Tanaka S, Toyonaga T, Kawara F, et al. Novel per‐oral endoscopic term follow-up study. Gastrointest Endosc. 1997;45(5):349-53. myotomy method preserving oblique muscle using two 22. Moonen A, Annese V, Belmans A, et al. Long-term results of the penetrating vessels as anatomic landmarks reduces postoperative European achalasia trial: a multicentre randomised controlled gastroesophageal reflux. J Gastroenterol Hepatol. 2019;34(12):2158-63. trial comparing pneumatic dilation versus laparoscopic Heller 38. Werner YB, Hakanson B, Martinek J, et al. Endoscopic or surgical myotomy. Gut. 2016;65(5):732-9. myotomy in patients with idiopathic achalasia. N Engl J Med. 23. Yaghoobi M, Mayrand S, Martel M, et al. Laparoscopic Heller’s 2019;381(23):2219-29. myotomy versus pneumatic dilation in the treatment of idiopathic 39. Ramchandani M, Pal P. Management of achalasia in 2020: per-oral achalasia: a meta-analysis of randomized, controlled trials. endoscopic myotomy, Heller’s or dilatation? Int J Gastrointest Gastrointest Endosc. 2013;78(3):468-75. Interv. 2020;9:53-61.

MU-139.indd 906 29-01-2021 14:57:30 CHAPTER

Non-Variceal Upper GI Bleed— 140 Clinical Approach

Bhabadev Goswami, Preeti Sarma

Abstract Non-variceal upper GI bleed could be caused by peptic ulcer disease, Mallory Weiss tear, erosive gastritis/duodenitis, esophagitis, and malignancy. The resuscitation and management go hand in hand. The hematocrit may be initially high due to adjustments in the vascular spaces and the physician should not be misled by it. Gastrointestinal endoscopy has revolutionized both the diagnosis and treatment of non-variceal upper GI bleed. Risk stratification tools enable physicians to assess the risks of mortality and rebleeding.

Introduction Initial Assessment Upper gastrointestinal (GI) bleed with source of bleeding History and Physical Examination: Simultaneous to in esophagus, stomach, or proximal duodenum comprises resuscitation, history taking and initial assessment of the major cases of non-variceal upper GI bleed of which the vital signs is done. It is important to ask for history peptic ulcer disease (related to Helicobacter pylori of nasopharyngeal malignancy, hemoptysis, heartburn, infection, use of NSAIDs, low dose aspirin) happens to be alcohol use, use of medicines (NSAIDs, aspirin), dysphagia, 1 the most common cause. Despite great advances in the excessive vomiting, liver disease, chronic kidney disease.3 field of medical gastroenterology, the annual incidence Regarding physical examination, special attention remains at around 50–150 per 100,000 population with a should be paid to signs of hypovolemia like tachycardia, 2 mortality of around 10–35%. hypotension, orthostatic hypotension along with a close The common causes of non-variceal upper GI bleed are examination of the skin, lips, and buccal mucosa. The peptic ulcer (20–50%), Mallory Weiss tear (15–20%), erosive abdomen should be examined for tenderness, scar or any gastritis/duodenitis (10–15%), esophagitis/esophageal ulcer lump along with a rectal examination. Signs of chronic (5–10%), malignancy (1–2%), angiodysplasias/vascular liver disease should be specifically looked for as they can 2 malformations (5%). Severe GI bleeding is described as help us differentiate variceal from non-variceal bleed. GI bleeding that is associated with shock or orthostatic hypotension, decrease in hematocrit by 6% or decrease in hemoglobin by 2 g/dL or transfusion requirement of Laboratory Studies at least two units of PRBCs. Occult GI bleed describes In addition to routine tests, it is important to do the blood subacute bleeding that is not clinically visible. Obscure GI grouping and cross matching of the patient as PRBC bleed refers to a type of bleeding wherein the site of bleed transfusion may be needed. The hematocrit of the patient could not be determined after routine upper GI endoscopy, may not reflect the actual amount of blood loss in the colonoscopy, and even a small bowel radiography.3 immediate period as the vascular space needs time to

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adjust to the blood loss and administration of crystalloid „„ Correction of coagulopathy and decreased platelet intravenous fluid. Special attention should be paid to the count is paramount. mean corpuscular volume (MCV), serum ferritin, total „„ Emergency versus urgent endoscopy—those patients iron binding capacity (TIBC), total leukocyte count (TLC), who have active high volume bleed need to undergo platelet count, prothrombin time (INR). The blood urea emergency endoscopy (within 6 hours) after medical nitrogen (BUN) is usually higher than the serum creatinine resuscitation and preferably after having access to an in upper GI bleed cases due to intestinal bacteria acting ICU bed. Urgent endoscopy (within 12 hours) is suitable on the blood proteins and increasing absorption of urea. for patients who do not have ongoing hemorrhage and Elderly patients, especially those who are known cases of are hemodynamically stable.3 cardiac ailment, need to have an ECG done. „„ Role of gastric lavage in upper GI bleed cases is controversial as some societies do not approve of Management it. However, in cases with large volume bleeding, A case of upper GI bleed necessitates hospital admission, but careful gastric lavage and prokinetic agents like those patients having mild bleed, being hemodynamically metoclopramide or erythromycin can help in stable, near normal blood tests, with easy access to hospital endoscopic visualization. care may be treated on outpatient basis. On the other hand, „„ Around 1% of patients may experience complications those patients who are hemodynamically unstable, have like aspiration pneumonia, inadvertent bleeding, lost a large amount of blood, are having serious associated perforation, hypotension, hypoxia. comorbidities need ICU admission. Endoscopic techniques of hemostasis have Treatment of an upper GI bleed patient should start revolutionized the management of upper GI bleed. along with the examination and history taking. Once Amongst these techniques are the contact probes of intravenous access has been established, crystalloids like which the multipolar electrocoagulation probe is the normal saline are the fluid of choice and attempt should most commonly used. It enables to tamponade a bleeding be made to keep the pulse below 100/min and the systolic vessel and then thermal energy is used to seal off the blood pressure above 100 mm Hg. Blood transfusion with offending vessel. Risks include perforation, coagulation PRBC may be needed to keep Hb >7 g/dL.4 The hematocrit injury. Another useful technique is the use of endoscopic level should be monitored every 4–8 hours. In cases of injection therapy mostly done with epinephrine, diluted to severe acute upper GI bleed or in patients with altered a concentration of 1:10,000 or 1:20,000 into or around the mental status, endotracheal intubation may be needed. site of bleeding. It is easily available, cheap, safe in patients The advent of proton pump inhibitors (PPIs) has with coagulopathy, less chances of perforation or thermal revolutionized the management of non-variceal upper burns. Then there are the endoscopic hemoclips that apply GI bleed along with availability of endoscopic therapy. mechanical pressure to the bleeding site. Hemostatic But then there are cons of PPIs like no change in blood spray is a kind of inorganic powder with clotting abilities. transfusion requirements and no change in rebleeding rates (except in cases of PUD).3 Risk Stratification There are several stratification tools to help patients with Role of Endoscopy non-variceal upper GI bleed. These scores help identify GI endoscopy has brought in major advantages in the patients with higher risk of mortality and rebleeding.5,6 management of upper GI bleed, be it variceal or non- It enables physicians to assess patients who need higher variceal. Important points to note are: medical care or urgent endoscopy. Amongst these scores, „„ Patient must be hemodynamically stable with heart the pre-endoscopy scores are: rate of less than 100/min and systolic blood pressure „„ BLATCHFORD SCORE—includes blood pressure, greater than 100 mm Hg. BUN, hemoglobin, heart rate, syncope, melena, liver „„ There must be no respiratory difficulty, altered disease, heart failure sensorium or ongoing hematemesis as these cases „„ CLINICAL ROCKALL SCORE—includes patient’s age, might needs endotracheal intubation first. presence of shock, coexisting illnesses

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„„ ARTIFICIAL NEURAL NETWORK SCORE- includes 21 Patients with active arterial, NBVV, adherent clot variables to predict the presence of stigmata of recent are at high risk for rebleeding and would benefit from hemorrhage and the need for endoscopic therapy. endoscopic therapies. Adherent clot is defined as a blood „„ AIMS65—agregate of five variables like albumin clot overlying an ulcer that is resistant to several minutes <3 g/dL, INR >1.5, altered mental status, systolic BP of vigorous jet water irrigation. When a clean based ulcer is ≤90 mm Hg, age >65 years. found at the time of endoscopy, the chances of rebleeding Amongst the post-endoscopy scores, COMPLETE are less than 5%. However, if it is a clean-based ulcer in the ROCKALL SCORE is most popularly used. It includes the stomach, it is suggested that a biopsy of the ulcer edge and Clinical Rockall Score and the endoscopic findings. This the gastric mucosa should be taken to rule out malignancy. scoring system correlates well with mortality but not with In cases of gastric and duodenal ulcer suspected to be due risk of rebleeding. to H. pylori infection, endoscopic mucosal biopsies of the normal looking antrum and greater curvature (midbody) Role of Surgery3 should be taken. The role of PPIs in reducing rebleedingin peptic ulcer cases is more pronounced in people of There are some situations where surgery plays an Asian origin than others. Luminal gastric pH needs to be important role in non-variceal upper GI bleed cases: higher than 6.8 is needed for normal clotting function. H2 „„ Cases of severe and ongoing hemorrhage wherein receptor antagonists can do this job but tolerance to this endoscopy and colonoscopy procedures fail to localize drug is the major hindrance. In case of PPIs this problem the bleeding site and control it. does not occur, thereby ensuring mortality benefit „„ Cases of massive hemorrhage who are hemo­ especially in Asian patients.3 dynamically unstable need either an urgent angio­ Routine second look endoscopy in bleeding peptic graphy or urgent surgical exploration. ulcers is not always recommended8 unless the first „„ Cases of severe, recurrent obscure GI bleed may examination was inadequate due to poor visualization, benefit from surgical exploration. technical issues with hemostasis or clinically significant rebleeding has occurred. Repeat upper GI endoscopy Individual Etiologies is advisable in cases of gastric ulcer after 6–10 weeks of acid suppression therapy. Those patients who continue We shall now address some special issues pertaining to bleeding despite two sessions of endoscopic hemostasis non-variceal upper GI bleed. are suitable for angiographic embolization or surgery. Peptic ulcer: With the advent of PPIs, it has been observed Urgent surgery is advisable for those patients who have that worldwide, incidence of bleeding peptic ulcers has massive hemorrhage, who cannot be resuscitated. Also, if decreased whereas, bleeding from ulcers due to intake of the endoscopic expertise is not available for treatment of NSAIDs, aspirin have gradually increased. However, in the a large or pulsating visible vessel and if on endoscopy, a developing countries it has been seen that the prevalence bleeding malignant ulcerated mass is found, surgery is a of H. pylori infection is nearly 80% whereas, in the more suitable option. developed countries it ranges between 20–50%. Amongst Following endoscopic hemostasis of patients with the patients taking NSAIDs gastric ulcers tend to be more high-risk endoscopic stigmata (active arterial bleeding/ common than duodenal ulcers. The Forrest classification7 NBVV/adherent clot), patient should be put on high dose is used in cases of bleeding peptic ulcers to categorize the intravenous PPI in a hospital setting. Drugs like NSAIDs, endoscopic findings: warfarin should be withheld. Those patients who need Forrest 1A—active spurting bleed aspirin for cardiovascular illnesses may be started on the Forrest 1B—oozing bleed drug by day 7. Forrest 2A—non bleeding visible vessel (NBVV) It is recommended to test all cases of bleeding due to Forrest 2B—adherent clot peptic ulcer disease for H. pylori infection. Bleeding can Forrest2C—flat pigmented spot however cause false negative result of H. pylori. Antibiotic Forrest 3—clean based ulcer therapy should be initiated for those found to be positive

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for H. pylori infection. It is important to confirm the Usually the patients with Mallory-Weiss tear, present with eradication of H. pylori once treatment is completed.3 In non-bloody vomiting that is followed by hematemesis, cases of bleeding due to aspirin use, concomitant therapy probably due to raised intra-abdominal pressure. This with a PPI in future can reduce the rebleeding rates lesion usually self heals but in cases with severe bleeding, significantly. On the other hand, those patients who need endoscopic hemostasis may be attempted with hemoclips to continue NSAIDs long-term, need to opt for selective or multipolar electrocoagulation.3 COX2 inhibitors. Cameron’s lesion: This lesion is described as linear Esophagitis: Esophagitis may be caused due to erosions or ulcerations in the proximal stomach at the end gastroesophageal reflux disease (GERD), infections like of a hiatus hernia sac, near the diaphragmatic pinch due Candida, Herpes simplex virus, Cytomegalovirus and also to mechanical trauma and local ischemia. It is a common pill induced esophagitis,ultimately leading to upper GI cause of obscure GI bleed. Medical management is done bleed. GERD causing esophagitis and upper GI bleed is with PPI and Iron supplements if needed.3 treated with a PPI for a period of at least 8–12 weeks along Neoplastic etiology: Tumors of the upper GI tract, mostly with lifestyle modifications. It is essential that these cases esophagus, stomach, or duodenum that are large, need to undergo a repeat endoscopy and biopsy to rule out ulceroproliferative masses can present with upper GI Barrett’s esophagus. For all the rest etiologies, endoscopic bleed. Endoscopic hemostases is a temporary measure till biopsy/brushing is taken and treatment is done according to etiology.9 the definitive management can be initiated. Those tumors that continue to bleed despite endoscopic hemostases Ulcer hemorrhage in hospitalised patients: There are two need to undergo angiography with embolization. Wherever types of conditions usually seen in cases presenting with possible, GIST tumors should undergo resection.3 ulcer hemorrhage within the hospital—Stress Related Mucosal Injury/Stress Ulcer(SRMI) and Inpatient Ulcers. Gastric antral vascular ectasia (GAVE): This type of SRMI is characterized by diffuse bleeding from erosions lesion is characterized by rows of ecstatic mucosal blood and superficial ulcers, usually due to decreased mucosal vessels that start from around the pylorus and extend protection and mucosal ischemia. It is most commonly proximally to the antrum. Also called “Watermelon seen in the stomach, and the most common risk factors Stomach”, the exact cause of this lesion is not known, but are severe coagulopathy and mechanical ventilation for may be due to mucosal trauma from contraction waves more than 48 hours. Prophylactic treatment with an H2 in the antrum. It has been found to be associated with receptor antagonist or PPI can prevent bleeding in cases cirrhosis, scleroderma, end stage renal disease. GAVE is who are at high risk for SRMI. In those cases who present targeted with endoscopic hemostatic methods like laser, with UGI bleed, whether it is due to SRMI or inpatient MPEC, argon plasma coagulation. Besides these, medical ulcers, good medical treatment can help heal the lesions. management of anemia like iron supplements, blood Endoscopic therapy is feasible only in focal inpatient ulcer transfusion may be needed. 10 hemorrhage. Portal hypertensive gastropathy: This comprises of ectatic Dieulafoy’s lesion: This lesion comprises of a large blood vessels in the proximal gastric body, cardia due submucosal artery that protrudes through the mucosa to increased portal venous pressure and severe mucosal and can cause massive bleeding. Most commonly, such hyperemia. Management options are with beta-blockers, lesions occur in the gastric fundus, within 6 cm of the TIPS, liver transplantation. Endoscopic management does gastroesophageal junction. Whenever such a lesion is not have much role. identified and treated endoscopically, it is suggested to Hemobilia: Patients of hemobilia present with upper GI mark the site with submucosal injection of ink for future 3 bleed and deranged liver function tests. It may occur as need of easy identification and retreatment. a complication in cases of liver biopsy, ERCP, TIPS or Mallory-Weiss tears: This is characterized by mucosal or those who are suffering from hepatocellular carcinoma submucosal lacerations that start at the gastroesophageal or parasitic infection of the hepatobiliary system. Side junction and extend to a hiatus hernia sac distally. viewing endoscopy (SVE) is needed for diagnosis and

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arterial embolization with arteriography may be used for References treatment. . 1 Lanas A, Dumonceau JM, Hunt RH, et al. Non-variceal upper Hemosuccus pancreaticus: This kind of lesion is associated gastrointestinal bleeding. Nat Rev Dis Primers. 2018;4:18020. with pancreatic pathology or as a complication of ERCP . 2 CB Ferguson, RM Mitchell. Non-variceal upper gastrointestinal bleeding. Ulster Med J. 2006;75(1):32-9. or due to rupture of splenic artery aneurysm into the 3. Savides TJ, Jensen DM. Sleisenger & Fordtran’s Gastrointestinal and pancreatic duct. SVE is needed for diagnosis while Liver Disease Tenth edition. Gastrointestinal Bleeding ;pg 297-335. angiographic embolization or surgery is needed for 4. Kim SY, Hyun JJ, Lee SW, et al. Management of non-variceal upper treatment purposes. gastrointestinal bleeding. Clin Endosc. 2012;45(3):220-3. . 5 Garmin AN, Bardou M, Kuipers EJ, et al. International consensus Aortoenteric fistula: This is a condition wherein patient recommendations on the management of patients with presents with acute and massive hemorrhage with very nonvariceal upper gastrointestinal bleeding. Ann Intern Med. high mortality rates. In some cases, there might be a herald 2010;152(2):101-13. bleed that may precede. Primary aortoenteric fistula is . 6 Tham J, Stanley A. Clinical utility of pre-endoscopy risk scores in upper gastrointestinal bleeding. Expert Rev Gastroenterol Hepatol. the communication between native abdominal aorta and 2019;13(12):1161-7. third part of duodenum. Secondary aortoenteric fistula . 7 Forrest JA, Finlayson ND, Sherman DJ, et al. Endoscopy in is a communication between the small intestine (most gastrointestinal bleeding. Lancet. 1974;2(7877):394-7. commonly, third part of duodenum) and an infected 8. Imperials TF, Kong N. Second-look endoscopy for bleeding peptic abdominal aortic surgical graft. In both the cases, surgery ulcer disease: a decision-effectiveness and cost-effectiveness analysis. J Clin Gastroenterology. 2012;46(9):71-5. plays the more important role in management, and 9. Antunes C, Sharma A. Esophagitis. In: StatPearls. 2020. endoscopic hemostasis has no role. 10. Spirt MJ. Stress-related mucosal disease. Curr Treat Options Gastroenterol. 2003;6(2):135-45. Conclusion The resuscitation and management of non-variceal upper GI bleed goes hand in hand. Prompt action on the part of the treating physicians as well as timely use of endoscopy for diagnosis and management can help save valuable lives.

MU-140.indd 911 29-01-2021 14:57:11 CHAPTER

Recent Updates in 141 Management of IBS

Nikhil Gupta, Manisha Dwivedi, SP Misra

Abstract Irritable bowel syndrome is a symptom complex resulting from an interplay of various gastrointestinal and extraintestinal factors. Previously thought to have been resulted as a pathology in the gut brain axis, the pathophysiology and management of IBS has been reconditioned recently. The introduction of new diagnostic criteria and concept of mutidimensional clinical profile has changed the management of IBS completely. In this chapter we have concised the most updated knowledge on the diagnosis and management of IBS and its various subtypes.

Introduction and Epidemiology Rome IV Criteria for Diagnosis of IBS: Irritable bowel syndrome (IBS) is a functional Something New Something Borrowed gastrointestinal (GI) disorder characterized by chronic Manning and Thompson in 1978 introduced the concept abdominal pain and altered bowel habits, which are of making positive diagnosis of IBS using a set of criteria,10 1 unexplained by any organic cause during routine workup. which led to an exemplar shift in the diagnostic approach It is not a disease, but a complex of symptoms arising in patients with IBS. out of pathologies of diverse clinical significance. IBS This was followed by Rome I, Rome II, and Rome is a global problem with prevalence ranging anywhere III criteria pertaining to the origin of newer scientific from 1% to 45% of the general population having evidences. symptom complex satisfying the diagnostic criteria of The Asian consensus11 was published in 2010 IBS.2,3 considering the differences in dietary habits and More than one third of patients in GI practice have stool frequency patterns in Asians, which was functional GI disorders (FGID) and of all the FGIDs, different from the criteria used to define stool IBS accounts for the most common diagnosis.4 The frequency and stool form as they were based on the documented prevalence of IBS in Asians ranges from Western studies. 4% to 9% depending on the criteria used.5-7 IBS is twice Rome IV criteria were published in 2016,12 a decade after as prevalent in women as compared to men globally.8 Rome III was introduced. Rome IV criteria emphasized on However, there is no sex predilection in South Asia, South the gut brain interaction rather than the older concept of America, and Africa.9 IBS significantly affects the quality psychogenic predominant pathogenesis of IBS. of life and imposes a large burden to the patient and the As per the Rome IV criteria IBS is defined as—Recurrent health-care system. abdominal pain on average at least 1day/week in the last

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3 months, associated with two or more of the following In context to Asian population, a Chinese study criteria:* compared the diagnosis of IBS using the Rome III criteria „„ Related to defecation as well as Rome IV criteria and showed lower sensitivity „„ Associated with change in frequency of stool of Rome IV as compared to Rome III in Asian population „„ Associated with change in form (appearance) of stool and concluded that Rome IV positive patients were *Criteria fulfilled for the last 3 months with symptom onset at least 6 subgroup of Rome III with more severe manifestations of months prior to diagnosis. the disease.15 Following changes are notable in Rome IV as compared Rome IV also recognizes overlap syndrome amongst to ROME III: various FGIDs as observed in various studies.16-18 This is an „„ Term abdominal discomfort has been deleted important step based on scientific evidence as it will help considering the dubious nature of the term and also the clinicians to diagnose and manage such patients. that it is not present in every language. In 2019, Second Asian consensus on IBS19 was „„ Abdominal pain to be present on at least 1 day/week published representing the current knowledge and 13 based on scientific evidence management protocols in context to Asian population. „„ Bloating and distention are recognized as common The consensus emphasized that IBS is a disorder of symptoms Gut brain interaction rather than predominantly the „„ Improvement with defecation has been replaced with psychopathological phenomenon. The consensus also related to defecation as it has been encouraged the treatment based on micro-organic „„ Found that many patients report increase in pain with pathology. defecation ROME III Criteria: At least 3 months, with onset at least Subtyping and Assessing the Severity of 6 months previously of recurrent (at least 3 days/month) abdominal pain or discomfort associated with two or more IBS: The Concept of Multidimensional of the following: Clinical Profile „„ Improvement with defecation The concept of multidimensional clinical profile was „„ Onset associated with a change in frequency of stool introduced to categorize patients on the basis of the „„ Onset associated with a change in form of stool severity of their symptoms along with psychological ASIAN Consensus: Recurrent abdominal pain, bloating, evaluation and physiological dysfunction (Table 1). This or other discomfort for ≥3 months associated with one or helps the physicians to address other issues apart from more of the following: only the categorical diagnosis. „„ Relief with defecation Severity assessment helps physicians to rationally „„ Change in stool form (show patient the Bristol Stool approach any patient, and necessitate the aggressive Scale) management of patients with severe symptoms. Various „„ Change in stool frequency scales have been used to assess the severity of IBS, but ROME IV Criteria: Recurrent abdominal pain on average none have been accepted till date. at least 1 day/week in the last 3 months, associated with Multidimensional clinical profile also emphasizes two or more of the following criteria:* on the micro-organic basis of IBS such as abnormal gut „„ Related to defecation transit, post-infectious IBS, low-grade inflammation, „„ Associated with change in frequency of stool gut dysbiosis, dietary intolerance, abnormal intestinal „„ Associated with change in form (appearance) of stool permeability, and central as well as peripheral nervous *Criteria fulfilled for the last 3 months with symptom onset at least 6 dysregulation (Flowchart 1). months prior to diagnosis. Subtyping of IBS is essential as it helps in defining Rome IV also mentions about the location of pain, the targeted therapy and those with mixed type which can be present anywhere in the abdomen in and unclassified types need modifications of the contrast to the older criteria which considered lower pathophysiological process such as alteration of Gut abdominal pain as consistent with IBS.14 microbiota or neurohumoral regulation.

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TABLE 1 Severity assessment of IBS patients on the MDCP model20

Clinical features Mild Moderate Severe Psychometric correlate FBDSI, <36 FBDSI, 36–109 FBDSI, >110 IBS-SSS, 75–175 IBS-SSS, 175–300 IBS-SSS, >300 Physiological factors Primarily bowel dysfunction Bowel dysfunction and CNS pain Primarily CNS pain dysregulation dysregulation Psychosocial difficulties None or mild psychosocial Moderate psychosocial distress High psychosocial distress, distress catastrophizing, abuse history Sex Men = women Women > men Women >>> men Age Older > younger Older = younger Younger > older Abdominal pain Mild/intermittent Moderate, frequent Severe/very frequent or constant Number of other symptoms Low (1–3) Medium (4–6) High (≥7) Health-related quality of life Good Fair Poor Health-care use 0–1/yr 2–4/yr ≥5/yr Activity restriction Occasional (0–15 days) More often (15–50 days) Frequent/constant (>50 days) Work disability <5% 6–10% ≥11% IBS, irritable bowel syndrome; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; IBS-M, mixed IBS; FODMAP, fermentable oligo-, di-, monosaccharides, and polyols.

Multidimensional Clinical Profile of TABLE 2 Current step up therapy for treatment of IBS

Irritable Bowel Syndrome Predominant First step Second step „„ Categorical diagnosis (symptom-based criteria) symptom „„ Clinical modifier (IBS-C, IBS-D, IBS-M, post-infectious, Constipation zz Fiber supplementation zz Lubiprostone FODMAP sensitive) zz Polyethylene glycol zz Linaclotide „„ Impact (mild, moderate, severe) zz Lactulose/Lactitol zz Prucalopride „„ Psychosocial modifier zz Stool softener zz Sodium picosulfate zz Bisacodyl „„ Physiological dysfunction and biomarkers Diarrhea Loperamide zz 5HT3 antagonist (alosetron) Treatment zz Bile acid sequestrant An incorporative approach including patient education, (cholestyramine) zz Rifaximin cognitive behavioral therapy, diet, and lifestyle zz Clonidine modification are required for the management of IBS. This usually needs an involvement of the dietician and Pain zz Antispasmodic zz Tricyclic anti­ (anticholinergics) depressants (TCA) a clinical psychologist. zz Peppermint oil zz SSRI A step up approach depending on the severity zz SNRI of the predominant symptom and the multi-disciplinary zz Psychological clinical profile is helpful in guiding the treatment therapy (Table 2). Bloating zz Diet modification zz Probiotic The current first-line therapies are directed toward zz Treat constipation zz Rifaximin individual symptoms; however, the newer therapies are zz TCA based on altering the micro-organic pathophysiology. zz SSRI

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Flowchart 1: Diagnostic algorithm and management of IBS

Newer Therapies for IBS Rifaximin was tested initially in small scale trials in patients with IBS.22,23 Subsequently, in a large randomized Lumen Directed Therapy: Targeting the Low trial,24 positive effects were found in 8–10% patients of IBS Grade Inflammation Dysbiosis and Intestinal who did not have constipation. This effect was present Permeability during the 10 weeks of follow-up; however, the effect gradually decreased thereafter. Therefore in another Nonabsorbable Antibiotics retreatment trial25 repeat administration of rifaximin was Multiple case control studies from around the globe have assessed and it was found that retreatment was efficacious inferred microbial dysbiosis in patients with IBS.21 Thus, as in naïve patients without the concern of antibiotic use of non-absorbable antibiotics for management of IBS resistance. was suggested. Rifaximin has pleiotropic effects on the gut apart from Neomycin was initially used in patients with IBS; managing the gut dysbiosis. Variable effects include anti- however, the use was limited due to adverse effects. inflammatory effects, restoring the gut barrier function

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and effects on visceral hyperalgesia through unknown also involved in pathogenesis of visceral hypersensitivity in mechanisms. patients with IBS.32 Mast cell stabilizer ketotifen was found to increase the discomfort threshold to rectal distension in Pre-Probiotics and Synbiotics patients with IBS and had significant effects on abdominal Probiotics are live microorganism, which when consumed pain and QOL.33 This effects was hypothesized due to H1 in prescribed amounts confer multiple health benefits. receptor antagonism of ketotifen, which is a secondary The available data26 exhibit an overall positive effect of pre- action. Another H1 receptor antagonist, Ebastine, was also probiotics on the symptoms of IBS; however, comparative found to significantly decrease abdominal pain over a 12- analysis of the bacterial species is lacking. week treatment period.34 Probiotics affect the luminal dysbiosis, low grade inflammation, and helps restoring the mucosal integrity in Dietary Modifications patients with IBS. Apart from the direct effects, probiotics also indirectly modulate the gut-brain interaction.27,28 Worsening of symptoms has been reported by many patients Synbiotics are combinations of pre- and probiotics after ingestion of certain foods. It has been postulated that with synergistic actions. Synbiotics are hypothesized to food acts through various mechanisms including osmotic, be beneficial in IBS; however, results are inconsistent and chemical, mechanical and neuroendocrine effects. These data is sparse. pathologic mechanisms can potentiate the already present microbiologic pathology present in the gut. It has also Fecal Microbiota Transplant (FMT) been found that food material containing incompletely Alteration in gut microbiota is one of the proposed digestible carbohydrates, fats, and high caloric diet are mechanisms in the pathogenesis of IBS. Fecal incompletely absorbed in the small intestine and are a microbiota has been efficacious in treating patients with cause of significant bloating and abdominal discomfort pseudomembranous colitis with great success. Hence, due to fermentation by the gut microbiota. Thus, current its role in other luminal as well as non-luminal disorders recommendations evaluate patients after modifying has been hypothesized. So far many small case series and intake of such food as well as alcohol, caffeine, milk, or any randomized trials have been published and have assessed lactulose containing diet. IBS severity score as the outcome measure. However, the If these recommendations are cashed on improving 35 results were conflicting. symptoms the FODMAP diet (Fig. 1) eliminating foods Sahly et al.29 in 2020 published a double blind containing fermentable oligosaccharides, disaccharides, 19 randomized controlled trial assessing the efficacy of single monosachharides, and polyols are adviced. donor FMT in 30 gm and 60 gm doses as compared to Food eliminating Gluten has also been advocated placebo and found significant response (89.1% vs. 23.6% in non-celiac IBS patients on the basis of evidence of p<0.0001) in reduction in IBS symptoms. However, mild decrease in intestinal inflammation and mucosal injury self limiting GI symptoms after FMT need a word of on gluten free diet. caution. Therapeutic Updates on Constipation Mast Cell Stabilizer and Other Predominant IBS Anti-inflammatory Drugs Low grade inflammation in the gut as well as presence of Guanylate Cyclase C Agonist inflammatory cells especially lymphocytes and mast cells The stimulation of enterocyte guanylate cyclase c (GCC) have been found in patients with IBS and are considered receptors activates the apical CFTR that leads to water as one of the microbiologic change. secretion by the gut mucosa.36 Linaclotide is an orally Mesalazine, used as an anti-inflammatory drug in IBD administered 14 amino acid containing peptide that was found to have no role in patients with IBS.30,31 acts as an agonist of GCC. In a dose dependent manner Mast cells being predominant inflammatory cells are linaclotide softens the stools and also improves symptoms one of the targets for recent therapies of IBS. Mast cells are of abdominal pain, bloating, and discomfort.

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Fig. 1: Low foodmap diet

290 µg daily was shown to improve stool frequency 5-HT4 agonist Tegaserod was shown to be efficacious and ease of defecation.37,38 The most common side effect in management of IBS-c; however, it was withdrawn owing is diarrhea, which can be managed by reducing the dose. to potential cardiovascular risks.40,41

Plecanatide is another 16 amino acid GCC agonist A novel 5-HT4 receptor agonist Prucalopride has approved for management of chronic constipation and been approved for treatment of chronic constipation and recently FDA approved for IBS-C. has been evaluated in IBS-C considering the anecdotal reports of improvement in bloating, abdominal pain, and Lubiprostone discomfort in the trials for constipation.42 It is a fat soluble molecule that activates type 2 chloride Ghrelin Receptor Agonists channels in the enterocytes releasing more water into the Ghrelin is a gut hormone involved in appetite control intestinal lumen increasing water content of the stool. At and gut motility in upper as well as lower GI tract. a dose of 8 µg twice daily lubiprostone has shown efficacy Relamorelin is a novel injectable ghrelin receptor agonist in reduction of symptoms and stool consistency.39 Most studied as a motility amplifier in patients with diabetic common side effects are nausea and diarrhea. gastroparesis.43 It has also been evaluated in women with chronic constipation and has been found to improve 5-HT4 Agonists gastric emptying rate and stool frequency but had no effect

Activation of 5-HT4 enhances the gut motility by amplifying on stool consistency. Further studies are warranted in the release of acetylcholine from nerve endings. patients with IBS-C.

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Tenapanor Small molecule inhibitor of GI N+/H+ exchanger isoform 3, tenapanor increases water secretion in the gut improving global symptoms of IBS-C. At a dose of 50 mg BD tenapanor offers a newer mode of treatment in this class.44

Therapeutic Updates on Diarrhea Predominant IBS Eluxadoline This is a novel mixed µ opioid receptor and κ receptor agonist and δ agonist evaluated for treatment of IBS-D. It was studied in a dose of 75 mg and 100 mg per day for 26– 52 weeks.45 Eluxadoline helps improve overall symptoms and particularly stool consistency and frequency. Fig. 2: IBStim device However, pertaining to risk of pancreatitis due to sphincter of Oddi dysfunction it should not be used in patients with history of pancreatitis, SOD or alcohol abuse On the contrary, increased bile acids in the lumen or any liver dysfunction. stimulate water secretion and motility and improve constipation. Chenodeoxycholic acid was found to 5-HT3 Antagonists improve bowel function and bowel motility when tested.51 Serotonin modulates the gut motility and sensitivity Elobixibat or A3309, through antagonism of ileal bile

through a variety of receptors. Alosetron is a 5-HT3 acid transporter reduces reuptake, and hence increases antagonist was found to be efficacious in treatment of luminal bile acid content. Elobixibat has also been found IBS-D.46 However, this drug was associated with risk of to improve colonic transit and improve symptoms in ischemic colitis and severe constipation. patients with IBS-C.52 47 Ramosteron is a novel 5-HT3 antagonist found to be effective in improving global symptoms of IBS-D including Modulating the Central Pain Mechanism pain scores, which were not improved by Ondansetron when compared for management of IBS-D. IBStim Device: The Cranial Nerve Stimulator (Fig. 2) Recently approved for use in patients for modulating Drugs Acting on Bile Acids abdominal pain in IBS patients, this device is approved Bile acids are known to be important in stimulating for adolescents of age group 11–18 years. It modulates secretion in the bowel and enhance gut motility that are the pain pathways in the CNS by low frequency electrical relevant in causing diarrhea. Several studies have revealed stimulation of peripheral cranial nerves. It is single use 48 the increase bile acid loss as a cause of IBS-D. FGF19 device and works for 5 days.53 is produced from the ileum that acts as an important factor in regulating bile acid synthesis in the liver. In bile Conclusion acid diarrhea there is reduced feedback inhibition by FGF19. Cholestyramine is most commonly used bile acid IBS is chronic relapsing remitting functional GI disorder. sequestrant along with newer agents like colestipol and With enhanced understanding of the micro-organic basis of colesevelam.49 the disorder newer therapies are directed at modifying the Farnesoid X activated receptor is also involved pathology of the disease rather than the individual symptoms. in inhibition of bile acid synthesis in liver by various It is however very necessary to clinically diagnose the patient mechanisms. Obeticholic acid is one of the various FXR with respect to the recent diagnostic criteria and order important battery of investigations for making a positive receptor agonists that has been found to reduce bile acid diagnosis of IBS. synthesis and improve secondary bile acid diarrhea.50

MU-141.indd 918 29-01-2021 14:57:08 Recent Updates in Management of IBS CHAPTER 141 919

References 19. Gwee KA, Gonlachanvit S, Ghoshal UC, et al. Second Asian consensus on irritable bowel syndrome. J Neurogastroenterol . 1 Chang L, Lembo A, Sultan S. American Gastroenterological Motil. 2019;25(3):343-62. Association Institute Technical Review on the pharmacological 20. Drossman DA, Chang L, Bellamy N, et al. Severity in irritable management of irritable bowel syndrome. Gastroenterology. bowel syndrome: a Rome Foundation Working Team report. Am J 2014;147:1149-72. Gastroenterol. 2011;106:1749-59. . 2 Lovell RM, Ford AC. Global prevalence of, and risk factors for, 21. Zhuang X, Xiong L, Li L, et al. Alterations of gut microbiota in irritable bowel syndrome: a meta-analysis. Clin Gastroenterol patients with irritable bowel syndrome: a systematic review and Hepatol. 2012;10:712-21. meta-analysis. J Gastroenterol Hepatol. 2017;32:28-38. 3. Quigley EM, Abdel-Hamid H, Barbara G, et al, A global perspective 22. Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed on irritable bowel syndrome: a consensus statement of the World oral antibiotic (rifaximin) on the symptoms of the irritable bowel Gastroenterology Organisation Summit Task Force on Irritable Bowel Syndrome. J Clin Gastroenterol 2012;46:356-66. syndrome: a randomized trial. Ann Intern Med. 2006;145:557-63. . 4 Russo M, Gaynes B, Drossman D. A national survey of practice 23. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind patterns of gastroenterologists with comparison to the past two placebo-controlled trial of rifaximin in patients with abdominal decades. J Clin Gastroenterol. 1999;29:339-43. bloating and flatulence. Am J Gastroenterol. 2006;101:326-33. . 5 Gwee KA, Lu CL, Ghoshal UC. Epidemiology of irritable bowel 24. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients syndrome in Asia: something old, something new, something with irritable bowel syndrome without constipation. N Engl J Med. borrowed. J Gastroenterol Hepatol. 2009;24:1601-7. 2011;364:22-32. . 6 Ghoshal UC, Abraham P, Bhatt C, et al. Epidemiology and clinical 25. Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin profile of irritable bowel syndrome in India: report of the Indian is safe and effective in patients with diarrhea predominant irritable Society of Gastroenterology Task Force. Indian J Gastroenterol. bowel syndrome. Gastroenterology. 2016;151:1113-21. 2008;27:22-8. 26. Hungin APS, Mitchell CR, Whorwell P, et al. Systematic review: . 7 Han SH, Lee OY, Bae SC, et al. Prevalence of irritable bowel probiotics in the management of lower gastrointestinal syndrome in Korea: population-based survey using the Rome II symptoms—an updated evidence-based international consensus. criteria. J Gastroenterol Hepatol. 2006;21:1687-92. Aliment Pharmacol Ther. 2018;47:1054-70. . 8 Mulak A, Taché Y. Sex difference in irritable bowel syndrome: do 27. Quigley EM. Probiotics in irritable bowel syndrome: the science and gonadal hormones play a role? Gastroenterol Pol. 2010;17:89-97. the evidence. J Clin Gastroenterol. 2015;49(Suppl. 1):S60-4. . 9 Lovell RM, Ford AC. Effect of gender on prevalence of irritable 28. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk bowel syndrome in the community: systematic review and meta- product with probiotic modulates brain activity. Gastroenterology. analysis. Am J Gastroenterol. 2012;107:991-1000. 2013;144:1394-401. 10. Manning AP, Thompson WG, Heaton KW, et al. Towards positive 29. El-Salhy M, Hatlebakk JG, Gilja OH, et al. Efficacy of faecal microbiota diagnosis of the irritable bowel. Br Med J. 1978;2:653-4. transplantation for patients with irritable bowel syndrome in 11. Gwee KA, Bak YT, Ghoshal UC, et al. Asian consensus on irritable a randomised, double-blind, placebo-controlled study. Gut. bowel syndrome. J Gastroenterol Hepatol. 2010;25:1189-205. 2020;69(5):859-67. 12. Drossman DA, Hasler WL. Rome IV-functional GI disorders: disorders 30. Barbara G, Cremon C, Annese V, et al. Randomised controlled trial of of gut-brain interaction. Gastroenterology. 2016;150:1257-61. mesalazine in IBS. Gut. 2016;65(1):82-90. 13. Palsson OS, Whitehead WE, Tilburg MAL, et al. Development and 31. Lam C, Tan W, Leighton M, et al. A mechanistic multicentre, parallel validation of the Rome IV diagnostic questionnaire for adults. group, randomised placebo-controlled trial of mesalazine for the Gastroenterology. 2016;150:1481-91. treatment of IBS with diarrhoea (IBS-D). Gut. 2016;65(1):91-9. 14. Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 32. Barbara G, Wang B, Stanghellini V, et al. Mast cell-dependent 2016;150:1393-407, e5. excitation of visceral-nociceptive sensory neurons in irritable bowel 15. Bai T, Xia J, Jiang Y, et al. Comparison of the Rome IV and Rome III criteria for IBS diagnosis: a cross-sectional survey. J Gastroenterol syndrome. Gastroenterology. 2007;132(1):26-37. Hepatol. 2017;32:1018-25. 33. Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser 16. Ghoshal UC, Abraham P, Bhatt C, et al. Epidemiological and clinical ketotifen decreases visceral hypersensitivity and improves profile of irritable bowel syndrome in India: report of the Indian intestinal symptoms in patients with irritable bowel syndrome. Gut. Society of Gastroenterology Task Force. Indian J Gastroenterol. 2010;59(9):1213-21. 2008;27:22-8. 34. Wouters MM, Balemans D, Van Wanrooy S, et al. Histamine 17. Ghoshal UC, Singh R. Frequency and risk factors of functional gastro- receptor H1-mediated sensitization of TRPV1 mediates visceral intestinal disorders in a rural Indian population. J Gastroenterol hypersensitivity and symptoms in patients with irritable bowel Hepatol. 2017;32:378-87. syndrome. Gastroenterology. 2016;150(4):875-87. 18. Wang A, Liao X, Xiong L, et al. The clinical overlap between 35. Halmos EP, Power VA, Shepherd SJ, et al. A diet low in FODMAPs functional dyspepsia and irritable bowel syndrome based on Rome reduces symptoms of irritable bowel syndrome. Gastroenterology. III criteria. BMC Gastroenterol. 2008;8:43. 2014;146(1):67-75.

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36. Bharucha AE, Waldman SA. Taking a lesson from microbial 45. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable diarrhea genesis in the management of chronic constipation. bowel syndrome with diarrhea. N Engl J Med. 2016;374(3):242-53. Gastroenterology. 2010;138(3):813-7. 46. Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and 37. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel 5-HT4 agonists in irritable bowel syndrome: systematic review and syndrome with constipation: a 26-week, randomized, double- meta-analysis. Am J Gastroenterol. 2009;104(7):1831-43. blind, placebo-controlled trial to evaluate efficacy and safety. Am J 47. Fukudo S, Ida M, Akiho H, et al. Effect of ramosetron on stool Gastroenterol. 2012;107(11):1702-12. consistency in male patients with irritable bowel syndrome with 38. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled diarrhea. Clin Gastroenterol Hepatol. 2014;12(6):953-9. trial with a 4-week randomized withdrawal period to evaluate the 48. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on efficacy and safety of linaclotide in irritable bowel syndrome with faecal bile acids and bowel functions in diarrhoea‐predominant constipation. Am J Gastroenterol. 2012;107(11):1714. irritable bowel syndrome. Aliment Pharmacol Ther. 2015;41(5): 39. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone 438-48. in patients with constipation‐associated irritable bowel syndrome– 49. Aziz I, Mumtaz S, Bholah H, et al. High prevalence of idiopathic bile results of two randomized, placebo‐controlled studies. Aliment acid diarrhea among patients with diarrhea-predominant irritable Pharmacol Ther. 2009;29(3):329-41. bowel syndrome based on Rome III criteria. Clin Gastroenterol 40. Gershon MD, Tack J. The serotonin signaling system: from basic Hepatol. 2015;13(9):1650-5. understanding to drug development for functional GI disorders. 50. Walters JR, Johnston IM, Nolan JD, et al. The response of patients Gastroenterology. 2007;132(1):397-414. with bile acid diarrhoea to the farnesoid X receptor agonist 41. Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular obeticholic acid. Aliment Pharmacol Ther. 2015;41(1):54-64. safety profile of 5‐HT 4 agonists developed for gastrointestinal 51. Nakajima A, Seki M, Taniguchi S. Determining an optimal clinical disorders. Aliment Pharmacol Ther. 2012;35(7):745-67. dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, 42. Tack J, Stanghellini V, Dubois D, et al. Effect of prucalopride on in Japanese patients with chronic constipation: a phase II, symptoms of chronic constipation. Neurogastroenterol Motil. multicenter, double-blind, placebo-controlled randomized clinical 2014;26(1):21-7. trial. J Gastroenterol. 2018;53(4):525-34. 43. Camilleri M, McCallum RW, Tack J, et al. Efficacy and safety 52. Chey WD, Camilleri M, Chang L, et al. A randomized placebo- of relamorelin in diabetics with symptoms of gastroparesis: controlled phase IIb trial of a 3309, a bile acid transporter a randomized, placebo-controlled study. Gastroenterology. inhibitor, for chronic idiopathic constipation. Am J Gastroenterol. 2017;153(5):1240-50. 2011;106(10):1803. 44. Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in 53. Kovacic K, Hainsworth K, Sood M, et al. Neurostimulation for treating patients with irritable bowel syndrome with constipation: abdominal pain-related functional gastrointestinal disorders in a 12-week, placebo-controlled phase 3 trial (T3MPO-1). Am J adolescents: a randomised, double-blind, sham-controlled trial. Gastroenterol. 2020;115(2):281-93. Lancet Gastroenterol Hepatol. 2017;2(10):727-37.

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142 Evaluation of Occult GI Bleed

Sanjay Bandyopadhyay

Abstract Occult gastrointestinal bleeding signifies bleeding from the gastrointestinal tract that often goes unrecognized by the patient. It usually manifests as positive fecal occult blood test, or if continues for a long period of time, it may progress to iron deficiency anemia. A thorough evaluation of gastrointestinal tract including esophago-gastro-duodenoscopy and colonoscopy clinches the diagnosis in most of the cases. Recently, introduction of capsule endoscopy and balloon enteroscopy have made a major impact by identifying small bowel causes of bleeding. The primary concern is to rule out malignant causes, particularly in elderly. For patients with no identifiable pathology, long-term prognosis appears favorable with oral supplement of iron.

Introduction studies on patients with occult GI bleeding, majority was found to have upper GI source (29–56%) followed Gastrointestinal (GI) bleeding can have a multitude colorectal source (20–30%). Surprisingly, synchronous of clinical presentation. The bleeding may be mild, lesions were found in up to 17% cases. All these studies moderate, or severe depending on the severity or rapidity used only OGD and colonoscopy, and hence, no source of bleeding. Patient may present with clinically obvious was identified in 29–52% cases. Table 1 shows the potential symptoms of hematemesis, melaena, hematochezia, or, causes of Occult GI bleeding. in some cases, fresh bleeding per rectum. Furthermore, bleeding may be hidden with patient totally unaware of its existence. This review will focus on this later type of History and Physical Examination bleeding called occult GI bleeding. A detail history and targeted physical examination should Occult GI bleeding is defined as bleeding that is un­ form the basis of clinical evaluation. Abdominal pain with known to the patient, and includes patients with positive aspirin or other non-steroidal anti-inflammatory drug use fecal occult blood test (FOBT) and/or iron deficiency anemia suggests ulcerative mucosal injury. Unintentional weight 1 (IDA). On the other hand, obscure GI bleeding is that which loss suggests a malignancy. A past history of GI bleeding or is evident to the patient but is from a source that is not readily abdominal surgery may give important diagnostic clues. identifiable by routine esophagogastroduodenoscopy Initiation of anticoagulants or antiplatelet medications 1 (EGD) and/or colonoscopy. in the preceding weeks may precipitate bleeding in an undiagnosed lesion. A family history of GI bleeding may Causes suggest hereditary hemorrhagic telangiectasia (associated Any lesion presents anywhere in the GI tract may present with vascular lesions on the lips, tongue, or palms) or blue with occult GI bleeding.2 In a review of five prospective rubber bleb nevus syndrome (a syndrome with venous

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of duodenum can be detected by EGD. Classically, TABLES 1 Causes of occult gastrointestinal bleeding small bowel bleedings are evaluated by enteroscopy. Mass lesions zz Carcinoma (common) Older methods like Push enteroscopy reach only the zz Adenoma (usually > 1.5 cm) proximal small intestine. However, bleeding sources Inflammation zz Erosive esophagitis (common) in mid and distal small bowel need evaluation with zz Ulcer (any site, including peptic ulcer, common) wireless capsule endoscopy (WCE), deep enteroscopy, zz Cameron lesions and computed tomography (CT) or magnetic resonance zz Erosive gastritis (MR) enterography.4 Lower GI bleeding (colonic and zz Celiac disease terminal ileal source) can be detected with colonoscopy. zz Ulcerative colitis zz Crohn’s disease Laparotomy with intraoperative enteroscopy remains an zz Colitis (non-specific) option for those rare patients who have recurrent bleeding zz Idiopathic cecal ulcer from a source not yet identified with the previously Vascular zz Vascular ectasia (common) mentioned methods. Small bowel barium studies have zz Varices (any site, rare) a very low diagnostic yield and been largely replaced by zz Portal hypertensive gastropathy (PHG) (common) capsule endoscopy. EGD and colonoscopy will find the zz Portal colopathy bleeding source in 48–71% of patients. In patients with zz Gastric antral vascular ectasia (GAVE) recurrent bleeding, repeat EGD and colonoscopy may find zz Dieulafoy’s ulcer (rare) zz Hemosuccus pancreaticus (rare) missed lesions in up to 35% of those who had negative 3 zz Hemobilia (rare) initial findings. If a cause is not found after EGD and Infection zz Hookworm colonoscopy had been performed, capsule endoscopy has zz Whipworm a diagnostic yield of 63–74%.4 zz Strongyloidiasis zz Ascariasis Capsule Endoscopy and Different zz Tubercular enterocolitis zz Amebiasis Methods of Enteroscopy Other zz Long-distance running These tools are particularly useful for establishing the zz Factitious source of bleeding in small intestine—a notoriously difficult site to examine with other methods. Capsules used for endoscopy contain light-emitting malformations in the GI tract, soft tissues, and skin). A diodes, a lens, a camera, batteries, and a radiofrequency history of gastric bypass surgery may suggest impaired transmitter (Figs. 1A and B). Captured images are iron absorption.1 Examination of skin may indicate the transmitted to a data recording device worn by the patient, presence of an underlying condition like dermatitis downloaded to a computer workstation, where the images herpetiformis (in celiac disease); erythema nodosum (in are analyzed.5 The capsule is disposable and, because of Crohn disease); an atrophic tongue and brittle, spoon- its small size, readily passes through the GI tract. Capsule shaped nails (Plummer-Vinson syndrome); and freckles retention is a potential complication but, fortunately, on the lips and in the mouth (Peutz-Jeghers syndrome).3 occurs in less than 1%.6 Stigmata of chronic liver disease may suggest bleeding due Push enteroscopy consists of per oral insertion of a to portal hypertension. Anemia may be obvious on clinical specialized, long, flexible tube up to 50–60 cm beyond the examination. Palpable hard nodular liver or palpable ligament of Treitz. This allows thorough examination of abdominal lump may be signs of underlying advanced the distal duodenum and proximal jejunum, and biopsies disease. can be taken if needed. It is rarely practiced nowadays. Deep enteroscopy has been a major advance in the Diagnostic Studies evaluation of the small bowel as it offers scope for therapy The choice of diagnostic modality should depend on and tissue biopsy, though multiple sessions may be needed clinical suspicion of potential site and probable cause for complete examination.7 There are several forms of of underlying disease, and any associated symptoms. deep enteroscopy, including double-balloon enteroscopy Upper GI bleeding from lesions up to the second part (DBE), single-balloon enteroscopy (SBE), and spiral

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A B Figs. 1A and B: Components and designs of capsule endoscopy system: (A) Capsule; (B) Schematic diagram of components of capsule

enteroscopy (SPIRUS) (Figs. 2A to C).7-9 The principle cause any visible change in the color of the stool.11 FOBT, involves the use of an endoscope and an overtube, usually classic guaiac-based tests, is often used in day-to- although procedures are emerging that may not require an day clinical practice by physicians. Other types of FOBT overtube. Initially scopes are inserted as deep as possible; like fecal immunochemical tests and the heme porphyrin careful withdrawal of the scope then allows evaluation test are not available in India. The likelihood of positive of the entire small bowel. With DBE, balloons are used test depends not only on the sensitivity of a particular test to grip the intestine while inserting the endoscope. By but also on the frequency and rate at which the causative inflating the overtube balloon enough to grip the intestinal lesion bleeds, bowel motility, and the anatomic site of wall, the endoscope can be inserted further without the bleed.12 Guaiac-based tests are best at detecting forming redundant loops in the small intestine and then blood from the lower rather than the upper GIT as the the overtube can in turn be inserted while the endoscope pseudoperoxidase activity of heme, detected by guaiac- balloon is inflated. The single balloon technique in theory based tests, is continuously degraded as it moves down is technically simpler than DBE. Spiral enteroscopy uses a the GIT. special overtube with raised helices at the distal end, and Oral iron therapy is commonly believed to cause clockwise rotation of the overtube pleats the small bowel positive guaiac tests, but prospective studies have proven 13 onto the overtube and prevents looping. Data to date this belief to be wrong. Finally, bismuth (found in certain suggest that DBE allows greater depth of insertion than the antacids and antidiarrheal drugs) makes the stool dark other two.7 and even black in appearance, but does not cause a blue guaiac reaction and should not be mistaken for blood. Evaluation Flowchart 1 illustrates the approach proposed by the American Gastroenterological Association (AGA) for There are two different clinical presentations of occult GI patients with positive FOBT.4 Colonoscopy is preferred bleed: because of its high sensitivity for detecting colonic „„ Positive FOBT without iron deficiency anemia mucosal lesions, and its intervention capabilities with „„ Iron deficiency anemia with or without a positive biopsy, polypectomy, and treatment of bleeding lesions.4 FOBT Barium studies have lower sensitivity than colonoscopy and are generally not recommended. CT colonography Positive FOBT without Iron Deficiency Anemia may be an alternative to colonoscopy, if bowel preparation Normal fecal blood loss varies from 0.5 to 1.5 mL/day.10 is a problem.14 However, it does not have therapeutic However, loss of up to 100 mL of blood per day may not capabilities.

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A B

Figs. 2A to C: Different types of deep enteroscopy: (A) Double- balloon enteroscopy; (B) Single-balloon enteroscopy; (C) Spiral C overtube enteroscopy

Identification of an abnormality consistent with regulated at the level of intestinal mucosa. Average daily the magnitude of bleeding makes further workup after loss of iron is 1 mg coming from microscopic GI bleeding colonoscopy unnecessary. If colonoscopy is negative, and sloughed intestinal cells.16 In India, more than 50% of further studies are not required in the asymptomatic population is iron-deficient.17 patient unless anemia develops.4 Exceptions are patients The approach recommended by AGA for evaluation with upper GI symptoms, in whom EGD should be of patients who have IDA with or without a positive performed along with colonoscopy. FOBT has been illustrated in Flowchart 2.18 Men and Fecal blood content in therapeutically anticoagulated postmenopausal women with IDA are assumed to patients is usually within normal limits. Hence, a positive have GI blood loss, unless proved otherwise. However, FOBT should not be attributed to low-dose aspirin premenopausal women who have IDA that cannot or anticoagulation, and as such, will require at least be explained by heavy menses, or those who have GI endoscopic evaluation.15 symptoms, should be evaluated for a GI cause. Endoscopic evaluation should start with EGD and Iron Deficiency Anemia with or colonoscopy. During EGD, biopsies should be taken without a Positive FOBT from duodenal mucosa to look for celiac disease, an Worldwide IDA is the most common cause of anemia. often ignored cause of IDA.19 If EGD and colonoscopy Under normal circumstances, iron balance is tightly are normal, they are called obscure occult GI bleed.

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Flowchart 1: Evaluation of the patient with a positive FOBT Flowchart 2: Proposed algorithm for diagnosis of iron deficiency anemia with or without a positive FOBT

EGD, esophagogastroduodenoscopy; FOBT, fecal occult blood test; GI, gastrointestinal

The prevalent expert opinion suggests that they should undergo repeat upper endoscopy and colonoscopy, at least once. If these repeat studies are negative, capsule endoscopy should be the next investigative procedure with a focus on small bowel. Whenever capsule endoscopy identifies a lesion on small bowel, further course of action depends on the nature of the lesion. „„ If the identified lesion needs a tissue diagnosis or if the lesion requires endotherapy (like endoscopic hemostasis, endoluminal ablation, resection, or dilatation), balloon enteroscopy should be performed. The choice of route of balloon enteroscope insertion (either antegrade, i.e., orally or retrograde, i.e., inserted anally) will depend on the estimated site of lesion as observed on running the capsule endoscopy video. „„ If capsule endoscopy shows a lesion that can be managed medically or that requires surgery, balloon CT, computed tomographic; EGD, esophagogastroduodenoscopy; enteroscopy is not justified. FOBT: fecal occult blood test If capsule endoscopy fails to identify a lesion, it may be repeated on another occasion (second-look capsule Surprisingly, in some cases, the diagnosis may be obvious endoscopy). Alternatively, CT or MR enterography may be on CT or MR precluding the need for capsule endoscopy. considered. Radioisotope scan using radioactive technetium bound Sometimes, CT or MR enterography are performed red blood cells (RBCs) are not favored due to significant before capsule endoscopy to check for luminal patency radiation exposure, imprecise localization, and lack sufficient to allow unobstructed passage of the capsule.20 of therapeutic potential.21 Angiography and guided

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intervention is reserved for acute brisk bleeding that do . 5 Goenka MK, Mojumder S, Goenka U, et al. Capsule endoscopy: not fall in the category of occult GIB or IDA.20,22 present status and future expectation. World J Gastroenterol. A small percentage of cases may not have any lesion 2014;20(29):10024-37. . 6 Sears DM, Avots-Avotins A, Culp K, et al. Frequency and clinical identified even after exhaustive evaluation. In them, outcome of capsule retention during capsule endoscopy for GI covert non-GI blood loss should be considered. Also, the bleeding of obscure origin. Gastrointest Endosc. 2004;60(5):822-7. diagnosis and type of anemia need to be rechecked by a . 7 Moeschler O, Mueller MK. Deep enteroscopy—indications, hematologist.1 diagnostic yield and complications. World J Gastroenterol. 2015;21(5):1385-93. . 8 Mans L, Arvanitakis M, Neuhaus H, et al. Motorized spiral Treatment enteroscopy for occult bleeding. Dig Dis. 2018;36(4):325-7. Essentially, the treatment should focus on the underlying . 9 Otani K, Watanabe T, Shimada S, et al. Clinical utility of capsule cause of occult bleeding. Anemia is treated with oral endoscopy and double-balloon enteroscopy in the management of obscure gastrointestinal bleeding. Digestion. 2018;97(1):52-8. ferrous sulfate in a dose of 325 mg twice or thrice daily. 10. Rockey DC, Auslander A, Greenberg PD, et al. Detection of Ferrous fumarate or gluconate is acceptable alternative upper gastrointestinal blood with fecal occult blood tests. Am J for those unable to tolerate ferrous sulfate. Parenteral Gastroenterol. 1999;94(2):344-50. iron therapy is reserved for those with malabsorption 11. Ahlquist DA, McGill DB, Schwartz S, et al. Fecal blood levels in disorders or severe oral intolerance.23 For patients with health and disease. A study using HemoQuant. N Engl J Med. 1985;312(22):1422-8. positive FOBT but no identifiable GI pathology, the long- 12. Ahlquist DA, McGill DB, Fleming JL, et al. Patterns of occult bleeding term prognosis appears favorable. Majority of these true in asymptomatic colorectal cancer. Cancer. 1989;63(9):1826-30. 24 obscure cases respond to oral iron thrapy. 13. Laine LA, Bentley E, Chandrasoma P, et al. Effect of oral iron therapy on the upper gastrointestinal tract. A prospective evaluation. Dig Dis Sci. 1988;33(2):172-7. Conclusion 14. Rockey DC, Paulson E, Niedzwiecki D, et al. Analysis of air contrast A multitude of diseases of GIT can present as occult GI bleed, barium enema, computed tomographic colonography, and manifesting as a positive FOBT or IDA. Majority of these bleeds colonoscopy: prospective comparison. Lancet. 2005;365(9456): 305-11. are caused by ulcerative diseases of the upper GIT while 15. Jaffin BW, Bliss CM, LaMont JT, et al. Significance of occult malignancy is rare. Routine endoscopy (UGI endoscopy and gastrointestinal bleeding during anticoagulation therapy. Am J colonoscopy) is the first step in evaluation of these patients. Med. 1987;83(2):269-72. Some patients have common lesions but with an unusual 16. Hentze MW, Muckenthaler MU, Andrews NC, et al. Balancing or atypical appearance; others may harbor rare/uncommon acts: molecular control of mammalian iron metabolism. Cell. diseases. Capsule endoscopy and deep (often balloon-assisted) 2004;117(3):285-97. enteroscopy are useful to identify the diseases of small bowel. 17. WHO. Worldwide prevalence of anaemia. 1993-2005. The later often offers scope for curative intervention. The 18. American Gastroenterological Association (AGA) medical position outcome of therapy depends on identification of a specific statement: evaluation and management of occult and obscure bleeding lesion, severity of bleeding, and, finally, access to gastrointestinal bleeding. Gastroenterology. 2000;118(1):197-201. advanced diagnostic/therapeutic modalities. 19. Fine KD. The prevalence of occult gastrointestinal bleeding in celiac sprue. N Engl J Med. 1996;334(18):1163-7. 20. Morrison TC, Wells M, Fidler JL, et al. Imaging workup of acute and occult lower gastrointestinal bleeding. Radiol Clin North Am. References 2018;56(5):791-804. 1. Rockey DC. Occult and obscure gastrointestinal bleeding: causes and 21. Filippone A, Cianci R, Milano A, et al. Obscure and occult management. Nat Rev Gastroenterol Hepatol. 2010;7(5):265-79. gastrointestinal bleeding: comparison of different imaging . 2 Rockey DC. Occult gastrointestinal bleeding. N Engl J Med. modalities. Abdom Imaging. 2012;37(1):41-52. 1999;341(1):38-46. 22. Kim BS, Li BT, Engel A, et al. Diagnosis of gastrointestinal bleeding: . 3 Zuckerman GR, Prakash C, Askin MP, et al. American a practical guide for clinicians. World J Gastrointest Pathophysiol. Gastroenterological Association (AGA) technical review on the 2014;5(4):467-78. evaluation and management of occult and obscure gastrointestinal 23. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients bleeding. Gastroenterology. 2000;118(1):201-21. with iron deficiency anemia. N Engl J Med. 1993;329(23):1691-5. . 4 Raju GS, Gerson L, Das A, et al. American Gastroenterological 24. McLoughlin MT, Tham TC. Long-term follow-up of patients with iron Association (AGA) Institute technical review on obscure deficiency anaemia after a negative gastrointestinal evaluation. Eur gastrointestinal bleeding. Gastroenterology. 2007;133(5):1697-717. J Gastroenterol Hepatol. 2009;21(8):872-6.

MU-142.indd 926 29-01-2021 14:57:03 CHAPTER

Endoscopic Ultrasound 143 for the Internist

Surinder S Rana

Abstract Endoscopic ultrasound (EUS) is a relatively new innovation in the field of gastrointestinal (GI) endoscopy that combines the endoscope and ultrasound transducer for examining the GI tract wall and structures beyond. The ability to place the ultrasound transducer very close to the structures/organs being evaluated allows use of high frequencies that provide very high resolution images. EUS is used for both diagnostic as well as therapeutic purposes. The diagnostic indications can be either for primary diagnosis where EUS is used as a primary diagnostic modality for diagnosing diseases like evaluation of idiopathic acute pancreatitis as well as diagnosis of chronic pancreatitis or as a secondary diagnostic modality for detailed evaluation of already diagnosed disease like submucosal lesions, dilated bile duct, and pancreatic cystic lesions or EUS guided FNA of GI as well as surrounding structures like lymph nodes or locoregional staging of GI cancers. Therapeutic EUS has phenomenally expanded in last one decade and a number of procedures like pseudocyst/walled off necrosis drainage, celiac plexus blockade/neurolysis, intra-abdominal abscess drainage, mediastinal abscess drainage, vascular interventions, intratumoral therapy, and biliary as well as pancreatic drainage can be safely done under EUS guidance. Development of newer technologies like EUS elastography and contrast EUS is going to further expand the role of EUS. It is important for an internist to be aware of the indications and strengths of EUS in various abdominal, thoracic as well as pelvic diseases.

Introduction by transabdominal ultrasound as well as other cross- sectional imaging techniques. Therefore, there has been Endoscopic ultrasound (EUS) is a relatively new gradual expansion in its clinical indications and it has innovation in the field of gastrointestinal (GI) endoscopy that combines the endoscope (for visualizing the mucosa evolved from a purely diagnostic modality to an important of the GI lumen) and ultrasound transducer for examining therapeutic tool. Its advent has made the locoregional the GI tract wall and structures beyond it.1 The desire staging of many GI cancers accurate and also made a to see the structures beyond the GI lumen led on to number of GI therapeutic procedures safer. The advent of development of EUS. Over last three decades, EUS has EUS guided fine needle aspiration (FNA) has made it the evolved tremendously from a research tool to important procedure of choice for tissue diagnosis of various benign investigational tool in routine clinical practice. The as well as malignant GI lesions. It has changed the daily ability to place the ultrasound transducer very close to clinical practice of not only gastroenterologists, but also the structures/organs being evaluated allows use of high surgical gastroenterologists, oncologists, pulmonologists, frequencies that provide very high resolution images.2 radiologists, as well as internists. Therefore, it is very These images are much better than those obtained important for an internist to be aware of the current

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indications, strengths as well as limitations of EUS. This diagnostic indications can be either for primary diagnosis review discusses in brief the diagnostic and therapeutic where EUS is used as a primary diagnostic modality for indications of EUS. diagnosing diseases like evaluation of idiopathic acute pancreatitis as well as diagnosis of chronic pancreatitis or Types of EUS Scopes as a secondary diagnostic modality for detailed evaluation of already diagnosed disease like submucosal lesions Broadly, there are two types of EUS scopes (echo­ (SMLs), dilated bile duct and pancreatic cystic lesions endoscopes). The first developed echoendoscope was (PCL) or EUS guided FNA of GI as well as surrounding a radial echoendoscope with a 360-degree transducer structures like lymph nodes or locoregional staging of GI that has a scanning plane of ultrasound perpendicular cancers. to the long axis of the echoendoscope. This is a purely Therapeutic EUS has phenomenally expanded in last diagnostic echoendoscope and no intervention or FNA one decade and a number of procedures like pseudocyst/ can be done with this scope. To overcome this limitation, walled off necrosis drainage, celiac plexus blockade/ linear echoendoscopes were developed in which the neurolysis, intra-abdominal abscess drainage, mediastinal scanning plane of transducer is parallel to the long axis of abscess drainage, vascular interventions, intratumoral the echoendoscope so that the entire needle can be seen 3 therapy and biliary as well as pancreatic drainage can be in real time during FNA/interventions. safely done under EUS guidance. Apart from these two commonly echoendoscopes, a new echoendoscope has recently been developed. EUS as a Primary Diagnostic Modality The forward viewing echoendoscope has a forward endoscopic view instead of oblique endoscopic view of Idiopathic Acute Pancreatitis linear echoendoscope and has a shorter and more flexible EUS provides high-resolution images of pancreas and tip. Therefore, it is more easily maneuverable and can be biliary tract, and therefore is an important investigation for used instead of oblique viewing echoendoscope in difficult evaluation of patients with idiopathic acute pancreatitis. anatomical situations. However, absence of elevator at the It is an excellent modality for diagnosis of occult tip of echoendoscope makes the interventions difficult cholelithiasis or choledocholithiasis, microlithiasis, or with this scope. Therefore, this scope is usually used in gallbladder sludge (Fig. 1), pancreatic duct anomalies those situations where linear echoendoscope cannot be like pancreas divisum, occult pancreatic neoplasm and used because of anatomical constraints. importantly, exclude chronic pancreatitis.4 Studies have shown that EUS is a useful and minimally invasive tool Indications of EUS for the diagnostic evaluation of idiopathic pancreatitis The clinical indications for EUS can be divided into two and in case of negative EUS examination relapses of broad categories: diagnostic and therapeutic (Table 1). The pancreatitis are infrequent.5,6 EUS may also help in

TABLE 1 Indications for EUS

Diagnostic EUS Therapeutic EUS Primary diagnostic modality zz Drainage of pancreatic fluid collections zz Idiopathic acute pancreatitis zz Biliary and pancreatic duct drainage in cases of failed ERCP zz Diagnosis of chronic pancreatitis especially early chronic pancreatitis zz Transmural gallbladder drainage zz Secondary diagnostic modality EUS-guided celiac plexus neurolysis/blockade zz Drainage of mediastinal and intra-abdominal abscesses and zz Dilated common bile duct collections zz Pancreatic cystic lesions zz EUS-guided vascular interventions zz GI submucosal lesions zz EUS-guided palliative oncological interventions zz Locoregional staging of GI cancers zz EUS-guided gastrojejunostomy zz EUS guided fine needle aspiration or biopsy zz EUS guided aspiration of minimal pleural effusion/ascites

ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; GI, gastrointestinal

MU-143.indd 928 29-01-2021 14:56:55 Endoscopic Ultrasound for the Internist CHAPTER 143 929

Fig. 1: EUS: gallbladder sludge in idiopathic acute pancreatitis Fig. 2: EUS in a patient with chronic pancreatitis. Ductal calculi (arrow) noted

diagnosing uncommon causes for AP such as pancreatico- elastography that evaluate the stiffness of pancreas appear biliary ascariasis and parathyroid adenomas. to be promising techniques for confident diagnosis of early CP. 7 However, further studies are required to determine Diagnosis of Chronic Pancreatitis their exact role in diagnosis of early CP. EUS has unique capability of demonstrating subtle structural alterations in the pancreatic parenchyma as EUS as a Secondary Diagnostic Modality well as ducts even before conventional imaging modalities EUS for Submucosal Lesions demonstrate any abnormality (Fig. 2).7 The conventional SMLs are usually asymptomatic lesions with normal imaging modalities like computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) overlying mucosa detected on routine endoscopy and can pick up advanced morphological changes of chronic require further evaluation for confirmatory diagnosis. pancreatitis (CP) only, and therefore they have very low Endoscopy and biopsy have limited role in evaluation of sensitivity for diagnosis of early CP. EUS by demonstrating SMLs because of normal overlying mucosa. The ability of early parenchymal and ductal changes can help in early EUS to image structures beyond GI lumen makes it ideal diagnosis of CP. In patients with presumed acute recurrent modality for investigations of SMLs. EUS is an excellent pancreatitis, EUS can help in excluding underlying CP. modality to differentiate extramural compression and SML 8-10 However, EUS is not a panacea for diagnosis of CP. as well as determine the type and nature of SML. EUS Being a highly sensitive imaging modality, there is a can help in presumptive diagnosis of SML by accurately concern for overdiagnosis of CP. To overcome these estimating the size, the layer of origin, the echo-pattern limitations, advanced and complicated scoring systems and the margins of the lesion. The diagnostic accuracy of incorporating multiple parenchymal and ductal EUS EUS can further be enhanced by cytological or histological features have been used for diagnosis of CP. Despite analysis of specimens obtained by EUS guided FNA/fine these scoring systems, concerns about interobserver needle biopsy (FNB). variability as well as aging, smoking, obesity, and chronic alcohol consumption causing EUS changes in pancreas EUS for Unexplained Dilated Common Bile Duct mimicking CP persist. Therefore, EUS findings of CP EUS transducer from duodenum closely images the should be interpreted in an appropriate clinical context CBD, and therefore has very high diagnostic accuracy for and, if required, should be confirmed and followed up by lower and mid CBD lesions.11-13 Isolated CBD dilatation serial EUS examinations. Newer EUS techniques like EUS is commonly encountered in clinical practice because

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Fig. 3: EUS in dilated common bile duct (CBD). A stone noted in Fig. 4: EUS: mucinous cystadenoma of pancreas lower CBD (arrow)

of wide spread use of cross-sectional imaging modalities like contrast-enhanced EUS, EUS guided cystoscopy, for patients with non-specific abdominal symptoms. In needle-based confocal laser endomicroscopy, and many of these patients cross-sectional imaging modalities through-the-needle forceps biopsy provide important like ultrasound, CT, and MRCP fail to identify the etiology information for accurate diagnosis of PCL. of dilated CBD and many of these patients required endoscopic retrograde cholangiopancreatography EUS for Locoregional Staging of GI Cancers (ERCP) for confirming the diagnosis. ERCP is an invasive EUS can accurately define the walls of the GI tract and procedure with inherent risks of serious adverse effects like thus is an accurate modality to assess the transverse post ERCP pancreatitis. In these clinical situations EUS has spread of malignant lesion. It can also accurately assess been demonstrated to be an excellent diagnostic modality the extraluminal involvement of the malignant lesion by for identifying underlying etiology of unexplained CBD identifying lymph nodal as well as arterial and venous dilatation (Fig. 3). More importantly, if EUS is normal, involvement. Therefore, over last decade EUS has thus there is extremely less likelihood of presence of any become an important investigation for preoperative significant underlying disease and patient therefore should be reassured and no further follow-up is required.11-13 assessment for majority of the GI cancers including esophageal, gastric, pancreaticobiliary, as well as rectal 18 EUS in Pancreatic Cystic Lesions cancers. EUS from esophagus can also evaluate the mediastinum, and therefore EUS is an important imaging Evaluation of patients with PCL requires a confident modality for accurate staging of non-small cell lung differentiation of malignant, potentially malignant and cancer. Combining EUS with endobronchial ultrasound benign PCL. EUS is a useful modality for evaluation of (EBUS) allows access to all mediastinal lymph node PCL as it can provide information about the detailed stations, and therefore is an important staging modality morphology of cysts (Fig. 4) as well as enable guided FNA for lung cancer.18,19 to obtain cyst fluid for cytological, biochemical as well as molecular analysis.14-17 Cyst fluid carcinoembryonic antigen (CEA) levels more than 192 ng/mL have been EUS-guided Tissue Acquisition shown to have highest sensitivity and specificity for Linear echoendoscope is used to perform EUS-guided differentiating mucinous from non-mucinous PCL.14 Cyst FNA with great precision in real time as the needle is fluid molecular markers hold considerable promise for visualized in real time throughout the procedure. The proper evaluation of PCL. New EUS based technologies advantage of EUS-guided FNA is its ability to acquire

MU-143.indd 930 29-01-2021 14:56:56 Endoscopic Ultrasound for the Internist CHAPTER 143 931

Fig. 5: EUS-guided FNA from preaortic lymph node Fig. 6: EUS-guided drainage of pancreatic pseudocyst

tissue from difficult to access anatomical locations in EUS is its ability to provide a real time imaging of the abdomen, retroperitoneum, mediastinum, and perirectal targeted area and also, importantly, avoiding adjacent spaces.20 EUS guided FNA is now routinely used in clinical vascular and other structures.27 Various EUS guided practice to acquire tissue for histological diagnosis from interventional procedures that are being performed pancreas, lymph nodes in mediastinum and abdomen are drainage of pancreatic fluid collections, biliary (Fig. 5), GI SMLs, perirectal lesions, left lobe of liver, left and pancreatic duct drainage in cases of failed ERCP, adrenal, and mediastinal masses. EUS can also be used transmural gallbladder drainage, celiac plexus neurolysis for aspirating minimal amount of ascites and pleural (CPN)/blockade, drainage of mediastinal and intra- effusion.21-23 It can also be used for visualizing as well as abdominal abscesses and collections, various vascular sampling peritoneal as well as pleural deposits in patients interventions, endoscopic gastrojejunostomy and is useful with undiagnosed pleural effusion as well as ascites.21,23,24 for targeted chemotherapy and radiotherapy. Despite being in GI endoscopy practice for more than CPN is a procedure of chemical ablation of the celiac a decade, EUS FNA has important limitations like false plexus using absolute alcohol or phenol for relief of positivity in pancreatic masses in CP and autoimmune intractable pain because of pancreatic cancer. It is usually pancreatitis and false negativity because of technical done under ultrasound, or CT guidance or surgically. difficulty, marked desmoplastic background, sampling Advent of EUS guided CPN has made this procedure very error, or interpretative errors. Moreover, certain diseases safe with rare adverse effects. Although EUS, CPN is safe like lymphoma and autoimmune pancreatitis require and effective, but the pain relief is usually short lasting and cote biopsy for confident diagnosis. To overcome these patient may require repeated procedures for effective pain limitations of EUS FNA, newer FNB needles have been relief.28 developed for use with EUS.25,26 EUS guided FNB has EUS guided transmural drainage of pancreatic fluid been demonstrated to provide samples with increased collections including pseudocysts (Fig. 6) as well as cellularity along with preserved histologic architecture, walled off necrosis has evolved as its treatment of choice and therefore seems to be an ideal tissue acquisition and is preferred over surgical as well as percutaneous technique for histological as well as molecular testing. drainage.29,30 Being minimally invasive, safe, effective, and absence of external percutaneous drainage catheter Therapeutic EUS are important advantages of EUS guided drainage of EUS has the ability to visualize organs and lesions adjacent pancreatic fluid collections. Developments of fully to GI tract and thus provide an opportunity to target them covered lumen apposing metal stents (LAMS) have further for various therapeutic procedures. The advantages of improved results of EUS guided drainage of pancreatic

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fluid collections. Similarly, abscesses or collections in References locations adjacent to GI tract like mediastinal, left lobe . 1 Friedberg SR, Lachter J. Endoscopic ultrasound: current roles and of liver, lesser sac, and pelvic collections can be drained future directions. World J Gastrointest Endosc. 2017;9(10):499-505. 27 under EUS guidance. 2. Godfrey EM, Rushbrook SM, Carroll NR, et al. Endoscopic ultrasound: EUS-guided transmural drainage of biliary tract and a review of current diagnostic and therapeutic applications. pancreatic duct is an effective alternative to percutaneous Postgrad Med J. 2010;86(1016):346-53. or surgical drainage of these ducts in patients with . 3 Caddy GR, Chen RY. Current clinical applications of endoscopic failed ERCP.27 Although these procedures are effective ultrasound. ANZ J Surg. 2007;77(3):101-11. 4. Rana SS, Bhasin DK, Rao C, et al. Role of endoscopic ultrasound in but are technically challenging, and therefore should be idiopathic acute pancreatitis with negative ultrasound, computed performed only by experts in centers with radiological and tomography, and magnetic resonance cholangiopancreatography. surgical back up. Similarly, EUS can be used for draining Ann Gastroenterol. 2012;25(2):133-7. gallbladder in cases of acute cholecystitis not responding 5. Somani P, Sunkara T, Sharma M, et al. Role of endoscopic ultrasound to antibiotics and has been shown to be safer and effective in idiopathic pancreatitis. World J Gastroenterol. 2017;23(38): alternative to percutaneous drainage of gallbladder with 6952-61. added advantage of absence of percutaneous drain. 6. Wilcox CM, Seay T, Kim H, et al. Prospective endoscopic ultrasound- based approach to the evaluation of idiopathic pancreatitis: causes, Advancement in accessories for EUS has led on to response to therapy, and long-term outcome. Am J Gastroenterol. exploration of unthinkable therapeutic areas. Various 2016;111(9):1339-48. palliative oncological interventions like EUS-guided . 7 Rana SS, Vilmann P. Endoscopic ultrasound features of chronic brachytherapy, fiducial marker placement, ethanol pancreatitis: a pictorial review. Endosc Ultrasound. 2015;4(1):10-14. ablation, and EUS-guided delivery of antitumor agents can . 8 Landi B, Palazzo L. The role of endosonography in submucosal be performed and studies have shown them to be safe and tumours. Best Pract Res Clin Gastroenterol. 2009;23(5):679-701. . 9 Reddy Y, Willert RP. Endoscopic ultrasound: what is it and when effective.27 EUS has expanded into vascular interventions should it be used? Clin Med (Lond). 2009;9(6):539-43. field also with various EUS guided interventions like EUS 10. Chung IK, Hawes RH. Advantages and limitations of endoscopic guided glue or coil injections into gastric/ectopic varices ultrasonography in the evaluation and management of as well as pseudoaneurysms being safely performed. patients with gastrointestinal submucosal tumors: a review. Rev EUS-guided intrahepatic portosystemic shunt has also Gastroenterol Disord. 2007;7(4):179-92. been performed as an alternative to TIPS (transjugular 11. De Angelis C, Marietti M, Bruno M, et al. Endoscopic ultrasound in intrahepatic portosystemic shunt) for the treatment of common bile duct dilatation with normal liver enzymes. World J Gastrointest Endosc. 2015;7(8):799-805. consequences of portal hypertension. Advancement in 12. Holm AN, Gerke H. What should be done with a dilated bile duct? EUS had made it possible to perform various surgical Curr Gastroenterol Rep. 2010;12(2):150-6. procedures like gastrojejunostomy safely in a minimally 13. Rana SS, Bhasin DK, Sharma V, et al. Role of endoscopic ultrasound invasive fashion under EUS guidance.31 in evaluation of unexplained common bile duct dilatation on magnetic resonance cholangiopancreatography. Ann Conclusion Gastroenterol. 2013;26(1):66-70. 14. Lévy P, Rebours V. The role of endoscopic ultrasound in the diagnosis EUS is an important investigation in the armamentarium of of cystic lesions of the pancreas. Visc Med. 2018;34(3):192-6. an endoscopist. EUS has been shown to have a significant 15. Ohno E, Hirooka Y, Kawashima H, et al. Endoscopic ultrasonography impact in management of patients with various GI disorders for the evaluation of pancreatic cystic neoplasms. J Med Ultrason. with significant change in both the diagnosis as well as 2020:47(3):401-11. management.3 The advent of EUS-guided FNA for tissue 16. Pausawasdi N, Ratanachu-Ek T. Endoscopic ultrasonography diagnosis as well as therapeutic EUS has led on to wider evaluation for pancreatic cysts: necessity or overkill? Dig Endosc. clinical applications of EUS. Locoregional staging of various 2017;29(4):444-54. GI cancers is one of the important clinical applications of EUS 17. Westerveld DR, Ponniah SA, Draganov PV, et al. Diagnostic yield in clinical practice. Development of newer technologies like of EUS-guided through-the-needle microforceps biopsy versus EUS elastography and contrast EUS is going to further expand EUS-FNA of pancreatic cystic lesions: a systematic review and meta- the role of EUS. It is important for an internist to be aware of analysis. Endosc Int Open. 2020;8(5):656-67. the indications and strengths of EUS in various abdominal, 18. Lennon AM, Penman ID. Endoscopic ultrasound in cancer staging. thoracic, as well as pelvic diseases. Brit Med Bull. 2007;84(1):81-98.

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19. Ang TL, Kwek ABE, Wang LM, et al. Diagnostic endoscopic 26. Park JK, Lee KH. Present and future of endoscopic ultrasound- ultrasound: technique, current status and future directions. Gut guided tissue acquisition in solid pancreatic tumors. Clin Endosc. Liver. 2018;12(5):483-96. 2019;52(6):541-8. 20. Rana A, Rana SS. Endoscopic ultrasound-guided tissue acquisition: 27. Sharma V, Rana SS, Bhasin DK, et al. Endoscopic ultrasound techniques and challenges. J Cytol. 2019;36(1):1-7. guided interventional procedures. World J Gastrointest Endosc. 21. Rana SS, Bhasin DK, Srinivasan R, et al. Endoscopic ultrasound- 2015;7(6):628-42. guided fine needle aspiration of peritoneal nodules in patients with 28. Wyse JM, Sahai AV. Endoscopic ultrasound-guided management of ascites of unknown cause. Endoscopy. 2011;43(11):1010-3. pain in chronic pancreatitis and pancreatic cancer: an update. Curr 22. Rana SS, Sharma R, Gupta R, et al. Endoscopic ultrasound-guided Treat Options Gastroenterol. 2018;16(4):417-27. transesophageal thoracentesis for minimal pleural effusion. Indian 29. Guo J, Saftoiu A, Vilmann P, et al. A multi-institutional consensus J Gastroenterol. 2018;37(3):231-4. on how to perform endoscopic ultrasound-guided peri-pancreatic 23. Rana SS, Sharma R, Srinivasan R, et al. Contrast-enhanced EUS in the fluid collection drainage and endoscopic necrosectomy. Endosc evaluation of peritoneum and omentum in undiagnosed ascites. Endosc Ultrasound. 2020;9(1):69-70. Ultrasound. 2017;6(5):285-91. 24. Rana SS, Gupta P, Sharma RK, et al. Pleural metastasis detected 30. Rana SS, Sharma V, Sharma R, et al. Endoscopic ultrasound guided by transesophageal endoscopic ultrasonography. JGH Open. transmural drainage of walled off pancreatic necrosis using a 2019;3(5):441-3. “step–up” approach: a single centre experience. Pancreatology. 25. DeWitt J, Cho CM, Lin J, et al. Comparison of EUS-guided tissue 2017;17(2):203-8. acquisition using two different 19-gauge core biopsy needles: a 31. Braden B, Gupta V, Dietrich CF, et al. Therapeutic EUS: new tools, multicenter, prospective, randomized, and blinded study. Endosc new devices, new applications. Endosc Ultrasound. 2019;8(6): Int Open. 2015;3(5):471-8. 370-81.

MU-143.indd 933 29-01-2021 14:56:56 CHAPTER

Gastroesophageal Reflux 144 Disease—What’s New!

Piyush Dadhich, Shraddha Sharma, Shreyans Singhvi, Gautam Bhandari, Sunil Kumar Dadhich

Abstract Gastroesophageal reflux disease (GERD) is a frequently encountered disease in clinical practice that significantly hampers the quality of life of patients. Long-term complications of GERD are another area of concern that necessitates timely diagnosis and treatment. Both acid and non-acid reflux have been implicated into the pathophysiology of GERD. Ambulatory 24-hour pH monitoring is the gold standard test for diagnosis. Proton pump inhibitors (PPIs) along with lifestyle modifications are the mainstay of treatment. However, they have their own range of side effects, which precludes their long-term use. Moreover, 20–40% patients show persistent symptoms despite adequate PPI therapy. Management

of refractory GERD requires optimization of PPI therapy, addition of a nighttime H2 receptor antagonist, baclofen and neuromodulators. However, promising results have not been obtained with any of these so far. Newer enantiomers of PPI, potassium-competitive acid blockers, and TLESR-reducers are under trial phase. However, due to the disturbing recurrent nature of symptoms, patients’ preference for surgical and endoluminal therapies is apparent. This chapter briefly outlines the pathophysiology and current treatment options for GERD with focus on recent advancements in medical, endoluminal, and surgical management strategies of the disease.

Introduction into the esophagus, oropharynx, and/or respiratory tract. Gastroesophageal reflux disease (GERD) is a global „„ NERD—GERD symptoms without erosions on disease. While the prevalence in western population is endoscopy in absence of recent acid-suppressive 18.1–27.8%, it is believed to be lower in the East Asian therapy. population (<10%). The overall prevalence of GERD in „„ Erosions on endoscopy (EE)—EE with/without India is 7.6%.1,2 GERD symptoms. GERD is associated with deleterious effects on day-to- „„ Barrett’s esophagus (BE)—Endoscopic presence, day activities, reduced work efficiency, and sleep, ultimately confirmed histologically of columnar-lined esophagus. affecting the quality of life. Further, long-term complications It is known to have malignant potential. like stricture, Barrett’s esophagus, and adenocarcinoma „„ Extraesophageal GERD syndrome—This includes: also necessitate timely diagnosis and treatment. —— Conditions with established association with 3 GERD (cough, laryngitis, asthma, and dental Definitions erosions). „„ GERD—Troublesome symptoms sufficient to impair —— Conditions with only a proposed association an individual’s quality of life or injury or complications (pharyngitis, sinusitis, idiopathic pulmonary that result from the retrograde flow of gastric contents fibrosis).

MU-144.indd 934 29-01-2021 14:56:45 Gastroesophageal Reflux Disease—What’s New! CHAPTER 144 935

Causative and Protective Factors Clinical Features „„ Causative Factors „„ GERD symptoms can be classified into typical and 3 Older age Pregnancy atypical: Obesity Smoking and alcohol Typical Atypical symptoms Anxiety/depression Less physical activity symptoms Large meals just before sleep High dietary fat intake zz Heartburn zz Nausea, zz Chest pain Certain medication like NSAIDs, zz Regurgitation vomiting zz Nocturnal awakening calcium channel blockers zz Water brash zz Belching zz Chronic cough zz Early satiety zz Asthma „„ Protective Factors: Helicobacter pylori infection and zz Epigastric pain zz Chronic sinusitis physical activity seem to play a protective role. zz Hoarseness zz Recurrent sore throat zz Globus 4 sensation Pathophysiology zz Dental enamel GERD is the disease of lower esophageal sphincter (LES). loss

The acid reflux is most commonly caused due to transient „„ Atypical extraesophageal symptoms lead to difficult relaxation of lower esophageal sphincter (TLESRs), which and delayed diagnosis. is a physiological phenomenon and increases in frequency „„ They have poor response to conventional therapy. postprandially. 3,5-8 Other factors that contribute to acid reflux include: Diagnosis „„ Decreased LES pressure The initial diagnosis is usually made on the basis of „„ Increased intra-abdominal pressure cardinal symptoms and response to PPI therapy. „„ Hiatal hernia In presence of atypical symptoms, it is important „„ Poor esophageal acid clearance to rule out other gastrointestinal disorders (e.g., ulcers, „„ Delayed gastric emptying malignancy) and non-gastrointestinal diseases (e.g., Non-acid Reflux5 ischemic heart disease). „„ Undoubtedly, acid reflux is the chief cause of symptoms PPI Diagnostic Test in GERD patients, making gastric acid suppressive therapy (proton pump inhibitor, PPI) the mainstay of „„ Patients with typical symptoms can be put on PPI treatment. therapy and followed up to 8 weeks. „„ Almost 20–40% patients continue to be symptomatic „„ In patients with symptoms despite acid suppression, the culprit in more than 80% cases is non-acid reflux even on adequate PPI treatment. (pH>4). „„ The patients with inadequate response and those with „„ Three types of refluxes have been defined based on pH: alarm symptoms need further evaluation. —— Acid reflux—pH<4 Alarm features —— Weakly acidic reflux—pH 4–7 Dysphagia Early satiety —— Weakly alkaline reflux—pH>7 Odynophagia Vomiting „„ The proposed mechanisms are: Gastrointestinal bleeding Age > 55 years —— Duodenogastric-esophageal reflux—Regurgitation Weight loss Family history of upper GI of duodenal contents, containing biliary and malignancy pancreatic secretions into stomach and esophagus. Iron deficiency anemia —— Large volume of refluxate triggering symptoms irrespective of its acidity by mechanical stimulation Upper Gastrointestinal (UGI) Endoscopy of esophagus. „„ UGI endoscopy should be done in all patients with —— Greater proximal esophageal extent of reflux —— Alarm features resulting in increased likelihood of symptoms. —— Suboptimal response to PPI therapy.

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—— Long standing GERD, endoscopy is necessary to Barium Esophagogram assess for complications. „„ It has no role in diagnosing GERD „„ Erosive esophagitis should be graded on the basis of „„ It helps in detecting achalasia, esophageal stricture, or endoscopy findings as follows: hiatus hernia. Los Angeles classification of erosive esophagitis3 Grade A One or more mucosal breaks, ≤5 mm, none of which EndoFLIP (Endoscopic Functional Luminal extends between the tops of the mucosal folds Imaging Probe) System Grade B One or more mucosal breaks, >5 mm long, none of which „„ It assesses the distensibility of esophageal body and GE extends between the tops of two mucosal folds junction at various volume-controlled (usually 20–30 Grade C Mucosal breaks that extend between the tops of two or more mucosal folds, but which involve <75% of the mL) distending pressures esophageal circumference „„ GERD patients seem to have increased GE junction Grade D Mucosal breaks that involve at least 75% of the distensibility esophageal circumference „„ FLIP can also identify esophageal motility disorders „„ It serves as a useful tool in anti-reflux procedures „„ Endoscopy guided biopsy is indicated in patients where eosinophilic esophagitis is suspected and in those with Barrett’s esophagus. Multichannel Intraluminal Impedance Monitoring „„ To diagnose non-acid reflux, pH monitoring is not Ambulatory 24-hour pH Monitoring quite helpful as it uses acidity as marker of reflux but not the actual reflux. „„ It is the gold standard for diagnosis of GERD „„ Multichannel intraluminal impedance monitoring „„ It is used to quantify: combined with pH monitoring can reliably identify —— Esophageal acid exposure time (EAT) non-acid reflux. —— Number of reflux events (events when pH „„ The technique uses changes in resistance to electrical decreases to <4) currents to detect the presence of intraluminal liquid. —— Nature of refluxate (acidic/neutral/alkaline) „„ An EAT of more than 6% and a total of more than 80 3,7 reflux episodes in 24 hours are considered abnormal. Treatment „„ Normally carried out for 24 hours, the test can be extended up to 96 hours using Bravo esophageal pH Lifestyle Modifications recorder capsule. In patients with uncomplicated GERD, the initial step of „„ It is done: management is lifestyle modifications which include: —— Off PPI: „„ Elevation of head end of bed by 4–8 inches In patients with unproven GERD (no or LA grade „„ Dietary changes A/B esophagitis) —— Avoiding fatty, spicy, large meals Before surgery —— Avoiding late evening snacks Atypical presentations —— Avoiding chocolate, citrus foods, caffeine, —— On PPI: carbonated drinks In proven GERD (LA grade C/D esophagitis) or BE „„ Minimizing smoking and alcohol > 1 cm or prior abnormal pH study „„ Weight reduction To establish causation of refractory symptoms „„ Avoid NSAIDs

Esophageal Manometry Medical Management „„ It does not help in diagnosis of GERD This comprises of acid-neutralizing (antacids) and acid- „„ It is used to localize LES before placement of capsule in suppressing (H2RA, PPI) agents. 24-hour pH metry. „„ Antacids: „„ It helps to diagnose motor disorders like achalasia. —— Mostly used for occasional or short-term symptoms

MU-144.indd 936 29-01-2021 14:56:46 Gastroesophageal Reflux Disease—What’s New! CHAPTER 144 937

—— Include sodium, calcium, aluminum, magnesium „„ This leads to excessive cost of therapy as well as salts, and alginate containing agents adverse effects „„ Histamine type-2 receptor antagonists (H2RA): „„ Most of the side effects are mild and self-limiting like —— Better efficacy and prolonged action than antacids headache, nausea, abdominal pain, and flatulence —— However, tachyphylaxis (usually within 2 weeks) „„ Recent studies, however, reveal association of PPI with is an issue some serious adverse effects —— Should not be given at same time as PPI —— Currently, there are four FDA-approved H2RAs: Refractory GERD9,10 cimetidine, famotidine, nizatidine, and ranitidine Refractory heartburn is defined as symptoms of reflux of —— Lavoltidine and lafutidine are under trial gastric content that do not respond to a double dose of a „„ Proton pump inhibitors: PPI given for at least 8 weeks. —— Most potent and hence, the mainstay of treatment Functional heartburn and reflux hyper-sensitivity are —— PPIs have a better, faster, and long-lasting effect in the most common underlying mechanisms. Other less both NERD and EE common mechanisms include psychological factors, —— Most effective when taken 30 minutes before functional bowel disorders, delayed gastric emptying, bile meals reflux, rapid PPI metabolism, PPI resistance or improper Acid suppression can be achieved in the following PPI timing. three ways: Every patient with refractory GERD should also be „„ Step-up therapy: evaluated for Eosinophilic esophagitis (EoE), achalasia —— Starting with less potent agent and moving up for and Zollinger-Ellison syndrome. response —— Patient is first started on H2RA The management of refractory GERD includes: —— If no response is seen for 2 weeks, patient is shifted „„ Optimization of PPI therapy to PPI followed by double dose of PPI —— Lifestyle modifications „„ Step-down therapy: —— Better compliance —— Patient is started with twice daily dose of PPI —— Proper dosing time —— When response is achieved, he is switched to once —— Splitting the dose daily dose followed by on-demand dose —— Shifting to another PPI „„ On-demand therapy: „„ Adding a night-time H2 receptor antagonist. —— Here patient is given standard dosage of H2RA or „„ Baclofen- A gamma-aminobutyric acid-B agonist (5-20 PPI as and when needed mg three times a day) reduces gastroesophageal reflux by decreasing TLESR rate. Side Effects of PPI „„ Neuro-modulators (like tricyclic-antidepressants, „„ The efficacy and ease of availability of PPI has led to its selective serotonin-reuptake inhibitors, serotonin- misuse norepinephrine reuptake inhibitors and trazodone) „„ Patients either self-treat themselves or once prescribed, are effective in patients with functional heartburn or continue them for prolonged periods without re- reflux hypersensitivity. evaluation „„ Endoscopic treatment „„ Antireflux surgery. Side effects of PPIs 11 Pneumonia Vitamin B12 deficiency Recent Developments in Medical Management C. difficile diarrhea Iron deficiency „„ Extended-release PPIs: In order to increase their Risk of fractures Thrombocytopenia potency, PPIs have been modified into enantiomers Hypomagnesemia Rhabdomyolysis that undergo slower hepatic metabolism and maximum absorption and thus increased bioavailability. Acute interstitial nephritis Enteric infections and neoplasms —— Dexlansoprazole MR:

MU-144.indd 937 29-01-2021 14:56:46 938 SECTION 10 Gastroenterology

 Dual delayed-release formulation of dexlanso­ —— At least a partial response to PPI treatment prazole (R-enantiomer of lansoprazole) —— Preference for nonmedical, nonsurgical therapy  Two peaks of drug release; at 1–2 hours and at „„ Contraindications: 4–5 hours —— Morbid obesity  Can be given irrespective of meal timings —— Esophageal motility disorder (e.g., achalasia, —— Tenatoprazole and S-Tenatoprazole: scleroderma)  Contain an imidazopyridine molecule (not a —— Prior esophageal/gastric surgery benzimidazole molecule like other PPIs) —— Esophageal stricture or Barrett esophagus  Offer better night-time control, due to —— Esophageal/gastric varices prolonged half-life —— Pregnant/lactating women —— Esomeprazole strontium delayed-release „„ Basic techniques of endotherapy: (Esomezol) —— Constriction of LES by using thermal energy —— Ilaprazole —— Augmenting LES pressure by injecting bulking „„ PPI combinations: agent —— PPI-VB101 (Vecam): Combination of omeprazole —— Mechanical alteration of gastroesophageal and succinic acid that increases activation of junction (GEJ) 12 proton-pumps in parietal cells „„ Currently, three endoluminal methods are in practice: —— OX-17: Omeprazole plus famotidine —— Stretta procedure: —— NMI-826: Nitric-oxide-enhanced PPI  Here, compliance of LES is reduced by using —— Secretol: Omeprazole plus lansoprazole radiofrequency ablation „„ Potassium-competitive acid blockers (P-CABs):  This decreases frequency of TLESRs and + + „„ Act by reversibly inhibiting gastric H /K -ATPase by hence, reflux + competing with K —— Transoral incisionless fundoplication (TIF): „„ Do not need prior proton pump activation  Here using the Esophyx Z device, an anterior „„ Have a faster onset of action; hence, useful as on- full thickness fundoplication is done demand therapy  This constructs a valve 3–5 cm in length and „„ Linaprazan, Soraprazan, Revaprazan, and TAK-438 are greater than 270 degrees circumferential wrap P-CABs under trials around LES „„ Associated with side effects like hepatotoxicity. „„ Ultrasonic surgical endostapler „„ TLESR reducers: —— This technique makes use of a modified „„ Cannabinoid Receptor-agonists: Delta-9- endoscope that incorporates a miniature camera, tetrahydrocannabinol (CB1/CB2 receptor agonist), an ultrasound probe, and a stapler on its tip Rimonabant (CB1 receptor antagonist) —— With the use of this endoscope, an anterior full- „„ Cholecystokinin/Gastrin Receptors-antagonist: thickness fundoplication is done Itriglumide, Loxiglumide „„ Endoscopic procedures still under development are: „„ GABA-B agonists: Baclofen, Lesogaberan —— Anti-reflux mucosectomy —— Endoscopic full thickness plication Endoscopic Management —— Submucosal injection of a biocompatible „„ Endoluminal procedures offer a less invasive means of substance treating GERD 3,7 „„ Patients suitable for endotherapy are those with: Surgical Management —— Typical symptoms of GERD „„ The anti-reflux surgery is said to have only marginal —— Low-grade EE (Los Angeles Grades A and B) long-term benefit over PPI therapy —— Endoscopy negative with abnormal esophageal „„ Patients with typical symptoms respond better to acid exposure surgery than those with atypical or extra-esophageal —— No or small hiatal hernia (<3 cm) symptoms

MU-144.indd 938 29-01-2021 14:56:47 Gastroesophageal Reflux Disease—What’s New! CHAPTER 144 939

„„ Approximately half of the patients will still need anti- References reflux medications, post-surgery . 1 El-Serag HB, Sweet S, Winchester CC, et al. Update on the „„ Further, postoperative complications like solid food epidemiology of gastrooesophageal reflux disease: a systematic dysphagia, diarrhea, and early satiety have been review. Gut. 2014;63(6):871-80. reported in 7–10% patients 2. Bhatia SJ, Reddy DN, Ghoshal UC, et al. Epidemiology and symptom „„ Surgery does not prevent progression to adeno­ profile of gastroesophageal reflux in the Indian population: report carcinoma of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol. 2011;30(3):118-27. „„ Patients who will be benefitted the most from surgery . 3 Hunt R, Armstrong D, Katelaris PH, et al. World Gastroenterology are those with: Organisation Global Guidelines. Global perspective on —— No response, non-compliance or intolerance to gastroesophageal reflux disease. J Clin Gastroenterol. medical therapy 2017;51(6):467-78. 4. Herregods TV, Bredenoord AJ, Smout AJ, et al. Pathophysiology of —— Complications like refractory esophagitis, stric­ gastroesophageal reflux disease: new understanding in a new era. ture, and BE Neuro Gastro Enteral Motil. 2015;27(9):1202-13. —— Large hiatus hernia (>5 cm) . 5 Karamanolis G, Tutuian R. Role of non-acid in patients with non- —— Documented acid reflux with defective anti-reflux erosive reflux disease. Ann Gastroenterol. 2013;26(2):100-3. barrier 6. Boeckxstaens GE, Smout A. Systematic review: role of acid, weakly —— Cardiac dysfunction acidic and weakly alkaline reflux in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2010;32(3):334-43. —— Normal gastric emptying and esophageal motility TM 13 . 7 Bhatia SJ, Makharia GK, Abraham P, et al. Indian consensus on „„ Linx reflux management system: gastroesophageal reflux disease in adults: a position statement —— This device is in the form of a ring made by series of the Indian Society of Gastroenterology. Indian J Gastroenterol. of titanium beads with a magnetic core connected 2019;38(5):411-40. with titanium wires . 8 Kwiatek MA, Kahrilas K, Soper NJ, et al. Esophagogastric junction distensibility after fundoplication assessed with a novel functional —— This ring is placed, laparoscopically, around the luminal imaging probe. J Gastrointest Surg. 2010;14(2):268-76. lower end of distal esophagus 9. Fass R, Gasiorowska A. Refractory GERD: what is it? Curr Gastroenterol —— It prevents reflux by augmenting LES Rep. 2008;10(3):252-7. —— Short-term studies are promising with more than 10. Fass R. Therapeutic options for refractory gastroesophageal reflux 90% patients reporting improvement in quality of disease. J Gastroenterol Hepatol. 2012;27(3):3-7. life 11. Maradey-Romero C, Fass R. New and future drug development for gastroesophageal reflux disease, J Neurogastroenterol Motil. —— However, dysphagia was seen in 68% patients 2014;20(1):6-16. 12. Nabi Z, Reddy DN. Endoscopic management of gastroesophageal Conclusion reflux disease: revisited. Clin Endosc. 2016;49(5):408-16. 13. Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device GERD is a common gastrointestinal disorder with significant for gastroesophageal reflux disease. N Engl J Med. 2013;368(21): impact on quality of life. PPIs, though mainstay of treatment, 2039-40. have got serious long-term side-effects and are less promising in patients with non-acid reflux and extra-esophageal manifestations. There may be a rise in patient’s interest in anti-reflux surgery and endoluminal therapy in future; thus, highlighting the need to explore beyond the conventional therapy.

MU-144.indd 939 29-01-2021 14:56:47 CHAPTER

Post-Infectious Irritable 145 Bowel Syndrome

BK Tripathi

Abstract Post-infectious irritable bowel syndrome (PI-IBS), a subclass of IBS, where this clinical entity has been linked with occurrence of various gastrointestinal infections, bacterial, protozoal, viral, etc. Studies have clearly shown its occurrence in different ethnicity and every part of the world. As it starts after an episode of GI infection, a few studies throw some light toward its mechanism. Its pathophysiology, clinical features, prognosis, and possible treatment have been discussed here.

Introduction BOX 1 Factors involved in PI-IBS Many patients of IBS, on being enquired, when did their zz Genetic susceptibility symptom begin, will struggle to give a correct date. But zz Intestinal inflammation some occasional patients would come out with an answer, zz Intestinal permeability suggest a specific date, saying I was fine until……..Such zz Altered visceral sensitivity patients who connect onset of their symptoms to an zz Severity of infection episode of disorder infectious gastroenteritis, appear to be zz Psychiatric disturbances a little different from others. This subset of patients may be zz Pathogens involved labeled as post-infectious irritable bowel syndrome (PI- zz Host factors IBS). However, most patients of PI-IBS cannot recognize their illness by the past events because either they do suffered from enteric infection. Since then a number of not remember or they do not give much importance to studies in various parts of the world have reported such any such episode. The clinical syndrome, PI-IBS, denotes illnesses. The incidence or prevalence of PI-IBS, 5–32%, persistence of abdominal discomfort, bloating, and in such studies tell us that it is a global phenomenon and constipation diarrhea, which continue despite absence of not related to a particular ethnic group or environment inciting pathogens. A met analysis in the past concluded (Box 1).2,3 The wide variation in this reported incidence that the risk of developing PI-IBS increases sixfold after GI or prevalence may be because of differences in study infection and remains elevated for next 1–3 years.1 methodology, inclusion criteria, definition of IBS, etc. Table 1 describes the prevalence of PI-IBS in some of these Epidemiology countries.4 The prevalence rate of PI-IBS (11.5%) does A link between enteric infection and IBS dates back not vary much, if we take into account the post-infection to the Second World War when numerous cases of GI period, that is, 3, 6, 12, 13–59, or more than 60 months.5 discomfort were seen in British troupes that had earlier But initial infective organisms matter and overall, the rate

MU-145.indd 940 29-01-2021 14:56:41 Post-Infectious Irritable Bowel Syndrome CHAPTER 145 941

significantly higher in patients of PI-IBS as compared to TABLE 1 Prevalence of PI-IBS in different areas patients of IBS, a fact confirmed by rectal-sigmoid and ileal Canada 14.9% mucosal biopsy. US 17.6% Norway 54.3% Risk Facors for Development of PI-IBS UK 14.9% Female sex is associated with 2.2 times higher risk. Smoking is not considered a risk factor. Prevalent Denmark 20.9% anxiety and depression at the time of infective enteritis is Germany 45.8% associated with PI-IBS development more often. Similarly, France 4.5% somatization and neuroticism, at the time of infection, 6,9 Italy 4.5–24.0% are risk factors. Host immune status of elderly persons protects against infection and thus lowers risk of its Spain 11.4% development.2 Bangladesh 16.5% The nature of pathogen too influences the risk of developing IBS, post infection. The hazard ratio is 4.3 for E. coli, 2.9 for C. jeuni, 2.5 for Salmonella spp, and 2.2 for of PI-IBS was the highest after protozoa/parasitic infective viral gastroenteritis. The mechanism of low-hazard ratio enteritis, followed by bacterial and the lowest rates were for viral etiology is poorly understood. It is possible that seen with viral infection.6 viral enteritis is associated with less mucosal damage and poor structural and immunological alteration.10 However, Pathophysiology the high incidence of PI-IBS after an attack of protozoal IBS is a disease where diagnosis is based on clinical enteritis (Giardiasis) merits attention as it shows the prevalence much higher, i.e. 39–89%.11 criteria in absence of any organic changes. Though gut mucosa of patients of IBS are endoscopically normal, recently complex alteration in digestive mucosa has been Clinical Features identified in PI-IBS patients. These changes mainly alter The diagnosis of IBS is always symptom based and the integrity of intestinal epithelial barrier. It results in is mostly challenging. Similarly, there are no definite paracellular permeability, which can encourage exposure diagnostic criteria for post-infectious IBS. The element of and migration of microflora or food borne antigens. This “new onset IBS after an episode of acute gastroenteritis in turn stimulates intestinal mucosal immunity, leading to in patients who never had IBS previously” should always persistent intestinal microinflammation. The possibility of be given significance. There is strong relation between inflammatory state of intestinal mucosa is substantiated by traveler’s diarrhea (TD) and PI-IBS. Self reported TD was the occurrence of infiltration of T lymphocytes, mast cells, associated more often than laboratory confirmed TD (1.5- and enterochromaffin cells. These cells are responsible fold rise in RR). for release of cytokines and mediators of inflammation. There might be some subtle differences in PI-IBS In one study, increased intestinal permeability was from IBS, which has greater stool frequency and loose associated with increased stool frequency and was proved stools as compared to IBS. All different subtypes of IBS by demonstrating increased lactulose-mannitol fractional are recognized, and the frequency is IBS-mixed, 46%, excretion ratio in patients, 2 years after a water borne IBS diarrhea, 39%, and IBS constipation, 15% in some outbreak of gastroenteritis involving Campylobacter studies.12,13 Emphasis should be laid before making a jejuni and Escherichia coli.7,8 These changes suggest diagnosis of PI-IBS to exclude alarm signs and checking a pathophysiological model of PI-IBS and genesis of for preliminary investigations, that is, CBC, ESR, CRP, symptoms of IBS, where symptoms start after a bout of stool culture, etc. in one study, PI-IBS was found to be infection rather than its absence. An increased number of associated with post-infectious malabsorption syndrome mast cells in rectal mucosa and mucosal cellularity were (PI-MAS), popularly known as tropical sprue.14 Small

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intestinal bacterial overgrowth (SIBO) has been linked TABLE 2 Major classes of drugs in IBS management with IBS, particularly IBD-D type. Other similar conditions like acquired lactase deficiency IBS symptom Drugs in therapy following gastroenteritis, bile acid malabsorption, Abdominal pain zz Antispasmodics inflammatory bowel disease, or lymphocytic colitis should Diarrhea zz Loperamide^ always be taken into account as differential diagnosis. zz Diphenoxylate^ zz Cholestyramine^ zz Probiotics^ Prognosis Constipation zz Bulking agents PI-IBS too lasts for a long time. In one study, the rate of zz Polyethylene glycol ^ spontaneous remission was 27% in a year. The proportion zz Osmotic or stimulating laxatives zz Prucalopride^ of patients who improved (as assessed by ROME III criteria) zz Lubiprostone^ varied across the age group (23% in younger population of zz SSRIs^ 21–30 years and 37.5% in older population if more than 70 zz Probiotics^ years (p=0.18). Other factors responsible for poor recovery Bloating/abdominal zz Probiotics^ ^ are female sex, patients from North America and Europe, distension/meteorism/ zz Rifaximin flatulence and those with history of somatization.12 Patients with ^ longer history of IBS symptoms exhibited poor recovery. Recommended in a few patients based on individual clinical profile SSRIs, selective serotonin reuptake inhibitors. Despite different pathogenesis, surprisingly, prognosis Source: Adapted from Tripathi BK, Soni A. Irritable bowel syndrome in in PI-IBS does not differ much from non PI-IBS with patient management. In: Arulrhaj S (Ed). Medicine Update. New Delhi: recovery of one in four patients in first year. Still, it is very Jaypee Brothers Medical Publishers; 2020. pp. 633-7. encouraging to learn that over half of patients of PI-IBS return to their preinfection state. However, it may take IBS might overlap with tropical sprue in which SIBO years for symptoms to disappear completely. is common.14 Rifaximin is a locally acting antibiotic, which targets SIBO, has shown benefit in IBS-D patients. Treatment Bile salt malabsorption may develop following acute It is legitimate to think that traditional approach of gastroenteritis. Several studies have demonstrated that PI- treatment aiming only at attenuating symptoms, must give IBS can respond to cholecystokinin. However, intolerance 19 place to addressing new pathological targets (intestinal to this drug discourages its use. permeability, microinflammation, mast cells, serotonin, Despite all these novel and experimental therapies, visceral hypersensitivity, etc.) However, approaches to treatment of PI-IBS is frequently symptom directed and tackle such anomalies have not met with much success. matches closely with treatment of IBS. Table 2 summarizes In a small study, treatment with prednisolone, in PI-IBS, measures, which help treating patients of PI-IBS. on presumption of immunological genesis has not shown any benefit.15 Another RCT of an anti-inflammatory agent, Diet mesalazine, showed overall no benefit in IBS patients with Many patients describe a chronological link between IBS with diarrhea, but a post hoc subgroup analysis did onset and worsening of symptoms with a particular food. suggest some response in PI-IBS.16 Furthermore, treatment However, in majority of patients there is no compelling with E. coli 0147 infection with mesalazine appeared to data to recommend an exclusion diet. The knowledge of reduce the risk of developing PI-IBS.17 Increased 5HT enhanced intestinal permeability may suggest food allergy available in small intestine in PI-IBS patients enhances on the premise of penetration of food antigens and their visceral hypersensitivity which can be blocked by 5HT contact with immunocompetent cells. Possible exclusion receptor antagonist, ondansetron. This theory encouraged of such items by patients may be helpful rarely.20 A low randomized trial of ondansetron in IBS with diarrhea, fiber diet with soluble fiber will help to some extent. The which showed relief of symptoms, particularly urgency.18 consumption of poorly absorbed fermentable oligo-, SIBO is seen in rats of PI-IBS after campylobacter di-, mono-saccharide and polyols (FODMAPs) may be infection. A recent study in India suggested that PI- a trigger for symptoms too. FODMAPs and insoluble

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role in diseases like IBS, IBD, chronic constipation, TABLE 2 Major classes of drugs in IBS management TABLE 3 FODMAP (high and low dietary sources) etc. In one study role of FMT was studied in recurrent IBS symptom Drugs in therapy High FODMAP foods Low FODMAP foods Clostridium difficile infection (CDI) by Mattila et al.22 In Abdominal pain zz Antispasmodics Vegetables Asparagus, onions, Alfalfa, bean sprouts, this study, symptoms resolved in all patients who did not ^ garlic, sugar, peas, green beans, capsicum, Diarrhea zz Loperamide have strain 027 CDI during the first three months Out of 36 ^ beetroot, cabbage, carrot, fresh herbs, zz Diphenoxylate patients who had 027 infection, 32 (89.7%) had a favorable ^ cauliflower, celery, sweet cucumber, lettuce, zz Cholestyramine ^ corn, and mushrooms tomato, and zucchini response. Unfortunately rest four patients had history of zz Probiotics Fruits Apples, apricots, Banana, blueberries, long standing diarrheal disease with comorbidities did Constipation zz Bulking agents figs, pears, mango, strawberries, cherries, zz Polyethylene glycol not improve and died. However, no human trial of FMT ^ watermelon, peaches, kiwi, orange, grapes, and zz Osmotic or stimulating laxatives is available in PI-IBS but success in other areas offers ^ and plums melon zz Prucalopride legitimacy for using this therapy and conducting a large zz Lubiprostone^ Grains Rye, wheat containing Gluten-free bread, oats, zz SSRIs^ breads, wheat-based gluten-free pasta, rice, trial. zz Probiotics^ cereals with dried fruit, and quinoa ^ wheat pasta, and barley Bloating/abdominal zz Probiotics Conclusion distension/meteorism/ zz Rifaximin^ Meat Meats, fish, and chicken flatulence Dairy Cow’s milk, custard, and Lactose-free milk and Post-infectious IBS represents a frequently occurring new ^Recommended in a few patients based on individual clinical profile ice cream yoghurt clinical entity which has led to better understanding of SSRIs, selective serotonin reuptake inhibitors. Alternatives Legumes/pulses, Tofu, almonds the factors involved in pathophysiology of IBS. ROME IV Source: Adapted from Tripathi BK, Soni A. Irritable bowel syndrome in cashews, and pistachios (<10 nuts) and pumpkin recognizes post-infectious IBS, a multidimensional clinical patient management. In: Arulrhaj S (Ed). Medicine Update. New Delhi: seeds chronic inflammation triggered by enteric infection. Present Jaypee Brothers Medical Publishers; 2020. pp. 633-7. Source: Adapted from Tripathi BK, Soni A. Irritable bowel syndrome in literature on IBS is very descriptive and large randomized patient management. In: Arulrhaj S (Ed). Medicine Update. New Delhi: trials are lacking. Future research is needed to establish a Jaypee Brothers Medical Publishers; 2020. pp. 633-7. link between hosts and microbes in which participants are subdivided according to underlying mechanisms. The response of each subgroup will provide new tools for prevention and fibers may enhance osmotic pressure in large intestine management. and provide a substrate for bacterial fermentation. Low FODMAPs can change intestinal microbiota and reduce IBS symptoms (Table 3). More so, different gastrointestinal References cell types that produce hormones, which regulate appetite 1. Ruigomez A, Garcia Rodriguez, Panes J, et al. Risk of irritable bowel and food intake, show dysfunction too. This, in turn, syndrome after an episode of bacterial gastroenteritis in general increase food intake and weight gain. Though, linkage of practice: influence of co-morbidities. Clin Gastroenterol Hepatol. IBS and obesity is poorly understood, low FODMAPs and 2007;5:465-9. insoluble fibers, probiotics, and regular exercise are to be . 2 Neal KR, Hebden J, Spiller R, et al. Prevalence of gastrointestinal recommended.21 symptoms six months after bacterial gastroenteritis and risk factors for development of irritable bowel syndrome: postal survey of patients. BMJ. 1997;314(7083):779-82. Probiotics and Fecal Microbial . 3 Stermer E, Lubezky A, Potasman J, et al. Is traveller’s diarrhea Transplantation a significant risk factor for the development of irritable bowel syndrome? A prospective study. Clin Infect Dis. 2006;43(7):898-901. A number of probiotics are tested in IBS. The results are `. 4 Giovanni B, Grover M, Premyesvi B, et al. Rome foundation encouraging, particularly in relieving excessive flatulence. working team report on post-infection irritable bowel syndrome. In fact, administration of probiotics during an attack of Gastroentrology. 2019;156(1):46-58. acute gastroenteritis of bacterial origin has a protective . 5 Kliem F, Wadhwa A, Prosokop L, et al. Prevalence, Risk Factors, effect on intestinal epithelial barrier. The role of probiotics and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis Gastroenterology. is seen in animal model of PI-IBS in a favorable manner. 2017;152(5):1042-54. Fecal microbial transplantation (FMT) may be, probably, . 6 Gwee KA, Leong YL, Graham C, et al. The role of psychological more beneficial as human feces is the ultimate human and biological factors in post infective gut dysfunction. Gut. probiotic. A number of studies have proved its beneficial 1999;44(3):400-6.

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