Section 10
Section Editor: Rajesh Upadhyay
Gastroenterology
124. Type 2 Diabetes Mellitus Originates
from Fatty Liver
Rajesh Upadhyay, Ankit Gupta
125. Non-Pharmacological Management of
NAFLD/NASH (Diet, Exercise, and Role of
Intermittent Fasting)
Sundeep Kumar Goyal
126. Medical Management of Acute Pancreatitis
D Nageshwar Reddy, Hardik Rughwani
127. Functional Gastrointestinal Disorders
Uday C Ghoshal
128. Variceal Bleed Management
Srikanth Gopi, Deepak Gunjan
129. Hepatorenal Syndrome: Current
Diagnosis and Management
Shri Krishna Gautam
130. Hepatic Encephalopathy: Management
Sudhir Maharshi, Barjesh Chander Sharma
131. The Healthy Indian Gut Microbiota
Rupjyoti Talukdar
132. Celiac Disease: Who to Screen and How to Screen?
Ashish Agarwal, Archita Makharia, Govind K Makharia
133. Differentiating Crohn’s Disease from Intestinal
Tuberculosis: A Diagnostic Challenge
Pabitra Sahu, Saurabh Kedia, Vineet Ahuja
134. Acute Liver Failure and Acute-on-Chronic-Liver
Failure in India: How They Are Different from West?
Subrat Kumar Acharya
Section-10.indb 785
135. Proton Pump Inhibitors—Long-term Use:
Boon or Bane?
Manish Manrai, Rohit Upreti
136. Eosinophilic Esophagitis—
An Underdiagnosed Entity
Goundappa Loganathan, H Leena Shree
137. Non-Cirrhotic Portal Hypertension in India
Srikant Mohta, Anoop Saraya
138. Drug-induced Liver Injury
Harshad Devarbhavi
139. Achalasia Cardia—Diagnosis and
Endoscopic Treatment
Mohan Ramchandani, Partha Pal
140. Non-Variceal Upper GI Bleed—Clinical Approach
Bhabadev Goswami, Preeti Sarma
141. Recent Updates in Management of IBS
Nikhil Gupta, Manisha Dwivedi, SP Misra
142. Evaluation of Occult GI Bleed
Sanjay Bandyopadhyay
143. Endoscopic Ultrasound for the Internist
Surinder S Rana
144. Gastroesophageal Reflux Disease—What’s New!
Piyush Dadhich, Shraddha Sharma, Shreyans Singhvi,
Gautam Bhandari, Sunil Kumar Dadhich
145. Post-Infectious Irritable Bowel Syndrome
BK Tripathi
28-01-2021 12:10:33
Section-10.indb 786 28-01-2021 12:10:33
 CHAPTER

124 Type 2 Diabetes Mellitus

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

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

Section-10.indb 787 28-01-2021 12:10:33

 788 SECTION 10 Gastroenterology

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

Section-10.indb 788 28-01-2021 12:10:34

 Type 2 Diabetes Mellitus Originates from Fatty Liver CHAPTER 124 789

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

Section-10.indb 789 28-01-2021 12:10:35

 790 SECTION 10 Gastroenterology
mass of beta cells is not permanently damaged but
became metabolically inactive. Thus, pancreatic fat (PF)
accumulation is an important precursor for development
of diabetes. The amount of PF is greater in diabetics and
increases with the duration of diabetes. Patients with PF
have a higher prevalence of T2DM than non-PF controls
(12.6% vs. 5.2%) and T2DM was independently associated
with PF.5 A cohort of patients with biopsy proven NASH
had more PF in diabetics compared to patients without
diabetes.6 The fatty liver cells are overdistended with fat
which is then transported to different organs including
the pancreas as free circulating fatty acids and VLDL
particles which lead to tissue IR and PF accumulation.
There is evidence to suggest this cross talk between the
fatty liver and PF.7 Fat in pancreas may lead to metabolic
suppression of beta cells causing pancreatic failure
and reduced insulin production leading to T2DM. This
hypothesis appears attractive but needs to be evidence
based. There are studies on post-bariatric surgery patients
demonstrating lowering of pancreatic triglyceride content
with simultaneous increase in insulin secretion. Bariatric
surgery leads to fat mobilization from various tissues and
liver/pancreas are the earliest targets of mobilization
leading to reduction in liver and PF causing improvement
in insulin sensitivity and insulin production. Hence,
improvement in blood glucose in post-bariatric surgery
patients occurs early even before body weight loss and this
improvement in blood glucose has linear correlation with
reduction in fat content of liver and improved sensitivity
to insulin and the normalization of fasting blood glucose
which occurred within 7 days. 8 PF content reduction
occurred in 8 weeks and was accompanied by restoration
of first phase insulin.9
Treatment of Fatty Liver can Ameliorate IR
and Prevent Diabetes
In a rodent model, it was found that there was early
development of hepatic IR without significant changes
in insulin-stimulated glucose utilization or body weight
in rodents fed with high fat diet.10 In a study in T2DM
patients subjected to a moderately hypocaloric and very
low-fat diet, 81% reduction in intrahepatic fat content
and improvement in basal and insulin-stimulated hepatic
glucose metabolism was noted; however, effects on
insulin-stimulated peripheral glucose uptake were
not significant.11 So dietary modification can improve
Section-10.indb 790
hepatic insulin sensitivity. Weight loss interventions
are also associated with improvement in liver histology
and transaminases. Metformin an oral antidiabetic drug
reduces plasma glucose via activation of AMP kinase,
and reduces hepatic glucose synthesis. This enzyme also
decreases lipid synthesis and enhances fat oxidation.
Metformin treatment thus can improve insulin sensitivity
and liver transaminases in patients with fatty liver disease.
Thiazolidinediones are insulin sensitizers and can
improve hepatic as well as peripheral insulin sensitivity.
They can induce adipocyte differentiation, reduce free
fatty acid levels, and thus decrease their delivery to liver.
They also increase adiponectin levels and can increase
lipid oxidation of fatty acid in liver. They also reduce TNF-
alpha and C-reactive protein, which play important role
in IR. Therefore, there are ample evidences to suggest2
that targeting fatty liver can lead to improvement of IR.
It is a well-known fact that persons with fatty liver have
higher prevalence of T2DM (22.4%) and NASH (43.6%) as
compared to 8.5% in general population.12 This suggests
that fatty liver is a risk factor for T2DM and increases the
risk of development of T2DM by 2–3 folds. The risk of
development of T2DM may be even higher in patients
with more severe liver disease which suggests that fibrosis
increases the risk. About 30% patients with cirrhosis of
liver have diabetes.13
Evidence Suggesting Fatty Liver
Leads to T2DM
Over the past 15 years there have been numerous
observational studies suggesting that fatty liver is an
independent risk factor for development of diabetes
(Table 1).
Secondary Diabetes is Related to
Liver Disease
Liver is the most important organ for regulation of blood
sugar. It is therefore, a simple understanding that chronic
liver disease is associated with impaired glucose tolerance
and development of diabetes. Glucose intolerance can be
seen in about 80% of patients, and diabetes in about 30–
60% of patients with chronic liver disease.14,15 Apart from
fatty liver disease, other conditions like hemochromatosis,
cystic fibrosis, chronic liver disease due to alcohol abuse,
chronic hepatitis C, and glycogen storage disorders are
also associated with development of diabetes.
28-01-2021 12:10:35
 Type 2 Diabetes Mellitus Originates from Fatty Liver CHAPTER 124 791

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.

Section-10.indb 791 28-01-2021 12:10:36

 792 SECTION 10 Gastroenterology
References
1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev
Gastroenterol Hepatol. 2013;10:686-90.
2. Patel H, Verma YN. Prevalence of non-alcoholic fatty liver disease in
type-2 diabetes mellitus patients. Int J Res Med Sci. 2018;6:1322-6.
3. Douros JD, Tong J, D’Allesio D. The effects of bariatric surgery on
islet function, insulin secretion, and glucose control, endocrine
reviews. Endocr Rev. 2019;40(5):1394-1423.
4. Steven S, Hollingsworth KG, Al-Mrabh A, et al. Very low-calorie
diet and 6 months of weight stability in type 2 diabetes:
pathophysiological changes in responders and non responders.
Diabetes Care. 2016;39(5):808-15.
5. Wang CY, Ou HY, Chen MF, et al. Enigmatic ectopic fat: prevalence
of nonalcoholic fatty pancreas disease and its associated factors in
a Chinese population. J Am Heart Assoc. 2014;3:e000297.
6. Idilman IS, Tuzun A, Savas B, et al. Quantification of liver, pancreas,
kidney and vertebral body MRI-PDFF in non alcoholic fatty liver
disease. Abdom Imaging. 2015;40;1512-9.
7. Jaghutriz B, Wagner R, Machann J. Association of pancreatic fat with
impaired insulin secretion depends on liver fat and circulating fatty
acids. Diabetes. 2018:67(Suppl 1).
8. Lim EL, Hollingworth KG, Arbisala BS, et al. Normalisation of beta
cell function in association with decreased pancreas and liver
triglycerol. Diabetologia. 2011;54:2506-14.
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9. Steven S, Hollingsworth KG, Small PK, et al. Weight loss decreases
excess pancreatic triglycerol specificallty in type 2 diabetes.
Diabetes Care. 2016:39;158-65.
10. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin
resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;
279:32345-53.
11. Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic
hepatic steatosis, hepatic insulin resistance, and hyperglycemia
by moderate weight reduction in patients with type 2 diabetes.
Diabetes. 2005;54:603-8.
12. Gastadelli A, Cusi K. From NASH to diabetes and from diabertes to
NASH: mechanisms and treatment options. JHEP Rep. 2019;1(4):
312-28.
13. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, et
al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical
implications and management. World J Gastrenterol. 2009:15(3)
280-8.
14. Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev.
1994;2:1-18.
15. García-Compean D, Jaquez-Quintana JO, Maldonado-Garza H.
Hepatogenous diabetes: current views of an ancient problem. Ann
Hepatol. 2009;8:13-20.
16. DeFronzo RA. From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes mellitus. Diabetes.
2009;58:773-95.
28-01-2021 12:10:36
 CHAPTER Non-Pharmacological
Management of NAFLD/NASH
125 (Diet, Exercise, and Role of
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

MU-125.indd 793 29-01-2021 15:00:00

 794 SECTION 10 Gastroenterology
Fig. 1: Effect of weight loss on NASH8
adult. An average deficit of 500 kcal/day should result
in an initial weight loss of about 0.5 kg/week. Both lean
body mass and body fat decreases with weight loss and
reach plateau after 3–6 months. Further caloric restriction
and increased physical activity required to overcome this
plateau effect.9 Aim of weight loss is to preserve muscle
mass and decrease visceral fat.
Types of diet: Planning a diet requires the selection of
caloric intake and then choice of foods according to
local culture and palatability. Replacement of food by
low-calorie meals containing 250–350 kcal/package in
form of nutrition bars, frozen food, and prepackaged
meals resulted in early initial weight loss, which then
was maintained over long term (4 year follow-up).10
The Mediterranean diet includes consuming high
level of monounsaturated fat relative to saturated fat;
moderate consumption of alcohol, mainly as wine, a high
consumption of vegetables, fruits, legumes, and grains, a
moderate consumption of milk and dairy products, mostly
in the form of cheese, and a relatively low intake of meat
and meat products. Adherence to the Mediterranean
dietary pattern leads to a significant decrease in liver fat
and insulin resistance among overweight patients with
NAFLD.11
Dietary Composition
Carbohydrate: Low- and very low-carbohydrate (60–130
gm and <60 gm, respectively) diets have been more
effective for short-term weight loss than low-fat diets, but
not for long-term weight loss, compared with a low-fat
diet.12,13 Restriction of carbohydrates less than 50 gm/day-
MU-125.indd 794
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
consuming foods with a lower glycemic index (GI)
or glycemic load. High-glycemic-load foods increase
postprandial glycemia and insulinemia, particularly in
patients with insulin resistance. Since the duration of post-
meal satiety is related to postprandial glycemia, low-GI
foods have been hypothesized to reduce hunger signals
and delay the onset of the next meal. Meals with high GI
were found to be associated with high-grade liver steatosis
(assessed by ultrasound), particularly in insulin-resistant
subjects.16
Fructose: Fructose mainly derived from table sugar (50%
fructose) and corn syrup (55% fructose). High intake of
sugar-sweetened foods in general contributes to weight
gain and high liver fat due to their high-energy density,
glycemic load, and palatability. Fructose role has been
implicated in alteration of gut microbiome, increasing
gut permeability, endotoxemia and hyperuricemia.17,18
Soft drinks contain caramel coloring rich in advanced
glycation end products, which increases insulin resistance
and liver injury.19
Fat: The quality of fat consumed and its food sources
appear to be more important for health than total fat
intake. Trans fatty acids and saturated fatty acids have
been associated with metabolic derangement (increase
LDL, low HDL), and an elevated cardiovascular risk.20
Saturated fat promotes visceral and liver fat deposition.21
Assessment of dietary pattern in NASH patients showed
higher saturated fat and cholesterol intake and lower
polyunsaturated fatty acids (PUFA), fiber, vitamin C and E
consumption.22
Monounsaturated fatty acids (oleic acid, palmitoleic
acid in canola and olive oil) consumption favors
accumulation of fat in adipose tissues rather than the
liver in animal models.23 In type 2 diabetic patients, an
29-01-2021 15:00:01
 Non-Pharmacological Management of NAFLD/NASH (Diet, Exercise, and Role of Intermittent Fasting)
isocaloric diet enriched in MUFA compared with a diet
higher in carbohydrate and fiber was associated with a
significant fat reduction in liver (measured by proton
magnetic resonance spectroscopy) despite a stable
weight in both groups.24 Polyunsaturated fatty acids (n-
6: linoleic acid, arachidonic acid and n-3: α-linolenic
acid, eicosapentaenoic acid, docosahexaenoic acid)
are abundant in fish oil. Low intake n-3 fatty acids and
higher n-6/n-3 ratio is found in NAFLD patients than
healthy controls.25 It is associated with a proinflammatory
state and increased lipogenesis leading to steatosis. 26
Conversely, n-3 PUFAs down-regulate sterol regulatory
element binding protein 1c (SREBP-1c) and up-regulate
peroxisome proliferator activated receptor α (PPAR-α)
that would favor fatty acid oxidation and reduce steatosis.27
PUFA Supplementation is effective in reducing total liver
fat but not beneficial in histological improvement in terms
of inflammation and fibrosis.28
High cholesterol consumption (>500 mg/day) was
associated with higher risk of cirrhosis or liver cancer,
instead of total fat consumption.29
Protein: High-protein diets have been recommended for
the treatment of obesity because they are more satiating
and stimulate thermogenesis. Higher-protein diets
may improve weight maintenance. Total red meat and
processed red meat intake are both positively associated
with risk of coronary artery disease.30
Fiber has several beneficial metabolic effects, including
increased satiety, increased incretin secretion, reduced
absorption rate of CHO and proteins, modulation of gut
microbiota, and increased fermentation products, such as
butyrate.
Increased coffee consumption has been associated
inversely with the risk of cirrhosis or progression of fibrosis
but not with steatosis.31 In epidemiological studies, coffee
consumption is associated with a lower risk of metabolic
syndrome. 32 Animal studies suggest, coffee exerts its
effects by reducing hepatic fat accumulation, systemic and
liver oxidative stress and liver inflammation.33 Drinking
coffee reduces HCC risk. 34 For the majority of healthy
adults, consuming less than 400 mg of caffeine a day
appears to be safe.
Intermittent Fasting
Intermittent fasting strategies, including alternate-day
fasting (25% of total energy consumed on “fast” days and
MU-125.indd 795
CHAPTER 125 795
125% consumed on “feast” days) and time-restricted
feeding (TRF) (cessation of eating by a certain time
each day) have been used as approaches to weight loss.
Short-term TRF trials have shown that the alignment of
the feeding period with circadian rhythms may result in
weight loss and improve metabolic parameters. 35 The
mechanisms by which intermittent fasting affect health
may include improved insulin sensitivity and anti-
inflammatory effects.
Summary of diet recommendations for NASH:2
„„ Calorie restriction (500–1000 kcal/day)
„„ Low-carbohydrate (<40%) diet—replace calories with
PUFA, MUFA
„„ Low-fat diet—replace calories with low-GI foods
„„ Reduce trans FA (<1%), saturated fats (<7%), and
cholesterol (<200 mg/day)
„„ Proteins from fish, poultry, nuts, and legumes & restrict
unprocessed red meats (<300 g/week), processed
meats (<2/week)
„„ Increase the intake of cereal-derived non-soluble fiber
(whole grain) (25 g/day)
„„ Vegetables (3–5 servings/day), fruits (2–4 servings/
day), nuts (4 servings/week), olive oil, and low-fat
dairy products.
Physical Activity
Sedentary behavior is a component of reduced life
expectancy. The energy expenditure is sum of resting
metabolic rate (RMR), the thermic effect of feeding (TEF),
and physical activity. Exercise (aerobic and resistance) is
planned form of physical activity. While it may be difficult
to lose weight with exercise alone, exercise programs
added to moderate to severe caloric restriction have
additional effect upon weight loss.36 If a patient burn 100
calories during exercise each day (700 calories per week),
it would take almost 5 weeks to utilize the energy (3,500
calories) in half kg of fat. Exercise alone, in the absence of
any change in body weight or composition, may enhance
peripheral insulin sensitivity and glucose homeostasis
mediated by insulin-receptor up regulation in muscle
tissue, enhancing whole-body lipid oxidation, decreased
hepatic triglyceride accumulation and lower hepatic FFA
uptake (Fig. 2). Increased physical activity attenuates the
diet-induced loss of muscle mass, which in turn increases
physical functioning and insulin sensitivity.37 Both aerobic
or resistance exercise are effective in reducing liver
29-01-2021 15:00:01
 796 SECTION 10 Gastroenterology
Fig. 2: Exercise effect in NAFLD and effect on liver, adipose tissue, and muscles
fat.38 The addition of resistance exercise to weight-loss
programs can help prevent the reduction in muscle and
bone mass. Patients with poor cardiorespiratory reserve
may better tolerate resistance exercise. Weight training
results in greater increases in fat-free mass.39
The recommendation by American Heart Association
of intense cardiorespiratory activity (aerobic & resistance)
for at least 150 minutes (preferably 300 minutes) per
week, or at least 75 minutes (preferably 150 minutes) is
adapted by EASL for NASH patients.40 The clinician needs
to be aware for identifying high-risk patients who may
require a more thorough evaluation before beginning an
exercise program. The major hurdle is obtaining long-
term compliance—especially in individuals who are not
accustomed to regular intense exercise.
Conclusion
The primary approach to treat NAFLD focuses on the control of
the underlying risk factors like diabetes, hyperlipidemia, obesity,
and other comorbidities through diet and lifestyle changes.
After the initial weight-loss phase, the weight-maintenance
phase is key for preventing long-term complications. Strategies
to enhance long-term adherence to lifestyle interventions, with
a multidisciplinary approach should be included.
MU-125.indd 796
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1. Eslam M, Sanyal AJ, George J, et al. MAFLD: A consensus-driven
proposed nomenclature for metabolic associated fatty liver
disease. Gastroenterology. 2020;158(7):1999-2014.
2. Barrera F, George J. The role of diet and nutritional intervention
for the management of patients with NAFLD. Clin Liver Dis.
2014;18(1):91-112.
3. Barrera FGJ. Non-alcoholic fatty liver disease: more than just ectopic
fat accumulation. Drug Discov Today Dis Mech. 2013;10(1-2):47-54.
4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis
stage in nonalcoholic fatty liver disease: systematic review and
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5. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and
opportunities in drug and biomarker development for nonalcoholic
steatohepatitis: findings and recommendations from an American
Association for the Study of Liver Diseases-U.S. Food and Drug
Administration Joint Workshop. Hepatology. 2015;61(4):1392-405.
6. Harrison SA, Fecht W, Brunt EM, et al. Orlistat for overweight subjects
with nonalcoholic steatohepatitis: a randomized, prospective trial.
Hepatology. 2009;49(1):80-6.
7. Promrat K , Kleiner DE, Niemeier HM, et al. Randomized
controlled trial testing the effects of weight loss on nonalcoholic
steatohepatitis. Hepatology. 2010;51(1):121-9.
8. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight
loss through lifestyle modification significantly reduces features of
nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367-78.
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
and weight loss effects of long-term dietary intervention in obese
patients: four-year results. Obes res. 2000;8(5):399-402.
11. Ryan MC, Itsiopoulos C, Thodis T, et al. The mediterranean diet
improves hepatic steatosis and insulin sensitivity in individuals with
non-alcoholic fatty liver disease. J hepatol. 2013;59(1):138-43.
12. Bueno NB, de Melo IS, de Oliveira SL, et al. Very-low-carbohydrate
ketogenic diet v. low-fat diet for long-term weight loss: a meta-
analysis of randomised controlled trials. Br j nutr. 2013;110(7):
1178-87.
13. Hu T, Mills KT, Yao L, et al. Effects of low-carbohydrate diets versus
low-fat diets on metabolic risk factors: a meta-analysis of randomized
controlled clinical trials. Am J Epidemiol. 2012;176(Suppl 7):44-54.
14. Hall KD, Chen KY, Guo J, et al. Energy expenditure and body
composition changes after an isocaloric ketogenic diet in
overweight and obese men. The Am J Clin Nutr. 2016;104(2):324-33.
15. Kirk E, Reeds DN, Finck BN, et al. Dietary fat and carbohydrates
differentially alter insulin sensitivity during caloric restriction.
Gastroenterology. 2009;136(5):1552-60.
16. Valtuena S, Pellegrini N, Ardigo D, et al. Dietary glycemic index and
liver steatosis. Am J clin nutr. 2006;84(1):136-42.
17. Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver
disease. Hepatology. 2013;57(6):2525-31.
18. Choi JW, Ford ES, Gao X, et al. Sugar-sweetened soft drinks, diet
soft drinks, and serum uric acid level: the Third National Health
and Nutrition Examination Survey. Arthritis Rheum. 2008;15;59(1):
109-16.
19. Hyogo H, Yamagishi S, Iwamoto K, et al. Elevated levels of serum
advanced glycation end products in patients with non-alcoholic
steatohepatitis. J Gastroenterology and Hepatol. 2007;22(7):1112-9.
20. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart
disease of increasing polyunsaturated fat in place of saturated fat:
a systematic review and meta-analysis of randomized controlled
trials. PLoS Medicine. 2010;23;7(3):e1000252.
21. Rosqvist F, Iggman D, Kullberg J, et al. Overfeeding polyunsaturated
and saturated fat causes distinct effects on liver and visceral fat
accumulation in humans. Diabetes. 2014;63(7):2356-68.
22. Musso G, Cassader M, Rosina F, et al. Impact of current treatments
on liver disease, glucose metabolism and cardiovascular risk in non-
alcoholic fatty liver disease (NAFLD): a systematic review and meta-
analysis of randomised trials. Diabetologia. 2012;55(4):885-904.
23. Bessesen DH, Vensor SH, Jackman MR. Trafficking of dietary oleic,
linolenic, and stearic acids in fasted or fed lean rats. Am J Physiol
Endocrinol Metabol. 2000;278(6):1124-32.
24. Bozzetto L, Prinster A, Annuzzi G, et al. Liver fat is reduced by an
isoenergetic MUFA diet in a controlled randomized study in type 2
diabetic patients. Diabetes Care. 2012;35(7):1429-35.
25. Cortez-Pinto H, Jesus L, Barros H, et al. How different is the dietary
pattern in non-alcoholic steatohepatitis patients? Clin Nutr.
2006;25(5):816-23.
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26. Molendi-Coste O, Legry V, Leclercq IA. Why and how meet
n-3 PUFA dietary recommendations? Gastroenterol Res Pract.
2011;2011:364040.
27. Pettinelli P, Del Pozo T, Araya J, et al. Enhancement in liver SREBP-1c/
PPAR-alpha ratio and steatosis in obese patients: correlations with
insulin resistance and n-3 long-chain polyunsaturated fatty acid
depletion. Biochim Biophys Acta. 2009;1792(11):1080-6.
28. Parker HM, Johnson NA, Burdon CA, et al. Omega-3 supplementation
and non-alcoholic fatty liver disease: a systematic review and meta-
analysis. J Hepatol. 2012;56(4):944-51.
29. Ioannou GN, Morrow OB, Connole ML, et al. Association between
dietary nutrient composition and the incidence of cirrhosis or liver
cancer in the United States population. Hepatology. 2009;50(1):
175-84.
30. Bernstein AM, Sun Q, Hu FB, et al. Major dietary protein sources
and risk of coronary heart disease in women. Circulation.
2010;122(9):876-83.
31. Bambha K, Wilson LA, Unalp A, et al. Coffee consumption in NAFLD
patients with lower insulin resistance is associated with lower risk of
severe fibrosis. Liver Int. 2014;34(8):1250-8.
32. Shang F, Li X, Jiang X. Coffee consumption and risk of the metabolic
syndrome: a meta-analysis. Diabetes Metab. 2016;42(2):80-7.
33. Vitaglione P, Morisco F, Mazzone G, et al. Coffee reduces liver damage
in a rat model of steatohepatitis: the underlying mechanisms
and the role of polyphenols and melanoidins. Hepatology.
2010;52(5):1652-61.
34. Setiawan VW, Wilkens LR, Lu SC, et al. Association of coffee intake
with reduced incidence of liver cancer and death from chronic
liver disease in the US multiethnic cohort. Gastroenterology.
2015;148(1):118-25.
35. Stockman MC, Thomas D, Burke J, et al. Intermittent fasting: is the
wait worth the weight? Curr Obes Rep. 2018;7(2):172-85.
36. Catenacci VA, Wyatt HR. The role of physical activity in producing
and maintaining weight loss. Nat Clin Pract Endocrinol Metabol.
2007;3(7):518-29.
37. Pownall HJ, Bray GA, Wagenknecht LE, et al. Changes in body
composition over 8 years in a randomized trial of a lifestyle
intervention. Obesity. 2015;23(3):565-72.
38. Bacchi E, Negri C, Targher G, et al. Both resistance training and
aerobic training reduce hepatic fat content in type 2 diabetic
subjects with nonalcoholic fatty liver disease. Hepatology.
2013;58(4):1287-95.
39. Ballor DL, Keesey RE. A meta-analysis of the factors affecting
exercise-induced changes in body mass, fat mass and fat-free mass
in males and females. Int J Obes. 199115(11):717-26.
40. European Association for the Study of the Liver (EASL); European
Association for the Study of Diabetes (EASD); European Association
for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice
Guidelines for the management of non-alcoholic fatty liver disease.
J Hepatol. 2016;64(6):1388-402.
29-01-2021 15:00:02
 CHAPTER

126 Medical Management of

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

Acute pancreatitis (AP) is a common gastrointestinal tract
(GIT) disease causing enormous physical, emotional,
and socioeconomic human burden. The first clinical
description of AP was given by Dutch anatomist Nicholaeus
Tulp in 1652. Incidence of AP varies from 30–80/100,000
population. In India, approximately 74% of patients of
AP are men with the mean age being 40 years, which is a
younger age group compared to other parts of the world.
Definitions1
objective terms to define the local complications of AP,
which are described as follows.
Definitions and Classification: Proposed
to be Used in Clinical and Research
Communications
Diagnosis of AP
The diagnosis of AP requires two out of following three
features:
„„ Pain abdomen suggestive of AP (acute onset severe,

ATL ANTA 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.

MU-126.indd 798 29-01-2021 14:59:40

 Medical Management of Acute Pancreatitis CHAPTER 126 799

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
improvement after 48–72 hours (e.g., persistent pain,
nausea, fever, inability of start oral feeds), imaging using
CECT or MRI is recommended for assessment of local
complications such as peripancreatic fluid collection or
pancreatic necrosis.
Onset of AP
The onset of AP is defined by the time when the typical
abdominal pain first begins and not by the time when
patient first seeks hospital care. This time of onset of pain
abdomen is crucial to define the further complications of
AP.
Types of AP
AP can be subdivided into two types based on presence or
absence of necrosis:
„„ Interstitial pancreatitis—in the absence of pancreatic
necrosis, the edematous pancreas in mild disease, is
defined as interstitial pancreatitis;
„„ Necrotizing pancreatitis—in about 5–10% of patients,
AP evolves to produce necrosis of pancreatic
parenchyma, the peripancreatic tissue or both.
Pancreatic necrosis is defined as focal or diffuse areas
of nonviable parenchyma which is 30% of the pancreas or
3 cm in size.
Organ Failure—Definition
Organ failure is defined based on the assessment of three
major organ systems:
„„ Cardiovascular
„„ Respiratory, and
„„ Renal. Modified Marshall scoring system (Table 1) is
used to define organ failure.
Local Complications—Definition
The concept of local complications following AP was
defined by the Original ATLANTA classification (1992).
Since then with the advancement of the understanding
of pathophysiology and improvement of imaging has led
to better characterize the local complications as acute
peripancreatic fluid collection, pancreatic pseudocyst
(Fig. 1), acute necrotic collection, and walled-off necrosis
(Fig. 2) based on the presence and absence of necrosis
and time from the onset of pain abdomen, each of which
has been defined by the revised ATLANTA classification1
(2013) (Table 2). Gastric outlet obstruction, splenic vein
and portal vein thrombosis are some of the other local
complications of AP.
Systemic Complications—Definition
Any exacerbation of previous comorbid conditions such as
chronic lung disease, or coronary artery disease, by AP is
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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 800 SECTION 10 Gastroenterology
Fig. 1: Contrast enhanced CT axial images showing small
pseuodcysts in the uncinate process and neck of pancreas
TABLE 2 Terminology based on fluid collection1 (local complications)
Type of pancreatitis First 4 weeks
Interstitial pancreatitis Acute peripancreatic fluid collection
Necrotizing pancreatitis Acute necrotic collection (ANC)
Phases2
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
mortality: Early and Late phase. These two phases are
considered separately.
Early Phase
The early phase involves first week of disease presentation,
but may sometimes be prolonged into the second week
also. During the early phase, manifestations are due
to the response to local pancreatic inflammation and
injury. Pancreatic inflammation, in turn, activates
cytokine cascade, which clinically manifests as systemic
inflammatory response syndrome (SIRS) (Table 3). There
is an increased risk of developing organ failure if SIRS is
persistent. The presence and duration of organ failure in
the early phase determines the severity of AP. If the organ
failure resolves within 48 hours, it is defined as “Transient
organ failure,” and if it persists for more than 48 hours, it
is defined as “Persistent organ failure.” Multiorgan failure
MU-126.indd 800
Fig. 2: Contrast enhanced CT axial images showing large
peripancreatic walled off necrosis (WON) around body and tail of
pancreas
After 4 weeks
Pseudocyst
Walled off necrosis (WON)
(MOF) is defined when more than one organ develops
failure.
Late Phase
By definition, the late phase occurs only in patients with
moderately severe or severe AP. It is characterized by the
persistence of local complications or systemic signs of
inflammation.
Severity of AP—Definition
It is prudent to define and distinguish patients of AP based
on severity. The ATLANTA classification has defined three
major types of severity—mild, moderate, and severe AP
(Table 4).
Etiology2
The most common causes of AP are gallstones (40–
70%) and alcohol (25–35%). Other etiologies being post
ERCP (5%), post trauma, especially in children (1%),
idiopathic (25%), and miscellaneous (5%). Alcohol-related
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 Medical Management of Acute Pancreatitis
TABLE 3 SIRS1
Signs of systemic inflammatory response syndrome (SIRS)
SIRS—defined by presence of two or more criteria:
zz Heart rate >90 beats/min
zz Core temperature <36°C or >38°C
3
zz White blood count <4000 or >12000/mm
zz Respirations >20/min or PCO <32 mm Hg
2
pancreatitis usually manifests as a spectrum, ranging from
distinct episodes of AP to chronic pancreatitis causing
irreversible changes silently.
Risk Stratification and Predicting Severe AP
For initial management and hospitalization, laboratory
investigations and imaging studies can be useful but
are unreliable to predict the severity of AP. Laboratory
investigations like hematocrit, blood urea nitrogen (BUN),
creatinine or CRP in the 1st 48 hours can be normal. Also,
cross sectional imaging cannot determine severity early in
disease course as necrosis is usually absent on admission
and may take 2–3 days to develop. Thus, as there is an
absence of any definite test to determine the severity of AP,
clinical assessment of third space fluid losses, shock and
signs and symptoms suggestive of organ dysfunction is of
paramount importance.
Management (Flowchart 1)
Pain Management (Analgesia)
Abdominal pain is the presenting and distressing symptom
in patients with AP. Effective and successful analgesia is an
important component of the management of AP. An added
desirable effect of the analgesic could be its impact on the
underlying inflammatory process. Both opioid analgesics
and nonsteroid anti-inflammatory agents (NSAIDs) have
been used in patients with AP for pain relief. However,
the evidence for their efficacy and safety profile is limited.
The concern with NSAIDs is adverse events such as
gastrointestinal bleeding and acute kidney injury. Opiates
have shown by a randomized controlled trial to have better
analgesic effect and safety profile compared to NSAIDs3 for
AP. Nalbuphine (an opioid with µ receptor antagonism) is
a latest armamentarium useful for AP pain.
MU-126.indd 801
CHAPTER 126 801
TABLE 4 Grades of severity1,2
Severity Local/systemic Organ failure
complications
Mild acute No No
Moderately acute Yes Transient (<48 hrs)
Severe acute Yes Yes (>48 hrs)
(15–20%)
Fluid Resuscitation—Importance of
Intravenous Hydration
Multiple factors are responsible for often causing
hypovolemia in patients affected by AP, such as vomiting,
third space loss, decreased oral intake, diaphoresis, and
increased respiratory losses. Besides, inflammation of
pancreas causes pancreatic edema and microcirculatory
effects causing decreased blood flow, which in turn
causes cell death, pancreatic tissue necrosis and
pancreatic enzymes release, activating further numerous
inflammatory cascades.
In AP, there is a median fluid loss of 3.2 liters. 4
The fluid should be given as 15–20 mL/kg bolus dose
followed by 1.5–3 mL/kg/hour, depending on the
response for the first 12–24 hours. Although the most
effective approach to early fluid resuscitation has yet
to be determined, studies have suggested that lactated
Ringer’s maybe the preferred solution for initial
hydration.5 Owing to its bicarbonate content and stable
pH, this isotonic solution, when compared to normal
saline, may prevent the development of metabolic
acidosis, which can complicate care in patients receiving
large-volume resuscitation using isotonic saline.
Also, there are theoretical advantages in stabilizing
the pancreas by preventing acidosis, which increases
degranulation, enzyme release. The goal of fluid therapy
is to achieve a mean arterial BP of minimum 70 mm
Hg, hematocrit of 40–42, urine output—0.5–1 mL/min.6
Monitoring of fluid therapy can be done using invasive
methods like central venous pressure, stroke volume,
arterial pressure wave-form, and noninvasive methods
like IVC diameter: <1.5 cm or >50% index-deficit, lung
ultrasound for fluid overload. Elderly patients and those
with history of cardiac and/or renal disease should be
taken carefully resuscitated.
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 802 SECTION 10 Gastroenterology

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

MU-126.indd 802 29-01-2021 14:59:47

 Medical Management of Acute Pancreatitis
antibiotics, or (b) Empirical use of antibiotics can be done
after obtaining necessary blood or urine culture sensitivity
for disease causing agents, without CT-guided FNA.
Infected necrosis warrants use of antibiotics which can
penetrate the necrosis, such as carbapenems, quinolones,
and metronidazole, as per the local pattern of sensitivity
of organisms. Timely use of antibiotics in such cases can
delay or sometimes avoid interventions, hence reducing
morbidity and mortality. Evidence of extra-pancreatic
infections like urinary tract infections, cholangitis,
catheter-acquired infections, bacteremia, and pneumonia
necessitates antibiotics. Routinely antifungal agents
along with antibacterial agents (used for prophylaxis or
treatment) are not recommended.
Nutrition in AP
Traditionally patients having AP were kept nil per mouth
(NPO) to theoretically provide rest to the organ. Multiple
experimental and clinical studies have subsequently
shown that bowel rest causes mucosal atrophy and
increases infectious complications due to bacterial
translocation from the gut. Also, studies have shown that
early enteral feeding in the course of AP reduces hospital
stay, and hence decreased morbidity. In mild AP, if there is
absence of vomiting, and if abdominal pain has improved,
oral feeds should be started as soon as possible. Oral
feeds in mild AP are introduced as a low-fat, low-residue,
light diet as the patient improves clinically. Polymeric
feeds (feeds containing all major nutrients) are preferred
consisting of 25–30 kcal/kg with 1.2–2 gm/kg protein. In
mild as well as severe AP, total parenteral nutrition ideally
should be avoided as it increases chances of infectious
complications and other peripheral or central line-related
complications.
Use of nasogastric tube for enteral nutrition appears
to be safe; however, the use of nasojejunal tube is typically
preferred to avoid gastric phase of pancreatic stimulation.
Nasogastric tube placement is far easier compared to
the nasojejunal tube (requires fluoroscopic guidance for
placement and is expensive), which is advantageous for
patients in intensive care unit (ICU) treatment. In patients
presenting as severe AP, on initial assessment, should
be started on enteral tube feeding as a part of primary
therapy. In the late phase of AP (2nd–3rd week) maintaining
nutrition is critical, the target should be to provide 1500–
2000 kcal diet.
MU-126.indd 803
CHAPTER 126 803
Endoscopic Retrograde Cholangiopancreatography
(ERCP)–Role in AP
As per the latest recommendations, patients with
concurrent AP and acute cholangitis with high clinical
suspicion of choledocholethiasis should undergo ERCP
with biliary stenting within 24 hours of admission as a
therapeutic procedure. Usually, in patients with gallstone
pancreatitis who lack laboratory or clinical evidence
of ongoing biliary obstruction, magnetic resonance
cholangiopancreatography (MRCP) or endoscopic
ultrasound (EUS) rather than ERCP should be used to
screen for choledocholithiasis.
Also, ERCP on one hand, it can be a therapeutic
modality for biliary pancreatitis, while on the other hand,
it can be an important and preventable etiology of AP.
The risk of post-ERCP pancreatitis is around 5%. Three
methods to reduce the risk of post-ERCP pancreatitis,
especially severe AP include:
„„ Pancreatic duct stents
„„ Use of guidewire for cannulation
„„ Rectal NSAIDs (diclofenac suppository) pre-procedure.
Infected Pancreatic Necrosis
The step-up approach is recommended with conservative
treatment in ICU 1st followed by percutaneous drainage,
which is followed by minimally invasive necrosectomy.7,8
Primarily conservative management results in mortality
comparable to surgery in patients with infected pancreatic
necrosis.9 If necrosectomy is required, endoscopic step-up
approach should be preferred.10,11
Conclusion
The diagnosis and optimal management of AP requires
a systematic approach and multidisciplinary decision-
making. Regardless of pancreatitis severity, recommended
medical management includes goal-directed intravenous
fluid resuscitation, early enteral feeding, avoidance of
antibiotics as prophylaxis and urgent ERCP for patients
with acute biliary pancreatitis complicated by cholangitis.
Hence to conclude the first 24–48 hours are critical, and
hence triaging of these patients on first presentation to
hospital is an important approach to enable appropriate level
of care.
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 804 SECTION 10 Gastroenterology
References
1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute
pancreatitis-2012: revision of the Atlanta classification and
definitions by international consensus. Gut. 2013;62(1):102-11.
2. Tenner S, Baillie J, DeWitt J, et al. American College of
Gastroenterology. American College of Gastroenterology
guideline: management of acute pancreatitis. Am J Gastroenterol.
2013;108(9):1400-15.
3. Mahapatra SJ, Jain S, Bopanna S, et al. Pentazocine, a Kappa-Opioid
agonist, is better than diclofenac for analgesia in acute pancreatitis:
a randomized controlled trial. Am J Gastroenterol. 2019;114(5):
813-21.
4. de-Madaria E, Banks PA, Moya-Hoyo N, et al. Early factors associated
with fluid sequestration and outcomes of patients with acute
pancreatitis. Clin Gastroenterol Hepatol. 2014;12(6):997-1002.
5. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution
reduces systemic inflammation compared with saline in patients
with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-7.
MU-126.indd 804
6. Haydock MD, Mittal A, Wilms HR, et al. Fluid therapy in acute
pancreatitis: anybody’s guess. Ann Surg. 2013;257(2):182-8.
7. Jiang K, Huang W, Yang X-N, et al. Present and future of prophylactic
antibiotics for severe acute pancreatitis. World J Gastroenterol WJG.
2012;18(3):279-84.
8. IAP/APA evidence-based guidelines for the management of acute
pancreatitis. Pancreatology. 2013;13(4.2):1-15.
9. Garg PK, Sharma M, Madan K, et al. Primary conservative treatment
results in mortality comparable to surgery in patients with infected
pancreatic necrosis. Clin Gastroenterol Hepatol. 2010;8(12):1089-94.
10. Lakhtakia S, Basha J, Talukdar R, et al. Endoscopic “step-up approach”
using a dedicated biflanged metal stent reduces the need for direct
necrosectomy in walled-off necrosis (with videos). Gastrointest
Endosc. 2017;85(6):1243-52.
11. Bang JY, Arnoletti JP, Holt BA, et al. An endoscopic transluminal
approach, compared with minimally invasive surgery, reduces
complications and costs for patients with necrotizing pancreatitis.
Gastroenterology. 2019;156(4):1027-40.
12. Feldman M, Friedman L, Brandt L. Sleisenger and Fordtran’s
Gastrointestinal and Liver Disease, 10th edition. Saunders; 2015.
29-01-2021 14:59:52
 CHAPTER

127 Functional Gastrointestinal

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

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

MU-127.indd 805 29-01-2021 14:59:32

 806 SECTION 10 Gastroenterology

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

MU-127.indd 807 29-01-2021 14:59:33

 808 SECTION 10 Gastroenterology
Rome IV criteria for the diagnosis of functional
TABLE 2
dyspepsia (FD)7
Functional dyspepsia
Diagnostic criteria
1.  One or more of the following:
a.  Bothersome postprandial fullness
b.  Bothersome early satiation
c.  Bothersome epigastic pain
d.  Bothersome epigastic burning
No evidence of structural disese (including at upper endoscopy)
that is likely to explain the symptoms

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.
Epigastric pain syndrome (EPS) and postprandial
distress syndrome (PDS) are the two subtypes of FD. In
practice, however, patients rarely present with pure EPS
or PDS, but most patients have overlapping symptoms.
The criteria, as suggested by the Rome IV Committee for
diagnosis of EPS and PDS, are presented in Table 3.7
Management of FD
Management of the patients with dyspepsia as per the
Rome IV system is presented in Flowcharts 1A and B. One
must not forget to look for alarm features (age >45 years,
history of GI bleeding, weight loss, family history of gastric
cancer, anemia, etc.). Patients with a history of alarm
features must undergo thorough investigations including
upper GI endoscopy and CT scan of the abdomen (in
patients with a family history of gastric cancer and
a high degree of clinical suspicion of gastric cancer)
before considering dyspepsia to be functional.7 It is also
important to note that the age cut off of 45 years may vary
depending on the local epidemiology of gastric cancer.
International societies, including experts in the Rome IV
committee, suggested that H. pylori infection, if present on
appropriate testing, should preclude the diagnosis of FD. If
eradication of infection improves dyspeptic symptoms, the
condition should instead be called H. pylori-associated
dyspepsia.7 The applicability of this international guideline
in India, however, may be viewed with skepticism. Though
Indian literature on this issue is scanty, yet considering
the high frequency of H. pylori infection in Indian adults,
this strategy may not be practicable. Treatment of FD
depends on its subtype. Whereas EPS, an uncommon
MU-127.indd 808
subtype is treated with proton pump inhibitors and
when unresponsive, antidepressants, PDS is treated with
prokinetics, fundic relaxants, and psychotropic agents.
Overlap syndrome is treated with combined therapeutic
agents. Table 4 lists the drugs available currently in the
Indian market for the treatment of two subtypes of FD.7
Irritable Bowel Syndrome
Diagnosis of IBS
IBS is one of the common FGIDs seen in clinical practice
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
failed to find a cause for the chronic lower GI symptoms.
Manning and Thompson, for the first time, introduced the
criteria-based diagnosis of IBS in 1978.8 Since then, the
Rome Foundation brought in several iterations of Rome
criteria for the diagnosis of IBS. Manning’s criteria (Box 1)
encourage a positive diagnosis of IBS without the need for
multiple unnecessary investigations to exclude organic
diseases before diagnosing IBS.8
However, it is essential to note that in the study by
Manning and Thompson, organic disorders excluded
were peptic ulcer disease, inflammatory bowel disease,
gastroesophageal reflux disease, gallstones, and
carcinoma of the colon and not the conditions which
closely mimic IBS such as lactose intolerance, celiac
disease, microscopic colitis, small intestinal bacterial
overgrowth, fecal evacuation disorder, collagenous colitis
and microscopic, etc. 2,8 Hence, over-reliance on such
symptom-based criteria to exclude every organic disorder
(some of which are rather micro-organic) may result in
overlooking such conditions. Another limitation of the
Manning criteria is the lack of due consideration for the
duration of symptoms. As some of the organic disorders
are expected to have a short duration of symptoms, the
importance of time of illness cannot be overestimated.
However, despite these limitations, Manning’s criteria
remain quite useful and popular in practice not only
among Gastroenterologists but also among Physicians.
In addition to the higher sensitivity of Manning’s criteria
as compared to the various iteration of Rome criteria in
India,4 the simplicity of the former is a significant reason
for its popularity.
29-01-2021 14:59:33
 Functional Gastrointestinal Disorders CHAPTER 127 809

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

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

MU-127.indd 809 29-01-2021 14:59:34

 810 SECTION 10 Gastroenterology

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
—— Bothersome postprandial fullness (i.e., severe enought to zz Lansoprazole zz Buspirone
zz Dexlansoprazole zz Mirtazapine
impact on usual activities)
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
a
Criteria 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
should generally not be considered as part of dyspepsia
zz Other individual digestive symptoms or gourps of symptoms,
e.g. from gastroesophageal reflux disease and the irritable bowel
syndrome may coexist with PDS
Epigastric pain syndrome
Recurrent abdominal pain, on average, at least 1 day per week in
the last 3 months, associated with two or more of the following
criteria:
zz Related to defecation
zz Associated with a change in frequency of stool
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

zz Other digestive symptoms (such as from gastroesophageal
Alarm Features
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

MU-127.indd 810 29-01-2021 14:59:34


before the diagnosis of IBS is made. Alarm features include
the age of onset at or more than 45 years, anemia, blood in
the stools, unintended weight loss, nocturnal symptoms,
fever, abdominal mass, and a family history of colorectal
cancer. As mentioned earlier, the age cut off of 45 years
may vary depending on the local epidemiology of gastric
cancer.
For clinical trials, all patients should have at least full
blood counts, erythrocyte sedimentation rate, C-reactive
protein, and limited colonoscopic examination, and other
investigations, if indicated.9
Multidimensional Clinical Profile
There has been a significant paradigm shift in the
management of FGIDs after the introduction of a
multidimensional clinical profile (MDCP) in the Rome IV
algorithm in 2016. Currently, experts, including the author,
are in the process of generating a plausibility consensus
in relation to organic issues on FGIDs. According to
MDCP, in addition to assigning the patients to a diagnostic
category, it is essential to evaluate the patients as a whole
rather than only a diagnostic label. Sir William Osler wrote
that it is better to treat the patient who has the disease
rather than treating the disease. MDCP necessitate the
physician to assess several critical issues in addition to the
categorical diagnosis of FGIDs such as IBS (Box 2).10
A component of MDCP includes subtyping
(Fig. 2) of FGIDs; for example, constipation-predominant
or diarrhea-predominant IBS (IBS-C, and IBS-D,
respectively), EPS or PDS subtypes of FDF, etc. As described
in the treatment of these disorders, such subtyping is the
cornerstone for the choice of appropriate drugs to treat
these disorders.9 Moreover, those with alternating (change
in symptoms over weeks to months) and mixed type is
more difficult to treat and may require pathophysiology
modifying measures such as an attempt at manipulating
gut microbiota.
Table 6 and Figure 3 list the biological factors that
may contribute to two subtypes of IBS, namely diarrhea-
predominant and constipation-predominant IBS.4
Treatment
In addition to pharmacological treatment, dietary
modification (low FODMAP diet) and management of
psychological issues may help in relieving symptoms
MU-127.indd 811
Functional Gastrointestinal Disorders CHAPTER 127 811
Multidimensional clinical profile in functional
BOX 2
gastrointestinal disorders10
zz Categorical diagnosis (symptom-based criteria)
zz Clinical modifier (e.g., IBS-C, D, M, post-infectious, FODMAP
sensitive)
zz Impact (mild, moderate, severe)
zz Psychosocial modifier
zz Physiological dysfunction and biomarker
IBS: irritable bowel syndrome, FODMAP: fermentable oligo- di-
monosaccharides and polyols.
and improving the quality of life. To address these issues,
dieticians and psychologists are essential members of the
team to manage these patients. Treatment would depend
on the predominant symptoms: diarrhea, constipation, or
pain/gas/bloat (Figure 3, Table 7).4
Initial treatment for patients with IBS should include
various combinations of antispasmodic, laxative, and
antidiarrheal agents as they are quite safe and relatively
inexpensive.12 Antispasmodics, which reduce abdominal
pain by reducing muscle spasm, include antimuscarinics,
smooth-muscle relaxants, and anticholinergics. 12
Common adverse effects include dry mouth, dizziness,
blurred vision, confusion, urinary retention, and
constipation, which are associated with anticholinergics.
Bulking agents are commonly prescribed drugs, especially
for IBS-C.12 However, bulking agents may even aggravate
abdominal pain and bloating.12 For the control of diarrhea,
loperamide has the best quality of evidence but has not
been shown to improve abdominal pain or distension.
Several visceral neuromodulators, which also
have central nervous system effect, such as tricyclic
antidepressants, serotonin reuptake inhibitors (SSRI),
and serotonin-norepinephrine reuptake inhibitors
(SNRI), relieve abdominal pain, diarrhea, insomnia, and
depression. These drugs are useful in the treatment of
IBS even in the absence of psychiatric illness.12 Another
approach to treating IBS is psychotherapy. 12 Aims of
psychotherapy include reframing maladaptive beliefs,
reduction of over-responsiveness to stress, reduction
of maladaptive psychological responsiveness, and
modification of maladaptive behaviors. Hypnotherapy is
one of the essential tools in psychotherapy. The essence
of hypnotherapy is to create a relaxing and calming
environment and allowing the patient to refocus away
29-01-2021 14:59:35
 812 SECTION 10 Gastroenterology

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

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

MU-127.indd 812 29-01-2021 14:59:35

MU-127.indd 813
Functional Gastrointestinal Disorders

Figure 3: Pathophysiological mechanisms of constipation and diarrhea-predominant irritable bowel syndrome (IBS-C and D) and possible therapeutic agents to target
these abnormalities. It is important to note that the therapeutic agents work in functional constipation and IBS-C and functional diarrhea and IBS-D comparably
(Source: Reproduced from Reference 4)
CHAPTER 127
813

29-01-2021 14:59:36
 814 SECTION 10 Gastroenterology

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
subjects, the patients reported symptoms following the
ingestion of this disaccharide than the controls, possibly
due to visceral hypersensitivity. Lactose is a component
of Fermentable Oligo-, Di-, Monosaccharide, and Polyol
(FODMAP) foods. All the high FODMAP foods lead
to pathophysiological effects, such as production of
osmotically active substances, and gas causing flatulence,
distension, and pain, somewhat similar to lactose, among
the patients with IBS. Hence, avoidance of high FODMAP
foods improves symptoms of IBS.16 FODMAP diet chart
is available from http://spreadhealth.in/New%20Folder/
High%20&%20low%20FODMAP%20foods.pdf.
Conclusion
FGIDs, including IBS and FD, are common in medical practice.
These disorders have multiple pathophysiological basis. Multi-
modality treatment directed to the subtypes and underlying
pathophysiological factors is often successful in managing
these patients.
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2. Barbara G, Feinle-Bisset C, Ghoshal UC, et al. The intestinal
microenvironment and functional gastrointestinal disorders.
Gastroenterology. 2016;150:1305-18.
3. Drossman DA, Hasler WL. Rome IV-Functional GI Disorders:
Disorders of Gut-Brain Interaction. Gastroenterology. 2016;
150(6):1257-61.
4. Ghoshal UC. Pros and cons while looking through an Asian
window on the Rome IV criteria for irritable bowel syndrome. Pros J
Neurogastroenterol Motil. 2017;23(3):334-40.
5. Ghoshal UC, Singh R. Frequency and risk factors of functional gastro-
intestinal disorders in a rural Indian population. J Gastroenterol
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6. Ghoshal UC. Marshall and Warren Lecture 2019: A paradigm shift
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irritable bowel syndrome. J Gastroenterol Hepatol. 2010;25(7):
1189-205.
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Functional Gastrointestinal Disorders CHAPTER 127 815
13. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients
with irritable bowel syndrome without constipation. N Engl J Med.
2011;364:22-32.
14. Gonlachanvit S, Mahayosnond A, Kullavanijaya P, et al. Effects
of chili on postprandial gastrointestinal symptoms in diarrhoea
predominant irritable bowel syndrome: evidence for capsaicin-
sensitive visceral nociception hypersensitivity. Neurogastroenterol
Motil. 2009;21(1):23-32.
15. Gupta D, Ghoshal UC, Misra A, et al. Lactose intolerance in patients
with irritable bowel syndrome from northern India: a case-control
study. J Gastroenterol Hepatol. 2007;22(12):2261-5.
16. Gibson PR, Shepherd SJ. Evidence-based dietary management of
functional gastrointestinal symptoms: The FODMAP approach. J
Gastroenterol Hepatol. 2010;25(2):252-8.
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

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

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 Variceal Bleed Management CHAPTER 128 817

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

MU-128.indd 817 29-01-2021 14:59:28

 818 SECTION 10 Gastroenterology

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
in cirrhotic patients.2 There is no recommendation for
use of platelet transfusion, intravenous vitamin K, or
tranexamic acid to halt the acute ongoing variceal bleed.
Transfusion of fresh frozen plasma or factor VIIa to correct
INR is not recommended.8
Any one of the vasoactive drugs (Table 1) and
antibiotic prophylaxis should be initiated at the earliest
prior to esophagogastroduodenoscopy (EGD). 4 These
vasoactive drugs cause splanchnic vasoconstriction
and reduce the portal pressure. Even in patients on
noradrenaline infusion for hypotension, one of the
vasoactive drugs should be continued. 9 Intravenous
antibiotic prophylaxis (ceftriaxone 1 g/24 hourly) prevent
the infectious complications and reduce mortality. A
nasogastric tube placement is usually not recommended
and prokinetic administration can enhance the gastric
mucosa visualization during endoscopy (erythromycin
250 mg IV 30–120 minutes before endoscopy, if no QT
prolongation on electrocardiography).
Endoscopic Treatment
There is no need to hurry for EGD to achieve hemostasis.
While the first and foremost step is hemodynamic
resuscitation and stabilization before sending the patients
for endoscopic hemostasis. EGD can be safely performed
between 6–24 hours after presentation to the emergency,
but it should be individualized if there is evidence of active
ongoing bleed despite vasoactive drugs, hemodynamic
instability due to blood loss despite resuscitation, actively

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 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

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

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

MU-128.indd 819 29-01-2021 14:59:29


MU-128.indd 820
TABLE 2 Drugs used in prophylaxis of esophageal variceal bleed (adapted from AASLD 2016 Practice Guidance4)
Drug Recommended dose
Oral non-selective beta Initiation dose: 20–40 mg BD for propranolol
blockers (Propranolol and 10–20 mg OD for nadolol
or Nadolol) Dose titration: Adjust every 2–3 days to
achieve maximally tolerated dose or therapy
goal achieved
Maximal daily dose:
For propranolol: 320 mg/day if no ascites and
160 mg/day if ascites present
For nadolol: 160 mg/day if no ascites and 80
mg/day if ascites present
Therapy goal: Resting heart rate of 55–60
beats/minute and systolic blood pressure
should not be < 90 mm Hg
Carvedilol Initiation dose: 3.125 mg OD
Dose titration: Adjust every 3 days to 6.25
mg BD
Maximal daily dose: 12.5 mg/day (except in
patients with persistent arterial hypertension)
Therapy goal: Systolic blood pressure should
not be <90 mm Hg
29-01-2021 14:59:29
Predominant mechanism of action
Reduce portal venous inflow by
splanchnic vasoconstriction (by
β2-blockade and unopposed
α-adrenergic activity) and decrease
cardiac output (by β1-blockade)
Non-selective beta-blocker (reduce
portal blood flow) with additional
anti-α1-adrenergic action (reduce
intrahepatic resistance)
820
SECTION 10
Significant adverse effects and contraindications
Gastroenterology
Common adverse events: fatigue, lightheadedness,
and shortness of breath
Contraindications: decompensated heart failure,
advanced heart block, severe sinus bradycardia, aortic
valve disease, advanced peripheral arterial disease,
obstructive pulmonary disease, insulin-dependent
diabetes
-In spontaneous bacterial peritonitis, refractory
ascites, and severe circulatory dysfunction like
hyponatremia (Na+ <130 meq/L) and hepatorenal
syndrome, the dose of NSBB should be reduced or
withheld temporarily till circulatory dysfunction or
sepsis improves
Common adverse events: orthostatic hypotension,
dizziness and fatigue
Contraindications: decompensated heart failure,
advanced heart block, obstructive airway disease, and
severe bradycardia
To be avoided in decompensated cirrhosis as it can
worsen ascites and renal dysfunction

mortality.4 Patient should be referred to higher center for
adequate and prompt management. If rebleed is mild (no
hemodynamic instability), a re-look endoscopy should be
attempted by experienced endoscopists.
Tamponade as Bridge Therapy
If the rebleeding is persisting despite first endoscopy
or the rebleed is massive (hemodynamic instability,
blood transfusion or 3 g/dL drop in hemoglobin) or the
second endoscopic attempt fails, balloon tamponade
(Sengstaken–Blakemore tube) or self-expandable metal
stent (SEMS) can be used as bridge therapy till definite
portal decompressive therapies is available. The balloon
tamponade can achieve hemostasis in ~80% cases
and should be used for maximum of 24 hours, but it is
associated with severe complications such as aspiration
and esophageal rupture. 5,13 SEMS is effective and safer
alternative than balloon tamponade for control of bleeding
and can be left in place for up to 7 days.14
Rescue or Salvage TIPS
This can effectively control bleeding in more than 90%
of refractory esophageal variceal bleeding cases, but
the mortality rate remains high (30–50%) as well as the
risk of encephalopathy.15 So, the patients with high-risk
of rebleed are to be identified and offered aggressive
strategies (like early TIPS) to prevent treatment failure.
Surgical shunts are rarely performed nowadays, may be
done in good surgical candidate (child A cirrhosis), when
TIPS is not technically feasible.
Patients who Recovered from Recent
Variceal Bleed and Secondary Prophylaxis
Untreated patients who recover from first episode of
bleed are at high-risk of rebleed (55–67% in first year)
and mortality (25–50%). 16 So, initiation of secondary
prophylaxis against rebleed is essential before hospital
discharge. Patients with indication for liver transplantation
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.
All guidelines recommend combination of NSBB
(propranolol or nadolol) with EVL as first-line management
for secondary prophylaxis. NSBBs (Table 2) form the
cornerstone of combination therapy; meta-analysis
showed an improvement in survival with the addition of
MU-128.indd 821
Variceal Bleed Management CHAPTER 128 821
NSBBs to EVL, while the addition of EVL to NSBBs has no
survival benefit.17 NSBBs can be used as monotherapy if
patients are unable or unwilling to undergo EVL.5 Currently
neither HVPG-guided therapy nor TIPS is recommended
for secondary prophylaxis. Unless contraindicated, TIPS
is the recommended treatment in patients with recurrent
bleed despite combination therapy and also in patients
who are intolerant to NSBBs (EVL alone cannot be used
as secondary prophylaxis) and especially if patient has
ascites also.
Screening and Primary
Prophylaxis for Varices
All cirrhotics should undergo variceal screening by
endoscopy. However, EGD can be avoided in patients
whose liver stiffness on transient elastography (TE) is <20
kPa with platelet count >1,50,000/µL (TE-based criteria);
or serum albumin >3.6 g/dL and platelets >1,20,000/mm3
(platelet-albumin criteria).6,18
There is no role of prophylaxis in cirrhosis with no
varices or low-risk varices. Primary prophylaxis must be
initiated in all cirrhosis with varices at high-risk of rupture.
High-risk varices are small varices with red color signs,
small varices in CTP C cirrhosis and medium or large
varices irrespective of CTP class. The choice between
NSBBs (Table 2) and EVL depends on variceal size, patient
preference, and local resources. A recent network meta-
analysis showed that NSBBs are associated with lower
mortality compared to EVL.19
Conclusion
Acute variceal bleed is an important prognostic event in the
natural history of cirrhosis. It is a medical emergency with high
mortality and must be managed with resuscitation, vasoactive
drugs, prophylactic antibiotics, and endoscopic treatment.
Non-selective beta blocker plays a crucial role in the primary
and secondary prophylaxis. TIPS has role in refractory bleed
and prevention of rebleed in high-risk patients.
References
1. Singh SP, Panigrahi MK. Spectrum of upper gastrointestinal
hemorrhage in coastal Odisha. Trop Gastroenterol. 2013;34:14-7.
2. Rout G, Shalimar, Gunjan D, et al. Thromboelastography-guided
blood product transfusion in cirrhosis patients with variceal
bleeding: a randomized controlled trial. J Clin Gastroenterol.
2020;54(3):255-62.
29-01-2021 14:59:29
 822 SECTION 10 Gastroenterology
3. Rout G, Sharma S, Gunjan D, et al. Development and validation of
a novel model for outcomes in patients with cirrhosis and acute
variceal bleeding. Dig Dis Sci. 2019;64(8):2327-37.
4. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive
bleeding in cirrhosis: risk stratification, diagnosis, and management:
2016 practice guidance by the American Association for the study
of liver diseases. Hepatology. 2017;65(1):310-35.
5. Angeli P, Bernardi M, Villanueva C, et al. EASL Clinical Practice
Guidelines for the management of patients with decompensated
cirrhosis. J Hepatol. 2018;69(2):406-60.
6. de Franchis R, Faculty BV. Expanding consensus in portal
hypertension: report of the Baveno VI Consensus Workshop:
stratifying risk and individualizing care for portal hypertension. J
Hepatol. 2015;63(3):743-52.
7. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute
upper gastrointestinal bleeding. N Engl J Med. 2013;368(14):1362-3.
8. Bosch J, Thabut D, Albillos A, et al. Recombinant factor VIIa for
variceal bleeding in patients with advanced cirrhosis: a randomized,
controlled trial. Hepatology. 2008;47(5):1604-14.
9. Osman D, Djibré M, da Silva D, et al. Management by the intensivist
of gastrointestinal bleeding in adults and children. Ann Intensive
Care. 2012;2(1):46.
10. Lau JYW, Yu Y, Tang RSY, et al. Timing of endoscopy for acute upper
gastrointestinal bleeding. N Engl J Med. 2020;382(14):1299-308.
11. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in
patients with cirrhosis and variceal bleeding. N Engl J Med.
2010;362(25):2370-9.
MU-128.indd 822
12. Merli M, Berzigotti A, Zelber-Sagi S, et al. EASL Clinical Practice
Guidelines on nutrition in chronic liver disease. J Hepatol.
2019;70(1):172-93.
13. Sarin SK, Nundy S. Balloon tamponade in the management of
bleeding oesophageal varices. Ann R Coll Surg Engl. 1984;66(1):
30-2.
14. Rodrigues SG, Cárdenas A, Escorsell À, et al. Balloon tamponade
and esophageal stenting for esophageal variceal bleeding in
cirrhosis: a systematic review and meta-analysis. Semin Liver Dis.
2019;39(2):178-94.
15. Vangeli M, Patch D, Burroughs AK, et al. Salvage tips for uncontrolled
variceal bleeding. J Hepatol. 2002;37(5):703-4.
16. Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet.
2003;361:952-4.
17. Albillos A, Zamora J, Mar tínez J, et al. Stratifying risk in
the prevention of recurrent variceal hemorrhage: results of
an individual patient meta-analysis. Hepatology. 2017;66(4):
1219-31.
18. Sharma S, Agarwal S, Gunjan D, et al. Deciding among noninvasive
tools for predicting varices needing treatment in chronic
liver disease: an analysis of Asian Cohort. Am J Gastroenterol.
2020;115(10):1650-6.
19. Sharma M, Singh S, Desai V, et al. Comparison of therapies
for primary prevention of esophageal variceal bleeding: a
systematic review and network meta-analysis. Hepatology. 2019;
69(4):1657-75.
29-01-2021 14:59:29
 CHAPTER

129 Hepatorenal Syndrome: Current

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

Hepatorenal syndrome (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.1
group of postoperative patients of biliary tract surgery. 2
International ascites club has formulated diagnostic
guidelines for HRS in 1994, which were modified in 2007.3
Diagnostic Criteria for HRS
See Box 1.

MU-129.indd 823 29-01-2021 14:59:15

 824 SECTION 10 Gastroenterology
BOX 1 Diagnostic criteria of HRS (EASL)
zz Cirrhosis with ascites
zz Serum creatinine 1.5 mg/dL (133 lmol/L)
zz Absence of shock
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
diuretics), and volume expansion with albumin at 1 g/kg/day up
to a maximum of 100 g/day
zz No current or recent treatment with nephrotoxic drugs
zz Absence of parenchymal renal disease as defined by proteinuria
0.5 g/day, no micro hematuria (50 rbc/high powered field), and
normal renal ultrasonography
Pathophysiology
The pathophysiology of HRS is poorly understood, three
essential components are:
„„ Arterial vasodilatation in the splanchnic and systemic
circulation,
„„ Renal vasoconstriction, and
„„ Cardiac dysfunction.
Several cytokines are involved which alter the renal
blood flow and glomerular microvasculature. Important
among them are cysteinyl leukotrienes, thromboxane
A2, F2-isoprostanes, and endothelin-1. Knowledge about
these vasoactive compounds is also important from
therapeutic and preventive point of view.
Arterial Vasodilatation in the Splanchnic and
Systemic Circulation
Splanchnic vasodilatation is the hallmark of portal
hypertension seen in chronic liver disease. Several
vasodilators like nitric oxide, glucagon, carbon mono
oxide, prostacyclin are released which are responsible
for these vasodilatory response.4-7 In the initial stages,
cardiac compensatory mechanism tends to counter the
vasodilation.8
Renal Vasoconstriction
Due to splanchnic vasodilatation and renal vasoconstriction
there is activation of the renin-angiotensin-aldosterone
system (RAAS). The clear pathway is not known but
cytokines like endothelins, prostaglandins, kallikreins,
and F2 isoprostanes are considered to cause renal vaso­
constriction.9-11
MU-129.indd 824
These hemodynamic changes in renal microvasculature
and splanchnic vasodilation compromises renal blood
flow leading to fall in glomerular filtration rate.5
So, HRS is initially a functional renal syndrome, which
later progresses to an organic disease.
Cardiac Dysfunction
The development of cirrhotic cardiomyopathy leads to
impairment of cardiac function, which may further lead
to a relative impairment of the compensatory increase in
cardiac output secondary to vasodilatation.
Risk Factors of HRS
Spontaneous bacterial peritonitis is an important risk
factor for development of HRS.12-14
About one third of patient of SBP develops HRS.12 The
outcome of HRS is very poor. Median survival time of all
patients with HRS is approximately 3 months only.15 High
MELD scores and type 1 HRS further worsen the prognosis.
Type 1 HRS patients if not treated have very poor outcome
with median survival of approximately 1 month.16
Clinical Features and Classification of HRS
Most common presentation of HRS is asymptomatic
followed by decrease in urine output. Due to acute kidney
injury (AKI), glomerular filtration rate (GFR) decreases
and the blood urea nitrogen (BUN) level increases which
may result in HE as the initial clinical presentation of HRS.
Based on clinical features and prognosis, HRS is of two
types (type 1 and type 2).3
Type 1 HRS
Type 1 HRS has worse prognosis than type 2 HRS. There
is very rapid deterioration in renal function in type 1 HRS.
Typically, the leve[0l] of serum creatinine rises to a value
higher than 2.5 mg/dL within 2 weeks or less. Most of time
type 1 HRS has a triggering event. These triggers interfere
with the renal blood flow.17 Some of the common triggers
are bacterial infections,18 GI bleeding, surgery, and acute
hepatic injury3,19
Among bacterial infections, SBP is the most important
trigger event to develop HRS. 20,21 There are certain
predisposing factors like high levels of inflammatory
markers, severe circulatory depression prior to the onset
29-01-2021 14:59:15
 Hepatorenal Syndrome: Current Diagnosis and Management
of infection, and adrenal insufficiency, which have more
chances of development of HRS.
Type 2 HRS
Type 2 HRS is more slowly progress[0i]ve than type 1 HRS,
but still carries a median survival of only approximately
6 months. Typically patient presents with pre-existing
resistant ascites with mild renal dysfunction (serum
creatinine < 2.5 mg/dL). Type 2 HRS patient can progress
into type 1 HRS after a triggering event.
Prevention of HRS
HRS has a very poor prognosis and very high mortality
rate. So prevention of HRS is an important aspect in
management of patients of chronic liver disease. Most
important strategy is to prevent depletion of intravascular
volume. Important causes of volume depletion are over
diuresis, diarrhea due to lactulose, variceal bleed, and
large volume paracentesis.
Use of nephrotoxic drugs should be avoided. Beside
these prevention of infection and its prompt treatment is
also very important for prevention of HRS.18
Treatment of HRS
HRS requires a very aggressive management considering
its poor prognosis. There are three treatment options
available for management of HRS:
„„ M2 4ed]ical therapies,
„„ Transjugular intrahep[0a] tic portosystemic shunt
(TIPS) placement,
„„ Liver transplantation.
Aim of medical therapy is to maintain intravascular
volume. Vasoconstrictors are used to counter splanchnic
vasodilatation. Colloid infusion is done for volume
expansion. Aim of the medical therapy is to act as a bridge
until definitive treatment of liver disease is done or until
the triggering event (SBP, UGI bleed) has subsided.
Medical Therapy
„„ Non-specific medical therapy:
—— Vitals monitoring and maintaining fluid balance
is very important. Monitoring of blood pressure,
central venous pressure, urine output helps in
maintaining fluid balance.
MU-129.indd 825
CHAPTER 129 825
—— Infection control: prophylactic antibiotic therapy
should be given if indicated for prevention of SBP.
Sepsis should be identified early using culture of
blood, urine, and ascetic fluid. There is no role of
antibiotic without proven infection.
—— Diuretic has to be stopped to prevent depletion of
intravascular volume.
„„ Specific therapies:
Vasoconstrictors: Aim is to reverse the splanchnic
vasodilatation to maintain the renal blood flow
vasopressin analogues are most commonly used
for vasoconstriction. Terlipressin has been studied
extensively in HRS patients.15,22
  Terlipressin improves renal function in about
40–50% patients of HRS15,23 The dose of terlipressin is
1 mg every 4–6 hours. It can be increased up to 2 mg
every 4–6 hours after 3 days if there is no improvement
in renal function (fall in serum creatinine by at least
25% of baseline). Terlipressin is discontinued if serum
creatinine comes below 1.5 mg/dL22 with improvement
in renal function there is increase in urine volume,
blood pressure, and serum sodium concentration.
Improvement is slow and can take up to 14 days for
renal function to become normal. Duration is shorter
with lower serum creatinine at the time of starting
terlipressin.24
Better response is observed in patients with baseline
serum bilirubin less than 10 mg/dL. 24 Also patients
who show reduction in mean arterial pressure of more
than 5 mm Hg after 3 days of medical therapy have
favorable response to medical therapy.24 Reoccurrence
after stopping terlipressin is rare. Terlipressin is effective
in reoccurrence.
Common side effects of terlipressin include
cardiovascular and ischemic complications. So terlipressin
is avoided in patients with known cardiovascular and
ischemic conditions. Patients of HRS are given albumin
along with terlipressin to maintain intravascular volume.
Albumin is given in a dose of 1 g/kg body weight.
Terlipressin shows improvement in renal function in
patients of type 2 HRS also,25 but there are limited studies
in patients of type 2 HRS.
There are other vasopressors that are used in type 1
HRS:
„„ Midodrine plus octreotide
„„ Noradrenaline
29-01-2021 14:59:15
 826 SECTION 10 Gastroenterology
Midodrine is an alpha adrenergic receptor agonist.
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
dose of 100 microgram tds and can be increased up to 200
microgram tds. There are only few studies with midodrine
and octreotide.26
Noradrenaline (0.5–3 mg/h) is a vasopressor drug.
Increased arterial pressure helps to maintain adequate
blood flow to kidneys.27 comparative studies between
noradrenaline and other vasoconstrictors drugs are the
area of research. Noradrenaline is given as continuous
infusion with an aim to keep systolic blood pressure above
110 mm Hg.
There have been few studies on prevention of HRS.
Short-term treatment (4 week) with pentoxifylline (400 mg
three times a day) in a randomized double-blind st[u8]dy
was shown to prevent the development of HRS in patients
with severe alcoholic hepatitis. In a recent study, long-
term treatment with pentoxifylline was not associated with
an improved survival but with reduced frequency of some
complications of cirrhosis, including renal failure, yet
this 7w as not the primary endpoint of the study. Finally,
norfloxacin (400 mg/day) reduced the incidence of HRS in
advanced cirrhosis.
Transjugular Intrahepatic Portosystemic Shunt
(TIPS)
TIPS has been used for treatment of portal hypertension
associated with cirrhosis.28 TIPS helps to control ascites
along with improvement in renal function in patients of
HRS.
Renal replacement therapy: Hemodialysis is used in
patients of HRS. Indication of hemodialysis is similar to
any cause of acute renal failure.29,30 There are no separate
studies to see results of hemodialysis in HRS patients.
Comparison of renal replacement therapy and medical
therapy for HRS is an area of further evaluation.
Liver Transplantation
Treatment of choice for both types of HRS is liver
transplantation. 31 Liver transplantation success rate
is about 65% in patients of type 1 HRS.31 Renal failure
subsides after liver transplantation. Patients who remain
on renal support therapy for more than 12 weeks should
be considered for combined liver kidney transplantation.
MU-129.indd 826
Conclusion
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, 32,33 but liver transplant remains to be the
mainstay of the treatment. The multiple aspects in the
pathophysiological process will likely be targeted by the future
treatment of HRS.
References
1. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic
criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
Hepatology. 1996;23(1):164-76.
2. Helvig F, Schutz C. A liver and kidney syndrome: clinical, pathological,
and experimental studies. Surg Gynecol Obstet. 1932;55:570-82.
3. Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment
of hepatorenal syndrome in cirrhosis. Gut. 2007;56(9):1310-8.
4. Angeli P, Merkel C. Pathogenesis and management of hepatorenal
syndrome in patients with cirrhosis. J Hepatol. 2008;48(1):S93-103.
5. Arroyo V, Fernandez J, Ginès P. Pathogenesis and treatment of
hepatorenal syndrome. Semin Liver Dis. 2008;28(1):81-95.
6. Bolognesi M, Sacerdoti D, Piva A, et al. Carbon monoxidemediated
activation of large conductance calcium-activated potassium
channel contributes to mesenteric vasodilation in cirrhotic rats. J
Pharmacol Exp Ther. 2007;321(1):187-94.
7. Ro J, Claria J, To-Figueras J, et al. Endogenous cannabinoids: a
new system involved in the homeostasis of arterial pressure in
experimental cirrhosis in the rat. Gastroenterology. 2002;122(1):
85-93.
8. Fernandez-Seara J, Prieto J, Quiroga J, et al. Systemic and regional
hemodynamics in patients with liver cirrhosis and ascites with
and without functional renal failure. Gastroenterology. 1989;97(5):
1304-12.
9. Munoz S. The hepatorenal syndrome. Med Clin N Am.
2008;92(4):813-37.
10. Salerno F, Gerbes A, Ginès P, et al. Authors’ response. Gut.
2008;57:139-40.
11. Neuhoffer W, Pittrow D. Role of endothelin receptor antagonists in
renal disease. Eur J Clin Invest. 2006;36(3):78-88.
12. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin
on renal impairment and mortality in patients with cirrhosis and
spontaneous bacterial peritonitis. N Engl J Med. 1999;341(6):403-9.
13. Fasolato S, Angeli P, Dallagnese L, et al. Renal failure and bacterial
infections in patients with cirrhosis: epidemiology and clinical
features. Hepatology. 2007;45(1):223-9.
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 Hepatorenal Syndrome: Current Diagnosis and Management
14. Thabut D, Massard J, Gangloff A, et al. Model for end-stage liver
disease score and systemic inflammatory response are major
prognostic factors in patients with cirrhosis and acute functional
renal failure. Hepatology. 2007;46(6):1872-82.
15. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med.
2009;361(13):1279-90.
16. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical
type predict prognosis in hepatorenal syndrome: relevance to liver
transplantation. Hepatology. 2005;41(6):1282-9.
17. Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis:
perspective in the age of MELD. Hepatology. 2003;37(2):233-43.
18. Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and
treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol.
2007;46(5):935-46.
19. Cardenas A, Ginès P, Uriz J, et al. Renal failure after gastrointestinal
bleeding in cirrhosis: incidence, clinical course, predictive factors,
and short term prognosis. Hepatology. 2001;34(4 Pt 1):671-6.
20. Terra C, Guevara M, Torre A, et al. Renal failure in patients with
cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis:
value of MELD score. Gastroenterology. 2005;129(6):1944-53.
21. Arroyo V, Fernandez J, Ginès P. Pathogenesis and treatment of
hepatorenal syndrome. Semin Liver Dis. 2008;28(1):81-95.
22. Kew MC, Varma RR, Sampson DJ, et al. The effect of octapressin
on renal and intrarenal blood flow in cirrhosis of the liver. Gut.
1972;13(4):293-6.
23. Moreau R, Lebrec D. The use of vasoconstrictors in patients with
cirrhosis: type 1 HRS and beyond. Hepatology. 2006;43(3):385-94.
24. Nazar A, Pereira GH, Guevara M, et al. Predictors of response to
therapy to terlipressin and albumin in patients with cirrhosis and
type 1 hepatorenal syndrome. Hepatology. 2010;51(1):219-26.
MU-129.indd 827
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25. Alessandria C, Venon WD, Marzano A, et al. Renal failure in cirrhotic
patients: role of terlipressin in clinical approach to hepatorenal
syndrome type 2. Eur J Gastroenterol Hepatol. 2002;14(12):1363-8.
26. Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal
syndrome with the administration of midodrine and octreotide.
Hepatology. 1999;29(6):1690-7.
27. Duvoux C, Zanditenas D, Hézode C, et al. Effects of noradrenalin and
albumin in patients with type I hepatorenal syndrome: a pilot study.
Hepatology. 2002;36(2):374-80.
28. Brensing KA, Textor J, Perz J, et al. Longterm outcome after
transjugular intrahepatic portosystemic-stent shunt in non-
transplant cirrhotics with hepatorenal syndrome: a phase II study.
Gut. 2000;47(2):288-95.
29. Keller F, Heinze H, Jochimson F, et al. Risk factors and outcome of
107 patients with decompensated liver disease and acute renal
failure (including 26 patients with hepatorenal syndrome): the role
of hemodialysis. Ren Fail. 1995;17(12):135-46.
30. Capling RK, Bastani B. The clinical course of patients with type
1 hepatorenal syndrome maintained on hemodialysis. Ren Fail.
2004;26(5):563-8.
31. Gonwa TA, Morris CA, Goldstein RM, et al. Long-term survival and
renal function following liver transplantation in patients with and
without hepatorenal syndrome—experience in 300 patients.
Transplantation. 1991;51(2):428-30.
32. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal
syndrome with selective endothelin-A antagonist. Lancet.
1996;347(918):1842-3.
33. Stanley AJ, Forrest EH, Dabos K, et al. Natriuretic effect of an
adenosine-1 receptor antagonist in cirrhotic patients with ascites.
Gastroenterology. 1998;115(2):406-11.
29-01-2021 14:59:16
 CHAPTER

130 Hepatic Encephalopathy:

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

MU-130.indd 828 29-01-2021 14:58:53

 Hepatic Encephalopathy: Management CHAPTER 130 829

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
features manifestations sleep rhythm, Impairment of
addition or subtraction, Minimal
lack of awareness, Anxiety
HE, hepatic encephalopathy
Lethargy, Disorientation for Gross disorientation, Confusion, Coma
time, Personality changes, Somnolence to semi stupor,
Inappropriate behavior, Bizarre behavior, Involuntary
Flapping tremors passage of urine and feces

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

MU-130.indd 829 29-01-2021 14:58:54

 830 SECTION 10 Gastroenterology

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

MU-130.indd 830 29-01-2021 14:58:55


are added rather than substituted to nonabsorbable
disaccharides. In a study, complete reversal of HE was
observed more with combination of lactulose and
rifaximin compared to lactulose alone (76% vs. 50.8%,
p=0.004) along with decreased mortality (23.8% vs. 49.1%,
P < 0.05).10 Hence, combination therapy is recommended
in the management of HE. If the precipitating factor
has been resolved and there is no recurrence of HE
for next 3 months, the rifaximin can be discontinued.
Neomycin, vancomycin, and metronidazole are other
alternatives of rifaximin but rifaximin is preferred as
it has less side effects. L-ornithine L-aspartate (LOLA)
and branch-chain amino acids (BCCA) are the next
in consideration for patients who do not respond to
conventional therapy.11,12
Hepatic Encephalopathy—Primary and
Secondary Prophylaxis
Lactulose and rifaximin are proved to be equally effective in
patients with acute variceal bleed for primary prophylaxis
of HE. In a study, HE developed in a smaller number of
cirrhotic patients with variceal bleed in lactulose group
compared to placebo group (14% vs. 40%, p=0.03). 13
In another study, lactulose and rifaximin were equally
effective. 14 Secondary prophylaxis of HE is defined as
preventing another episode of HE in patients who had
a previous episode of HE. In secondary prophylaxis
chronic therapy with lactulose or lactitol is indicated
and if HE recurs on lactulose therapy, combination
therapy including lactulose and rifaximin should be
considered.10,15,16 A published study revealed the efficacy
of lactulose in prevention of HE recurrence compared
to placebo (19.6% vs. 46.8%, p=0.001).16 Recurrence of
HE can also be prevented with the help of probiotics,
glycerol phenylbutyrate (PB), BCAA, and LOLA. 15-20
Patients with refractory HE may have large spontaneous
PSS. Refractory HE in these patients can be prevented
by PSS embolization and balloon occluded retrograde
transvenous obliteration (BRTO) of large spontaneous
splenorenal shunts.21,22 Fecal microbiota transplantation
(FMT) also prevents recurrence of HE, improve cognition
and dysbiosis without major side effects in patients with
cirrhosis.23 Liver transplant is the last resort in patients
with decompensated cirrhosis who present with recurrent
HE despite of being on above therapy.
MU-130.indd 831
Hepatic Encephalopathy: Management CHAPTER 130 831
Management of Minimal
Hepatic Encephalopathy
Patients with MHE have poor quality of life, increased risk
of OHE, require frequent hospitalization, and have high
mortality. The available treatment options for MHE are
disaccharides (lactulose, lactitol), rifaximin, probiotics,
and nutritional support.24-28 In a study that compared a
nutritional therapy of 30–35 kcal/kg and 1.0–1.5 g vegetable
protein/kg with no dietary intervention in 120 cirrhotic
patients with MHE, the rate of reversal of MHE was higher
in those receiving nutritional therapy (71.1% vs. 28.8%,
p=0.001). Prevention of OHE and improvement in quality
of life was also observed with nutritional therapy.28
Drugs Used in Management of
Hepatic Encephalopathy
Nonabsorbable Disaccharides
Lactulose and lactitol are nonabsorbable disaccharides
used as first-line treatment for HE. Lactulose reduces
formation and absorption of ammonia from the gut by
altering the microbiota, increases nitrogen excretion in
the feces and reduces production of toxic short chain
fatty acids. It works as an osmotic purgative, prebiotic,
and also leads to gut acidification.29 A Cochrane data base
review proved the efficacy of lactulose in HE management
compared to placebo or no intervention. Efficacy of
lactulose has been seen in the management of MHE, OHE,
and recurrent HE. It is also effective in reducing the risk
of variceal bleeding, spontaneous bacterial peritonitis,
hepatorenal syndrome, liver failure, and mortality. 30
Lactulose is well tolerated, and the main side effects
include abdominal cramps, diarrhea, and flatulence.
About 70–80% patients of HE responds to lactulose.31
Lactitol is as effective as lactulose, is more palatable, and
have less side effects.32,33
Nonabsorbable Antibiotics
Ammonia lowering effect has been observed with use of
antibiotics such as metronidazole, vancomycin, neomycin,
paromomycin, and rifaximin as they have activity against
urease-producing gut bacteria. As rifaximin has minimal
systemic absorption, broad spectrum, and less adverse
events, it is most commonly used. Rifaximin effectively
29-01-2021 14:58:55
 832 SECTION 10 Gastroenterology
prevented the recurrence of HE when used as an add-
on therapy for refractory HE, despite on appropriate
lactulose therapy. 11 Rifaximin is effective in recovery
from HE, secondary prophylaxis, and in reducing the
mortality as shown in a meta-analysis.34 It also enhances
the performance and health-related quality of life in
patients with MHE.35,36 Rifaximin had similar efficacy to
nonabsorbable disaccharides for acute and chronic HE,
and somewhat better tolerated. Although neomycin and
metronidazole have been used for the management of HE,
data are very old and inadequate. 37-39 These antibiotics
also have serious adverse events, like neomycin can
cause nephrotoxicity, ototoxicity, malabsorption, and
metronidazole can lead to peripheral neurotoxicity.
Branch Chain Amino Acids
Cirrhotic patients show reduce blood level of BCCA
(leucine, isoleucine, valine). The BCCA have a role in
skeletal muscle protein synthesis and detoxification of
ammonia. High ammonia level decreases protein synthesis
by diminishing the mTOR signaling in cirrhotic patients,
this effect is prevented by BCAAs. A Cochrane data base
review showed that BCAAs have a favorable effect on HE in
cirrhotic patients.40 Both oral and intravenous preparations
are effective. The BCCA helps in muscle building in all
cirrhotic patients with sarcopenia along with favorable
effects on HE which lead to improvement in quality of
life. There is no benefit of BCAA supplementation in
protein-tolerant patients. A recent randomized trial on
116 patients who had an episode of HE in the past, found
no benefit of BCAA on the prevention of recurrent HE,
although supplementation appeared to improve MHE
and muscle mass.20 Based on these results, dietary BCAA
supplementation is indicated only in severely protein-
intolerant patients.
L-Ornithine L-Aspartate
LOLA promotes ammonia detoxification as it works as
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 level, recovery time and duration of hospital
stay with use of intravenous LOLA along with lactulose.17
A Cochrane data base review revealed favorable effect of
LOLA on HE in cirrhotic patients and reduced mortality.41
This effect was observed with both oral and intravenous
MU-130.indd 832
preparations.42 Prophylactic LOLA infusion proved to be
effective in decreasing venous ammonia concentration
in patients who underwent TIPS placement. 43 LOLA is
ineffective in patients acute liver failure.
Probiotics
Prebiotics and probiotics reduce blood ammonia
concentrations by promoting colonization of acid-
resistant, non-urease producing bacteria. The most
efficacious species for HE appears to be Lactobacilli and
Bifidobacterium. Use of probiotics improves recovery
in HE, but when compared with lactulose they failed
to show a benefit in significant outcomes as shown in a
meta-analysis.44 Probiotics are effective in MHE, OHE, and
prevention of recurrent HE.27
Other Therapies
Large Spontaneous Portosystemic
Shunts Embolization
Improvement in OHE and recurrence of HE has been
observed with embolization of these shunts and BRTO of
splenorenal shunt without deteriorating ascites, variceal
bleed, and portal hypertensive gastropathy.21,22
Polyethylene Glycol
Polyethylene glycol (PEG) solution results in increase
excretion of ammonia in the stool by its purgative action
thus it helps in HE management. Although the efficacy
of PEG has been proved in a study, more such studies are
required for the same.45
Acarbose
Acarbose enhances the growth of gut saccharolytic
bacterial flora and diminishes proteolytic flora that
produces ammonia, mercaptans, and benzodiazepine-
like substances. Improvement in HE and reduction in
ammonia level has been observed with use of acarbose.46
Ammonia Lowering Agents
Ammonia lowering agents like PB, ornithine phenylacetate
(OPA), and benzoate binds to ammonia and leads to
excretion of nitrogen by urinary non-urea excretion. To
date there is no definite evidence for OPA and PB for the
management of HE. Sodium benzoate had similar efficacy
29-01-2021 14:58:55

to lactulose in the management of HE in a small study.47
Further studies are required to prove their efficacy.
Flumazenil
Use of flumazenil shows reduction in the GABA/
benzodiazepine receptor complex activity thus reversing
the neurological inhibition in HE. The short-term
(minutes) favorable effect of flumazenil on HE has been
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.
Zinc
Zinc has a role in few patients with recurrent HE, but more
studies are required to prove its efficacy.
Newer Therapies
Fecal Microbiota Transplant
In cirrhotic patients there is reduced level of favorable
bacterial families like Lachnospiraceae and Rumino­
coccaceae and rise of the pathogenic Enterobacteriaceae,
Streptococcaceae. Fecal microbiota transplant prevents
HE recurrence, improves cognitive function, and decreases
frequent hospitalization as shown in a randomized pilot
trial.23
Albumin
Albumin has anti-inflammatory properties; it binds and
clears many toxic substances, which accumulate in liver
failure. Lactulose with albumin has been proved to be
more effective than lactulose alone in treatment of HE
(75% vs. 53.3%, p=0.03).49
Other Experimental Therapy
Glutamine synthetase replacement, Liposome supported
peritoneal dialysis, Melatonin, L-carnitine, Glutamatergic
antagonist, serotonin antagonist, opioid antagonist, and
spherical carbon (AST-120).
Conclusion
Early detection and correction of precipitating factors is utmost
important in the management of HE. The most commonly used
therapy is still lactulose, which is effective in MHE, OHE, and
recurrent HE. Efficacy of rifaximin is similar to lactulose in the
MU-130.indd 833
Hepatic Encephalopathy: Management CHAPTER 130 833
treatment of HE with less side effects. In protein intolerant
patients, BCCA have a favorable effect on HE. Probiotics and
LOLA also have favorable effects in the treatment of HE.
Nutritional therapy and FMT are emerging therapies for HE
treatment but the data are limited. Combination of rifaximin
and lactulose is more effective in the management of overt and
recurrent HE. Liver transplant, embolization of large PSS, and
BRTO of splenorenal shunts are effective management options
in highly selected patients.
References
1. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose
and neomycin in the treatment of chronic portal-systemic
encephalopathy. A double blind controlled trial. Gastroenterology.
1977;72(4pt 1):573-83.
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
International Society for Hepatic Encephalopathy and Nitrogen
Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther.
2011;33(7):739-47.
3. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic
liver disease: 2014 Practice Guideline by the American Association
for the Study of Liver Diseases and the European Association for the
Study of the Liver. Hepatology. 2014;60(2):715-35.
4. Jepsen P, Ott P, Andersen PK, et al. Clinical course of alcoholic liver
cirrhosis: a Danish population-based cohort study. Hepatology.
2010;51(5):1675-82.
5. Sharma P, Sharma BC, Puri V, et al. Critical flicker frequency:
diagnostic tool for minimal hepatic encephalopathy. J Hepatol.
2007;47(1):67-73.
6. Prabhakar S, Bhatia R. Management of agitation and convulsions
in hepatic encephalopathy. Indian J Gastroenterol. 2003;22(Suppl
2):S54-8.
7. Bajaj JS. Review article: the modern management of hepatic
encephalopathy. Aliment Pharmacol Ther. 2010;31(5):537-47.
8. Maharshi S, Sharma BC, Srivastava S. Malnutrition in cirrhosis
increases morbidity and mortality. J Gastroenterol Hepatol.
2015;30(10):1507-13.
9. Amodio P, Bemeur C, Butterworth R, et al. The nutritional
management of hepatic encephalopathy in patients with cirrhosis:
International Society for Hepatic Encephalopathy and Nitrogen
Metabolism Consensus. Hepatology. 2013;58(1):325-36.
10. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-
blind, controlled trial comparing rifaximin plus lactulose with
lactulose alone in treatment of overt hepatic encephalopathy. Am
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.
12. Hudson M, Schuchmann M. Long-term management of hepatic
encephalopathy with lactulose and/or rifaximin: a review of the
evidence. Eur J Gastroenterol Hepatol. 2019;31(4):434-50.
13. Sharma P, Agrawal A, Sharma BC, et al. Prophylaxis of hepatic
encephalopathy in acute variceal bleed: a randomized controlled
trial of lactulose versus no lactulose. J Gastroenterol Hepatol.
2011;26(6):996-1003.
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 834 SECTION 10 Gastroenterology
14. Maharshi S, Sharma BC, Srivastava S, et al. Randomised controlled
trial of lactulose versus rifaximin for prophylaxis of hepatic
encephalopathy in patients with acute variceal bleed. Gut.
2015;64(8):1341-2.
15. Agrawal A, Sharma BC, Sharma P, et al. Secondary prophylaxis of
hepatic encephalopathy in cirrhosis: an open label, randomized
controlled trial of lactulose, probiotics and no therapy. Am J
Gastroenterol. 2012;107(7):1043-50.
16. Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of
hepatic encephalopathy: an open-label randomized controlled trial
of lactulose versus placebo. Gastroenterology. 2009;137(3):885-91.
17. Sidhu SS, Sharma BC, Goyal O, et al. L-ornithine L-aspartate in bouts
of overt hepatic encephalopathy. Hepatology. 2018;67(2):700-10.
18. Sharma BC, Maharshi S. Prevention of hepatic encephalopathy
recurrence. Clin Liver Dis. 2015;5(3):64-7.
19. Rocky DC, Vierling JM, Mantry P, et al. Randomized, double-
blind, controlled study of glycerol phenylbutyrate in hepatic
encephalopathy. Hepatology. 2014;59(3):1073-83.
20. Les L, Doval E, Martinez RG, et al. Effects of branched-chain amino
acids supplementation in patients with cirrhosis and a previous
episode of hepatic encephalopathy: a randomized study. Am J
Gastroenterol. 2011;106:1081-8.
21. Laleman W, Talero SM, Maleux G, et al. Embolization of large
spontaneous portosystemic shunts for refractory hepatic
encephalopathy: a multicenter survey on safety and efficacy.
Hepatology. 2013;57(6):2448-57.
22. Mukund A, Rajesh S, Arora A, et al. Efficacy of balloon-occluded
retrograde transvenous obliteration of large spontaneous
lienorenal shunt in patients with severe recurrent hepatic
encephalopathy with foam sclerotherapy: initial experience. J Vasc
Interv Radiol. 2012;23(9):1200-6.
23. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant
from a rational stool donor improves hepatic encephalopathy: a
randomized clinical trial. Hepatology. 2017;66(6):1727-38.
24. Sharma P, Sharma BC, Puri V, et al. An open-label randomized
controlled trial of lactulose and probiotics in the treatment of
minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol.
2008;20(6):506-11.
25. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy
is independently associated with poor survival and increased risk of
hospitalization. Am J Gastroenterol. 2014;109(11):1757-63.
26. Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive
functions and health-related quality of life in patients with
cirrhosis who have minimal hepatic encephalopathy. Hepatology.
2007;45(3):549-59.
27. Bajaj JS, Heuman DM, Sanyal AJ, et al. Modulation of the metabiome
by rifaximin in patients with cirrhosis and minimal hepatic
encephalopathy. PLoS One. 2013;8(4):e60042.
28. Maharshi S, Sharma BC, Sachdeva S, et al. Efficacy of nutritional
therapy for patients with cirrhosis and minimal hepatic
encephalopathy in a randomized trial. Clin Gastroenterol Hepatol.
2016;14(3):454-60.
29. Krnerup LS, Gluud LL, Vilstrup H, et al. Update on the therapeutic
management of hepatic encephalopathy. Curr Gastroenterol Rep.
2018;20(5):21.
30. Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for
hepatic encephalopathy: a systematic review and meta-analysis.
Hepatology. 2016;64(3):908-22.
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31. Sharma P, Sharma BC. Disaccharides in the treatment of hepatic
encephalopathy. Metab Brain Dis. 2013;28(2):313-20.
32. Blanc P, Daures JP, Rouillon JM, et al. Lactitol or lactulose in
the treatment of chronic hepatic encephalopathy: results of a
metaanalysis. Hepatology. 1992;15(2):222-8.
33. Camma C, Fiorello F, Tine F, et al. Lactitol in treatment of
chronic hepatic encephalopathy. A meta-analysis. Dig Dis Sci.
1993;38(5):916-22.
34. Kimer N, Krag A, Moller S, et al. Systematic review with meta-
analysis: the effects of rifaximin in hepatic encephalopathy. Aliment
Pharmacol Ther. 2014;40(2):123-32.
35. Rahimi RS, Rockey DC. Hepatic encephalopathy: pharmacological
therapies targeting ammonia. Semin Liver Dis. 2016;36(1):48-55.
36. De Las Heras J, Aldamiz-Echevarria L, Martinez-Chantar ML, et al. An
update on the use of benzoate, phenylacetate and phenylbutyrate
ammonia scavengers for interrogating and modifying liver nitrogen
metabolism and its implications in urea cycle disorders and liver
disease. Expert Opin Drug Metab Toxicol. 2017;13(4):439-48.
37. Fichet J, Mercier E, Genee O, et al. Prognosis and 1-year mortality of
intensive care unit patients with severe hepatic encephalopathy. J
Crit Care. 2009;24(3):364-70.
38. Gluud LL, Dam G, BorreM, et al. Lactulose, rifaximin or branched
chain amino acids for hepatic encephalopathy: what is the
evidence? Metab Brain Dis. 2013;28(2):221-5.
39. Oettl K, Stadlbauer V, Petter F, et al. Oxidative damage of albumin
in advanced liver disease. Biochim Biophys Acta Mol Basis Dis.
2008;1782(7-8):469-73.
40. Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for
people with hepatic encephalopathy. Cochrane Database Syst Rev.
2015;2017(5):CD001939.
41. Goh ET, Stokes CS, Sidhu SS, et al. L-ornithine L-aspartate for
prevention and treatment of hepatic encephalopathy in people
with cirrhosis. Cochrane Database Syst Rev. 2018;5(5):CD012410.
42. Bajaj JS, Lauridsen M, Tapper EB, et al. Important unresolved
questions in the management of hepatic encephalopathy: an
ISHEN consensus. Am J Gastroenterol. 2020.
43. Bai M, He C, Yin Z, et al. Randomised clinical trial: L-ornithine-L-
aspartate reduces significantly the increase of venous ammonia
concentration after TIPSS. Aliment Pharmacol Ther. 2014;40(1):63-71.
44. Dalal R, McGee RG, Riordan SM, et al. Probiotics for people
with hepatic encephalopathy. Cochrane Database Syst Rev.
2017;2(2):CD008716.
45. Rahimi RS, Singal AG, Cuthbert JA, et al. Lactulose vs polyethylene
glycol 3350—electrolyte solution for treatment of overt hepatic
encephalopathy: the HELP randomized clinical trial. JAMA Intern
Med. 2014;174(11):1727-33.
46. Gentile S, Guarino G, Romano M, et al. A randomized controlled trial
of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol.
2005;3(2):184-91.
47. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in
the treatment of acute hepatic encephalopathy: a double-blind
randomized trial. Hepatology. 1992;16(1):138-44.
48. Goh ET, Andersen ML, Morgan MY, et al. Flumazenil versus
placebo or no intervention for people with cirrhosis and hepatic
encephalopathy. Cochrane Database Syst Rev. 2017;2017:1-78.
49. Sharma BC, Singh J, Srivastava S, et al. Randomized controlled
trial comparing lactulose plus albumin versus lactulose alone for
treatment of hepatic encephalopathy. J Gastroenterol Hepatol.
2017;32(6):1234-9.
29-01-2021 14:58:55
 CHAPTER

131 The Healthy Indian

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,

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

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 836 SECTION 10 Gastroenterology
of birth, an abundance of Bifidobacterium was higher
in stools of the vaginally born infants while there was a
progressive increase in abundance of the Bacteroides-
Prevotella group in these infants from birth to 3 months of
life. Meanwhile, exclusively breast-fed infants had a higher
abundance of Enterobacteriaceae compared to those who
were additionally fed with supplemental cow’s milk.10
Age
Balamurugan et al. reported the first Indian study on 130
children and adolescents that demonstrated a dynamic
change in the gut bacterial composition.11 The study cohort
was fairly homogeneous and predominantly consumed
a lactovegetarian diet with infrequent meat intake.
Bifidobacterium longum showed predominance from
the age of 2–3 years but declined rapidly after reaching
adulthood. Similarly, Lactobacillus acidophilus was
predominant in the 2–3 years age group but progressively
declined as age progressed toward adulthood. On the
other hand, the Bacteroides-Prevotella-Porphyromonas
group which was low in early childhood constituted the
major organisms in later childhood and adolescence. The
study by Marathe et al. also suggested a change in the gut
microbiota with progressing age.12
Habitat and Geography
A multicenter study 13 from urban and adjacent rural
Delhi and Pune reported Prevotella, Megasphaera,
Faecalibacterium, Lactobacillus, Ruminococcus, and
Roseburia as the most dominant organisms. Interestingly,
the gut microbiota in these individuals could be divided
into two groups on the basis of the absolute counts of
Prevotella and Megasphaera. The microbial diversity was
significantly higher among the urban individuals.
Another subsequent study 14 that evaluated the gut
microbiota in rural and urban Ballabgarh (sea level) and
Ladakh (11,500 ft above sea level) demonstrated region-
specific differences in bacterial diversity. The genus and
species level diversity were least in the rural Ladakh region
while in individuals from urban Ballabgarh had high
alpha and beta diversity, while individuals from the rural
region had high alpha but low beta diversity.14 The genus
Parabacteroides, Blautia, Brevundimonas, Pelomonas, and
Megamonas were significantly higher in the Ballabgarh
rural cohort. On the other hand, while Lactobacillus was
abundant in the Ballabgarh urban cohort, Bacteroides,
MU-131.indd 836
Vibrio, Eggerthella, and Pseudomonas were high in both
the Ballabgarh cohorts.
The region-specific variation in the gut microbiota
in this study was also associated with enrichment of
xenobiotic metabolizing pathways in the Ballabgarh rural
and urban cohorts compared to the Ladakh population,
implying higher exposure to industrial chemical and drugs
in the Ballabgarh populations.
Another recent study 15 that evaluated the gut
microbiota in Bhopal (Central India) and Kerala (South
India) identified two distinct clusters of organisms.
Cluster 1 was enriched in organisms from the genera
Prevotella while Cluster 2 was enriched with species from
the genus Bifidobacterium, Ruminococcus, Clostridium,
and Faecalibacterium. Location-wise distribution revealed
Prevotella and Megasphaera to be predominant in Central
Indian cohort while the others including Bacteroides were
more abundant in the South Indian cohort. Moreover,
the authors also reported three characteristics fecal
metabolomic clusters among the study cohorts. The
Central Indian cohort abounded in metabolites such as
palmitic acid, stearic acid, and valeric acid, while in the
South Indian cohort, there was a significant enrichment
of BCAAs (especially isoleucine), cadaverine, propionate,
and lauric acid.
Ethnicity
Since tribal populations are closely attached to nature
and their lifestyle is largely determined by agriculture,
fishing, hunting, tribe specific dietary patterns, culture,
and traditions, they are likely to harbor an evolutionarily
conserved gut microbiota. India harbors the largest tribal
population in the world and thus constitutes the ideal for
evaluation of the “normal” gut microbiota. In the first and
so far, the largest study on the Indian tribal gut microbiota,16
we evaluated healthy tribal volunteers belonging to 15
tribes of Mongoloid or Proto-Australoid decent dispersed
over different geographic locations across Northeast
and Southern India. The genus Prevotella contributed to
40% of the genus across all tribes. The other genera that
constituted the core microbiota irrespective of geography
and ethnicity included Faecalibacterium, Eubacterium,
Clostridium, Blautia, Collinsella, Ruminococcus, and
Roseburia. In addition to these genera, Bacteroides, Dialster,
and Veillonella were found to abound the tribes from
Manipur while Bacteroides, Dialster, Bifidobacterium, and
29-01-2021 14:58:42

Lactobacillus abounded in the tribes from Sikkim. Tribes
from Manipur had the least abundance of Bifidobacterium.
Correlational analyses within the core microbiota revealed
that Prevotella had a negative correlation with Bacteroides,
Faecalibacterium, and Clostridium in the Telangana
tribes, with Faecalibacterium, Bacteroides, and Roseburia
in the Manipur tribes, and with Bacteroides, Clostridium,
Ruminococcus, and Blautia in the tribes from Sikkim.
Tribes from Sikkim had a significantly lower abundance of
Enterobacter compared to tribes from Assam, Telangana,
and Manipur.
Dietary Factors
Diet has been established as a major factor that shapes
the human gut microbiota. In the foregoing sections of
this review, even though there were variations in the
gut microbiota according to geography and habitat, a
closer look actually converges these variations to dietary
patterns. Overall, Prevotella, which is responsible for
complex plant-derived polysaccharide degradation,
was dominant in a majority of the study populations
implicating this as a signature genus in Indians.13,15-17
The study from Ballabgarh and Ladakh14 also suggested
that cooking oil and ghee could impact the Indian gut
microbial composition. For instance, individuals from
Ladakh consumed predominantly sunflower oil, which
has a high concentration of linoleic acid that is known to
be degraded by Roseburia. Similarly, Sporobacter was also
abundant in individuals consuming sunflower oil; while
Collinsella was specifically predominant in individuals
who consumed clarified butter (ghee).
In the tribal study by Dehingya et al.,16 the gut microbiota
was similar between tribes from Assam and Telangana
despite the geographic and ethnic differences. Therefore,
it appears likely that the carbohydrate and dietary fiber-
rich diet (including rice, whole grain, vegetables, fruits,
legumes, tubers) determines the core microbiota, which
is predominant in Prevotellaceae, Ruminococcaceae,
Lachnospiraceae, and Eubacteriaceae, which are enriched
in carbohydrate metabolizing enzymes. In the Lepcha,
Nepali, and Bhutia tribes from Sikkim the abundance of
Bifidobacterium and Lactobacillus can be explained by
the higher consumption of milk products and fermented
food. Among the Malayali tribes from Tamil Nadu, the
higher abundance of Bacteroidetes and Clostridium could
be explained by their daily intake of a moderate amount of
MU-131.indd 837
The Healthy Indian Gut Microbiota CHAPTER 131 837
pork meat, and non-intake of milk, and milk products due
to their religious beliefs.17
Comparison of Indian Gut Microbiota
with Worldwide Data
It has now been consistently shown that the Indian gut
microbiota differs significantly from that of other regions of
the world. In our study,16 we observed two distinct clusters,
the first involving the Hadza, Italian, and Americans
individuals that abounded in Faecalibacterium. The rest of
the tribal groups, including Indians, constituted the other
group with a higher abundance of Prevotella. Interestingly,
within this group there was close similarity of the Indian
tribal microbiome to the Mongolian tribal microbiota. Of
note, the origins of the Nepali and Tai-Phake tribes from
India can be mapped to Mongolians.
In the study by Bhute et al., 13 comparison of gut
microbiota of Western and North Indian cohorts with
Americans revealed 76 OTUs, out of which six, including
Prevotella, Lactobacillus, Lachnococcus, and Roseburia,
specifically belonged to the Indians. In this study, it was also
observed that Indians shared 25 OTUs with the Bangladeshi
cohort (majority belonging to families Lachnospiraceae,
Ruminococcaceae, and Enterobacteriaceae, and genus
Prevotella). Other than differences at the overall genera
and species level OTUs, differences were also noticed
between Indian and European cohorts even within the
same genus.13
Finally, a metagenome wide meta-analyses (MGWAS)
by Dhakan et al., which included datasets from India,
China, USA, and Denmark demonstrated completely
separate species level clustering of the Indian gut
microbiome compared to the American, Danish, and
Chinese microbiome. 15 Prevotellaceae emerged as the
most highly abundant bacterial family in the Indian
individuals. In addition, the Indian gut microbiota was
found to be enriched in functions that corroborate with a
carbohydrate-rich diet.
Conclusion
Results of gut microbiota studies can be influenced by several
technical factors such as sample size, sample collection and
storage, sequencing technique, reference database, and depth
of statistical and bioinformatics analyses.
Contd...
29-01-2021 14:58:43
 838 SECTION 10 Gastroenterology
Contd...
In this review, we discussed the gut microbiota in healthy
Indians based on the individual studies that involved small to
medium sample size and different techniques to evaluate the
microbiome. The ideal way to evaluate the true core Indian
gut microbiota would be to include a large homogeneous
population across the entire country and use the same
methods of sample processing, sequencing, and data analyses.
The LogMPIE (Landscape of gut microbiome-Pan India
Exploration) is such a study that was recently published.18 This
study evaluated 1,004 individuals from 14 centers across India
(4 from north, 3 from east, 4 from west, and 3 from south) and
bacterial metagenomic sequencing was performed in the Ion
oneTouch 2 system. There were 390 microorganisms that were
common in all the geographic locations, while 36 were unique
to north, 149 to south, 95 to west, and 62 to east India. The most
predominant organisms emerged to be Prevotella copri and
Faecalibacterium prausnitzii, thereby qualifying Prevotella and
Faecalibacterium.
References
1. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal
gut microbiota. World J Gastroenterol. 2015;21(29):8787-803.
2. Collado MC, Rautava S, Aakko J, et al. Human gut colonisation
may be initiated in utero by distinct microbial communities in the
placenta and amniotic fluid. Sci Rep. 2016;22;6:23129.
3. Stinson LF, Boyce MC, Payne MS, et al. The not-so sterile womb:
evidence that the human fetus is exposed to bacteria prior to birth.
Front Microbiol. 2019;10:1124.
4. Lim ES, Rodriguez C, Holtz LR. Amniotic fluid from healthy term
pregnancies does not harbor a detectable microbial community.
Microbiome. 2018;6(1):87.
5. Tito RY, Knights D, Metcalf J, et al. Insights from characterizing
extinct human gut microbiomes. PLoS One. 2012;7(12):e51146.
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6. Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact
the mouse gut microbiota promoting colitis and metabolic
syndrome. Nature. 2015;519(7541):92-6.
7. Tasnim N, Abulizi N, Pither J, et al. Linking the gut microbial
ecosystem with the environment: does gut health depend on
where we live? Front Microbiol. 2017;8:1935.
8. Biodiversity in India. Available from https://indiabiodiversity.org/
page/4246006 [Accessed October, 2019].
9. Pandey PK, Verma P, Kumar H, et al. Comparative analysis of fecal
microflora of healthy full-term Indian infants born with different
methods of delivery (vaginal vs cesarean): Acinetobacter sp.
prevalence in vaginally born infants. J Biosci. 2012;37(6):989-98.
10. Kabeerdoss J, Ferdous S, Balamurugan R, et al. Development of the
gut microbiota in southern Indian infants from birth to 6 months: a
molecular analysis. J Nutr Sci. 2013;2:e18.
11. Balamurugan R, Janardhan HP, George S, et al. Bacterial succession
in the colon during childhood and adolescence: molecular studies
in a southern Indian village. Am J Clin Nutr. 2008;88(6):1643-7.
12. Marathe N, Shetty S, Lanjekar V, et al. Changes in human gut flora
with age: an Indian familial study. BMC Microbiology. 2012:12:22.
13. Bhute S, Pande P, Shetty SA, et al. Molecular characterization and
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
rural and urban healthy indians living in sea level and high-altitude
areas. Sci Rep. 2018;8(1):10104.
15. Dhakan DB, Maji A, Sharma AK, et al. The unique composition
of Indian gut microbiome, gene catalogue, and associated
fecal metabolome deciphered using multi-omics approaches.
Gigascience. 2019;8(3):1-20.
16. Dehingia M, Devi KT, Talukdar NC, et al. Gut bacterial diversity of the
tribes of India and comparison with the worldwide data. Sci Rep.
2015;5:18563.
17. Ramadass B, Rani BS, Pugazhendhi S, et al. Faecal microbiota
of healthy adults in south India: comparison of a tribal & a rural
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29-01-2021 14:58:43
 CHAPTER

132 Celiac Disease: Who to Screen

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

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

MU-132.indd 839 29-01-2021 14:58:25

 840 SECTION 10 Gastroenterology
Southern (Vellore), and Northeastern (Guwahati) regions
of India. The combined pan-India prevalence of CeD is
0.67% (1 in 140). Indeed, there is a regional variation in
the prevalence of CeD at this point of time, the highest
being in Northern India (1.23%), lowest in Southern India
(0.1%) and in between in the Northeastern region of India
(0.87%).4 This difference is likely related to the different
eating patterns, with rice being staple diet in Southern
India and wheat in Northern India. However, with increase
in the consumption of products made from wheat in rice
eating regions, it is very likely that CeD will emerge in such
populations also. With the Indian population of 120 crores,
it is estimated that approximately 60–80 lakhs of Indians
have CeD. Of this large estimated numbers of people
having CeD, only a minority have been diagnosed and a
large proportion of them (85–95%) exists in the population
but currently remain undiagnosed.
Where are They?
If there are so many patients with CeD both worldwide and
in India, then where are they? Why are we not able to pick
them up? There are multiple reasons:
„„ The lack of awareness amongst physicians about
changing epidemiology of this disease is the most
important reason. We do not think about this diagnosis
in appropriate clinical setting.
„„ It was believed that CeD affects only children, but now
it is known that CeD can affect people of all age groups.
Although not well established, it is however believed
that the pathophysiological changes in CeD starts
since early part of life. The clinical manifestations may
appear at different ages of life depending upon the
severity of the disease.
„„ While some patients have fully expressed disease with
obvious symptoms and manifests in childhood or
during adolescence, in others, the disease is expressed
in milder form, and hence may not come to clinical
attention till late. CeD is diagnosed nowadays more
often in adulthood and even in the elderly.
„„ The classical manifestations, as portrayed in the
older textbooks, draw our attention to mainly the
more classical form of disease (emaciated child with
diarrhea and anemia), which are present in those
having a more advanced disease. In early stages of the
disease, patients may not have any symptoms or have
only mild symptoms.
MU-132.indd 840
„„ While CeD is thought to be mainly a disease of
the intestine and recognized in those having
gastrointestinal symptoms, only half of the patients
however present with predominant gastrointestinal
manifestations. The GI symptoms (Classical CeD)
include chronic diarrhea, malabsorption, failure to
thrive, abdominal distension, and weight loss (Fig. 1).
„„ Approximately half of all the patients with CeD
present to a clinician with predominant non-GI
symptoms such as short stature, liver abnormalities,
infertility, endocrinopathies, etc. in the absence of
or with minimal GI symptoms. The diagnosis of CeD
is often not suspected in such patients, since most
physicians believe that patients with CeD should have
GI manifestations (Fig. 1).
Therefore, patients with CeD can present to an
internist/gastroenterologists with symptoms of chronic
diarrhea, anemia, fatigability, to a pediatrician with
irritability, diarrhea, failure to thrive and anemia, to a
hematologist with anemia refractory or unresponsive
to iron supplementation, to an endocrinologist with
type 1 diabetes, hypothyroidism, or growth failure, to
a dermatologist with dermatitis herpetiformis, to a
neurologist with ataxia, peripheral neuropathy, and to a
gynecologist with menstrual abnormalities or infertility.
Thus, there is an increased need for increasing
awareness amongst primary care physicians, internists,
gastroenterologists, hematologists, endocrinologists,
and neurologists about a wide and varied spectrum of
manifestations of CeD so that these patients are diagnosed
early. An early diagnosis and initiation of gluten-
free diet in them can control and the symptoms, and
prevent consequences of malabsorption and nutritional
deficiencies and prevent adverse health consequences.5
Therefore, CeD should be suspected in the patients even
in the absence of typical gastrointestinal manifestations.
We have summarized below the diseases or symptoms
where screening for CeD should be done.
Who should be Screened for CeD (Table 1)
Patients having Diseases and Symptoms
Secondary to CeD
Chronic Diarrhea with Features of Malabsorption
Patients having intermittent or chronic diarrhea with
features of malabsorption, such as anemia, growth
29-01-2021 14:58:26
 Celiac Disease: Who to Screen and How to Screen? CHAPTER 132 841

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

MU-132.indd 841 29-01-2021 14:58:27

 842 SECTION 10 Gastroenterology
3.3% of them had CeD more so in those having mainly IBS-
diarrhea predominant and IBS-mixed subtypes.7
Iron Deficiency Anemia
Between 50–80% of patients with CeD have anemia and
that occurs most commonly because of iron deficiency.
Anemia secondary to B12 and folate deficiency in addition
to iron deficiency has also been described.
On the other hand, it has been observed that 3.2%
(95% CI 2.6–3.9%) of all patients with iron deficiency
anemia, when screened for CeD, are found to have CeD.8
That would mean than 1 of every 31 patients with iron
deficiency anemia has CeD. In a study from India, almost
1 in 10 with iron deficiency anemia had CeD. Thus, all
patients with iron deficiency anemia should be screened
for CeD.
Short Stature/Growth Failure
Almost one third of the adult patients and half of the
adolescent patients with CeD have short stature. Since
height can increase only till 18 years of age, it is really
important to make a diagnosis of CeD much before that
age. A timely treatment of CeD can lead to catch up growth
and attainment of a normal height.
On that other hand, of the patients presenting for the
evaluation of short stature, 6.6% (approximately 1 in 15)
have been found to have CeD. The proportion of patients
having CeD is still higher (13.4%; 1 in 8) in those having
idiopathic short stature, when all known causes have been
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
age, with or even without associated GI manifestations,
should be screened for CeD.
Dermatitis Herpetiformis
Dermatitis herpetiformis (DH) is characterized by clusters
of papules and vesicles associated with intense pruritus.
The typical sites for DH lesions include extensor surfaces
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.
DH shows an excellent response to GFD with complete
resolution of skin lesions. Thus, all patients with DH must
be screened for CeD.
MU-132.indd 842
Infertility
Menstrual abnormalities including delayed menarche
and secondary amenorrhea are quite frequent in patients
with CeD. Furthermore, patients with CeD have been
found to have a low rate of fertility. Patients with CeD are
at three-times higher risk for infertility than the general
population. On the other hand, 2.3% of patients with
infertility have been found to have CeD.9 As CeD is one of
the few treatable causes of infertility, all women patients
with infertility should be screened for CeD.
Liver Abnormalities
Almost one-fourth patients with CeD have asymptomatic
elevation of serum transaminases at the time of diagnosis
which normalize within 1 year of GFD in majority. If this
liver injury is not recognized and remains untreated,
it can lead to cirrhosis of the liver. In fact, CeD has
been found to be one of the causes of cryptogenic
cirrhosis. Furthermore, approximately 7% of all those
who have hypertransaminasemia and 5% of those having
cryptogenic liver disease have been found to have CeD.10,11
Treatment of CeD in these patients has been shown to
lead to an improvement in the liver disease. Therefore,
all patients with cryptogenic hypertransaminasemia
and cryptogenic cirrhosis of liver should be screened for
CeD. As discussed below, as anti-tissue transglutaminase
antibody may be falsely positive in those with cirrhosis;
therefore, a more reliable screening test in this setting is
anti-endomysial antibody.
Neurological Disorders
Some of the patients with cerebellar ataxia, especially
those having idiopathic ataxia, have been found to have
gluten-related disorders and CeD. The treatment of
CeD has also been shown to lead to some improvement
in ataxia. Therefore, patients with idiopathic ataxia
should be screened for gluten-related disorders. In
such patients both anti-gliadin antibody and anti-tissue
transglutaminase antibodies should be used for screening.
First-degree Relatives of Patients with CeD
As we know, genes play a major role in the pathogenesis
of CeD. The first-degree relatives of index patients with
CeD are at much higher risk of developing CeD. A recent
29-01-2021 14:58:27
 Celiac Disease: Who to Screen and How to Screen?
meta-analysis including 10,252 FDRs of patients with CeD
has shown that 7.5% of first-degree relatives of CeD have
CeD.12 Furthermore, the sisters (1 in 7) and daughters (1
in 8) of the index patients with CeD are at the highest risks.
Thus, all the first-degree relatives of index patients with
CeD should be screened for CeD.
Type I Diabetes
CeD has been found to be strongly associated with type I
diabetes and a recent meta-analysis has shown that 6% of
all patients with type I diabetes have CeD.13 It means that
of 16 patients with type I diabetes, one will have associated
CeD. Many of them may have symptoms because of CeD,
but these symptoms are often considered to be due to
diabetes, and hence they are not specifically investigated
for CeD. Therefore, all patients with type I diabetes should
be screened for CeD.
Autoimmune Thyroid Disease
An association has been shown between CeD and
autoimmune thyroid disorders. Between 10–15% patients
with CeD have coexistent clinical hypo/hyperthyroidism.
In fact, a recent study showed that of 6,024 patients with
autoimmune thyroid disorders screened for CeD, 1.4%
patients had CeD.14 Thus, all patients with autoimmune
thyroid disorders should be screened for CeD.
Down’s Syndrome
Approximately 1%–19% patients with Down’s syndrome
have been reported to have CeD. A recent meta-analysis
of 31 studies and including 4,383 patients with Down’s
syndrome has reported that 5.8% of them have CeD, which
is much higher than that in the general population.15
Therefore, all patients with Down’s syndrome should be
screened for CeD.
Other Conditions
A higher prevalence of CeD has also been observed in
certain other conditions including patients having dental
enamel defects, other autoimmune disorders like systemic
lupus erythematosus, juvenile rheumatoid arthritis, and
autoimmune liver diseases, etc.; however, there is a lack of
robust data suggesting the utility of routine screening for
CeD in these patients.
MU-132.indd 843
CHAPTER 132 843
How do we Screen for CeD?
Once we suspect a patient to have CeD, the first-
line screening tests are the CeD specific serological
tests. Immunoglobulin subclass A (IgA) anti-tissue
transglutaminase, (IgA anti-tTG Ab), anti-endomysial
antibody (IgA EMA), and deamidated glutamine dipeptide
(IgA anti-DGP Ab) are the currently available assays for
screening for CeD. Of these, IgA anti-tTG is the most
commonly used test for the screening and diagnosis of
CeD because of the ease of detection and a high accuracy
with a sensitivity of 92.8% and specificity of 97.9% 16
(Table 2). While IgA EMA testing has a high specificity
of 99%, recent systematic review has reported a lower
sensitivity of 73%. Detection of anti-EMA requires indirect
immunofluorescence and it is not widely available. IgA
anti-DGP assay have a pooled sensitivity of 87.8% (95% CI,
85.6–89.9%), and specificity 94.1% (95% CI, 92.5–95.5%)
and thus have an inferior performance than anti-tTG
Ab (Table 2). Since all these antibodies are IgA based,
hence they may be falsely negative in patients having IgA
deficiency. In such situations, IgG based tests such as IgG
anti-DGP or IgG anti-tTG Ab should be done.17
ELISA kits for anti-tTG antibody are manufactured
by many companies and their performance varies
significantly. Furthermore, there are differences in the
cut-off values of the anti-tTG antibody amongst ethnically
different population. Hence, a clinician should be aware
about these limitations.18
Diagnosis of Celiac Disease (Flowchart 1)
If a patient screened for CeD is detected to have a positive
celiac specific serological assays, the diagnosis needs to
be confirmed by demonstration of villous abnormalities
in the intestinal mucosa, which is still the gold standard
Diagnostic performance of various serological
TABLE 2
assays for the diagnosis of celiac disease
Sensitivity Specificity
IgA anti-tTG 92.8% 97.9%
(95% CI, 90.3–94.8) (95% CI, 96.4–98.8)
EMA 73.0% 99.0%
(95% CI, 61.0–83.0) (95% CI, 98.0–99.0)
IgA anti-DGP 87.8% 94.1%
(95% CI, 85.6–89.9) (95% CI, 92.5–95.5)
29-01-2021 14:58:27
 844 SECTION 10 Gastroenterology
Flowchart 1: Algorithm for the diagnosis of celiac disease
for the diagnosis of CeD. Multiple biopsy specimens from
the second part of duodenum and at least one biopsy
specimen from the first part of the duodenum should
be taken for adequate histopathological assessment.19-21
Modified Marsh classification system is currently used
to grade the severity of villous abnormalities based on
identification of increased intraepithelial lymphocytes,
MU-132.indd 844
crypt hyperplasia, and villous atrophy. A diagnosis of CeD
is made in patients with villous abnormalities of modified
Marsh grade II or more.
The gold standard diagnostic criteria of CeD is based
on a combination of clinical manifestations, a positive
celiac specific serology and demonstration of villous
abnormalities of modified Marsh grade II or more. The
29-01-2021 14:58:28
 Celiac Disease: Who to Screen and How to Screen?
European Society of Gastroenterology, Hepatology and
Nutrition (ESPGHAN 2019) has suggested a Non-Biopsy
Approach for making of a diagnosis of CeD.20 This is based
on the evidences that suggest a high degree of prediction
of presence of villous abnormalities if anti-tTG Ab titers
are more than tenfolds higher above the cut-off value.
The ESPGHAN 2019 guidelines suggest that a non-biopsy
approach may be considered in children if their anti-
tTG Ab titer is more than tenfolds and there is a positive
anti-endomysial antibody in a second blood samples.
Otherwise, duodenal biopsies should be performed, if
anti-tTG titer is less than tenfolds. For adults patients,
most of the guidelines, including Indian, recommend a
confirmation of diagnosis of CeD with small intestinal
biopsy in patients having a positive serological test.19,21,22
More often around the world, the ESPGHAN guidelines
are misinterpreted and the diagnosis of CeD is made even
when anti-tTG Ab titer is less than tenfolds. A hurried diagnosis
based on incomplete evidence leads to problems during
follow-up. All efforts should be made for the confirmation of
the diagnosis before advising GFD. One should realize that
anti-tTG Ab, especially at low titer could be falsely positive
and the enteropathic changes are not specific for CeD and
they could be caused by many other conditions.
Conclusion
CeD has now become a global public health problem and
it affects approximately 1% of the world’s population. The
spectrum of clinical manifestations of CeD is wide include
both gastrointestinal and extra-intestinal manifestations. Many
patients with CeD do not have GI manifestations but present
solely with non-gastrointestinal manifestations. All patients with
high-risk of CeD should be screened using IgA anti-tTG antibody.
References
1. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease:
Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol.
2018;16:823-36.e2.
2. Sood A, Midha V, Sood N, et al. Prevalence of celiac disease among
school children in Punjab, North India. J Gastroenterol Hepatol.
2006;21(10):1622-5.
3. Makharia GK, Verma AK, Amarchand R, et al. Prevalence of celiac
disease in the northern part of India: a community based study. J
Gastroenterol Hepatol. 2011;26:894-900.
4. Ramakrishna BS, Makharia GK, Chetri K, et al. Prevalence of Adult
Celiac Disease in India: Regional Variations and Associations. Am J
Gastroenterol. 2016;111(1):115-23.
MU-132.indd 845
CHAPTER 132 845
5. Green PHR, Cellier C. Celiac Disease. N Engl J Med. 2007;357(17):
1731-43.
6. Sainsbury A, Sanders DS, Ford AC, et al. Prevalence of irritable bowel
syndrome-type symptoms in patients with celiac disease: a meta-
analysis. Clin Gastroenterol Hepatol. 2013;11(4):359-65.
7. Irvine AJ, Chey WD, Ford AC, et al. Screening for celiac disease in
irritable bowel syndrome: an updated systematic review and meta-
analysis. Am J Gastroenterol. 2017;112(1):65-76.
8. Mahadev S, Laszkowska M, Sundström J, et al. Prevalence of celiac
disease in patients with iron deficiency anemia—a systematic
review with meta-analysis. Gastroenterology. 2018;155(2):374-82.
9. Singh P, Arora S, Lal S, et al. Celiac disease in women with infertility:
a meta-analysis. J Clin Gastroenterol. 2016;50(1):33-9.
10. Annasamy C, Narayanasamy K, Karthick R, et al. Prevalence of Elevated
Serum Aminotransferases Among Asymptomatic Population of Tamil
Nadu, India. Biomed Pharmacol J. 2017;10:1249-57.
11. Sainsbury A, Sanders DS, Ford AC, et al. Meta-analysis: coeliac
disease and hypertransaminasaemia. Aliment Pharmacol Ther.
2011;34:33-40.
12. Singh P, Arora S, Lal S, et al. Risk of celiac disease in the first- and
second-degree relatives of patients with celiac disease: a systematic
review and meta-analysis. Am J Gastroenterol. 2015;110(11):1539-48.
13. Elfström P, Sundström J, Ludvigsson JF, et al. Systematic review with
meta-analysis: associations between coeliac disease and type 1
diabetes. Aliment Pharmacol Ther. 2014;40(10):1123-32.
14. Roy A, Laszkowska M, Sundström J, et al. Prevalence of celiac
disease in patients with autoimmune thyroid disease: a meta-
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.
16. Chou R, Bougatsos C, Blazina I, et al. Screening for celiac disease:
evidence report and systematic review for the US Preventive
Services Task Force. JAMA. 2017;317(12):1258-68.
17. Villalta D, Tonutti E, Prause C, et al. IgG antibodies against
deamidated gliadin peptides for diagnosis of celiac disease in
patients with IgA deficiency. Clin Chem. 2010;56(3):464-8.
18. Singh P, Singh A, Silvester JA, et al. Inter- and Intra-assay
Variation in the Diagnostic Performance of Assays for Anti-tissue
Transglutaminase in 2 Populations. Clin Gastroenterol Hepatol.
2020;18(11):2628-30.
19. Husby S, Murray JA, Katzka DA, et al. AGA Clinical practice update
on diagnosis and monitoring of celiac disease-changing utility of
serology and histologic measures: expert review. Gastroenterology.
2019;156:885-9.
20. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society
Paediatric Gastroenterology, Hepatology and Nutrition Guidelines
for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr.
2020;70(1):141-56.
21. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management
of adult coeliac disease: guidelines from the British Society of
Gastroenterology. Gut. 2014;63:1210-28.
22. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines:
diagnosis and management of celiac disease. Am J Gastroenterol.
2013;108:656-76.
29-01-2021 14:58:28
 CHAPTER
Differentiating Crohn’s Disease
133 from Intestinal Tuberculosis:
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-

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

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 Differentiating Crohn’s Disease from Intestinal Tuberculosis: A Diagnostic Challenge CHAPTER 133 847

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 Pseudosacculation
zz <3 segment

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
seen in either of two diseases. Despite some heterogeneity
most studies reported diarrhea, hematochezia, perianal
disease, and EIMs as being more common in CD whereas
partial bowel obstruction, night sweat, and ascites
predominate in ITB (Table 1).10-13 Longer disease duration
also supports the diagnosis of CD over ITB, but a specific
cut off for duration is not available.12 A recent meta-analysis
reported that diarrhea, hematochezia, perianal disease, and
EIMs favored the diagnosis of CD, while fever, night sweats,
lung involvement, and ascites favored the diagnosis of ITB.14
Endoscopic Appearance
Endoscopic features in CD and ITB have been well
described. Albeit some overlap, left colonic involvement,
presence of longitudinal ulcers, aphthous ulcers,
cobblestoning, and skip lesions are more common in
CD whereas presence of transverse ulcers and patulous
ileocecal valve are more common in ITB (Table 1 and
Figs. 1A to D).10,11,13,14 Lee et al. described a predictive
model based on four common endoscopic findings in
CD (anorectal lesion, longitudinal ulcers, aphthous
ulcers, and cobblestone appearance) and ITB (less than 4
segment involvement, patulous IC valve, transverse ulcers,
and pseudopolyps). A score of +1 and –1 was assigned for
each parameter of CD and ITB respectively. Total score
>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
Histopathology
Both these diseases are chronic granulomatous disease
of the GI tract and share many histopathological features

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 848 SECTION 10 Gastroenterology

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

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 Differentiating Crohn’s Disease from Intestinal Tuberculosis: A Diagnostic Challenge
TABLE 2 Sensitivity of different microbiological tests for ITB
Diagnostic tests Sensitivity
AFB smear 20-22
(2.7–37.5)%
Culture (LJ/BACTEC)21-23 (19–50)%
TB-PCR 24
47%
Gene-Xpert MTB/RIF20,25 (8.1–32)%
gold standard, it has been replaced largely by BACTEC
culture which is less time consuming. Most of the studies
have reported less than 50% culture positivity rate in
biopsy from ITB patients.8,21-23 Polymerase chain reaction
targeted against IS6110 (TB-PCR) as a stand-alone test is
not diagnostic for ITB but can help in diagnosis. Jin et al. in
his meta-analysis reported a pooled sensitivity of 47% and
specificity of 95% for TB-PCR in intestinal biopsy.24 Gene-
Xpert MTB/RIF in the intestinal biopsies has not been well
studied in patients with ITB. In a study of 37 ITB patients
it showed sensitivity of 8.1% and specificity of 100%. 20
Another study by Bellam et al. reported sensitivity of 32%
and specificity of 100%.25
Radiology
CT/MR enterography are the preferred imaging modalities
for evaluating and differentiating between patients with
ITB and CD. Along with access to whole of the GI tract,
cross sectional imaging has additional advantage as it
can detect other significant findings like peritoneal or
omental involvement and mesenteric or intra-abdominal
lymphadenopathy. CT findings commonly seen in
patients with CD are left colonic involvement, multifocal
(>3 segments) or long-segment involvement, comb sign,
and pseudosacculation. On the other hand, involvement
of ileocecal area, short segment involvement (<3 cm),
and presence of lymph nodes larger than 1 cm are more
common in ITB.26,27 A predictive model based on three
characteristics [long segment (>3 cm) involvement, >1
cm lymph node, ileocecal involvement] had a specificity
of 90% in differentiating CD from ITB.27 A meta-analysis
involving six studies concluded that necrotic lymph
nodes had the highest diagnostic accuracy (sensitivity
23%, specificity 100%) for ITB diagnosis, and comb
sign (sensitivity 82%, specificity 81%) followed by skip
lesions (sensitivity 86%, specificity 74%) had the highest
diagnostic accuracy for CD diagnosis28 (Figs. 2A to D).
MU-133.indd 849
CHAPTER 133 849
Patients with ITB may also have evidence of
concomitant pulmonary involvement. 3–25% of ITB
patients show evidence of healed or active pulmonary
TB on chest X-ray.29 Data from our centre (not published)
indicates addition of CT chest (in place of chest X-ray) with
CT enterography can significantly increase the sensitivity
of diagnosing ITB.
Adjunct Tests
Both interferon gamma release assays (IGRA) and
Mantoux are predictive of latent TB rather than active TB;
hence, a positive or a negative IGRA will neither rule in nor
rule out the diagnosis of ITB. Positive Mantoux has been
reported in 50–100% patients with ITB patients whereas
meta-analysis on IGRA reported a pooled sensitivity of
74% and specificity of 87% in differentiating ITB from
CD.30,31 Both these tests provide supporting evidence but
are not diagnostic.
Another serological test, anti-saccharomyces cerevisiae
antibody (ASCA), has been investigated for this purpose
but one study from India and a recent meta-analysis
denied any significant role.32,33
Therapeutic ATT Trial
As we have discussed above, all these investigations have
limited diagnostic accuracies and despite all these tests, in
some cases it is nearly impossible to conclusively diagnose
ITB or CD. Treating with steroid in such cases can be
disastrous if the patient has underlying ITB, so trial of
ATT is almost imperative for further management of such
a case. A recent retrospective study from Korea reported
that 17.9% CD patients were misdiagnosed as ITB and
10.8% patients of ITB were misdiagnosed as CD before
the correct diagnosis being made. Forty-eight percent of
ITB patients required therapeutic ATT trial for the final
diagnosis. 34 Asia-Pacific consensus statements for CD
have also advocated ATT trial in a patient with CD/ITB
dilemma, and the diagnosis of CD should be considered in
a patient who does not respond to ATT, and subsequently
responds to CD-specific therapy.35 But the big question
is the timeline of ATT trial, when to say a patient as non-
responder and how to assess response. A recent study from
our centre compared the response between two groups
(CD patients who received ATT as therapeutic trial and
ITB patients). By 3 months more than 90% of patients with
29-01-2021 14:58:21
 850 SECTION 10 Gastroenterology

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

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 Differentiating Crohn’s Disease from Intestinal Tuberculosis: A Diagnostic Challenge
Flowchart 2: Algorithm for follow-up of a patient with CD/ITB
dilemma who has been initiated on a therapeutic ATT trial
Predictive Models
Due to limitation in accuracy and sensitivity of any single
characteristic, several multiparametric predictive models
incorporating more than one feature across single or
multiple diagnostic modalities have been described. A
multicentre study from India described hematochezia,
weight loss, sigmoid colon involvement, and focal
enhanced colitis as independent predictors for diagnosis
of CD/ITB, and a score based on these variables had an
AUC of 0.91 in differentiating CD from ITB. 10 Another
Korean study included age, gender, diarrhea, transverse
ulcer, longitudinal ulcer, sigmoid colon involvement, and
suspicion of pulmonary TB in their predictive models.
The AUC for differentiating CD and ITB was 0.98, and on
validation in a separate cohort, the accuracy was similar
MU-133.indd 851
CHAPTER 133 851
with an AUC of 0.92.40 But most of these predictive models
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
with CD. A value of more than 32.5% for FOXP3+ cells
in peripheral blood could differentiate ITB and CD with
75% sensitivity and 90.6% specificity.45 This has also been
validated in a separate cohort of 73 patients.46 VF/SF ratio
and circulating FOXP3+ cells in peripheral blood are
specially helpful where differentiation between CD and
ITB is not possible on the basis of routine radiological,
histological, and microbiological evidence.
One recent study reported that immune-histochemistry
(IHC) for CD-73 in biopsies could differentiate granulomas
of CD and ITB with high diagnostic specificity but it has
not been replicated in other studies.47
He et al. developed a nomogram based on seven
parameters that were significant on regression analysis
including age, transverse ulcer, rectum involvement,
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 852 SECTION 10 Gastroenterology
skipped small bowel involvement, target sign, comb sign,
and IGRA (for model 1) or Mantoux test (for model 2),
respectively. Nomogram 1 showed a sensitivity of 86.8%
and specificity of 90.9% while nomogram 2 showed 84.2%
sensitivity and 100% specificity for differentiating CD from
ITB in the validation cohort.48
One of the most significant findings was described
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
disease compared to patients who are ATT naive (OR:
11.05; 95% CI 3.17–38.56, p <0.001) and they also have
higher risk of surgery than ATT naive patients (HR: 3.22;
95% CI, 1.46–7.12, p = 0.004) on long-term follow-up.49
This finding can challenge our practice of therapeutic ATT
trial in cases with diagnostic dilemma. This also highlights
the importance of accurate discrimination between these
two diseases right at the outset and the importance of
close follow-up and early assessment in suspected cases.
TB on CD: The New Challenge
As more and more patients of CD are now being treated
with anti-TNF therapy in developing countries like India,
a new challenge is setting in. Agarwal et al. reported that
11.6% IBD patients on infliximab therapy developed
reactivation of tuberculosis despite that all these patients
were screened for latent TB before the initiation of therapy
and most of them developed it within 1st year of therapy.50
Similar findings have also been reported in other studies.51
A recent meta-analysis compiled 128 studies (130,114 IBD
patients) and reported a pooled prevalence of 0.08% for
developing TB on anti-TNF therapy. The risk increased
with increasing TB burden, pooled prevalence being
0.02%, 0.21%, and 1.59% for low, intermediate, and high
TB burden countries, respectively. Seventy-three percent
of patients who developed TB had no evidence of latent
TB on screening. Apart from therapeutic challenge, this
tubercular reactivation poses a new set of diagnostic
dilemma, as to decide whether it was ITB to start with or it
is only tubercular reactivation on immunosuppression.52
Conclusion
Since time long the deceptive similarities between CD and
ITB has been a matter of debate among clinical practitioners.
With scientific advances and availability of newer radiological
MU-133.indd 852
tools and biomarkers, we have made significant progress in
solving the clinical dilemma. But it needs careful interpretation
of all diagnostic evidence and clinical judgment on case to
case basis. And with newer challenges like “TB on CD” or ATT
complicating disease course of CD patients, we need to be
more accurate, more precise, and more vigilant in diagnosing
and managing patients with ITB and CD.
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19. Du J, Ma YY, Xiang H, et al. Confluent granulomas and ulcers lined
by epithelioid histiocytes: new ideal method for differentiation of
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20. Kumar S, Bopanna S, Kedia S, et al. Evaluation of Xpert MTB/RIF
assay performance in the diagnosis of abdominal tuberculosis.
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21. Sekine K, Nagata N, Shindo T, et al. Combined identifying
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22. Dutta AK, Sahu MK, Gangadharan SK, et al. Distinguishing Crohn’s
disease from intestinal tuberculosis-a prospective study. Trop
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24. Jin T, Fei B, Zhang Y, et al. The diagnostic value of polymerase
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25. Bellam BL, Mandavdhare HS, Sharma K, et al. Utility of tissue Xpert-
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26. Sharma R, Madhusudhan KS, Ahuja V. Intestinal tuberculosis versus
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28. Kedia S, Sharma R, Sreenivas V, et al. Accuracy of computed
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Crohn’s disease: a systematic review with meta-analysis. Intest Res.
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29. Kedia S, Das P, Madhusudhan KS, et al. Differentiating Crohn’s
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30. Hallur V, Sharma M, Sethi S, et al. Development and evaluation of
multiplex PCR in rapid diagnosis of abdominal tuberculosis. Diagn
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31. Chen W, Fan JH, Luo W, et al. Effectiveness of interferon-gamma
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8133-40.
32. Ghoshal UC, Ghoshal U, Singh H, et al. Anti-Saccharomyces
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33. Ng SC, Hirai HW, Tsoi KK, et al. Systematic review with meta-
analysis: accuracy of interferon-gamma releasing assay and anti-
Saccharomyces cerevisiae antibody in differentiating intestinal
tuberculosis from Crohn’s disease in Asians. J Gastroenterol
Hepatol. 2014;29(9):1664-70.
34. Seo H, Lee S, So H, et al. Temporal trends in the misdiagnosis
rates between Crohn’s disease and intestinal tuberculosis. World J
Gastroenterol. 2017;23(34):6306-14.
35. Ooi CJ, Makharia GK, Hilmi I, et al. Asia Pacific Association of
Gastroenterology (APAGE) Working Group on Inflammatory Bowel
Disease. Asia Pacific Consensus Statements on Crohn’s disease.
Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific
Crohn’s Disease Consensus—Part 1). J Gastroenterol Hepatol.
2016;31(1):45-55.
36. Pratap Mouli V, Munot K, Ananthakrishnan A, et al. Endoscopic
and clinical responses to anti-tubercular therapy can differentiate
intestinal tuberculosis from Crohn’s disease. Aliment Pharmacol
Ther. 2017;45(1):27-36.
37. Lin PY, Wang JY, Hsueh PR, et al. Lower gastrointestinal tract
tuberculosis: an important but neglected disease. Int J Colorectal
Dis. 2009;24(10):1175-80.
38. Samant H, Desai D, Abraham P, et al. Acid-fast bacilli culture
positivity and drug resistance in abdominal tuberculosis in
Mumbai, India. Indian J Gastroenterol. 2014;33(5):414-9.
39. Aggarwal P, Kedia S, Sharma R, et al. Tubercular intestinal strictures
show a poor response to anti-tuberculous therapy. Dig Dis Sci.
2017;62(10):2847-56.
40. Jung Y, Hwangbo Y, Yoon SM, et al. Predictive factors for
differentiating between Crohn’s disease and intestinal tuberculosis
in Koreans. Am J Gastroenterol. 2016;111(8):1156-64.
41. Ko JK, Lee HL, Kim JO, et al. Visceral fat as a useful parameter in the
differential diagnosis of Crohn’s disease and intestinal tuberculosis.
Intest Res. 2014;12(1):42-7.
42. Yadav DP, Madhusudhan KS, Kedia S, et al. Development and
validation of visceral fat quantification as a surrogate marker for
differentiation of Crohn’s disease and intestinal tuberculosis. J
Gastroenterol Hepatol. 2017;32(2):420-6.
43. Kedia S, Madhusudhan KS, Sharma R, et al. Combination of
increased visceral fat and long segment involvement: development
and validation of an updated imaging marker for differentiating
Crohn’s disease from intestinal tuberculosis. J Gastroenterol
Hepatol. 2018;33(6):1234-41.
44. Ahuja V, Subodh S, Tuteja A, et al. Genome-wide gene expression
analysis for target genes to differentiate patients with intestinal
tuberculosis and Crohn’s disease and discriminative value of FOXP3
mRNA expression. Gastroenterol Rep (Oxf ) 2016;4:59-67.
45. Tiwari V, Kedia S, Garg SK, et al. CD4+ CD25+ FOXP3+ T cell frequency
in the peripheral blood is a biomarker that distinguishes intestinal
tuberculosis from Crohn’s disease. PLoS One. 2018;13:e0193433.
46. Rampal R, Kedia S, Wari MN, et al. Prospective validation of CD4+
CD25+ FOXP3+ T-regulatory cells as an immunological marker to
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differentiate intestinal tuberculosis from Crohn’s disease. Intest Res
2020. doi: 10.5217/ir.2019.09181.
47. Banerjee R, Balaji M, Sasikala M, et al. Granulomas of intestinal
tuberculosis and Crohn’s disease can be differentiated by CD73
cell surface marker expression: a pilot study. Dig Dis Sci. 2013;58(8):
2301-7.
48. He Y, Zhu Z, Chen Y, et al. Development and validation of a
novel diagnostic nomogram to differentiate between intestinal
tuberculosis and Crohn’s disease: a 6-year prospective multicenter
study. Am J Gastroenterol. 2019;114(3):490-9.
49. Gupta A, Mouli VP, Mohta S, et al. Antitubercular therapy given
to differentiate Crohn’s disease from intestinal tuberculosis
predisposes to stricture formation. J Crohn’s Colitis. 2020;jjaa091.
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50. Agarwal A, Kedia S, Jain S, et al. Very high rate of tuberculosis
complicating infliximab therapy for inflammatory bowel disease
despite tuberculosis screening in India. Intest Res. 2018;16(4):
588-98.
51. Puri AS, Desai D, Sood A, et al. Infliximab-induced tuberculosis in
patients with UC: experience from India—a country with high
prevalence of tuberculosis: infliximab-induced tuberculosis: India. J
Gastroenterol Hepatol. 2017;32(6):1191-4.
52. Kedia S, Mouli VP, Kamat N, et al. Risk of tuberculosis in patients
with inflammatory bowel disease on infliximab or adalimumab
is dependent on the local disease burden of tuberculosis: a
systematic review and meta-analysis. Am J Gastroenterol. 2020;
115(3):340-9.
29-01-2021 14:58:23
 CHAPTER Acute Liver Failure and
Acute-on-Chronic-Liver
134 Failure in India: How They
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
usually denotes loss of these functions, often threatening
life.1 The concept of liver failure is getting clarified over
time and have several phenotypes. The most frequent
form of liver failure encountered in clinical practice is
the chronic liver failure as in cirrhosis of the liver. In such
patients, development of varices, ascites, variceal bleed,
encephalopathy, renal failure, and infections gradually
sets in over a long period, in many months to many year.2 In
of them do present with rapid and sudden deterioration
in their liver function and liver reserve resulting in
features of acute decompensation (AD) (sudden and
rapid development of ascites, encephalopathy, variceal
bleed), often with occurrence of jaundice, prolonged
International Normalized Ratio (INR) with or without
kidney failure and infrequently with involvement of other
extrahepatic organ dysfunction or failure over few days or
weeks. Such rapid AD usually ensues subsequent to an

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 856 SECTION 10 Gastroenterology

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

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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West? CHAPTER 134 857

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

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 858 SECTION 10 Gastroenterology

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
Laboratory Parameter
Transaminases
Not identified—primay cause of
liver damage causes liver failure
Markedly raised 15–30 times ULN
Not identified—Primary
cause with impaired
regeneration cause liver
failure
Moderately raised—5–10
times ULN
Usally present—Sepsis, variceal bleed, super
infection, Superadded DILI, alcoholic binge,
flare of underlying cause of chronic liver
disease, idiopathic
Minimally or moderately raised depending
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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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West? CHAPTER 134 859

onset of symptoms. A few patients presenting with sALI
mostly due to DILI may develop encephalopathy later
than 4 weeks up to 8 weeks.”7 Further, because the etiology
of ALF is heterogenous in the West, all patients clinically
do not have similar natural course and subclassification of
ALF depending upon the interval between onset of acute
hepatitic illness and encephalopathy has been suggested
by British and French. 7-9 The French subclassification
categorizes ALF in to:
„„ Fulminant Liver failure (encephalopathy occurring
within 2 weeks of onset of jaundice) and
„„ Subfulminant (encephalopathy occurring between 2
and 12 weeks of jaundice).
The British subcategorizes them to three groups:
„„ Hyperacute liver failure (encephalopathy within 7 days
of onset of jaundice
„„ ALF (encephalopathy between 7 days and 4 week)
„„ Subacute hepatic failure (SHF) (encephalopathy
within 5–24 weeks of onset of jaundice).11
These regions noticed that those presenting with
hyperacute or fulminant liver failure had better survival
than the other ones and therefore subcategorized them
and such events do influence on deciding high risk patients
for liver transplantation. However, in India, large series
have reported that rapidity of onset of encephalopathy
(hyperacute) and the others had similar outcome probably
due to homogeneous etiology. Therefore, in India, most
patients are either hyperacute or acute without any
difference in outcome and practically do not need any
subcategorization.11
Etiology
The differences in etiology of ALF among the adults
across the world are striking (Tables 2 and 3).7,9 In India,
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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 860 SECTION 10 Gastroenterology

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

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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West?
methods, presence of intracranial hypertension due to
cerebral edema has been documented in all patients
with ALF irrespective of the grades of encephalopathy.9
However, in the West, over the years, improvement
in awareness about ALF, early referral to tertiary care
center and improved intensive unit care, frequency of
cerebral edema in the West is being reported to be less
frequent than in former years.9
„„ Sepsis: Infection in ALF is frequent and reported from
both West and India.9 ALF is a condition associated
with innate immune system compromise occurring
rapidly. 7 Therefore infection in them occur very
early in the course of the disease. 9,12 The incidence
of infection in the authors’ experience, from a single
center in India is around 55%, the most common site
of infection is respiratory tract and the commonest
organisms are Gram-negative bacilli.9,11 Quarter of the
patient in the series reported by the author had also
fungal infections.11 From the UK, the report on ALF in
early series, identified that about 90% of their patients
develop infection, which included bacterial sepsis in
80% and 32% had fungal infection. 9 In more recent
reports the predominant organisms reported from the
West are Gram-negative but the initial reports from the
UK the gram positive organisms were isolated more
frequently.13
Key points: Complications
zz Renal failure in ALF is frequent in the West, because the bulk of
the patients are due to drugs (Acetaminophen is associated with
direct nephrotoxicity)
zz Renal failure in ALF is infrequent in India because of predominant
viral etiology
zz Sepsis is frequent in ALF. In the West and the bacterial species
are mixed between Gram-positive and Gram-negative whereas
Gram-negative organisms are common in India. In about quarter
of Indian patients’ fungal infection has also been documented
Gender, Pregnancy, and Acute Liver Failure
All over the globe, in ALF females predominates except in
Japan where the sex distribution is even between the two
genders. Despite the fact that the etiology across the region
are distinct, the predilection of female sex to develop ALF
remains unclear. In India as described earlier, hepatitis
virus(es) are the major etiological agent particularly HEV.
Various epidemiological as well as sporadic studies reveal
that pregnant females are more prone than nonpregnant
females and males to contact HEV infection and also
MU-134.indd 861
CHAPTER 134 861
develop severe liver diseases than similar male and
nonpregnant females patients.7,9 Further, it is believed that
pregnant women with ALF than the ALF in nonpregnant
women and males are more sick with higher complication
rates and mortality. However, the later conjecture was
not evidence based and a large study on pregnant ALF
due to viral hepatitis from India disproved this conjecture
indicating that in India pregnant females with ALF (except
in Acute Fatty Liver of Pregnancy or severe pre-eclamptic
toxemia induce ALF) do not benefit from the termination
of pregnancy.14 A summary of studies reporting pregnancy
and ALF is shown in Table 4.7,9
The number of pregnant patients developing ALF is
relatively small in the West and therefore do not constitute
a major problem in management. In India, about 60% of
the females with ALF in the child bearing age are pregnant
whereas, the fertility rate among similar population
in general is 2.9%.9,14 It is believed that pregnancy is a
immunocompromised state with predilection to contact
various infections and manifest usually in more severe
form. Multiple epidemics of HEV infection have been
documented in India.7 During such epidemics, pregnant
females had more frequent infection (12–20%) than
the men and nonpregnant women (2–4%) for unclear
reasons.9,15 The frequency of ALF among the pregnant
females was also higher (10–22%) than similar men and
nonpregnant women (1–2%).7,9 This observation indicate
that pregnant females are more prone as well develop
more severe liver disease subsequent to HEV infection,
which is the major cause of viral hepatitis as well as
ALF in India. Therefore, the mortality was significantly
higher among pregnant women with epidemic hepatitis
(10–39%) than in the general population affected with
similar hepatitis (0.06–12%).9,11 In the sporadic setting,
HEV is one of the most important etiology of ALF in India
accounting for about 30–45% of patients hospitalized with
ALF (Table 2). However, the mortality in pregnant females
has been found to be similar to that of nonpregnant
females and males and is independent of the cause
or trimester.14 The reason for predilection of pregnant
females to contact HEV and severe liver disease remains
unclear. To elucidate this, viral and host factors in HEV-
ALF were evaluated in one study.15 The study reported
more frequent progesterone receptor (PR) gene mutations
(PROGINS) associated with reduced expression of PR
and progesterone induced blocking factor (PIBF), a
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 862 SECTION 10 Gastroenterology

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
associated these changes to the poor outcome in HEV-ALF
in pregnant females. Pregnancy as a predisposition to ALF
in India could be due to: (1) large number of pregnant
population (3%); (2) unavailability of clean drinking
water; (3) predilection of pregnant females to contact
HEV infection. Hepatitis E virus has been identified as
a very important cause of severe liver disease in areas
of world where more than 70% of the global population
resides. The Global Disease Burden study by World Health
zoonotic transmission is considered to be the cause of
infection of human beings, leading to autochthonous
acute HEV. Genotypes 3 and 4 have not been reported to
be associated with severe liver disease and the majority of
cases appear to represent subclinical infection.19
Key Points: ALF in Pregnancy
zz West and Europe: Pregnant females account for 1–3% of cases
zz India: 40–60% of females of child-bearing age with ALF are
pregnant and HEV is the most frequent cause in them
zz Mortality is not increased in pregnant ALF than the others

zz Termination of pregnancy not indicated in such patients

Organization identified that, approximately 3.7 million
people are infected by HEV annually and 70,000 of them
die due to HEV induced severe liver disease of whom a
large proportion are pregnant.16
Acute fatty liver of pregnancy (AFLP) on the other hand
is more frequent in the West than in India.7 Termination
of pregnancy is required for improving prognosis in
AFLP. However, termination of pregnancy may not be
appropriate in pregnant females with HEV-ALF, because:
„„ ALF-HEV, in comparison to other causes of ALF, has
lowest mortality,17
„„ the mortality in ALF-HEV with pregnancy, ALF-HEV
in females without pregnancy and males with ALF-
HEV are similar and not higher, indicating that in the
pregnancy once ALF develops does not influence the
natural course.14
Genotypes 1 and 2 of hepatitis E virus are prevalent
in hyperendemic regions where the reservoir for HEV
seems to be human, and cause outbreaks, sporadic
acute hepatitis, ALF, and ACLF.18 Genotypes 3 and 4 are
more prevalent in the USA, Europe, and Japan, where
the reservoir seems to be represented by pigs, and the
zz AFLP: Genetic predisposition, termination of pregnancy
improves prognosis
Outcome
The etiology of ALF, which is regionally varied, influences
outcome, particularly in the West where the etiology
is heterogeneous. Paracetamol is the major cause of
ALF in the West. Paracetamol induced ALF presents
rapidly (hyperacute) with a spontaneous survival rate of
64% which is significantly higher than similar outcome
due to other causes such as ALF due to idiosyncratic
drug toxicity (spontaneous survival in 20% cases). 9,11
However, paracetamol induced ALF may progress very
rapidly in some. The paracetamol being the frequent
etiology in the West constitutes the bulk of all ALF
patients in these regions and therefore the total number
of deaths due to paracetamol toxicity exceeds all other
diagnoses. Nearly one third of these patients who develop
encephalopathy die. Paracetamol overdose whether
suicidal or unintentional presenting with ALF has similar
outcomes.20

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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West?
In the India, acetaminophen overdose induced
ALF is infrequent. The drug induced ALF are due to
antituberculosis therapy (ATT).21 The mortality in ATT-
ALF has been reported to be 70%. 21 In India, about
90–95% of ALF are due to hepatitis viruses (homogeneous
etiology).7,9,11,12 ATT induced ALF constitutes about 6–7%
of all ALFs.21 Therefore, etiology could not be identified
as an independent predictor of mortality.9,12,21 However,
when HEV as a separate group was compared with
each individual other etiologies, such as ATT induced
ALF and non-A non-E–ALF, etc. the survival frequency
among HEV was reported to be significantly superior to
other etiologies.18,21 These survival frequencies reported
are transplant-free survivals. Liver transplantation is
established therapy in all end stage liver disease and with
transplantation, overall survival exceeds 75%.7,9
Key points: Outcome
zz West: Etiology affects the outcome, because etiology is
heterogeneous
zz India: Etiology in general does not influence the outcome,
because etiology is almost due to hepatitis virus(es)
zz Among hepatitis virus induced ALF, HEV has a better prognosis
zz Commonest cause of drug induced ALF in India is antitubercular
drugs and have high mortality
Prognostic Models7,9,12
Liver transplantation has been well established as
a curative option in ALF. 9,11 Prognostic models are
therefore necessary to identify patients who will need
transplantation or should continue on medical therapy.
Many prognostic models from all around the globe
have been described.7,9 Each of the prognostic models
in summary have highlighted the following important
facts. Age and etiology in most reports are important
variables influencing survival. HAV, HEV, acetaminophen
toxicity, and acute fatty liver of pregnancy induced
ALF, survive more frequently. 7,9,12 Patients with drug
induced, autoimmune, HBV, and cryptogenic ALF all have
spontaneous survival of less than 30%. 7,9,18,21,22 Wilson’s
disease with ALF survive rarely.7 Among the dynamic
variables, the degree of encephalopathy was documented
to influence survival—Patients with encephalopathy
grade of III or more in comparison to less advanced
encephalopathy (I & II) die more frequently.7,9,21,22
Among the prognostic models, King’s College Hospital
Criteria (KCC) for liver transplantation were proposed by
O’Grady, and have been widely used.22 Although these
MU-134.indd 863
CHAPTER 134 863
criteria are specific, they are not very sensitive in predicting
cases that will need transplantation. Unfortunately,
none of the currently available models have consistently
demonstrated reliable accuracy in predicting outcome.23
Multiple prognostic models have been reported from
India.7,9,12 A report from North India, the following variables
present at admission were identified as independent
predictors for poor outcome:
„„ age 40 years or more;
„„ bilirubin 15 mg/dL or more;
„„ PT prolongation 25 seconds or more; and
21
„„ clinical features of overt cerebral edema. With
increasing number of above risk factors, mortality
increased; with three or more factors it was 93%.11,12,24
In another study from India, clinical prognostic
indicators (CPI) included age 50 years or more,
jaundice encephalopathy interval (JEI) more than
7 days, grade 3 or 4 encephalopathy, presence of
cerebral edema, PT ≥35 seconds, and creatinine ≥1.5
mg/dL. Presence of any 3 of 6 CPIs was superior to
model for end stage liver disease (MELD) or King’s
College hospital (KCH) criteria in identifying survivors
and nonsurvivors.9
ALF is a dynamic process in which variables
determining prognosis at admission change over time,
and thus the clinical course varies accordingly. A new
prognostic model, ALF early dynamic (ALFED) model was
reported which included four variables: arterial ammonia,
serum bilirubin, INR, and hepatic encephalopathy more
than grade II, which were identified as the independent
predictor of outcome at admission. 7,24 This model
evaluated the dynamicity of these four variables over 3
days and documented that the prediction of outcome
using these variables on day 3 was markedly superior to
the prediction based on admission parameters. Recently,
the INASL recommended the ALFED prognostic model to
be more appropriate for the Indian subcontinent because
it was derived from the cohort of Indian patients who had
predominantly viral etiology unlike in the West where viral
etiology as a cause of ALF is infrequent.7
This is one of the first dynamic models to assess and
stratify ALF patients dynamically over a period of 3 days
rather than considering variables at baseline. ALFED
model study identified four prognostically significant
variables: arterial ammonia, serum bilirubin, INR, and
hepatic encephalopathy more than grade II. This ALFED
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 864 SECTION 10 Gastroenterology
TABLE 5 ALFED Score7,24
Variables over 3 days Score assigned
Hepatic encephalopathy 2 Intensive care unit, organ support system, nutrition, electrolyte
(Persistent or progressed to grade >2)
INR 1 Identification and removal of precipitating factors:
(Persistent or increased to ≥5)
Arterial ammonia 2 constipation, psycho-active drugs.
(Persistent or increased to ≥123 μmol/L)
Serum bilirubin 1 Lactulose (not used), antibiotics, enema
(Persistent or increased to ≥15 mg/dL)
Each of the variables above on the day 3 of hospitalization carries
a score determined on the strength of the beta integer of the odd’s
ratio identified in multivariate analysis to predict mortality. Each of
the above variables were independent predictors of mortality. On
day 3 a score of 4 is associated with 90% mortality where as score 1 is
associated with about 5% mortality. With increasing score mortality
increases
model had an AUROC of 0.91 in the derivation cohort and
of 0.92 in the validation cohort. The model showed similar
increase in mortality with increasing risk scores from 0 to
6 (Table 5). The performance of the ALFED model was
found to be superior to the KCH and the MELD score,
even when their 3-day serial values were considered. An
ALFED score of ≥4 had a high PPV (85%) and NPV (87%)
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
survival frequency of about 80% or more and those with ≥4
had a mortality risk of more than 80%.7,24 These parameters
at baseline were also independent predictors of mortality,
but the dynamic assessment made these parameter as also
model for survival. In India ALF etiology is hepatitis virus
and usually individuals without any underlying chronic
liver pathology develop ALF. In ALF along with hepatic
necrosis, the liver regeneration simultaneously kicks
off. Therefore, with liver regeneration, these predictive
parameters change, and hence dynamic assessment are
important to identify the outcome more accurately. The
management and pathogenesis in ALF need another
chapter and particularly the therapeutic approach against
specific drivers of pathogenesis need special mention
(Table 6).
Summary
„„ ALF in India and the West have different etiology and
natural course, and therefore the prognostic models
MU-134.indd 864
TABLE 6 Principles in the management of ALF
Aggressive supportive therapy:
correction, hypoglycemia prevention, monitoring, hydration
Control of GI bleed, sepsis, hyponatremia, renal failure,
Reduction of nitrogenous load from the Gut:
Manipulation of neurotransmitters:
Flumazenil, branched chain amino acids (not used)
Cerebral edema:
IV Mannitol, thiopentone, hypertonic saline, hypothermia (not
used), IV phenytoin (not used)
Ammonia lowering therapy:
L-ornithine L-aspartate (LOLA- not used), L-ornithine phenyl acetate
(LOPA), sodium benzoate, hypothermia (not used), CRRT, plasma
exchange
Novel therapies:
Molecular adsorption various bioartificial support system,
recirculating system (MARS, promethus), probiotics with increased
capacity to consume ammonia (not found beneficial)
Liver
Transplantation: LDLT (living donor liver transplant), DDLT
(deceased donor liver transplant), auxiliary LT, split LT
are different. In India, the etiology is homogenous in
contrast to the West where it is heterogeneous
„„ In the West: Drug induced ALF and in the East: Viral
etiology is the most common
„„ Outcome of viral (HAV, HEV) and Drug (paracetamol)
are better than other etiologies, but antitubercular
drug-ALF has high mortality
„„ In India, pregnant females are more prone for ALF but
not so in the West
„„ Prognostic models described across the world;
dynamic models have been described recently from
India and are appropriate for Indian patients
„„ Management: conservative, organ support and liver
transplantation in select group
Acute-on-Chronic-Liver Failure
Introduction
In the early sections of the present chapter the concept of
liver failure in general and ALF, ACLF, and chronic liver
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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West?
failure as well as SHF in particular has been highlighted.
Table 1 depicts the essential phenotypic difference
between ALF, SHF, and ACLF.
Patients with decompensated cirrhosis clinically
presents with heterogeneity with variable prognosis.
AD in cirrhosis usually denotes appearance of ascites,
encephalopathy, variceal bleeding or combination of any
later three.4,5 Since liver transplantation in such patients
is probably is the only curative option, there short-term
survival prediction (usually in 2 years) has been used
at many centers. 2 Three states with increasing risk of
death have been proposed for decompensated cirrhosis
defined by the occurrence of a first variceal bleeding alone
(without other decompensating events—mortality 20%),
any first non-bleeding decompensating event alone (80%
ascites—mortality 24%), or any second decompensating
event (mortality—50–78%). 25 However, recent reports
indicate that, a more advanced rapid AD state do occur
with a very high short-term 28 days mortality of around
20–90% depending upon degree and extent of associated
extrahepatic organ failure. 25 These are patients, who
developed systemic inflammatory response through
proinflammatory precipitating factors (sepsis, excessive
alcohol consumption, sudden reactivation of previous
chronic liver disease inducing further acute hepatic
necrosis) who are usually jaundiced with prolonged INR
and develop various organ failures (OF) probably because
of cytokine storm effecting extrahepatic organs resulting
from the proinflammatory precipitating events. These are
patients with ACLF.
Definitions and Concept
The term ACLF was first introduced to identify the above
mentioned often observed but not categorized entity
in 2002. 26 The first consensus definition on ACLF was
provided by APASL (Asian Pacific Association for the
Study of Liver) as “an acute hepatic insult manifesting
as jaundice (total bilirubin ≥5 mg/dL) and coagulopathy
(INR ≥1.5), complicated within 4 weeks by ascites and/or
encephalopathy in a patient with chronic liver disease.”3
However, it was slightly modified in 2014 in which chronic
liver disease was modified to “with previously diagnosed
or undiagnosed chronic liver disease/cirrhosis” and a
“high 28 days mortality” was added.27 With this APASL
criteria, 28 days mortality was reported by the APASL
between 25–34%. 27 However, certain patients with AD
having above criteria with OF had markedly higher
mortality than those without. Therefore, the EASL-AASLD
MU-134.indd 865
CHAPTER 134 865
(European Association for the Study of Liver-American
Association for the Study of Liver) defined ACLF as
“Acute deterioration of pre-existing, chronic liver disease,
usually related to a precipitating event and associated
with increased mortality at 28 days due to multisystem
organ failure.” Some report suggested and documented
that severity of OF assessed by sequential organ failure
assessment (SOFA) scores could differentiate patients with
various prognosis (58% with OF vs. 8% without OF).31
The first prospective, observational, multicentric
European study known as CANONIC study documented
the distinction between AD without OF and AD with OF
(which according to Western concept was ACLF). Among
patients with known cirrhosis admitted with AD (ascites,
variceal bleed, encephalopathy, infection; n=1,343), the
28 days and 90 days mortality in those with OF versus
those without OF were 34% and 51% versus 5% and 14%,
respectively. Thus, this study provided the documentation
that patients with AD who were hospitalized with or
developed OF after hospitalization were distinct and
were named as—ACLF and justified their definition
(EASL-CLIF—European Association for the Study of
Liver-Chronic Liver Failure definition).28 North American
Consortium for the Study of End-Stage Liver Disease
(NACSELD) defined ACLF by the presence of at least two
very severe extrahepatic OFs (shock, grade III/IV HE,
renal replacement therapy, or mechanical ventilation),
which are much more stringent criteria than those of the
EASL-CLIF consortium or the APASL. The NACSELD-
defined ACLF is associated with a 30-day mortality
rate of 41% compared to 7% for patients without ACLF.
Accordingly, by definition, the main difference between
traditional AD and ACLF is the short- and medium-term
prognosis. To unify the definition on ACLF the WGO
(World Gastroenterology Association) suggested that
“ACLF is a syndrome in patients with chronic liver disease
with or without previously diagnosed cirrhosis, which is
characterized by acute hepatic decompensation resulting
in liver failure (jaundice and prolongation of the INR) and
one or more extrahepatic organ failures that is associated
with increased mortality within a period of 28 days and up
to 3 months from onset”(Fig. 3).4
Components of ACLF
All the above definitions and concept irrespective in their
disagreement and region of origin elucidated that there
should be five components in ACLF:
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 866 SECTION 10 Gastroenterology
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
(APASL excluded known decompensated liver
disease and emphasized that only non-cirrhotics
or compensated cirrhosis of any etiology should be
included as underlying silent liver disease, which
may have been diagnosed or undiagnosed previously;
however, the EASL-CANONIC study as described
earlier did not exclude patients with chronic liver
disease with previous history of decompensation and
WGO in an effort to unify these categorized underlying
Chronic liver Disease to A-CLD without cirrhosis,
B-compensated Cirrhosis and C-Cirrhosis with
previous history of decompensation—Fig. 3).
„„ There should be a precipitating factor causing acute
hepatic insult with systemic inflammatory response
which were different regionally (described below)
which should result in overt acute deterioration of
hepatic function as well as reserve, resulting in features
overt liver failure (CANONIC study defined them as AD
and included both hepatic and extrahepatic insult but
APASL excluded extrahepatic insults like variceal bleed
and sepsis and emphasized on only acute hepatic
insult to be further qualified by presence of conjugated
hyperbilirubinemia of more than 5 mg/dL with INR
more than 1.5 accompanied with development AD in
the form of ascites and/or encephalopathy; there by
MU-134.indd 866
quantifying the severity of the hepatic insult resulting
in AD).
„„ The above-mentioned acute deteriorations should
occur within a short period of time (APASL defined it
to be within 4 weeks).
„„ The presence or development of hepatic failure
should be associated with extrahepatic organ failure
like encephalopathy, respiratory failure, renal failure,
coagulation abnormality, circulatory compromise in
form of hemodynamic instability as per the EASL-
AASLD and NASCLED definition but APASL did not
include it and suggested that only with liver failure
the mortality exceeded 30% and should be enough
to define ACLF and extrahepatic organ failures are
the sequels of ACLF. However, the INASL consortium
experiences documented that indeed occurrence of
the extrahepatic organ failure imparts high short-term
mortality.29-31
„„ As has been elucidated earlier, these patients with
CLD are distinct from AD and should be categorized
as another form of liver failure and to be termed as
ACLF. By now both APASL and Western group agree
that they have high 28 days mortality (various reports
from different region describe it to a tune of around
50%).1,5 The mortality, however, linearly increases with
increases in number of extrahepatic OF (20% with one
OF to 90% with >4 extrahepatic OF) (Table 7).28,31
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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West? CHAPTER 134 867

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

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 868 SECTION 10 Gastroenterology
organs, the course in ACLF is dynamic and usually unfolds
over subsequent few days usually between 3–7 days.33,34
Types/Categorization of ACLF
The canonic study first tried to identify and qualify the
extrahepatic organ failure by quantifying the change in the
sequential organ failure assessment (SOFA).28,31 The study
included six organs to be evaluated for SOFA score (Liver,
Kidney, Brain, Coagulation, Circulation, and Respiration)
and graded their dysfunction based on values of serum
bilirubin, creatinine, INR, mean arterial pressure (MAP),
and ratio between PaO2/FiO2 or SpO2/FiO2, respectively
and allocated 1–3 point scores to these values. Patients
with score 2 for each parameter were considered as organ
dysfunction (OD) like liver dysfunction (LD), kidney
dysfunction (KD), brain dysfunction (BD), circulatory
dysfunction (CD), coagulation dysfunction or respiratory
dysfunction (RD) and patients with score 3 were defined
as individual organ failure. This score was named as
EASL, CLIF, SOFA score and depending on these scores as
mentioned above. No OD and OF were defined for each
of the six organs and then the ACLF in patients with AD
were graded as No ACLF, ACLF grade 1–3 depending upon
presence or subsequent development of number of OD/
OF. With increasing grade, the 28 days mortality increased
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
MU-134.indd 868
(Table 7). Since OF were not included in APASL definition,
the ACLF was not categorized or typed in APASL cohorts
collated subsequently. However, in APASL cohort and
many other reports on ACLF which included large cohorts
of patients with ACLF reported that occurrence of OF was
major determinant of outcome and prognosis.32 Further
the admission grading or status of organs were dynamic
and the outcome prediction based on the OF on day 3–7
were more accurate predictors of outcome. Both EASL-
CLIF (CLIF-C-ACLF) score and APASL groups have defined
their dynamic prognostic scores, which simply reflect the
dynamic changes of variable organ parameters.3,33
Pathogenesis (Flowchart 1)26,31
Pathogenesis in ACLF is unclear. However, the severe
cytokine storm in ACLF has been documented to be more
pronounced (documented by enhanced C-reactive protein
response, neutrophilic leukocytosis, tumor necrosis
α, IL18) than in patient with AD as well as in patients
with compensated cirrhosis without AD.31 The ammonia
levels also have been recently identified to be markedly
increased in such patients than in the other groups.32 The
Cause of Cytokine Storm has been briefly explained in the
Flowchart 1. The DAMP (damage associated molecular
pathogen) due to liver cell damage in diseases causing
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 Acute Liver Failure and Acute-on-Chronic-Liver Failure in India: How They Are Different from West?
TABLE 9 Principles in management of ACLF
zz Intensive care unit, organ support system, nutrition, electrolyte
zz Treatment of infection with appropriate antibiotics with
monitoring of renal function and maintenance of serum albumin
values with albumin replacement preventing volume overload
zz Treatment of precipitating factors:
—— antivirals in HBV reactivation
—— steroid in alcoholic ACLF after ruling out infection
—— specific management for acute variceal bleeding if occurs, d)
withdrawal of hepatotoxic drug, CAM
zz Specific organ failure management:
—— For RF/RD—CRRT
—— Noradrenaline if needed to maintain MAP>70 mm Hg
—— Treatment for encephalopathy if occurs
—— Adrenal insufficiency (may occurs in some)-IV hydrocortisone
zz Treating systemic inflammatory response:
—— Molecular Adsorbtion Recirculating System(MARS)—till date
no evidence that it improves survival
—— plasma exchange—experimental
zz Immunomodulatory/Regenerative therapy: G-CSF has been
tried in small studies, but needs to be validated in large
multicentric studies
zz Fecal microbial transplantation: has been tried in alcoholic ACLF
in small studies with promising results
zz Liver transplantation if needed
super added injury to liver or sepsis or bleeding causing
ischemia to liver are recognized by the innate immune
systems presence in liver cells such as TLRs and other
Innate immune PRR (pathogen recognizing receptors)
sensors and produce various cytokines which cause
neutrophilic recruitment and also attracts the immune
cells of adaptive immune system resulting in release of
various proinflammatory cytokines which may spill over
to systemic circulation effecting various extrahepatic
organs. Perpetuating the events by the transmigration
of gut microbes due to a leaky gut documented in such
patients further enhance such response and also induces
endothelial nitric oxide by upregulating the nitric oxide
synthase enzyme.32 These events result in various organ
dysfunction or OF depending upon the severity of the
cytokine storm and the degree of liver injury resulting in
ACLF.
Management
The management principles comprise of:
„„ Treating the precipitating factors
„„ Support to the failing organ
„„ Continuous assessment and by day 3–7 decision for
liver transplant.
MU-134.indd 869
CHAPTER 134 869
The Model for End Stage Liver Disease (MELD) score
and addition of sodium value (MELD-Na) score in addition
to the scores of failing organs have been the principles to
prognosticate and transplant such patients to improve
survival.32-34 Table 9 briefly provides the components of
management in ACLF.
Conclusion
ACLF is a syndromic condition that occurs in patients with
underlying chronic liver disease (CLD) irrespective of the cause
of CLD. These patients develop intense systemic inflammation,
organ failure, and high short-term mortality and ensue in
close temporal relationship with a precipitating event, which
is regionally variable. Whether extrahepatic organ failure is an
integral part of the syndrome or consequence is the difference
in defining the syndrome in the West and Asia. Bacterial
infection is frequent in these patients and in the West it is
considered as a precipitating event, but in Asia it is considered
as a frequent association in ACLF. However, irrespective the
differences between the West and Asia the syndrome is seen
across the world and about half of them need liver transplant.
References
1. Olson JC. Acute-on-chronic and decompensated chronic liver
failure: definitions, epidemiology, and prognostication. Crit Care
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2. D’Amico G, Morabito A, D’Amico M, et al. New concepts on
the clinical course and stratification of compensated and
decompensated cirrhosis. Hepatol Int. 2018;12(Suppl 1):34-43.
3. Sarin SK, Kumar A, Almeida JA, et al. Acute-on chronic liver failure:
consensus recommendations of the Asian Pacific Association for
the study of the liver (APASL). Hepatol Int. 2009;3(1):269-82.
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.
5. Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure
in cirrhosis. Nat Rev Dis Primer. 2016;2:16041.
6. Koch DG, Speiser JL, Durkalski V, et al. The natural history of severe
acute liver injury. Am J Gastroenterol. 2017;112(9):1389-96.
7. Anand AC, Nandi B, Acharya SK, et al. Indian National Association
For the Study of Liver Consensus Statement on Acute Liver
Failure(Part 1): Epidemiology, Pathogenesis, Presentation. J Clin Exp
Hepatol. 2020;10(4)339-76.
8. Wlodzimirow KA, Eslami S, Abu-Hanna A, et al. Systemic review:
acute liver failure—one disease, more than 40 definitions. Aliment
Pharmacol Ther. 2012;35(11):1245-56.
9. Shalimar, Acharya SK, Lee W. World wide differences in acute
liver failure. Future Medicine. 2013. Available from https://www.
futuremedicine.com/doi/abs/10.2217/ebo.12.326.
10. Tandon BN, Bernauau J, O’Grady J, et al. Recommendations of the
international association for the study of the liver subcommittee on
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nomenclature of acute and subacute liver failure. J Gastroenterol
Hepatol. 1999;14(5):403-4.
11. Acharya SK, Panda SK, Saxena A, et al. Acute hepatic failure in India:
a perspective from the East. J Gastroenterol Hepatol. 2000;15(5):
473-9.
12. Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in a
tropical population: clinical course, cause, and early predictors of
outcome. Hepatology. 1996;23(6):1448-55.
13. Karvellas CJ, Pink F, McPhail M, et al. Predictors of bacteraemia and
mortality in patients with acute liver failure. Intensive Care Med.
2009;35(8):1390-6.
14. Bhatia V, Singhal A, Panda SK, et al. A 20-year single-center
experience with acute liver failure during pregnancy: is the
prognosis really worse? Hepatology. 2008;48(5):1577-85.
15. Bose PD, Das BC, Kumar A, et al. High viral load and deregulation
of the progesterone receptor signaling pathway: association
with hepatitis E-related poor pregnancy outcome. J Hepatol.
2011;54(6):1107-13.
16. Rein DB, Stevens GA, Theaker J, et al. The global burden of hepatitis
E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55(4):988-97.
17. Shalimar, Kedia S, Gunjan D, et al. Acute liver failure due to hepatitis
E virus infection is associated with better survival than other
etiologies in Indian Patients. Dig Dis Sci. 2017;62(4);1058-66.
18. Aggarwal R. Hepatitis E. Historical, contemporary and future
perspectives. J Gastroenterol Hepatol. 2011;26(Suppl 1):72-82.
19. Acharya SK, Panda SK. Hepatitis E. Water, water everywhere—now a
global disease. J Hepatol. 2011;54(1):9-11.
20. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced
acute liver failure: results of a United States multicenter, prospective
study. Hepatology. 2005;42(6):1364-72.
21. Kumar R, Shalimar, Bhatia V, et al. Antituberculosis therapy-induced
acute liver failure: magnitude, profile, prognosis, and predictors of
outcome. Hepatology. 2010;51(5):1665-74.
22. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators
of prognosis in acute liver failure liver. Gastroenterology.
1989;97(2):439-45.
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23. Shalimar, Sonila U, Kaur H, et al. Comparison of dynamic changes
among various prognostic scores in viral hepatitis-related acute
liver failure. Ann Hepatol. 2018;17(3):403-12.
24. Kumar R, Shalimar, Sharma H, et al. Prospective derivation and
validation of early dynamic model for predicting outcome in
patients with acute liver failure. Gut. 2012;61(7):1068-75.
25. Gustot T, Richard M. Acute-on-chronic liver failure Vs traditional
decompensation of cirrhosis. J Hepatol. 2018;69(6):1384-93.
26. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological
basis of therapeutic options. Blood Purif. 2002;20(3):252-61.
27. Sarin SK, Kedarisetty CK, Zaigham, et al. Acute-on-chronic
liver failure: consensus recommendations of the Asian Pacific
Association for the Study of the Liver (APASL) 2014. Hepatol Int.
2014;8(4):453-71.
28. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure
is a distinct syndrome that develops in patients with acute
decompensation of cirrhosis. Gastroenterology. 2013;144(7):
1426-37.
29. Shalimar, Kumar D, Vadiraja PK, et al. Acute-on-chronic liver failure
because of acute hepatic insults: etiologies, course, extrahepatic
organ failure and predictors of mortality. J Gastroenterol Hepatol.
2016;31(4):856-64.
30. Shalimar, Saraswat V, Singh SP, et al. Acute-on-chronic liver failure
in India: The Indian National Association for the Study of Liver
consortium experiences. J Gastroenterol Hepatol. 2016;31(10):1742-9.
31. Arroyo V, Moreau R, Jalan R. Acute-on-chronic-liver failure. New Eng
J Med. 2020;380:2137-45.
32. Shalimar, Sheikh ML, Mookerjee RP, et al. Prognostic role of
ammonia in patients with cirrhosis. Hepatology. 2019;70(3):980-94.
33. Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic
liver failure: consensus recommendation of the Asian Pacific
Association For the Study for Liver(APASSL);An update. Hepatol Int.
2019;13(4):353-90.
34. Jalan R, Saliba F, Paveshi M, et al. Development and validation of
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29-01-2021 14:58:16
 CHAPTER

135 Proton Pump Inhibitors—

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

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 872 SECTION 10 Gastroenterology

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., 2012 10

Decreased incidence
prophylaxis
PPIs have statistically proven benefit over placebo/H2RAs
GERD Pace et al., 200511 Decreased recurrence
in management of diseases associated with increased
acid production. The indications for PPI therapy, which
are approved by FDA include Gastroesophageal Reflux
patients without any maintenance therapy.11,12 Long-term
Disease (GERD), erosive esophagitis, peptic ulcer, NSAID-
administration of PPIs may also prevent transformation
induced ulcer (treatment and prophylaxis), Helicobacter
of Barrett’s esophagus to a neoplastic lesion.13 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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 Proton Pump Inhibitors—Long-term Use: Boon or Bane? CHAPTER 135 873

TABLE 2 Adverse effects of long-term use of PPIs

Gastric neuroendocrine tumor—Prolonged PPI
use leads to increased intra-gastric pH thereby causing
Side effect Study Inference increased plasma gastrin concentration, thus stimulating
SIBO Lo WK et al., 2013 22
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
Acute interstitial 31
Xie et al., 2016 Increased risk scarce.20 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.
Hypomagnesemia Park CH et al., 201433 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
37
due to PPIs leads to an increase in the microbial density
Bone fracture Nassar et al., 2018 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
Adverse effects of PPI based on their property of increased risk of SIBO in PPI users. Therefore, prolonged
TABLE 3 PPI administration is considered a risk factor for SIBO
acid inhibition or unrelated to it
(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.

MU-135.indd 873 29-01-2021 14:58:06

 874 SECTION 10 Gastroenterology
Atrophic gastritis—PPIs can alter the gastric mucosal
architecture and Li et al. found in a meta-analysis in 2017
that there was a higher presence of gastric atrophy in PPI
group compared to the control group.27
Respiratory
Pneumonia—PPIs increase gastric pH by suppressing
gastric acid release, promoting bacterial overgrowth which
in turn leads to colonization of trachea and pneumonia.
There is evidence to suggest that immune cell function
may also be impaired by PPIs, thereby augmenting the
risk of infectious complications.28 Wongtrakul et al. in their
recent meta-analysis concluded a significantly higher risk
of development of pneumonia in cirrhotic patients with
a history of PPI use than those without. Thus, prudent
use of PPIs in patients with definite indication may be
suggested.29
Renal
Acute interstitial nephritis—In patients on PPI treatment,
an allergic reaction to the drug may cause interstitial
nephritis.30 As many as 70% of acute interstitial nephritis
was reportedly related to drugs, of which 14% were caused
by PPIs in biopsy-proven cases.31
Chronic kidney disease—The mechanism by which
PPI use can lead to CKD is not well understood. One of the
mechanisms proposed is the acute interstitial nephritis
caused by PPI. Other postulated mechanisms include
lysosomal acidification hydrogen/potassium adenosine
triphosphatase enzyme system abnormalities, reduced
renal tubular cells regeneration, altered gene expression,
and elevated oxidative stress.32 Although, there is a need of
more data to ascertain this association, it is suggested that
the indication of initiation as well as continuation of PPIs
should be carefully assessed in patients with pre-existing
risk factors for CKD development.
Nutrient Absorption
Hypomagnesemia—One of the postulated mechanism for
hypomagnesemia related to PPI use is a reduction in the
affinity of magnesium to its transport receptors caused
by the pH change thereby decreasing the active transport
of magnesium across the intestinal lumen. Park et al., in
their meta-analysis, showed an increased incidence of
hypomagnesemia in PPI users.33
MU-135.indd 874
Vitamin B12—The acidic environment of the stomach
assists in the release of Vit. B12 bound with food and
subsequently helps its binding to intrinsic factor. Lam et al.
in 2013 found a 65% increased risk of B12 deficiency in PPI
users more than 2 years.34
Neurological
Dementia—Long-term PPI use inhibits beta and gamma
secretase, which may lead to an increase in the amyloid
beta peptide levels in the brain. Khan et al. in their
systematic review found lack of evidence pertaining to the
proposed suggestion of PPI use and an increased risk of
dementia.35 They recommended that PPI use should not
be curtailed because of concerns about dementia risk.
Drug Interactions
Anti-platelets—There is competitive inhibition of CYP2C19
to variable grades by PPIs, thus affecting the metabolism of
clopidogrel. Omeprazole is the most noteworthy inhibitor
of CYP2C19. The two meta-analyses done in this regard
found an increased rate of adverse cardiovascular events
in patients on simultaneous PPI-clopidogrel therapy.36
While the pharmacological interaction between these two
drugs is established beyond doubt, more data is required
to ascertain the clinical significance of this interaction.
Endocrine
Alteration in bone density—The bone health and increased
fracture susceptibility due to PPIs may be linked to
impaired calcium absorption (acid suppression leads
to decreased release of ionized calcium from insoluble
calcium salts) and hypergastrinemia. In a meta-analysis
conducted by Nassar et al. published in JBM in 2018 it was
found that long-term PPI use might increase the fracture
risk but has no significant alteration of bone mineral
density (BMD).37 Presently there is insufficient evidence to
recommend regular BMD monitoring of patients on PPIs.
Hematological
PPIs have their anti-inflammatory properties as they
can bind to neutrophils and can inhibit neutrophil
accumulation and release of ROS. However, long-term
use can also lead to neutropenia and thrombocytopenia.38
In general, the recognized theories are the immune-
29-01-2021 14:58:06
 Proton Pump Inhibitors—Long-term Use: Boon or Bane?
Flowchart 1: The algorithm for deprescribing PPIs
mediated and the toxic mechanism. Drug-induced
antibodies against circulating hemocytes form the basis of
immune mediated mechanism whereas the toxic
mechanism is due to direct toxicity of the drug to
hematopoietic cells.
All-cause Mortality
Xie et al., in their cohort study, demonstrated an increased
risk of all-cause mortality in association with PPI use.39
The speculated mechanism for this association was the
probable role of oxidative stress, heme oxygenase-1 and
accelerated senescence of human endothelial cells.
The Road Ahead
Presently, PPIs are among the most frequently prescribed
class of drugs and are often continued for duration way
beyond the indication. In view of this and with many
recent studies suggestive of systemic adverse effects of
MU-135.indd 875
CHAPTER 135 875
long-term PPI use, a lot of research is going on to formulate
a well-structured model to deprescribe PPIs.
Deprescribing PPIs
Patients on PPIs should be monitored for symptom
recurrence and symptoms should gradually be managed
with on-demand PPIs, stepping down to H2RA therapy,
other over-the-counter agents (e.g., calcium carbonate)
or nonpharmacologic approaches (weight loss, avoid
meals 2–3 hours before bed time, head end elevation,
avoid dietary triggers). Stepping down to H2RA involves
discontinuation or tapering of the PPI followed by
prescription of an H2RA. Any H2RA at any approved dose
and dosing interval can be used.40 Implementation of
deprescription guidelines (Flowchart 1) will encourage
clinicians to carefully evaluate the ongoing use of
medications and potentially reduce the negative effects of
polypharmacy.
29-01-2021 14:58:07
 876 SECTION 10 Gastroenterology
Conclusion
PPIs have a robust helpful impact when used correctly for
the standard indications. However, PPIs have also been
incriminated with multiple systemic side effects. Although
the evidence is limited for causality at present and this is an
area of active research, there is enough evidence to indicate
a tendency to develop adverse effects with long-term use of
PPIs. Optimal strategy at this time for PPI prescription is to
advise it to patients with clear indications, following of clear
deprescription strategies and avoidance of broad off-label
usage.
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4. Nehra AK, Alexander JA, Loftus CG, et al. Proton pump inhibitors:
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5. Batuwitage BT, Kingham JG, Morgan NE, et al. Inappropriate
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6. Barletta JF, Lat I, Micek ST, et al. Critical Care Pharmacotherapy
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7. Hongo M, Fujimoto K. Gastric Polyps Study Group. Incidence and
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8. Labenz J, Armstrong D, Zetterstrand S, et al. Clinical trial: factors
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9. Kinoshita Y, Kato M, Fujishiro M, et al. Efficacy and safety of
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pump inhibitor: the Japan-based EXTEND study. J Gastroenterol.
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10. Sugano K, Kinoshita Y, Miwa H, et al. Esomeprazole NSAID
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11. Pace F, Annese V, Prada A, et al. Rabeprazole is equivalent to
omeprazole in the treatment of erosive gastro-oesophageal
reflux disease: a randomised, double-blind, comparative study of
rabeprazole and omeprazole 20 mg in acute treatment of reflux
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therapy with rabeprazole. Digest Liver Dis. 2005;37(10):741-50.
12. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment
of oesophagitis: clinical and functional correlates and further
validation of the Los Angeles classification. Gut. 1999;45(2):172-80.
13. Singh S, Garg SK, Singh PP, et al. Acid-suppressive medications
and risk of oesophageal adenocarcinoma in patients with
Barrett’s oesophagus: a systematic review and meta-analysis. Gut.
2014;63(8):1229-37.
14. Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages
of long-term proton pump inhibitor use. J Neurogastroenterol
Motil. 2018;24(2):182-96.
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.
16. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile
infection with acid suppressing drugs and antibiotics: meta-
analysis. Am J Gastroenterol. 2012;107(7):1011-9.
17. Freedberg DE, Salmasian H, Friedman C, et al. Proton pump
inhibitors and risk for recurrent Clostridium difficile infection
among inpatients. Am J Gastroenterol. 2013;108(11):1794-801.
18. Seto CT, Jeraldo P, Orenstein R, et al. Prolonged use of a proton
pump inhibitor reduces microbial diversity: implications for
Clostridium difficile susceptibility. Microbiome. 2014;2(1):42.
19. Lundell L, Vieth M, Gibson F, et al. Systematic review: the effects of
long-term proton pump inhibitor use on serum gastrin levels and
gastric histology. Aliment Pharmacol Ther. 2015;42(6):649-63.
20. Olbe L, Carlsson E, Lindberg P. A proton-pump inhibitor expedition:
the case histories of omeprazole and esomeprazole. Nat Rev Drug
Discov. 2003;2(2):132-9.
21. Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors
alter the composition of the gut microbiota. Gut. 2016;65(5):749-56.
22. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small
intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol
Hepatol. 2013;11(5):483-90.
23. Hidaka H, Nakazawa T, Wang G, et al. Long-term administration
of PPI reduces treatment failures after esophageal variceal
band ligation: a randomized, controlled trial. J Gastroenterol.
2012;47(2):118-26.
24. Khan MA, Kamal S, Khan S, et al. Systematic review and meta-
analysis of the possible association between pharmacological
gastric acid suppression and spontaneous bacterial peritonitis. Eur
J Gastroenterol Hepatol. 2015;27(11):1327-36.
25. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis
and Helicobacter pylori infection in patients with reflux esophagitis
treated with omeprazole or fundoplication. N Engl J Med.
1996;334(16):1018-22.
26. Cahan MA, Balduf L, Colton K, et al. Proton pump inhibitors reduce
gallbladder function. Surg Endosc. 2006;20(9):1364-7.
27. Li Z, Wu C, Li L, et al. Effect of long-term proton pump inhibitor
administration on gastric mucosal atrophy: a meta-analysis. Saudi J
Gastreneterol. 2017;23(4):222-8.
28. Bateman BT, Bykov K, Choudhry NK, et al. Type of stress ulcer
prophylaxis and risk of nosocomial pneumonia in cardiac surgical
patients: cohort study. Version 2. BMJ. 2013;347:f5416.
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29. Wongtrakul W, Charoenngnam N, Ungprasert P. Use of proton
pump inhibitors is associated with a higher risk of pneumonia
in cirrhotic patients: a systematic review and meta-analysis. Ann
Gastroenterol. 2020;33(3):277-84.
30. Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial
nephritis secondary to proton pump inhibitors: experience from a
single UK renal unit. Nephrol Dial Transplant. 2004;19(6):1441-6.
31. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute
interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis.
2014;64(4):558-66.
32. Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users
of proton pump inhibitors without intervening acute kidney injury.
Kidney Int. 2017;91(6):1482-94.
33. Park CH, Kim EH, Roh YH, et al. The association between the use
of proton pump inhibitors and the risk of hypomagnesemia: a
systematic review and meta-analysis. PLoS One. 2014;9(11):e112558.
34. Lam JR, Schneider JL, Zhao W, et al. Proton pump inhibitor and
histamine 2 receptor antagonist use and vitamin B12 deficiency.
JAMA. 2013;310(22):2435-42.
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35. Khan MA, Yuan Y, Iqbal U, et al. No Association Linking Short-
Term Proton Pump Inhibitor Use to Dementia: Systematic Review
and Meta-analysis of Observational Studies. Am J Gastroenterol.
2020;115(5):671-8.
36. Niu Q, Wang Z, Zhang Y, et al. Combination use of clopidogrel and
proton pump inhibitors increases major adverse cardiovascular
events in patients with coronary artery disease: a meta-analysis. J
Cardiovasc Pharmacol Ther. 2017;22(2):142-52.
37. Nassar Y, Richter S. Proton-pump inhibitor use and fracture risk:
an updated systematic review and meta-analysis. J Bone Metab.
2018;25(3):141-51.
38. Yu Z, Hu J, Hu Y. Neutropenia and thrombocytopenia induced
by proton pump inhibitors: a case report. Drug Saf Case Rep.
2018;5(1):28.
39. Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump
inhibitors: a longitudinal observational cohort study of United
States veterans. BMJ Open. 2017;7(6):e015735.
40. Farrell B, Pottie K, Thompson W, et al. Deprescribing proton pump
inhibitors: evidence-based clinical practice guideline. Can Fam
Physician. 2017;63(5):354-64.
29-01-2021 14:58:07
 CHAPTER

136 Eosinophilic Esophagitis—

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

MU-136.indd 878 29-01-2021 14:57:57

 Eosinophilic Esophagitis—An Underdiagnosed Entity
12–23% of gastroscopy for dysphagia, and is seen to be
increasing over time.7
„„ Course: EoE is a chronic and progressive disease.
Earlier symptoms in children are due to inflammation
and later in life due to subepithelial collagen deposition
resulting in fibro stenotic EoE. Presence of strictures
was observed in 17% and 71% with less than 2 years
and 20 years of symptoms thus emphasizing the need
for early diagnosis.
„„ Temporal trends: From 9 to 12.8/100,000 over 3 years
in Ohio, USA, 0.35 to 9.5/100,000 in Minnesota,
USA, over 15 years, 1.2 to 7.4/100,000 in Switzerland
over 20 years indicating that there is an increasing
incidence. The reasons for increase will be discussed
in etiopathobiology in addition to awareness and
increasing mucosal biopsies.
Etiopathobiology (Fig. 1)
„„ Allergen and Hygiene Hypothesis: 8 The strength of
evidence stems from increased prevalence and
incidence in developed countries which have better
hygiene and association with most of the allergic
disorders in a significant proportion. Aero-allergen
exposure gains support by the increased incidence
in summer or fall. Increased prevalence is noted in
arid region, cold weather lacking vegetation, rural
low density populated regions. This requires further
research. Food elimination results in improvement of
EOE, and hence is considered a risk. Various reasons
mentioned stay unproven. Allergen/infection in an
Fig. 1: Etiopathobiology shows the mechanism due to acid reflux, genetic, cytokine induced mechanisms
MU-136.indd 879
CHAPTER 136 879
unprimed host living in virtual hygienic environment
initiate Th2 response over Th1 which is mild and
protective.
„„ Helicobacter pylori (H. pylori)/Proton Pump Inhibitor
(PPI) Hypothesis—Harmful or protective: Presence of
H. pylori polarizes the immune system toward a Th1
response and the lack of it leads to Th2 response. EoE
has a strong inverse relationship with H. pylori and
atopic disorders.9
—— PPI is hypothesized to increase upper gastro­
intestinal tract (GIT) permeability facilitating new
route of antigen entry;
—— use of PPI is associated with food specific IgE
antibodies.
—— P P I h a s s h o w n a n t i - i n f l a m m a t o r y / a n t i -
eosinophilic effects.
  Use of PPI has resulted in histological resolution of
inflammation and eosinophils in 30–40% making use
of PPI as a candidate trial drug. PPI thus can cause
EoE indirectly by removing the protective barrier
and eliminating H. pylori; paradoxically PPI heals
EoE by its anti-inflammatory and anti-eosinophilic
activity; conclusive evidence is required to say if PPI is
causative or curative.10-17
„„ Early Life Exposure Hypothesis/Environmental
Factor:18-23 EoE is associated with use of antibiotics in
children delivered by caesarean, less than 1 year of age,
premature babies, non-exclusively breast fed babies.
Establishment of esophageal microbiome would help
in understanding microbial dysbiosis as the cause.
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 880 SECTION 10 Gastroenterology
„„ Familial/Genetic Susceptibility: EoE is associated with
connective tissue and auto-immune disorders. 24,25
EoE has racial and gender bias, predominance in
white ancestry, inherited in non-Mendelian manner,
a sibling risk ratio of 80%; parents had history of
esophageal stricture and eosinophilic infiltrate in 10%
and 8% respectively.
The new genetic, molecular, cellular, animal, and
translational studies help to postulate a detailed pathway.
This shows how, exposure to allergens results in a complex
and coordinated type 2 inflammatory cascade. Delayed
intervention can result in odynophagia, esophageal
strictures, and food impaction.26
The genetics, epigenetics, and transcriptional analysis,
the role of cytokines, chemokines, and other molecules,
pathological and protective cells including commensal
bacteria are vividly described.26-28
Diagnosis
The diagnosis of EoE is made on the constellation of
clinical manifestations, endoscopic and histological
findings.
„„ Clinical: There is a distinct phenotypic variability
in symptomatology amongst people in early and
advanced disease. Esophageal dysfunction symptoms
include esophageal dysphagia in 60–100%, food
impaction in 25%, heart burn in 30–60%, atypical chest
pain in 8–44% and 1–8% of those with refractory reflux
symptoms.29 Dysphagia, refractory heart burn, and
mucosal disruption on intubation are the predominant
symptom/sign in advanced disease. Vomiting, food
rejection and growth retardation are also observed.30
Association of symptoms of atopy adds to the diagnosis.
„„ Endoscopic: Endoscopic Reference Scoring (EREFS)
(Table 1) classification as given by Hirano et al. has
scoring for visually observed endoscopy findings
TABLE 1 Endoscopic reference scoring
Variable Grade 0 Grade 1
Edema Distinct Vascularity Decreased Vascularity
Rings None Mild ridges
Exudate None Mild <10% of surface area
Furrows None Mild
Stricture Absent Present
MU-136.indd 880
like edema, rings, exudates, furrows, and strictures
graded separately at upper, middle, and lower third of
esophagus. The inflammatory signs edema, exudates,
and furrows had a sensitivity of 89%, 96%, 89%, and
specificity of 88%, 76%. and 90%, respectively and
correlated with eosinophilia. Composite inflammatory
score, the sum of maximum of inflammatory variables
namely edema, rings, and exudate excluding furrows
and stricture showed a superior correlation amongst
the diagnostic and post-treatment cohorts. 31,32
Schatzki’s ring is one of the endoscopic manifestations
of EoE.
„„ Histologic: Biopsy is mandatory in patients clinically
suspected to have EoE even if the esophageal mucosa
looks normal. Endosonography guided deeper
biopsies would provide more information. A meta-
analysis of EoE endoscopic findings in isolation have
poor sensitivity, specificity, and predictive value33 and
the sensitivity increases to 100% when 6–9 esophageal
mucosal biopsies are taken. 34,35 Presence of >15
eosinophils/hpf confirms the diagnosis of EoE.
Newer principles36 (Fig. 2):
„„ Removal of age cut-off
„„ Removing PPI from list of diagnostic criteria
„„ Evaluate for condition causing esophageal eosinophilia
rather than excluding them
„„ Criteria should be clinically operational
„„ Should be utilizable in patients in whom diagnosis was
made using earlier criteria, applicable clinically widely
and for future research
Newer tools:
„„Tetsuo Shoda et al.37 using EoE diagnostic panel (EDP)
and Consortium of Eosinophilic Disease Researchers
(CEGIR), Endoscopic Reference Scoring (EREFS)
and histologic scoring system (HSS) analyzed the
Grade 2 Grade 3
Absent Vascularity
Moderate/Distinct rings Severe—Cannot pass scope
Severe > 10% of surface area
Severe
29-01-2021 14:57:58
 Eosinophilic Esophagitis—An Underdiagnosed Entity
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
features. This study characterized three endotypes
namely EoEe1, EoEe2, and EoEe3 each with distinct
genetic, clinical, endoscopic and histological features
providing effective therapeutic intervention (Table 2).
Diagnostic criteria:
„„ Symptoms suggestive of esophageal dysfunction
„„ Presence of eosinophilic infiltrate (>15 e/hpf ) on
esophageal biopsy
„„ Exclusion of other disease like Gastro Esophageal
Reflux Disease (GERD) and Proton Pump Inhibitor
Responsive Esophageal Eosinophilia (PPI-REE) after 8
weeks PPI trial.
AGREE Conference36 2018 includes the following:
„„ Symptoms of esophageal dysfunction.
„„ Esophageal mucosal biopsies with eosinophils >15/
hpf (60 eosinophils/smm).
„„ Presence of exudates, grooves, rings, stenosis, luminal
narrowing, and crepe’ mucosa.
„„ Concomitant atopic conditions.
„„ Esophageal eosinophilic infiltration in isolation.
„„ Evaluation of potential contributors of esophageal
eosinophilia.
„„ Updated diagnostic algorithm36 (Fig. 3)
„„ Emerging diagnostic tools: Transnasal endoscopy,
Endoscopic functional lumen imaging probe (FLIP),
Cytosponge to obtain biopsy have sensitivity and
specificity of 75% and 86%, respectively, esophageal
string test and real time mucosal impedance
MU-136.indd 881
CHAPTER 136 881
measurements.38 Absolute eosinophil count (AEC) is
the single biomarker of relevance as on this date.27
Treatment
Treatment principles include elimination of potential
antigen, attenuation or elimination of antigen induced
allergic/immunogenic pathway induced inflammation
early in the disease using PPI and steroids and
to treat fibrostenotic complications of like strictures
endoscopically in advanced disease. 3D acronym for Diet,
Drugs, and Dilatation forms the basis of treatment of EoE.
Diet: Elimination diet: Elemental diet still is the most
effective strategy but associated with poor compliance. A
meta-analysis by Arias et al. observed efficacy of elemental
diet in 90.8%, six food elimination diet (SFED—cow milk,
wheat, egg, soy, peanut, and seafood) in 72.1% and allergy
testing directed elimination diet in 45.5% of cases. 39 A
novel 2-4-6 step up elimination diet strategy with each
elimination diet step lasting for 6 weeks observed 43%
remission in Two Food Elimination Diet (TFED Milk and
gluten containing diet), 60% in those receiving TFED
and four food elimination with addition of eggs and
legumes (FFED) and 79% with six food elimination diet
by additionally excluding nuts and seafood. This method
helped to identify possible food antigen and avoided
unnecessary food elimination.40
Drugs:
„„ Steroids: Dampening of EoE associated inflammation,
improving mucosal barrier function and histologic
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 882 SECTION 10 Gastroenterology

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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 Eosinophilic Esophagitis—An Underdiagnosed Entity CHAPTER 136 883

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

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 884 SECTION 10 Gastroenterology
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27. Kedia S, Baruah BJ, Makharia G, et al. Eosinophilic esophagitis. Trop
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30. Gómez-Aldana A, Jaramillo-Santos M, Delgado A, et al. Eosinophilic
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31. Wechsler JB, Bolton SM, Amsden K, et al. Eosinophilic esophagitis
reference score accurately identifies disease activity and treatment
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32. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the
oesophageal features of eosinophilic oesophagitis: validation of a
novel classification and grading system. Gut. 2013;62(4):489-95.
33. Kim HP, Vance RB, Shaheen NJ, et al. The prevalence and diagnostic
utility of endoscopic features of eosinophilic esophagitis: a meta-
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34. Saffari H, Peterson KA, Fang JC, et al. Patchy eosinophil distributions
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38. Nhu QM, Moawad FJ. New developments in the diagnosis
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39. Arias A, González-Cervera J, Tenias JM, et al. Efficacy of dietary
interventions for inducing histologic remission in patients with
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40. Molina-Infante J, Arias Á, Alcedo J, Garcia-Romero R, et al.
Step-up empiric elimination diet for pediatric and adult
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41. Blanchard C, Mingler MK, Vicario M, et al. IL-13 involvement in
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45. Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of proton pump
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 CHAPTER

137 Non-Cirrhotic Portal

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

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 Non-Cirrhotic Portal Hypertension in India CHAPTER 137 887

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

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 888 SECTION 10 Gastroenterology

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

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 Non-Cirrhotic Portal Hypertension in India
Pathology
EHPVO can be reliably diagnosed by USG; however, a
liver biopsy may be needed to differentiate early cirrhosis
and NCPF. The characteristic pathological findings for
NCPF by phlebosclerosis, periportal, and perisinusoidal
fibrosis, aberrant vessels in portal tract, preserved lobular
architecture, and “obliterative portal venopathy.”12 In cases
of EHPVO, the PV is replaced by cluster of varying sized
vessels more so around the hilum. Nodular arrangement
and fibrosis, which are characteristic of cirrhosis are
absent.
Natural History
The natural course of NCPF is usually much more
predictable as compared to the complexity seen in EHPVO
sometimes. A likely reason for this is the early insult in
life, which leads to a long time available for the disease
to progress insidiously. It may lead to short stature,
parenchymal destruction, poor quality of life, hepatic
encephalopathy, and portal biliopathy.
Once GI bleed is controlled after variceal eradication,
long-term prognosis in NCPF is excellent. Liver cell failure
and decompensation is usually absent but may occur
at times of GI bleed or in nodular NCPF.13 Uncontrolled
upper GI bleeding from varices may lead to mortality.
While the general outcome of EHPVO is good, certain
complications need to be monitored and treated carefully.
Growth retardation occurs in up to half of the children.
The postulated mechanism behind this is deprivation
of hepatotropic factors and malabsorption due to portal
hypertensive enteropathy.14 They also have a poor health-
related quality of life.
Portal biliopathy is defined as cholangiographic
abnormalities, which occur in patients with portal
cavernoma. This may be intrahepatic or extrahepatic. Long
standing portal cavernoma in the biliary region causes
compressive and ischemic changes on the biliary tree.
Portal biliopathy usually remains asymptomatic may lead
to jaundice, biliary colic, abdominal pain, and recurrent
cholangitis. Another dreaded complication is minimal
hepatic encephalopathy (MHE). It is understandably
more after shunt surgery but it may occur even prior to
surgery.15 Usage of lactulose improves MHE. Prolonged
portal biliopathy leads to extinction of liver parenchyma
gradually and may mimic cirrhosis later. It may manifest
MU-137.indd 889
CHAPTER 137 889
as poor synthetic function, jaundice, and decompensation
in the form of ascites.
Treatment
The event that can change the natural history of a patient
with NCPH is massive upper GI bleed. Control of the index
bleed and prevention of further bleed is the focus in most
cases. Another aspect of the treatment is symptomatic
splenomegaly and hypersplenism. Rest of the treatment
revolves around complications like MHE, portal biliopathy,
and growth failure.
Control and Prophylaxis of Variceal Bleed
Variceal bleed is an important complication in NCPH.
In view of limited data as compared to variceal bleed,
guidelines recommend the principles of management to
remain same.16 The patient should be resuscitated with
fluids and be taken up for endoscopy within 24 hours.
Endotherapy in the form of endovascular ligation is
the mainstay of therapy in terms of intervention. Older
studies used more of sclerotherapy. These techniques are
successful in more than 80% patients. Vasoactive agents
should be started prior to endotherapy to reduce the
severity of bleed and possibly control it. The goal should
be variceal eradication as role of beta blockers is not very
clear although they are widely used. Non-selective beta
blockers should be used for secondary prophylaxis.
Transjugular Intrahepatic Portosystemic
Shunt (TIPS)
TIPS is an option for treatment for complicated NCPH,
especially those with recurrent or refractory bleed.
However, it is best avoided in cases of renal dysfunction,
malignancy, or prothrombotic conditions.
Surgery
The most common indication for surgical management
is recurrent bleed or bleed refractory to endotherapy.
Other indications are symptomatic hypersplenism,
hepatopulmonar y syndrome, or portopulmonar y
hypertension.17 Surgery has now mainly been replaced by
TIPS. The types of surgeries performed are:
„„ Shunt procedures : They bypass blood from the
portal system to systemic circulation removing
the carvernoma from the pathway. Shunts may be
29-01-2021 14:57:51
 890 SECTION 10 Gastroenterology
physiological or non-physiological depending on
whether they preserve the hepatic portal blood flow
or not (maintained in physiological). As is expected,
surgery reduces complications of PHT like varix
size and spleen size; however, adverse effects from
portosystemic shunting include risk of MHE and shunt
nephropathy.18 Selective shunts like distal splenorenal
shunt are associated with less complication than
proximal, non-selective shunts. Shunt surgery is
undertaken only after a particular age (generally
8 years) and with a favorable anatomy (adequate
shuntable vein diameter).19
„„ Ablative procedures: These surgeries are very morbid
and include visceral devascularization with or without
splenectomy. It has gone out of vogue due to advances
in endotherapy and is reserved for emergency
scenarios.
Salvage Emergency Therapy
In spite of newer endoscopic modalities, in 10% of the
cases endotherapy fails. Options then include ablative
procedures, TIPS, or balloon occluded retrograde
transvenous obliteration.16,17
Routine anticoagulation is not recommended in
EHPVO or NCPF according to the current available
data. The management for portal biliopathy is generally
supportive and not curative. Biliary stenting is done using
ERCP for biliary strictures.20
Miscellaneous Causes of NCPH
Although infrequently seen in clinical practice, a few
important causes of NCPH that merit discussion have
been described here.
Schistosomiasis
Schistosomiasis is one of the most common causes of
NCPH in the world but rarely seen in India. Schistosoma
mansoni and Schistosoma japonicum are the two main
species of Schistosoma that are known to cause liver
disease. S. japonicum is distributed throughout the
world and S. mansoni is endemic to Africa and Middle
East. Both are however not found in India. The eggs are
stuck in the portal venules and lead to granulomatous
inflammation. Over a period, fibrosis occurs and portal
pressures increase. 21 Chronic hepatic schistosomiasis
MU-137.indd 890
is characterized by hepatomegaly with features of PHT.
Diagnosis is based on detection of eggs in stool or rectal
biopsy or ELISA test for antigen. On ultrasound, PV
radicles show echogenic thickening giving the appearance
of a mesh of fish scales. There may be complete reversal
of periportal thickening with use of antihelminthic like
praziquantel.
Congenital Hepatic Fibrosis
Congenital hepatic fibrosis (CHF) is a developmental
disorder of the portobiliary system characterized
histologically by defective remodeling of the ductal
plate and progressive fibrosis of the portal tracts.22 It is
usually autosomal recessive in inheritance and presents
in the first or second decade of life. Autosomal recessive
polycystic kidney disease and ciliopathies are commonly
associated disorders. 23 Clinical findings include an
enlarged, abnormally shaped liver and splenomegaly
with preserved liver functions. Biliary complications
include cholangitis and an increased predisposition to
cholangiocarcinoma. Imaging reveals dilatation of biliary
system and enlarged caudate lobe and splenomegaly.
Since no specific therapies are available, treatment of
complications and eventually liver transplant may be
needed.
Nodular Regenerative Hyperplasia
Nodular regenerative hyperplasia (NRH) is a characte­
rized by widespread benign transformation of hepatic
parenchyma into small regenerative nodules. It is
common in Europe and Japan with preponderance
amongst octogenarians. 24 There is a limitation of
population based studies on NRH. It can be caused by
various drugs (commonly chemotherapeutic agents and
immunosuppressants), hematological, autoimmune,
inflammatory, and neoplastic disorders. Pathogenesis
appears to be related to adaptive hyperplastic reaction
of hepatocytes in response to mechanical or functional
abnormalities of portal hepatic blood flow. Pathologically,
it is differentiated from cirrhosis by absence of perinuclear
collagen and fibrous septa. Most patients remain
asymptomatic, but some present with NCPH. Treatment
is aimed at removal of inciting factor and management of
primary disease.25
29-01-2021 14:57:51
 Non-Cirrhotic Portal Hypertension in India
Conclusion
NCPH are important causes of PHT in developing countries
like India. The most important disorders are NCPF in adults and
EHPVO in children. The complications if managed well, patients
can have a good prognosis and leave a healthy life.
References
1. Sarin SK, Kumar A. Noncirrhotic portal hypertension. Clin Liver Dis.
2006;10(3):627-51.
2. Sarin SK, Kumar A, Chawla YK, et al. Non-cirrhotic portal fibrosis/
idiopathic portal hypertension: APASL recommendations for
diagnosis and treatment. Hepatol Int. 2007;1(3):398-413.
3. Goel A, Ramakrishna B, Zachariah U, et al. What makes non-cirrhotic
portal hypertension a common disease in India? Analysis for
environmental factors. Indian J Med Res. 2019;149(4):468-78.
4. Khanna R, Sarin SK. Non-cirrhotic portal hypertension—diagnosis
and management. J Hepatol. 2014;60(2):421-41.
5. Poddar U, Thapa BR, Rao KN, et al. Etiological spectrum of
esophageal varices due to portal hypertension in Indian children:
is it different from the West? J Gastroenterol Hepatol. 2008;23(9):
1354-7.
6. Yadav S, Dutta AK, Sarin SK, et al. Do umbilical vein catheterization
and sepsis lead to portal vein thrombosis? A prospective, clinical,
and sonographic evaluation. J Pediatr Gastroenterol Nutr.
1993;17(4):392-6.
7. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin
Liver Dis. 2002;22(1):43-58.
8. Madhu K, Avinash B, Ramakrishna B, et al. Idiopathic non-cirrhotic
intrahepatic portal hypertension: common cause of cryptogenic
intrahepatic portal hypertension in a Southern Indian tertiary
hospital. Indian J Gastroenterol. 2009;28(3):83-7.
9. Bajaj JS, Bhattacharjee J, Sarin S-K, et al. Coagulation profile
and platelet function in patients with extrahepatic portal vein
obstruction and non-cirrhotic portal fibrosis. J Gastroenterol
Hepatol. 2001;16(6):641-6.
10. Sarin SK, Shahi HM, Jain M, et al. The natural history of portal
hypertensive gastropathy: influence of variceal eradication. Am J
Gastroenterol. 2000;95(10):2888-93.
11. Glatard A-S, Hillaire S, d’Assignies G, et al. Obliterative portal
venopathy: findings at CT imaging. Radiology. 2012;263(3):741-50.
MU-137.indd 891
CHAPTER 137 891
12. Hillaire S, Bonte E, Denninger M-H, et al. Idiopathic non-cirrhotic
intrahepatic portal hypertension in the West: a re-evaluation in 28
patients. Gut. 2002;51(2):275-80.
13. Sawada S, Sato Y, Aoyama H, et al. Pathological study of idiopathic
portal hypertension with an emphasis on cause of death based
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
leads to growth retardation. Hepatology. 1992;15(2):229-33.
15. Chandra R, Kapoor D, Tharakan A, et al. Portal biliopathy. J
Gastroenterol Hepatol. 2001;16(10):1086-92.
16. de Franchis R, Baveno VF. Revising consensus in portal hypertension:
report of the Baveno V consensus workshop on methodology
of diagnosis and therapy in portal hypertension. J Hepatol.
2010;53(4):762-8.
17. Sarin SK, Sollano JD, Chawla YK, et al. Consensus on extra-hepatic
portal vein obstruction. Liver Int. 2006;26(5):512-9.
18. Pal S, Radhakrishna P, Sahni P, et al. Prophylactic surgery in non-
cirrhotic portal fibrosis: is it worthwhile? Indian J Gastroenterol.
2005;24(6):239-42.
19. Mack CL, Zelko FA, Lokar J, et al. Surgically restoring portal blood
flow to the liver in children with primary extrahepatic portal
vein thrombosis improves fluid neurocognitive ability. Pediatrics.
2006;117(3):405-12.
20. Dhiman RK, Puri P, Chawla Y, et al. Biliary changes in extrahepatic
portal venous obstruction: compression by collaterals or ischemic?
Gastrointest Endosc. 1999;50(5):646-52.
21. Ross AGP, Bartley PB, Sleigh AC, et al. Schistosomiasis. N Engl J Med.
2002;346(16):1212-20.
22. Shorbagi A, Bayraktar Y. Experience of a single center with
congenital hepatic fibrosis: a review of the literature. World J
Gastroenterol. 2010;16(6):683-90.
23. Srinath A, Shneider BL. Congenital hepatic fibrosis and autosomal
recessive polycystic kidney disease. J Pediatr Gastroenterol Nutr.
2012;54(5):580-7.
24. Wanless IR. Micronodular transformation (nodular regenerative
hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies
and a new classification of benign hepatocellular nodules.
Hepatology. 1990;11(5):787-97.
25. Hartleb M, Gutkowski K, Milkiewicz P, et al. Nodular regenerative
hyperplasia: evolving concepts on underdiagnosed cause of portal
hypertension. World J Gastroenterol. 2011;17(11):1400-9.
29-01-2021 14:57:51
 CHAPTER

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
Drug-induced liver injury (DILI) is underdiagnosed
and underappreciated as a cause or contributor to liver
injury. Drugs and toxins should be considered in the
differential diagnosis of all types of liver injury across all
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
intrinsic risk or because older people take more drugs and
therefore have more opportunities to experience adverse
drug reactions (ADRs). This review will focus on recent
concepts on DILI with particular emphasis on DILI from
India.
DILI is a diagnosis of exclusion. A high degree of
suspicion and consequently a careful histor y of
prescription medication and over the counter drugs
(pain killers) exposure as well as exposure to herbal and
traditional medicines or dietary supplements (often
overlooked by the physician) should be obtained. While
most patients experience DILI within the first 2–3 months
of therapy, in some instances (e.g. amoxicillin-clavulanate
related DILI) symptoms can present with up to a month
delay after treatment cessation or arise after months of
exposure to a drug such as nitrofurantoin, minocycline,
and alpha methyldopa.1
Causality Assessment
Since DILI is a diagnosis of exclusion there are no
established diagnostic markers. Causality assessment
methods are used to determine likelihood of a drug
causing liver injury and the best known is the Roussel
Ucla f cau sa l i t y a ss e ss m e nt m e t h o d ( RU C A M ) . 2
Information on time to onset (latency), course of
reaction upon medication discontinuation, time to
resolution, risk factors, concomitant drugs exclusion of
other causes, prior knowledge on DILI potential, and
response to readministration are variables required to
establish a compatible relationship with the suspected

MU-138.indd 892 29-01-2021 14:57:44


causative agent. The degree of causality is assessed
as definite (highly probable), probable, possible, and
unlikely in descending order of strength.2
Case Definitions and Severity
Transient asymptomatic minor elevation of aspartate
transaminase (AST) or alanine transaminase (ALT)
is common during routine evaluation. In one study
incidence of baseline liver chemistry abnormalities in a
population of over 18,000 patients (without underlying
liver disease), the baseline prevalence of any ALT elevation
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
exposure to medication and may resolve on its own or
with continuation of drugs or following decrease in dose.
This phenomenon (called adaptation) is characteristic
of antituberculosis (anti-TB) drug or statin therapy
and depends on the frequency of liver biochemistry
estimation. Awareness of this condition will prevent
inappropriate withdrawal of medications such as in
the treatment of tuberculosis where even a temporary
cessation of treatment may have adverse disease outcome
including risk of drug resistance.4 Transient elevation of
transaminases in patients with elevated liver enzymes
while on statin therapy (e.g. in patients with coronary
heart disease or diabetes)5 is not an indication to stop
therapy.
DILI is defined as an adverse hepatic reaction that is
unexpected on the basis of the pharmacological action
of the drug administered. International expert panel 1
recommended DILI to be considered when any one of
the following thresholds are met even in the absence of
symptoms:
„„ ALT or AST ≥ 5 × ULN
„„ ALP ≥ 2 × ULN in the absence of extrahepatic source
driving the rise in ALP level
„„ Total bilirubin concentration exceeding 2 × ULN
associated with any elevation of the aminotransferases
or alkaline phosphatase.1
In the presence of symptoms including extrahepatic
symptoms of hypersensitivity such as skin rashes or
eosinophilia, ALT or AST ≥ 3 × ULN is deemed to be DILI.
The symptoms related to DILI are often similar to that
of acute liver injury or cholestasis due to other etiology
MU-138.indd 893
Drug-induced Liver Injury CHAPTER 138 893
including any of the following: fever, nausea, vomiting,
jaundice, dark urine, right upper quadrant pain, skin
rashes, and itching.1
The level of elevation of liver enzymes alone does not
reflect liver function severity. Liver enzyme elevation is a
reflection of liver injury not function, whereas bilirubin
elevation (liver excretory function), or increased INR or
decreased albumin (liver synthetic function) are more
accurate indices of liver function. 6 The presence of
jaundice, or development of ascites, coagulopathy, and/
or encephalopathy indicates severe disease1 and connotes
poor prognosis.7
Hyman Zimmerman observed the presence jaundice
in the setting of DILI suggested severe hepatocellular
functional impairment with potential for liver failure and
10–50% mortality.6,8 Thus, “Hy’s law” is used clinically
and during drug evaluation to indicate highly significant
and severe hepatotoxic potential of a drug when patients
fulfill the following criteria, that is, AST or ALT more than
3 × ULN + bilirubin >2 × ULN (in absence of biliary tract
disease).8 Presence of jaundice during anti-TB therapy
results in a mortality of 16–26% in India.7,9 Patients with
anti-TB DILI who fulfill Hy’s law criteria have a mortality
of 17%. Furthermore, development of acute liver failure
during treatment of anti-TB drugs results in a mortality in
two-thirds of patients.10 Paradoxically in the Indian setting
a substantial proportion of individuals who develop anti-
TB DILI, never required the drugs in the first place, having
received anti-TB drugs empirically on a presumptive
basis.10,11 Therefore, great caution should be exercised
while administering anti-TB drugs empirically, especially
in women, the elderly, and those with comorbidities.12
Patterns of Liver Injury
Most patients with DILI in clinical practice are
characterized based on their liver biochemistry, these
are categorized as hepatocellular, cholestatic, or mixed
pattern of DILI. 1 Pattern of liver disease is based on
Ratio (R value) of ALT (or AST) activity expressed as fold
elevation over its ULN laboratory range to ALP activity.
Pattern of DILI is hepatocellular when R is ≥5, cholestatic
when R is ≤2 and mixed when R is 2–5.1 The pattern of
liver injury has implications for prioritizing immediate
29-01-2021 14:57:44
 894 SECTION 10 Gastroenterology
investigations essential to exclude alternative causes of the
event as well as prognosticate outcome.
Examples of drugs associated with above patterns and
other additional patterns are listed below:13
„„ Hepatocellular: Isoniazid, rifampicin, pyrazinamide,
diclofenac, lamotrigine, minocycline, nitrofurantoin,
nevirapine, efavirenz, sulfonamides, disulfiram.
„„ Cholestatic: Chlorpromazine, erythromycin, peni­
cillins, amoxicillin-clavulanate, sulfonamide, terbina­
fine, androgens, oral contraceptives.
„„ Mixed pattern: Phenytoin, carbamazepine, lamotrigine,
sulfonamides.
„„ Drug reaction with eosinophilia and systemic symptoms
(DRESS): Carbamazepine, phenytoin, phenobarbitone,
allopurinol, lamotrigine, cephalosporins, dapsone,
sulfonamide, nevirapine.
„„ Autoimmune like hepatitis: Nitrofurantoin, α-methyl-
dopa, minocycline, diclofenac, statins, adalimumab,
infliximab, herbals and complimentary medicines.
„„ Nonalcoholic fatty liver disease (NAFLD): Amiodarone,
methotrexate, tamoxifen, 5-fluorouracil, amiodarone,
didanosine, stavudine.
„„ Va n i s h i n g b i l e d u c t ( d u c t o p e n i c) s y n d ro m e :
Azathioprine, amoxicillin-clavulanate, carbamazepine,
chlorpromazine, erythromycin, phenytoin, terbinafine
and cotrimoxazole.
Causes
Antibiotics are the most common cause of idiosyncratic
DILI and drug-induced acute liver failure worldwide and
also in India.7,9,13-16 In India, first-line combination anti-
TB drugs, isoniazid, rifampicin, and pyrazinamide are
the commonest agents causing DILI accounting for 46%
of all cases followed by complementary and alternative
medicines at 14%.9 Combination anti-TB drugs accounts
for 67–72% of cases of drug-induced acute liver failure
followed by anti-epileptic drugs (10%), and dapsone
(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-
TB DILI occur within the first 2 months of administration
of drugs although the risk of DILI persists throughout
the course of treatment.19 Paradoxically paracetamol-
induced DILI and liver failure is very uncommon in India
and accounts for less than 1% of DILI or drug-induced
ALF.9,18 This is in stark contrast to the high incidence of
MU-138.indd 894
paracetamol hepatotoxicity in western countries. In a
prospective India nationwide study,9 drugs causing DILI in
the descending order of frequency were as follows:
„„ Combination anti-TB drugs (46.4%)
„„ Complementary and alternative medicines (13.9%)
„„ Antiepileptic drugs (AED) (8.1%)
„„ Non-anti-TB antimicrobials (6.5%)
„„ Antimetabolites (3.8%)
„„ Antiretroviral drugs (3.5%)
„„ NSAIDs (2.6%)
„„ Hormones (2.5%)
„„ Statins (1.4%)
„„ Others (11.3%)
Although patients with pre-existing liver disease are
not more likely than others to experience hepatic injury
on exposure to drug, recovery from DILI in patients with
chronic liver disease is generally poor.20 Complementary
and alternative medicines (73%) and anti-TB drugs (22%)
are responsible for 99% of cases of drug-induced acute
on chronic liver failure (ACLF) in India and Asia and is
associated with 46% mortality, much more than other
causes of ACLF.21
Mechanism of Liver Injury
Simplistically, the mechanism of DILI may be divided
into two broad groups, that is, direct hepatotoxicity as
exemplified by paracetamol overdose or idiosyncratic
injury wherein the characteristics of the individual
patient/subject plays a major role in causing DILI.20 In
idiosyncratic reaction, the dose of a drug does not play
a role although most DILIs are encountered following
exposure to drugs used in daily dose of 50 gm or higher.22
Table 1 summarizes the characteristics of mechanism of
injury. A recently described third category is the indirect
hepatotoxicity, wherein hepatotoxicity is secondary to
the indirect action of agent on liver or immune system
(Table 1).23
Management
The first consideration in the management of DILI is to
harbor a high index of suspicion regarding the role of
medications in causing liver injury. The drugs implicated
should be stopped immediately and alternate causes
including viral hepatitis especially hepatitis E (which
is common in Northern India) 24 and biliary causes
29-01-2021 14:57:44

TABLE 1 Mechanism of drug-induced liver injury and associated features
Basis for injury Dose Incidence in
dependence humans
Direct (intrinsic) Yes Common
hepatotoxicity (1–100%)
Idiosyncratic No Rare
(unpredictable reaction) (1:10000)
Indirect hepatotoxicity No Intermediate
( by ultrasonography) should be excluded. Most
episodes of DILI resolve with discontinuance of the
culprit drug and with supportive treatment. There are
very few antidotes for specific drugs producing DILI.
These include N-acetylcysteine for paracetamol toxicity,25
desferrioxamine for ferrous sulfate toxicity, L-carnitine
for valproate DILI, and cholestyramine for leflunomide
DILI. Patients who develop hypersensitivity skin rashes
and eosinophilia or DRESS should be considered for
steroid treatment, which should be continued for 4–8
weeks, although steroids have not been evaluated in a
randomized fashion.26
Reintroduction of anti-TB drugs after an episode
of anti-TB DILI needs special mention. The American
Thoracic Society guidelines are the most up to date and
elaborate.27,28 Ethambutol has no hepatotoxic potential and
needs to be continued during and after DILI. Rifampicin is
the least hepatotoxic drug and needs to be considered
first followed by isoniazid and pyrazinamide. These drugs
may be administered sequentially with staggered doses. In
case of a severe DILI at index presentation, pyrazinamide
should be omitted during rechallenge.27
Conclusion
Anti-tuberculosis drugs are the most common cause of DILI
and drug-induced acute liver failure in India. DILI is a diagnosis
of exclusion. Awareness of the fact that drugs can mimic all
forms of liver disease is crucial in diagnosing DILI. Occurrence
of hepatocellular jaundice entails a mortality of >10%, and
hence the implicated drug should be stopped immediately.
There is emerging evidence of the increasing role of traditional
and complimentary medicines in causing DILI all over the world
including India.
MU-138.indd 895
Drug-induced Liver Injury CHAPTER 138 895
Latent period Implicated agents
Often short Paracetamol, ferrous sulfate, i.v. amiodarone,
IV methotrexate, aspirin, cancer chemotherapy
Often long INH, rifampicin, pyrazinamide amox-clavulinate,
and variable sulfonamides, cephalosporins
Delayed Steroids, anti-TNF, Anti-CD20, checkpoint inhibitors,
(months) protein kinase inhibitors
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to drugs—I. A novel method based on the conclusions of
international consensus meetings: application to drug-induced
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chemistry abnormalities in a clinical trial population without
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injury. Am J Respir Crit Care Med. 2012;186(4):387-8.
5. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated
liver enzymes are not at higher risk for statin hepatotoxicity.
Gastroenterology. 2004;126(5):1287-92.
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for detecting liver injury-past, present, and future. Clin Pharmacol
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7. Devarbhavi H, Dierkhising R, Kremers WK, et al. Single-center
experience with drug-induced liver injury from India: causes,
outcome, prognosis, and predictors of mortality. Am J Gastroenterol.
2010;105(11):2396-404.
8. Senior JR. How can ‘Hy’s law’ help the clinician? Pharmacoepidemiol
Drug Saf. 2006;15(4):235-9.
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drug-induced liver injury: etiology, clinical features, outcome and
prognostic markers in 1288 patients. J Clin Exp Hepatol. 2021. DOI
10.1016/j.jceh.2020.11.002.
10. Devarbhavi H, Dierkhising R, Kremers WK. Antituberculosis therapy
drug-induced liver injury and acute liver failure. Hepatology.
2010;52(2):798-9.
11. Kumar R, Bhatia V, Khanal S, et al. Antituberculosis therapy-induced
acute liver failure: magnitude, profile, prognosis, and predictors of
outcome. Hepatology. 2010;51(5):1665-74.
12. Devarbhavi H. Gender enigma: increased occurence of anti-
tuberculosis drug-induced liver injury and acute liver failure
in women despite tuberculosis being more common in men.
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13. Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver
injury. Nat Rev Dis Primers. 2019;5(1):58.
14. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and
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15. Rathi C, Pipaliya N, Patel R, et al. Drug induced liver injury at a
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failure in children and adults: results of a single-centre study of 128
patients. Liver Int. 2018;38(7):1322-9.
18. Devarbhavi H, Joseph T, Kumar NS, et al. Causes, clinical features,
and outcome of patients with drug-induced acute liver failure
from a nationwide prospective study of drug-induced liver injury.
Hepatology. 2019;70(s1):513-4.
19. Devarbhavi H, Singh R, Patil M, et al. Outcome and determinants of
mortality in 269 patients with combination anti-tuberculosis drug-
induced liver injury. J Gastroenterol Hepatol. 2013;28(1):161-7.
20. Zimmerman HJ. Hepatotoxicity: the Adverse Effects of Drugs and
Other Chemicals on the Liver, 2nd edition. Philadelphia: Lippincott;
1999.
MU-138.indd 896
21. Devarbhavi H, Choudhury AK, Sharma MK, et al. Drug-induced
acute-on-chronic liver failure in Asian patients. Am J Gastroenterol.
2019;114(9):929-37.
22. Lammert C, Einarsson S, Saha C, et al. Relationship between daily
dose of oral medications and idiosyncratic drug-induced liver
injury: search for signals. Hepatology. 2008;47(6):2003-9.
23. Hoofnagle JH, Bjornsson ES. Drug-induced liver injury—types and
phenotypes. N Engl J Med. 2019;381(3):264-73.
24. Sarda P, Sharma SK, Mohan A, et al. Role of acute viral hepatitis
as a confounding factor in antituberculosis treatment induced
hepatotoxicity. Indian J Med Res. 2009;129(1):64-7.
25. Tujios SR, Lee WM. Acute liver failure induced by idiosyncratic
reaction to drugs: challenges in diagnosis and therapy. Liver Int.
2018;38(1):6-14.
26. Devarbhavi H, Raj S. Drug-induced liver injury with skin reactions:
drugs and host risk factors, clinical phenotypes and prognosis. Liver
Int. 2018;4:14004.
27. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement:
hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care
Med. 2006;174(8):935-52.
28. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic
Society/Centers for Disease Control and Prevention/Infectious
Diseases Society of America Clinical Practice Guidelines: Treatment
of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):147-95.
29-01-2021 14:57:44
 CHAPTER

139 Achalasia Cardia—Diagnosis

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

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 898 SECTION 10 Gastroenterology

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

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 Achalasia Cardia—Diagnosis and Endoscopic Treatment CHAPTER 139 899

The contracted LES in AC does not open spontaneously
and is usually traversed with a gentle pressure with the
endoscope unlike neoplastic/fibrotic strictures. 6 The
esophageal mucosa is usually normal in AC but can
develop erythema and ulceration due to food stasis (stasis
esophagitis). Stasis predisposes to esophageal candidiasis.
Tertiary contractions may be noticed during endoscopy
due to spontaneous, simultaneous contractions of
esophageal smooth muscles. An esophageal epiphrenic
diverticulum (EED) (pulsion type pseudodiverticulum)
can be associated with AC, which makes endoscopic
therapy challenging but yet feasible.11
Laboratory Work Up
Complete blood count, serum creatinine, serum electro­
lytes, liver function tests, and thyroid profile can be done
as a part of work up for endoscopic/surgical myotomy,
which requires general anesthesia.
Imaging
T i m e d b a r i u m e s o p h a g o g r a m : Ti m e d b a r i u m
esophagogram is the imaging of choice in AC. 100–250
mL of barium (45% weight/volume) is swallowed by
the patient over 15–20 seconds and X-ray done at 1, 2,
and 5 minutes. 12 The height and width of the barium
column in esophagus is measured at 1, 2, and 5 minutes
which denotes the esophageal emptying. In AC, there is
delayed emptying of barium from the esophagus, tertiary
contractions and bird-beak appearance (Figs. 1A and B).
It is done in both pre- and post-treatment states in AC to
evaluate response to therapy. Hugely dilated esophagus or
megaesophagus (>7 cm) can be seen in late/long standing
cases of AC. Dilated, tortuous esophagus in late stage AC
is termed as sigmoid esophagus. Both mega-esophagus
and sigmoid esophagus denote decompensated disease,
which implies poor response to therapy. Esophageal
epiphanic diverticulum (EED) can rarely be found in
association with AC.12
Other imaging: Chest X-ray may be required in AC
to evaluate for aspiration pneumonia. Computed
tomography (CT) of chest could be helpful to rule out
pseudoachalasia. Endoscopic ultrasound (EUS) findings
of marked (>10 mm)/asymmetric lower esophageal wall
thickening suggest underlying malignancy.13
High resolution manometry (HRM) (Table 3): HRM is
superior to conventional esophageal manometry for
diagnosis and classification of AC with higher sensitivity
and reproducibility. AC can be classified into three subtypes
according to Chicago classification 3.0 (Table 3) (Fig. 2A).4
Type I AC represents later stage disease leading to dilated
atonic esophagus due to minimal esophageal muscle
activity. Type II AC is characterized by panesophageal
pressurization indicating simultaneous contraction
of esophageal muscles between upper and LES due
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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 900 SECTION 10 Gastroenterology
(Fig. 2B). Panesophageal pressurization indicates that
esophageal smooth muscle tone is still intact, and hence
type II AC represents early stage of disease. Type II AC is
the most common subtype of AC and most responsive
to PD. Type III AC is characterized by premature, spastic
High resolution manometry diagnostic criteria of
TABLE 3
achalasia cardia27
Integrated relaxation pressure (IRP) > upper limit of normal with
100% failed peristalsis
zz Type I: No contractility, no esophageal pressurization,
IRP >10 mm Hg
zz Type II : Panesophageal pressurization in ≥20% swallows,
IRP> 15 mm Hg
zz Type III: Premature contractions (distal latency <4.5 s) in ≥20%
swallows, Segmental esophageal pressurization, IRP>15 mm Hg
A B
C pressurization and high integrated relaxation pressure (>15 mm Hg)
MU-139.indd 900
contraction of the distal esophagus (Fig. 2C). Type III AC
is least common and least responsive to both endoscopic
and surgical therapy.2
Differential Diagnosis (Table 4)
The differential diagnoses of AC are GERD, pseudo­
achalasia, esophageal motility disorders, and mechanical
dysphagia.
Management
The goal of management of AC is symptomatic relief
of dysphagia and associated complications. Treatment
directed at underlying pathology is not available as
pathophysiology is poorly understood. Treatment of AC is
directed by AC subtypes and surgical risk of the patient.2
Mechanical disruptions of LES by PD, LHM, or POEM
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
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
with high surgical risk and/or limited life expectancy,
biochemical reduction of LES pressure can be attempted
(botulinum toxin ± pharmacotherapy). In this review we
shall discuss endoscopic treatment of AC (botulinum
toxin, PD, and POEM).
safe.16 Repeat injections can be done for patients in whom
surgical risk remains high even on follow-up but it can
lead to fibrosis precluding continued BT injections/other
endoscopic therapy. Hence, repeated BT injections should
be used in patients with high surgical risk and poor life
expectancy.17

Botulinum Toxin Pneumatic Dilatation

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

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 902 SECTION 10 Gastroenterology
the incisors and GEJ is noted along length of endoscope.
Endoscope is then withdrawn maintaining position of the
catheter. Rigiflex balloon is passed over the guide wire into
the stomach marking a tape in the dilating ballon catheter
corresponding to distance from incisors to GEJ (balloon
catheter working length 90 cm and diameter is 14 Fr).
Alternatively small amount of radiographic contrast can
be injected at the GEJ prior to placing catheter to mark
the GEJ. Balloon (length 10 cm) is then placed across the
GEJ under fluoroscopic guidance (by help of radiopaque
marks in the balloon catheter). Small volume of dilute
contrast can be used for radiographic visualization of
balloon. As the placement of balloon waist is confirmed
across GEJ, the balloon is gradually inflated with air to 10–
15 psi until the balloon waist disappears and maintained
for 1 minute (Fig. 3). Adequacy of dilatation confirmed by
waist obliteration, blood smearing of the balloon, chest
pain, and mucosal tear/widening of GEJ. Adverse events
are esophageal perforation (3–5%), hematoma formation,
diverticula formation. 21 Incidence of GERD post PD is
around 2–4%. Tachycardia, persistent chest pain more
than 4 hours should alert the endoscopist for possible
perforation. Contrast esophagogram should be done if
perforation is suspected based. Small perforations can be
managed conservatively with antibiotics and parenteral
nutrition whereas large perforations with free flow of
barium into mediastinum warrant urgent thoracotomy
and repair. Hence, patients with high surgical risk should
Fig. 3: Pneumatic dilatation in achalasia by Rigiflex balloon dilator.
The waist of the balloon is seen between the two crus of diaphragm
and radiopaque marks can be seen in the balloon catheter
MU-139.indd 902
not be subjected to PD.21 Age less than 40 years, chest pain,
type III achalasia, and pretreatment esophageal diameter
less than 4 cm are poor predictors of treatment success
with PD. Response rate for chest pain is around 50%.22
Based on available evidence (meta-analysis of three RCTs
and one large RCT), clinical efficacy of PD is comparable
with LHM although long-term durability (especially in
young males) was higher in LHM compared to PD as higher
proportion (24%) of patients had recurrent symptoms after
PD requiring redilatation compared to LHM (14%).23,24 PD
was compared with POEM in a recent RCT which showed
significantly higher success rate at 2 years follow-up with
POEM compared to PD (92% vs. 54%). This low response
rate in PD could be due to dilatation with only 30–35 mm
balloon and inclusion of 40 mm balloon would increase
response rate to 76% (Table 5).25
Per Oral Endoscopic Myotomy
POEM is a form of natural orifice transluminal endoscopic
surgery (NOTES), which uses submucosal endoscopy to
perform myotomy and is efficacious for both treatment
naive and treatment failure cases. The procedure is done
under general anesthesia with endotracheal intubation
and carbon dioxide insufflation.26 There are four steps
of POEM: mucosal incision, creation of submucosal
tunnel, myotomy, and closure of mucosal incision
(Fig. 4). Normal saline (10 mL) mixed with 0.3% indigo-
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
and longitudinal muscle fibers. Prior to closure, 20 mL
saline with 80 mg gentamicin is injected into the tunnel
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
clips at a distance of 5 mm applying first clip at the distal
end of the longitudinal incision (Fig. 4D). A water soluble
contrast esophagogram is done at postoperative day 1
(POD1) to exclude leak and ascertain smooth passage
of contrast into stomach. Routine CT most procedure is
not warranted. Patients, who tolerate oral diet and timed
barium esophagogram has shown no leak, can be started
on liquid diet on POD1, pureed diet on POD2 and regular
diet from POD4. Initial clinical success with POEM is
82–100% and intermediate term efficacy at 2 years is
78–91% at 2 years follow-up.27-29 The choice of anterior (1
o’clock) or posterior myotomy (5–6 o’clock) is operator
dependent and based on clinical scenario as there is equal
efficacy of both the approaches with shorter procedure
time in posterior approach. 30,31Adverse events can be
insufflation related (pneumoperitoneum: 16–30%, 8%
require decompression, pneumomediastinum: 8.7–11%,
2.7% require decompression, mediastinal emphysema:
4.9%, and subcutaneous emphysema: 21–36%), bleeding
(early or delayed) an mucosal perforation (2.6%). 32
Low/extra low flow CO 2 can reduce the incidence of
pneumoperitoneum (up to 10%). Tense capnoperitoneum
manifested by high end tidal CO 2 can be treated with
Veress needle. 33 Minor bleeding during dissection can
be controlled with coagrasper or electrocautery knife.
Significant delayed bleeding is rare (0.7%) and can be
tackled by reentering the tunnel and coagulating the
culprit vessel.34 Mucosal perforation can be closed with
clips ± endoloops, fibrin glue, suturing by overstitch device
or fully covered metal stent. The prevalence of increased
esophageal acid exposure, reflux esophagitis, and GERD
symptoms after POEM ranges from 13% to 58%, 18% to
65%, and 17% to 40%, respectively.35 Novel modifications
of POEM by addition of fundoplication (POEM-F) like in
LHM have been shown to reduce reflux in pilot studies.36
Anterior gastric wall is retracted at GEJ to form endoscopic
fundoplication wrap. Increased procedure time, cost,
and uncertain durability are the drawbacks of this novel
procedure. Preservation of sling fibers by identifying
two penetrating vessels at distal end of myotomy can
reduce degree of esophagitis.37 A short course of proton
pump inhibitor (PPI) for 1 month is recommended for all
patients and further continuation of therapy should be
based on pH metry, symptoms, and endoscopic finding of
esophagitis.2
POEM has been shown to be superior to PD and non-
inferior to LHM in two recent RCTs. It is emerging as one
of the first-line options to treat AC (Table 5).25,38 Results of
POEM are better than LHM, especially in type III achalasia
due to ability to perform long myotomy based on length of
spastic distal segment of esophagus.2 POEM is also better
than LHM in case of sigmoid esophagus and other spastic
motility disorders.39

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 904 SECTION 10 Gastroenterology

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

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 Achalasia Cardia—Diagnosis and Endoscopic Treatment
Flowchart 1: Diagnosis and management algorithm for achalasia cardia
Conclusion
Diagnosis of achalasia is based on clinical history and
investigations like endoscopy, timed barium esophagogram,
and HRM. Treatment of achalasia should be individualized
(Table 6) (Flowchart 1). Patients with high surgical risk should
undergo BT/pharmacotherapy. For patients with low surgical
risk options are PD, LHM with fundoplication, and POEM. In
young (<40 years), type I achalasia POEM/LHM should be the
first option of treatment as response rates to PD is low. In
type II AC, PD can be used as initial option along with POEM/
LHM as results to PD is best in type II AC. For type III AC, POEM
with extended myotomy is recommended. On failure of
therapy, any of the three modalities can be used as salvage
therapy but POEM is preferred in both prior endoscopic failure.
Esophagectomy should be reserved for end stage AC that is
surgically fit with leg standing symptoms after repeated failure
of different therapies.
MU-139.indd 905
CHAPTER 139 905
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clinically relevant classification by high-resolution manometry.
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11. Fisichella PM, Jalilvand A, Dobrowolsky A, et al. Achalasia and
epiphrenic diverticulum. World J Surg. 2015;39(7):1614-9.
12. Neyaz Z, Gupta M, Ghoshal UC, et al. How to perform and interpret
timed barium esophagogram. J Neurogastroenterol Motil.
2013;19(2):251-6.
13. Agrusa A, Romano G, Frazzetta G, et al. Achalasia Secondary to
Submucosal Invasion by Poorly Differentiated Adenocarcinoma of
the Cardia, Siewert II: Consideration on Preoperative Workup. Case
Rep Surg. 2014;2014:654917.
14. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric botulinum
toxin for the treatment of achalasia. N Engl J Med. 1995;332(12):
774-8.
15. Vela MF, Richter JE, Wachsberger D, et al. Complexities of managing
achalasia at a tertiary referral center: use of pneumatic dilatation,
heller myotomy, and botulinum toxin injection. Am J Gastroenterol.
2004;99(6):1029-36.
16. van Hoeij FB, Tack JF, Pandolfino JE, et al. Complications of
botulinum toxin injections for treatment of esophageal motility
disorders. Dis Esophagus. 2017;30(3):1-5.
17. Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus
pneumatic dilatation in the treatment of achalasia: a randomised
trial. Gut. 1999;44(2):231-9.
18. Kadakia SC, Wong RK. Graded pneumatic dilation using Rigiflex
achalasia dilators in patients with primary esophageal achalasia.
Am J Gastroenterol. 1993;88(1):34-8.
19. Farhoomand K, Connor JT, Richter JE, et al. Predictors of outcome
of pneumatic dilation in achalasia. Clin Gastroenterol Hepatol.
2004;2(5):389-94.
20. Ghoshal UC, Chaudhuri S, Pal BB, et al. Randomized controlled
trial of intrasphincteric botulinum toxin A injection versus
balloon dilatation in treatment of achalasia cardia. Dis Esophagus.
2001;14(3-4):227-31.
21. Eckardt VF, Kanzler G, Westermeier T, et al. Complications and their
impact after pneumatic dilation for achalasia: prospective long-
term follow-up study. Gastrointest Endosc. 1997;45(5):349-53.
22. Moonen A, Annese V, Belmans A, et al. Long-term results of the
European achalasia trial: a multicentre randomised controlled
trial comparing pneumatic dilation versus laparoscopic Heller
myotomy. Gut. 2016;65(5):732-9.
23. Yaghoobi M, Mayrand S, Martel M, et al. Laparoscopic Heller’s
myotomy versus pneumatic dilation in the treatment of idiopathic
achalasia: a meta-analysis of randomized, controlled trials.
Gastrointest Endosc. 2013;78(3):468-75.
MU-139.indd 906
24. Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic
dilation versus laparoscopic Heller’s myotomy for idiopathic
achalasia. N Engl J Med. 2011;364(19):1807-16.
25. Ponds FA, Fockens P, Lei A, et al. Effect of peroral endoscopic
myotomy vs pneumatic dilation on symptom severity and
treatment outcomes among treatment-naive patients with
achalasia: a randomized clinical trial. JAMA. 2019;322(2):134-44.
26. Darisetty S, Nabi Z, Ramchandani M, et al. Anesthesia in per-oral
endoscopic myotomy: a large tertiary care centre experience.
Indian J Gastroenterol. 2017;36(4):305-12.
27. NOSCAR POEM White Paper Committee; Stavropoulos SN, Desilets
DJ, et al. Per-oral endoscopic myotomy white paper summary.
Gastrointest Endosc. 2014;80(1):1-15.
28. Inoue H, Sato H, Ikeda H, et al. Per-oral endoscopic myotomy: a
series of 500 patients. J Am Coll Surg. 2015;221(2):256-64.
29. Werner YB, Costamagna G, Swanström LL, et al. Clinical response to
peroral endoscopic myotomy in patients with idiopathic achalasia
at a minimum follow-up of 2 years. Gut. 2016; 65:899.
30. Ramchandani M, Nabi Z, Reddy DN, et al. Outcomes of anterior
myotomy versus posterior myotomy during POEM: a randomized
pilot study. Endosc Int Open. 2018;6(2):190-8.
31. Mohan BP, Ofosu A, Chandan S, et al. Anterior versus posterior
approach in peroral endoscopic myotomy (POEM): a systematic
review and meta-analysis. Endoscopy. 2020;52(4):251-8.
32. Haito-Chavez Y, Inoue H, Beard KW, et al. Comprehensive analysis
of adverse events associated with per oral endoscopic myotomy
in 1826 patients: an International Multicenter Study. Am J
Gastroenterol. 2017;112(8):1267-76.
33. Ramchandani M, Reddy DN, Darisetty S, et al. Peroral endoscopic
myotomy for achalasia cardia: treatment analysis and follow up
of over 200 consecutive patients at a single center. Dig Endosc.
2016;28(1):19-26.
34. Li QL, Zhou PH, Yao LQ, et al. Early diagnosis and management
of delayed bleeding in the submucosal tunnel after peroral
endoscopic myotomy for achalasia (with video). Gastrointest
Endosc. 2013;78(2):370-4.
35. Repici A, Fuccio L, Maselli R, et al. GERD after per-oral endoscopic
myotomy as compared with Heller’s myotomy with fundoplication:
a systematic review with meta-analysis. Gastrointest Endosc.
2018;87(4):934-43.
36. Inoue H, Ueno A, Shimamura Y, et al. Peroral endoscopic myotomy
and fundoplication: a novel NOTES procedure. Endoscopy.
2019;51(2):161-4.
37. Tanaka S, Toyonaga T, Kawara F, et al. Novel per‐oral endoscopic
myotomy method preser ving oblique muscle using two
penetrating vessels as anatomic landmarks reduces postoperative
gastroesophageal reflux. J Gastroenterol Hepatol. 2019;34(12):2158-63.
38. Werner YB, Hakanson B, Martinek J, et al. Endoscopic or surgical
myotomy in patients with idiopathic achalasia. N Engl J Med.
2019;381(23):2219-29.
39. Ramchandani M, Pal P. Management of achalasia in 2020: per-oral
endoscopic myotomy, Heller’s or dilatation? Int J Gastrointest
Interv. 2020;9:53-61.
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 CHAPTER

140 Non-Variceal Upper GI Bleed—

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

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 908 SECTION 10 Gastroenterology
adjust to the blood loss and administration of crystalloid
intravenous fluid. Special attention should be paid to the
mean corpuscular volume (MCV), serum ferritin, total
iron binding capacity (TIBC), total leukocyte count (TLC),
platelet count, prothrombin time (INR). The blood urea
nitrogen (BUN) is usually higher than the serum creatinine
in upper GI bleed cases due to intestinal bacteria acting
on the blood proteins and increasing absorption of urea.
Elderly patients, especially those who are known cases of
cardiac ailment, need to have an ECG done.
Management
A case of upper GI bleed necessitates hospital admission, but
those patients having mild bleed, being hemodynamically
stable, near normal blood tests, with easy access to hospital
care may be treated on outpatient basis. On the other hand,
those patients who are hemodynamically unstable, have
lost a large amount of blood, are having serious associated
comorbidities need ICU admission.
Treatment of an upper GI bleed patient should start
along with the examination and history taking. Once
intravenous access has been established, crystalloids like
normal saline are the fluid of choice and attempt should
be made to keep the pulse below 100/min and the systolic
blood pressure above 100 mm Hg. Blood transfusion with
PRBC may be needed to keep Hb >7 g/dL.4 The hematocrit
level should be monitored every 4–8 hours. In cases of
severe acute upper GI bleed or in patients with altered
mental status, endotracheal intubation may be needed.
The advent of proton pump inhibitors (PPIs) has
revolutionized the management of non-variceal upper
GI bleed along with availability of endoscopic therapy.
But then there are cons of PPIs like no change in blood
transfusion requirements and no change in rebleeding
rates (except in cases of PUD).3
Role of Endoscopy
GI endoscopy has brought in major advantages in the
management of upper GI bleed, be it variceal or non-
variceal. Important points to note are:
„„ Patient must be hemodynamically stable with heart
rate of less than 100/min and systolic blood pressure
greater than 100 mm Hg.
„„ There must be no respiratory difficulty, altered
sensorium or ongoing hematemesis as these cases
might needs endotracheal intubation first.
MU-140.indd 908
„„ Correction of coagulopathy and decreased platelet
count is paramount.
„„ Emergency versus urgent endoscopy—those patients
who have active high volume bleed need to undergo
emergency endoscopy (within 6 hours) after medical
resuscitation and preferably after having access to an
ICU bed. Urgent endoscopy (within 12 hours) is suitable
for patients who do not have ongoing hemorrhage and
are hemodynamically stable.3
„„ Role of gastric lavage in upper GI bleed cases is
controversial as some societies do not approve of
it. However, in cases with large volume bleeding,
careful gastric lavage and prokinetic agents like
metoclopramide or er ythromycin can help in
endoscopic visualization.
„„ Around 1% of patients may experience complications
like aspiration pneumonia, inadvertent bleeding,
perforation, hypotension, hypoxia.
E n d o s c o p i c t e c h n i q u e s o f h e m o s t a s i s h av e
revolutionized the management of upper GI bleed.
Amongst these techniques are the contact probes of
which the multipolar electrocoagulation probe is the
most commonly used. It enables to tamponade a bleeding
vessel and then thermal energy is used to seal off the
offending vessel. Risks include perforation, coagulation
injury. Another useful technique is the use of endoscopic
injection therapy mostly done with epinephrine, diluted to
a concentration of 1:10,000 or 1:20,000 into or around the
site of bleeding. It is easily available, cheap, safe in patients
with coagulopathy, less chances of perforation or thermal
burns. Then there are the endoscopic hemoclips that apply
mechanical pressure to the bleeding site. Hemostatic
spray is a kind of inorganic powder with clotting abilities.
Risk Stratification
There are several stratification tools to help patients with
non-variceal upper GI bleed. These scores help identify
patients with higher risk of mortality and rebleeding. 5,6
It enables physicians to assess patients who need higher
medical care or urgent endoscopy. Amongst these scores,
the pre-endoscopy scores are:
„„ BLATCHFORD SCORE—includes blood pressure,
BUN, hemoglobin, heart rate, syncope, melena, liver
disease, heart failure
„„ CLINICAL ROCKALL SCORE—includes patient’s age,
presence of shock, coexisting illnesses
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 Non-Variceal Upper GI Bleed—Clinical Approach
„„ ARTIFICIAL NEURAL NETWORK SCORE- includes 21
variables to predict the presence of stigmata of recent
hemorrhage and the need for endoscopic therapy.
„„ AIMS65—agregate of five variables like albumin
<3 g/dL, INR >1.5, altered mental status, systolic BP
≤90 mm Hg, age >65 years.
Amongst the post-endoscopy scores, COMPLETE
ROCKALL SCORE is most popularly used. It includes the
Clinical Rockall Score and the endoscopic findings. This
scoring system correlates well with mortality but not with
risk of rebleeding.
Role of Surgery3
There are some situations where surgery plays an
important role in non-variceal upper GI bleed cases:
„„ Cases of severe and ongoing hemorrhage wherein
endoscopy and colonoscopy procedures fail to localize
the bleeding site and control it.
„„ Cases of massive hemorrhage who are hemo­
dynamically unstable need either an urgent angio­
graphy or urgent surgical exploration.
„„ Cases of severe, recurrent obscure GI bleed may
benefit from surgical exploration.
Individual Etiologies
We shall now address some special issues pertaining to
non-variceal upper GI bleed.
Peptic ulcer: With the advent of PPIs, it has been observed
that worldwide, incidence of bleeding peptic ulcers has
decreased whereas, bleeding from ulcers due to intake of
NSAIDs, aspirin have gradually increased. However, in the
developing countries it has been seen that the prevalence
of H. pylori infection is nearly 80% whereas, in the
developed countries it ranges between 20–50%. Amongst
the patients taking NSAIDs gastric ulcers tend to be more
common than duodenal ulcers. The Forrest classification7
is used in cases of bleeding peptic ulcers to categorize the
endoscopic findings:
Forrest 1A—active spurting bleed
Forrest 1B—oozing bleed
Forrest 2A—non bleeding visible vessel (NBVV)
Forrest 2B—adherent clot
Forrest2C—flat pigmented spot
Forrest 3—clean based ulcer
MU-140.indd 909
CHAPTER 140 909
Patients with active arterial, NBVV, adherent clot
are at high risk for rebleeding and would benefit from
endoscopic therapies. Adherent clot is defined as a blood
clot overlying an ulcer that is resistant to several minutes
of vigorous jet water irrigation. When a clean based ulcer is
found at the time of endoscopy, the chances of rebleeding
are less than 5%. However, if it is a clean-based ulcer in the
stomach, it is suggested that a biopsy of the ulcer edge and
the gastric mucosa should be taken to rule out malignancy.
In cases of gastric and duodenal ulcer suspected to be due
to H. pylori infection, endoscopic mucosal biopsies of the
normal looking antrum and greater curvature (midbody)
should be taken. The role of PPIs in reducing rebleedingin
peptic ulcer cases is more pronounced in people of
Asian origin than others. Luminal gastric pH needs to be
higher than 6.8 is needed for normal clotting function. H2
receptor antagonists can do this job but tolerance to this
drug is the major hindrance. In case of PPIs this problem
does not occur, thereby ensuring mortality benefit
especially in Asian patients.3
Routine second look endoscopy in bleeding peptic
ulcers is not always recommended 8 unless the first
examination was inadequate due to poor visualization,
technical issues with hemostasis or clinically significant
rebleeding has occurred. Repeat upper GI endoscopy
is advisable in cases of gastric ulcer after 6–10 weeks of
acid suppression therapy. Those patients who continue
bleeding despite two sessions of endoscopic hemostasis
are suitable for angiographic embolization or surgery.
Urgent surgery is advisable for those patients who have
massive hemorrhage, who cannot be resuscitated. Also, if
the endoscopic expertise is not available for treatment of
a large or pulsating visible vessel and if on endoscopy, a
bleeding malignant ulcerated mass is found, surgery is a
more suitable option.
Following endoscopic hemostasis of patients with
high-risk endoscopic stigmata (active arterial bleeding/
NBVV/adherent clot), patient should be put on high dose
intravenous PPI in a hospital setting. Drugs like NSAIDs,
warfarin should be withheld. Those patients who need
aspirin for cardiovascular illnesses may be started on the
drug by day 7.
It is recommended to test all cases of bleeding due to
peptic ulcer disease for H. pylori infection. Bleeding can
however cause false negative result of H. pylori. Antibiotic
therapy should be initiated for those found to be positive
29-01-2021 14:57:11
 910 SECTION 10 Gastroenterology
for H. pylori infection. It is important to confirm the
eradication of H. pylori once treatment is completed.3 In
cases of bleeding due to aspirin use, concomitant therapy
with a PPI in future can reduce the rebleeding rates
significantly. On the other hand, those patients who need
to continue NSAIDs long-term, need to opt for selective
COX2 inhibitors.
Esophagitis : Esophagitis may be caused due to
gastroesophageal reflux disease (GERD), infections like
Candida, Herpes simplex virus, Cytomegalovirus and also
pill induced esophagitis,ultimately leading to upper GI
bleed. GERD causing esophagitis and upper GI bleed is
treated with a PPI for a period of at least 8–12 weeks along
with lifestyle modifications. It is essential that these cases
need to undergo a repeat endoscopy and biopsy to rule out
Barrett’s esophagus. For all the rest etiologies, endoscopic
biopsy/brushing is taken and treatment is done according
to etiology.9
Ulcer hemorrhage in hospitalised patients: There are two
types of conditions usually seen in cases presenting with
ulcer hemorrhage within the hospital—Stress Related
Mucosal Injury/Stress Ulcer(SRMI) and Inpatient Ulcers.
SRMI is characterized by diffuse bleeding from erosions
and superficial ulcers, usually due to decreased mucosal
protection and mucosal ischemia. It is most commonly
seen in the stomach, and the most common risk factors
are severe coagulopathy and mechanical ventilation for
more than 48 hours. Prophylactic treatment with an H2
receptor antagonist or PPI can prevent bleeding in cases
who are at high risk for SRMI. In those cases who present
with UGI bleed, whether it is due to SRMI or inpatient
ulcers, good medical treatment can help heal the lesions.
Endoscopic therapy is feasible only in focal inpatient ulcer
hemorrhage.10
Dieulafoy’s lesion: This lesion comprises of a large
submucosal artery that protrudes through the mucosa
and can cause massive bleeding. Most commonly, such
lesions occur in the gastric fundus, within 6 cm of the
gastroesophageal junction. Whenever such a lesion is
identified and treated endoscopically, it is suggested to
mark the site with submucosal injection of ink for future
need of easy identification and retreatment.3
Mallory-Weiss tears: This is characterized by mucosal or
submucosal lacerations that start at the gastroesophageal
junction and extend to a hiatus hernia sac distally.
MU-140.indd 910
Usually the patients with Mallory-Weiss tear, present with
non-bloody vomiting that is followed by hematemesis,
probably due to raised intra-abdominal pressure. This
lesion usually self heals but in cases with severe bleeding,
endoscopic hemostasis may be attempted with hemoclips
or multipolar electrocoagulation.3
Cameron’s lesion: This lesion is described as linear
erosions or ulcerations in the proximal stomach at the end
of a hiatus hernia sac, near the diaphragmatic pinch due
to mechanical trauma and local ischemia. It is a common
cause of obscure GI bleed. Medical management is done
with PPI and Iron supplements if needed.3
Neoplastic etiology: Tumors of the upper GI tract, mostly
esophagus, stomach, or duodenum that are large,
ulceroproliferative masses can present with upper GI
bleed. Endoscopic hemostases is a temporary measure till
the definitive management can be initiated. Those tumors
that continue to bleed despite endoscopic hemostases
need to undergo angiography with embolization. Wherever
possible, GIST tumors should undergo resection.3
Gastric antral vascular ectasia (GAVE): This type of
lesion is characterized by rows of ecstatic mucosal blood
vessels that start from around the pylorus and extend
proximally to the antrum. Also called “Watermelon
Stomach”, the exact cause of this lesion is not known, but
may be due to mucosal trauma from contraction waves
in the antrum. It has been found to be associated with
cirrhosis, scleroderma, end stage renal disease. GAVE is
targeted with endoscopic hemostatic methods like laser,
MPEC, argon plasma coagulation. Besides these, medical
management of anemia like iron supplements, blood
transfusion may be needed.
Portal hypertensive gastropathy: This comprises of ectatic
blood vessels in the proximal gastric body, cardia due
to increased portal venous pressure and severe mucosal
hyperemia. Management options are with beta-blockers,
TIPS, liver transplantation. Endoscopic management does
not have much role.
Hemobilia: Patients of hemobilia present with upper GI
bleed and deranged liver function tests. It may occur as
a complication in cases of liver biopsy, ERCP, TIPS or
those who are suffering from hepatocellular carcinoma
or parasitic infection of the hepatobiliary system. Side
viewing endoscopy (SVE) is needed for diagnosis and
29-01-2021 14:57:11
 Non-Variceal Upper GI Bleed—Clinical Approach
arterial embolization with arteriography may be used for
treatment.
Hemosuccus pancreaticus: This kind of lesion is associated
with pancreatic pathology or as a complication of ERCP
or due to rupture of splenic artery aneurysm into the
pancreatic duct. SVE is needed for diagnosis while
angiographic embolization or surgery is needed for
treatment purposes.
Aortoenteric fistula: This is a condition wherein patient
presents with acute and massive hemorrhage with very
high mortality rates. In some cases, there might be a herald
bleed that may precede. Primary aortoenteric fistula is
the communication between native abdominal aorta and
third part of duodenum. Secondary aortoenteric fistula
is a communication between the small intestine (most
commonly, third part of duodenum) and an infected
abdominal aortic surgical graft. In both the cases, surgery
plays the more important role in management, and
endoscopic hemostasis has no role.
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
CHAPTER 140 911
References
1. Lanas A, Dumonceau JM, Hunt RH, et al. Non-variceal upper
gastrointestinal bleeding. Nat Rev Dis Primers. 2018;4:18020.
2. CB Ferguson, RM Mitchell. Non-variceal upper gastrointestinal
bleeding. Ulster Med J. 2006;75(1):32-9.
3. Savides TJ, Jensen DM. Sleisenger & Fordtran’s Gastrointestinal and
Liver Disease Tenth edition. Gastrointestinal Bleeding ;pg 297-335.
4. Kim SY, Hyun JJ, Lee SW, et al. Management of non-variceal upper
gastrointestinal bleeding. Clin Endosc. 2012;45(3):220-3.
5. Garmin AN, Bardou M, Kuipers EJ, et al. International consensus
recommendations on the management of patients with
nonvariceal upper gastrointestinal bleeding. Ann Intern Med.
2010;152(2):101-13.
6. Tham J, Stanley A. Clinical utility of pre-endoscopy risk scores in
upper gastrointestinal bleeding. Expert Rev Gastroenterol Hepatol.
2019;13(12):1161-7.
7. Forrest JA, Finlayson ND, Sherman DJ, et al. Endoscopy in
gastrointestinal bleeding. Lancet. 1974;2(7877):394-7.
8. Imperials TF, Kong N. Second-look endoscopy for bleeding peptic
ulcer disease: a decision-effectiveness and cost-effectiveness
analysis. J Clin Gastroenterology. 2012;46(9):71-5.
9. Antunes C, Sharma A. Esophagitis. In: StatPearls. 2020.
10. Spirt MJ. Stress-related mucosal disease. Curr Treat Options
Gastroenterol. 2003;6(2):135-45.
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 CHAPTER

141 Recent Updates in

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:

Ir r itable b ow el syndrome (IB S) is a functional
gastrointestinal (GI) disorder characterized by chronic
abdominal pain and altered bowel habits, which are
unexplained by any organic cause during routine workup.1
It is not a disease, but a complex of symptoms arising
out of pathologies of diverse clinical significance. IBS
is a global problem with prevalence ranging anywhere
from 1% to 45% of the general population having
symptom complex satisfying the diagnostic criteria of
IBS.2,3
More than one third of patients in GI practice have
functional GI disorders (FGID) and of all the FGIDs,
IBS accounts for the most common diagnosis. 4 The
documented prevalence of IBS in Asians ranges from
4% to 9% depending on the criteria used.5-7 IBS is twice
as prevalent in women as compared to men globally.8
However, there is no sex predilection in South Asia, South
America, and Africa.9 IBS significantly affects the quality
of life and imposes a large burden to the patient and the
health-care system.
Something New Something Borrowed
Manning and Thompson in 1978 introduced the concept
of making positive diagnosis of IBS using a set of criteria,10
which led to an exemplar shift in the diagnostic approach
in patients with IBS.
This was followed by Rome I, Rome II, and Rome
III criteria pertaining to the origin of newer scientific
evidences.
The Asian consensus 11 was published in 2010
considering the differences in dietary habits and
st o o l f re q u e n c y p att e r n s i n A s i a n s, w h i c h wa s
different from the cr iter ia used to define stool
frequency and stool form as they were based on the
Western studies.
Rome IV criteria were published in 2016,12 a decade after
Rome III was introduced. Rome IV criteria emphasized on
the gut brain interaction rather than the older concept of
psychogenic predominant pathogenesis of IBS.
As per the Rome IV criteria IBS is defined as—Recurrent
abdominal pain on average at least 1day/week in the last

MU-141.indd 912 29-01-2021 14:57:06


3 months, associated with two or more of the following
criteria:*
„„ Related to defecation
„„ Associated with change in frequency of stool
„„ Associated with change in form (appearance) of stool
*Criteria fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis.
Following changes are notable in Rome IV as compared
to ROME III:
„„ Term abdominal discomfort has been deleted
considering the dubious nature of the term and also
that it is not present in every language.
„„ Abdominal pain to be present on at least 1 day/week
based on scientific evidence13
„„ Bloating and distention are recognized as common
symptoms
„„ Improvement with defecation has been replaced with
related to defecation as it has been
„„ Found that many patients report increase in pain with
defecation
ROME III Criteria: At least 3 months, with onset at least
6 months previously of recurrent (at least 3 days/month)
abdominal pain or discomfort associated with two or more
of the following:
„„ Improvement with defecation
„„ Onset associated with a change in frequency of stool
„„ Onset associated with a change in form of stool
ASIAN Consensus: Recurrent abdominal pain, bloating,
or other discomfort for ≥3 months associated with one or
more of the following:
„„ Relief with defecation
„„ Change in stool form (show patient the Bristol Stool
Scale)
„„ Change in stool frequency
ROME IV Criteria: Recurrent abdominal pain on average
at least 1 day/week in the last 3 months, associated with
two or more of the following criteria:*
„„ Related to defecation
„„ Associated with change in frequency of stool
„„ Associated with change in form (appearance) of stool
*Criteria fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis.
Rome IV also mentions about the location of pain,
which can be present anywhere in the abdomen in
contrast to the older criteria which considered lower
abdominal pain as consistent with IBS.14
MU-141.indd 913
Recent Updates in Management of IBS CHAPTER 141 913
In context to Asian population, a Chinese study
compared the diagnosis of IBS using the Rome III criteria
as well as Rome IV criteria and showed lower sensitivity
of Rome IV as compared to Rome III in Asian population
and concluded that Rome IV positive patients were
subgroup of Rome III with more severe manifestations of
the disease.15
Rome IV also recognizes overlap syndrome amongst
various FGIDs as observed in various studies.16-18 This is an
important step based on scientific evidence as it will help
the clinicians to diagnose and manage such patients.
In 2019, Second Asian consensus on IBS 19 was
published representing the current knowledge and
management protocols in context to Asian population.
The consensus emphasized that IBS is a disorder of
Gut brain interaction rather than predominantly the
psychopathological phenomenon. The consensus also
encouraged the treatment based on micro-organic
pathology.
Subtyping and Assessing the Severity of
IBS: The Concept of Multidimensional
Clinical Profile
The concept of multidimensional clinical profile was
introduced to categorize patients on the basis of the
severity of their symptoms along with psychological
evaluation and physiological dysfunction (Table 1). This
helps the physicians to address other issues apart from
only the categorical diagnosis.
Severity assessment helps physicians to rationally
approach any patient, and necessitate the aggressive
management of patients with severe symptoms. Various
scales have been used to assess the severity of IBS, but
none have been accepted till date.
Multidimensional clinical profile also emphasizes
on the micro-organic basis of IBS such as abnormal gut
transit, post-infectious IBS, low-grade inflammation,
gut dysbiosis, dietary intolerance, abnormal intestinal
permeability, and central as well as peripheral nervous
dysregulation (Flowchart 1).
Subtyping of IBS is essential as it helps in defining
the targeted therapy and those with mixed type
and unclassified types need modifications of the
pathophysiological process such as alteration of Gut
microbiota or neurohumoral regulation.
29-01-2021 14:57:06
 914 SECTION 10 Gastroenterology

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

zz Stool softener zz Sodium picosulfate

„„ Psychosocial modifier
zz Bisacodyl
„„ Physiological dysfunction and biomarkers
Diarrhea Loperamide zz 5HT3 antagonist
(alosetron)
Treatment zz Bile acid sequestrant

(cholestyramine)
An incorporative approach including patient education,
zz Rifaximin
cognitive behavioral therapy, diet, and lifestyle zz Clonidine
modification are required for the management of IBS.
Pain zz Antispasmodic zz Tricyclic anti­
This usually needs an involvement of the dietician and
(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
zz TCA
individual symptoms; however, the newer therapies are
zz SSRI
based on altering the micro-organic pathophysiology.

MU-141.indd 914 29-01-2021 14:57:06


Flowchart 1: Diagnostic algorithm and management of IBS
Newer Therapies for IBS
Lumen Directed Therapy: Targeting the Low
Grade Inflammation Dysbiosis and Intestinal
Permeability
Nonabsorbable Antibiotics
Multiple case control studies from around the globe have
inferred microbial dysbiosis in patients with IBS.21 Thus,
use of non-absorbable antibiotics for management of IBS
was suggested.
Neomycin was initially used in patients with IBS;
however, the use was limited due to adverse effects.
MU-141.indd 915
Recent Updates in Management of IBS CHAPTER 141 915
Rifaximin was tested initially in small scale trials in
patients with IBS.22,23 Subsequently, in a large randomized
trial,24 positive effects were found in 8–10% patients of IBS
who did not have constipation. This effect was present
during the 10 weeks of follow-up; however, the effect
gradually decreased thereafter. Therefore in another
retreatment trial25 repeat administration of rifaximin was
assessed and it was found that retreatment was efficacious
as in naïve patients without the concern of antibiotic
resistance.
Rifaximin has pleiotropic effects on the gut apart from
managing the gut dysbiosis. Variable effects include anti-
inflammatory effects, restoring the gut barrier function
29-01-2021 14:57:07
 916 SECTION 10 Gastroenterology
and effects on visceral hyperalgesia through unknown
mechanisms.
Pre-Probiotics and Synbiotics
Probiotics are live microorganism, which when consumed
in prescribed amounts confer multiple health benefits.
The available data26 exhibit an overall positive effect of pre-
probiotics on the symptoms of IBS; however, comparative
analysis of the bacterial species is lacking.
Probiotics affect the luminal dysbiosis, low grade
inflammation, and helps restoring the mucosal integrity in
patients with IBS. Apart from the direct effects, probiotics
also indirectly modulate the gut-brain interaction.27,28
Synbiotics are combinations of pre- and probiotics
with synergistic actions. Synbiotics are hypothesized to
be beneficial in IBS; however, results are inconsistent and
data is sparse.
Fecal Microbiota Transplant (FMT)
Alteration in gut microbiota is one of the proposed
m e c ha n i s m s i n t h e p at h o g e n e s i s o f I B S. Fe ca l
microbiota has been efficacious in treating patients with
pseudomembranous colitis with great success. Hence,
its role in other luminal as well as non-luminal disorders
has been hypothesized. So far many small case series and
randomized trials have been published and have assessed
IBS severity score as the outcome measure. However, the
results were conflicting.
Sahly et al. 29 in 2020 published a double blind
randomized controlled trial assessing the efficacy of single
donor FMT in 30 gm and 60 gm doses as compared to
placebo and found significant response (89.1% vs. 23.6%
p<0.0001) in reduction in IBS symptoms. However, mild
self limiting GI symptoms after FMT need a word of
caution.
Mast Cell Stabilizer and Other
Anti-inflammatory Drugs
Low grade inflammation in the gut as well as presence of
inflammatory cells especially lymphocytes and mast cells
have been found in patients with IBS and are considered
as one of the microbiologic change.
Mesalazine, used as an anti-inflammatory drug in IBD
was found to have no role in patients with IBS.30,31
Mast cells being predominant inflammatory cells are
one of the targets for recent therapies of IBS. Mast cells are
MU-141.indd 916
also involved in pathogenesis of visceral hypersensitivity in
patients with IBS.32 Mast cell stabilizer ketotifen was found
to increase the discomfort threshold to rectal distension in
patients with IBS and had significant effects on abdominal
pain and QOL.33 This effects was hypothesized due to H1
receptor antagonism of ketotifen, which is a secondary
action. Another H1 receptor antagonist, Ebastine, was also
found to significantly decrease abdominal pain over a 12-
week treatment period.34
Dietary Modifications
Worsening of symptoms has been reported by many patients
after ingestion of certain foods. It has been postulated that
food acts through various mechanisms including osmotic,
chemical, mechanical and neuroendocrine effects. These
pathologic mechanisms can potentiate the already present
microbiologic pathology present in the gut. It has also
been found that food material containing incompletely
digestible carbohydrates, fats, and high caloric diet are
incompletely absorbed in the small intestine and are a
cause of significant bloating and abdominal discomfort
due to fermentation by the gut microbiota. Thus, current
recommendations evaluate patients after modifying
intake of such food as well as alcohol, caffeine, milk, or any
lactulose containing diet.
If these recommendations are cashed on improving
symptoms the FODMAP diet (Fig. 1)35 eliminating foods
containing fermentable oligosaccharides, disaccharides,
monosachharides, and polyols are adviced.19
Food eliminating Gluten has also been advocated
in non-celiac IBS patients on the basis of evidence of
decrease in intestinal inflammation and mucosal injury
on gluten free diet.
Therapeutic Updates on Constipation
Predominant IBS
Guanylate Cyclase C Agonist
The stimulation of enterocyte guanylate cyclase c (GCC)
receptors activates the apical CFTR that leads to water
secretion by the gut mucosa.36 Linaclotide is an orally
administered 14 amino acid containing peptide that
acts as an agonist of GCC. In a dose dependent manner
linaclotide softens the stools and also improves symptoms
of abdominal pain, bloating, and discomfort.
29-01-2021 14:57:07

Fig. 1: Low foodmap diet
290 µg daily was shown to improve stool frequency
and ease of defecation.37,38 The most common side effect
is diarrhea, which can be managed by reducing the dose.
Plecanatide is another 16 amino acid GCC agonist
approved for management of chronic constipation and
recently FDA approved for IBS-C.
Lubiprostone
It is a fat soluble molecule that activates type 2 chloride
channels in the enterocytes releasing more water into the
intestinal lumen increasing water content of the stool. At
a dose of 8 µg twice daily lubiprostone has shown efficacy
in reduction of symptoms and stool consistency.39 Most
common side effects are nausea and diarrhea.
5-HT4 Agonists
Activation of 5-HT4 enhances the gut motility by amplifying
the release of acetylcholine from nerve endings.
MU-141.indd 917
Recent Updates in Management of IBS CHAPTER 141 917
5-HT4 agonist Tegaserod was shown to be efficacious
in management of IBS-c; however, it was withdrawn owing
to potential cardiovascular risks.40,41
A novel 5-HT 4 receptor agonist Prucalopride has
been approved for treatment of chronic constipation and
has been evaluated in IBS-C considering the anecdotal
reports of improvement in bloating, abdominal pain, and
discomfort in the trials for constipation.42
Ghrelin Receptor Agonists
Ghrelin is a gut hormone involved in appetite control
and gut motility in upper as well as lower GI tract.
Relamorelin is a novel injectable ghrelin receptor agonist
studied as a motility amplifier in patients with diabetic
gastroparesis.43 It has also been evaluated in women with
chronic constipation and has been found to improve
gastric emptying rate and stool frequency but had no effect
on stool consistency. Further studies are warranted in
patients with IBS-C.
29-01-2021 14:57:08
 918 SECTION 10 Gastroenterology

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.
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
or any liver dysfunction.
5-HT3 Antagonists
Serotonin modulates the gut motility and sensitivity
through a variety of receptors. Alosetron is a 5-HT 3
antagonist was found to be efficacious in treatment of
IBS-D.46 However, this drug was associated with risk of
ischemic colitis and severe constipation.
Ramosteron is a novel 5-HT3 antagonist47 found to be
effective in improving global symptoms of IBS-D including
pain scores, which were not improved by Ondansetron
when compared for management of IBS-D.
Drugs Acting on Bile Acids
Bile acids are known to be important in stimulating
secretion in the bowel and enhance gut motility that are
relevant in causing diarrhea. Several studies have revealed
the increase bile acid loss as a cause of IBS-D.48 FGF19
is produced from the ileum that acts as an important
factor in regulating bile acid synthesis in the liver. In bile
acid diarrhea there is reduced feedback inhibition by
FGF19. Cholestyramine is most commonly used bile acid
sequestrant along with newer agents like colestipol and
colesevelam.49
Farnesoid X activated receptor is also involved
in inhibition of bile acid synthesis in liver by various
mechanisms. Obeticholic acid is one of the various FXR
receptor agonists that has been found to reduce bile acid
synthesis and improve secondary bile acid diarrhea.50
Fig. 2: IBStim device
On the contrary, increased bile acids in the lumen
stimulate water secretion and motility and improve
constipation. Chenodeoxycholic acid was found to
improve bowel function and bowel motility when tested.51
Elobixibat or A3309, through antagonism of ileal bile
acid transporter reduces reuptake, and hence increases
luminal bile acid content. Elobixibat has also been found
to improve colonic transit and improve symptoms in
patients with IBS-C.52
Modulating the Central Pain Mechanism
IBStim Device: The Cranial Nerve Stimulator (Fig. 2)
Recently approved for use in patients for modulating
abdominal pain in IBS patients, this device is approved
for adolescents of age group 11–18 years. It modulates
the pain pathways in the CNS by low frequency electrical
stimulation of peripheral cranial nerves. It is single use
device and works for 5 days.53
Conclusion
IBS is chronic relapsing remitting functional GI disorder.
With enhanced understanding of the micro-organic basis of
the disorder newer therapies are directed at modifying the
pathology of the disease rather than the individual symptoms.
It is however very necessary to clinically diagnose the patient
with respect to the recent diagnostic criteria and order
important battery of investigations for making a positive
diagnosis of IBS.

MU-141.indd 918 29-01-2021 14:57:08


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29-01-2021 14:57:09
 CHAPTER

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

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

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 922 SECTION 10 Gastroenterology

TABLES 1 Causes of occult gastrointestinal bleeding

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

MU-142.indd 922 29-01-2021 14:56:58


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
involves the use of an endoscope and an overtube,
although procedures are emerging that may not require an
overtube. Initially scopes are inserted as deep as possible;
careful withdrawal of the scope then allows evaluation
of the entire small bowel. With DBE, balloons are used
to grip the intestine while inserting the endoscope. By
inflating the overtube balloon enough to grip the intestinal
wall, the endoscope can be inserted further without
forming redundant loops in the small intestine and then
the overtube can in turn be inserted while the endoscope
balloon is inflated. The single balloon technique in theory
is technically simpler than DBE. Spiral enteroscopy uses a
special overtube with raised helices at the distal end, and
clockwise rotation of the overtube pleats the small bowel
onto the overtube and prevents looping. Data to date
suggest that DBE allows greater depth of insertion than the
other two.7
Evaluation
There are two different clinical presentations of occult GI
bleed:
„„ Positive FOBT without iron deficiency anemia
„„ Iron deficiency anemia with or without a positive
FOBT
Positive FOBT without Iron Deficiency Anemia
Normal fecal blood loss varies from 0.5 to 1.5 mL/day.10
However, loss of up to 100 mL of blood per day may not
MU-142.indd 923
Evaluation of Occult GI Bleed CHAPTER 142 923
cause any visible change in the color of the stool.11 FOBT,
usually classic guaiac-based tests, is often used in day-to-
day clinical practice by physicians. Other types of FOBT
like fecal immunochemical tests and the heme porphyrin
test are not available in India. The likelihood of positive
test depends not only on the sensitivity of a particular test
but also on the frequency and rate at which the causative
lesion bleeds, bowel motility, and the anatomic site of
the bleed. 12 Guaiac-based tests are best at detecting
blood from the lower rather than the upper GIT as the
pseudoperoxidase activity of heme, detected by guaiac-
based tests, is continuously degraded as it moves down
the GIT.
Oral iron therapy is commonly believed to cause
positive guaiac tests, but prospective studies have proven
this belief to be wrong.13 Finally, bismuth (found in certain
antacids and antidiarrheal drugs) makes the stool dark
and even black in appearance, but does not cause a blue
guaiac reaction and should not be mistaken for blood.
Flowchart 1 illustrates the approach proposed by
the American Gastroenterological Association (AGA) for
patients with positive FOBT.4 Colonoscopy is preferred
because of its high sensitivity for detecting colonic
mucosal lesions, and its intervention capabilities with
biopsy, polypectomy, and treatment of bleeding lesions.4
Barium studies have lower sensitivity than colonoscopy
and are generally not recommended. CT colonography
may be an alternative to colonoscopy, if bowel preparation
is a problem. 14 However, it does not have therapeutic
capabilities.
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 924 SECTION 10 Gastroenterology
A B
C overtube enteroscopy
Identification of an abnormality consistent with
the magnitude of bleeding makes further workup after
colonoscopy unnecessary. If colonoscopy is negative,
further studies are not required in the asymptomatic
patient unless anemia develops.4 Exceptions are patients
with upper GI symptoms, in whom EGD should be
performed along with colonoscopy.
Fecal blood content in therapeutically anticoagulated
patients is usually within normal limits. Hence, a positive
FOBT should not be attributed to low-dose aspirin
or anticoagulation, and as such, will require at least
endoscopic evaluation.15
Iron Deficiency Anemia with or
without a Positive FOBT
Worldwide IDA is the most common cause of anemia.
Under normal circumstances, iron balance is tightly
MU-142.indd 924
Figs. 2A to C: Different types of deep enteroscopy: (A) Double-
balloon enteroscopy; (B) Single-balloon enteroscopy; (C) Spiral
regulated at the level of intestinal mucosa. Average daily
loss of iron is 1 mg coming from microscopic GI bleeding
and sloughed intestinal cells.16 In India, more than 50% of
population is iron-deficient.17
The approach recommended by AGA for evaluation
of patients who have IDA with or without a positive
FOBT has been illustrated in Flowchart 2. 18 Men and
postmenopausal women with IDA are assumed to
have GI blood loss, unless proved otherwise. However,
premenopausal women who have IDA that cannot
be explained by heavy menses, or those who have GI
symptoms, should be evaluated for a GI cause.
Endoscopic evaluation should start with EGD and
colonoscopy. During EGD, biopsies should be taken
from duodenal mucosa to look for celiac disease, an
often ignored cause of IDA.19 If EGD and colonoscopy
are normal, they are called obscure occult GI bleed.
29-01-2021 14:57:02
 Evaluation of Occult GI Bleed CHAPTER 142 925

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
enteroscopy is not justified.
If capsule endoscopy fails to identify a lesion, it may
be repeated on another occasion (second-look capsule
endoscopy). Alternatively, CT or MR enterography may be
considered.
Sometimes, CT or MR enterography are performed
before capsule endoscopy to check for luminal patency
sufficient to allow unobstructed passage of the capsule.20
CT, computed tomographic; EGD, esophagogastroduodenoscopy;
FOBT: fecal occult blood test
Surprisingly, in some cases, the diagnosis may be obvious
on CT or MR precluding the need for capsule endoscopy.
Radioisotope scan using radioactive technetium bound
red blood cells (RBCs) are not favored due to significant
radiation exposure, imprecise localization, and lack
of therapeutic potential. 21 Angiography and guided

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 926 SECTION 10 Gastroenterology
intervention is reserved for acute brisk bleeding that do
not fall in the category of occult GIB or IDA.20,22
A small percentage of cases may not have any lesion
identified even after exhaustive evaluation. In them,
covert non-GI blood loss should be considered. Also, the
diagnosis and type of anemia need to be rechecked by a
hematologist.1
Treatment
Essentially, the treatment should focus on the underlying
cause of occult bleeding. Anemia is treated with oral
ferrous sulfate in a dose of 325 mg twice or thrice daily.
Ferrous fumarate or gluconate is acceptable alternative
for those unable to tolerate ferrous sulfate. Parenteral
iron therapy is reserved for those with malabsorption
disorders or severe oral intolerance.23 For patients with
positive FOBT but no identifiable GI pathology, the long-
term prognosis appears favorable. Majority of these true
obscure cases respond to oral iron thrapy.24
Conclusion
A multitude of diseases of GIT can present as occult GI bleed,
manifesting as a positive FOBT or IDA. Majority of these bleeds
are caused by ulcerative diseases of the upper GIT while
malignancy is rare. Routine endoscopy (UGI endoscopy and
colonoscopy) is the first step in evaluation of these patients.
Some patients have common lesions but with an unusual
or atypical appearance; others may harbor rare/uncommon
diseases. Capsule endoscopy and deep (often balloon-assisted)
enteroscopy are useful to identify the diseases of small bowel.
The later often offers scope for curative intervention. The
outcome of therapy depends on identification of a specific
bleeding lesion, severity of bleeding, and, finally, access to
advanced diagnostic/therapeutic modalities.
References
1. Rockey DC. Occult and obscure gastrointestinal bleeding: causes and
management. Nat Rev Gastroenterol Hepatol. 2010;7(5):265-79.
2. Rockey DC. Occult gastrointestinal bleeding. N Engl J Med.
1999;341(1):38-46.
3. Zu c k e r m a n G R , Pr a k a s h C , As k i n M P, e t a l. A m e r i c a n
Gastroenterological Association (AGA) technical review on the
evaluation and management of occult and obscure gastrointestinal
bleeding. Gastroenterology. 2000;118(1):201-21.
4. Raju GS, Gerson L, Das A, et al. American Gastroenterological
Association (AGA) Institute technical review on obscure
gastrointestinal bleeding. Gastroenterology. 2007;133(5):1697-717.
MU-142.indd 926
5. Goenka MK, Mojumder S, Goenka U, et al. Capsule endoscopy:
present status and future expectation. World J Gastroenterol.
2014;20(29):10024-37.
6. Sears DM, Avots-Avotins A, Culp K, et al. Frequency and clinical
outcome of capsule retention during capsule endoscopy for GI
bleeding of obscure origin. Gastrointest Endosc. 2004;60(5):822-7.
7. Moeschler O, Mueller MK. Deep enteroscopy—indications,
diagnostic yield and complications. World J Gastroenterol.
2015;21(5):1385-93.
8. Mans L, Arvanitakis M, Neuhaus H, et al. Motorized spiral
enteroscopy for occult bleeding. Dig Dis. 2018;36(4):325-7.
9. Otani K, Watanabe T, Shimada S, et al. Clinical utility of capsule
endoscopy and double-balloon enteroscopy in the management
of obscure gastrointestinal bleeding. Digestion. 2018;97(1):52-8.
10. Rockey DC, Auslander A, Greenberg PD, et al. Detection of
upper gastrointestinal blood with fecal occult blood tests. Am J
Gastroenterol. 1999;94(2):344-50.
11. Ahlquist DA, McGill DB, Schwartz S, et al. Fecal blood levels in
health and disease. A study using HemoQuant. N Engl J Med.
1985;312(22):1422-8.
12. Ahlquist DA, McGill DB, Fleming JL, et al. Patterns of occult bleeding
in asymptomatic colorectal cancer. Cancer. 1989;63(9):1826-30.
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.
14. Rockey DC, Paulson E, Niedzwiecki D, et al. Analysis of air contrast
barium enema, computed tomographic colonography, and
colonoscopy: prospective comparison. Lancet. 2005;365(9456):
305-11.
15. Jaffin BW, Bliss CM, LaMont JT, et al. Significance of occult
gastrointestinal bleeding during anticoagulation therapy. Am J
Med. 1987;83(2):269-72.
16. Hentze MW, Muckenthaler MU, Andrews NC, et al. Balancing
acts: molecular control of mammalian iron metabolism. Cell.
2004;117(3):285-97.
17. WHO. Worldwide prevalence of anaemia. 1993-2005.
18. American Gastroenterological Association (AGA) medical position
statement: evaluation and management of occult and obscure
gastrointestinal bleeding. Gastroenterology. 2000;118(1):197-201.
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.
2018;56(5):791-804.
21. Filippone A, Cianci R, Milano A, et al. Obscure and occult
gastrointestinal bleeding: comparison of different imaging
modalities. Abdom Imaging. 2012;37(1):41-52.
22. Kim BS, Li BT, Engel A, et al. Diagnosis of gastrointestinal bleeding:
a practical guide for clinicians. World J Gastrointest Pathophysiol.
2014;5(4):467-78.
23. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients
with iron deficiency anemia. N Engl J Med. 1993;329(23):1691-5.
24. McLoughlin MT, Tham TC. Long-term follow-up of patients with iron
deficiency anaemia after a negative gastrointestinal evaluation. Eur
J Gastroenterol Hepatol. 2009;21(8):872-6.
29-01-2021 14:57:03
 CHAPTER

143 Endoscopic Ultrasound

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-

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

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 928 SECTION 10 Gastroenterology
indications, strengths as well as limitations of EUS. This
review discusses in brief the diagnostic and therapeutic
indications of EUS.
Types of EUS Scopes
Broadly, there are two types of EUS scopes (echo­
endoscopes). The first developed echoendoscope was
a radial echoendoscope with a 360-degree transducer
that has a scanning plane of ultrasound perpendicular
to the long axis of the echoendoscope. This is a purely
diagnostic echoendoscope and no intervention or FNA
can be done with this scope. To overcome this limitation,
linear echoendoscopes were developed in which the
scanning plane of transducer is parallel to the long axis of
the echoendoscope so that the entire needle can be seen
in real time during FNA/interventions.3
Apart from these two commonly echoendoscopes,
a new echoendoscope has recently been developed.
The forward viewing echoendoscope has a forward
endoscopic view instead of oblique endoscopic view of
linear echoendoscope and has a shorter and more flexible
tip. Therefore, it is more easily maneuverable and can be
used instead of oblique viewing echoendoscope in difficult
anatomical situations. However, absence of elevator at the
tip of echoendoscope makes the interventions difficult
with this scope. Therefore, this scope is usually used in
those situations where linear echoendoscope cannot be
used because of anatomical constraints.
Indications of EUS
The clinical indications for EUS can be divided into two
broad categories: diagnostic and therapeutic (Table 1). The
TABLE 1 Indications for EUS
Diagnostic EUS
Primary diagnostic modality
zz Idiopathic acute pancreatitis
zz Diagnosis of chronic pancreatitis especially early chronic pancreatitis
Secondary diagnostic modality
zz Dilated common bile duct
zz Pancreatic cystic lesions
zz GI submucosal lesions
zz Locoregional staging of GI cancers
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
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
(SMLs), dilated bile duct and pancreatic cystic lesions
(PCL) 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.
EUS as a Primary Diagnostic Modality
Idiopathic Acute Pancreatitis
EUS provides high-resolution images of pancreas and
biliary tract, and therefore is an important investigation for
evaluation of patients with idiopathic acute pancreatitis.
It is an excellent modality for diagnosis of occult
cholelithiasis or choledocholithiasis, microlithiasis, or
gallbladder sludge (Fig. 1), pancreatic duct anomalies
like pancreas divisum, occult pancreatic neoplasm and
importantly, exclude chronic pancreatitis.4 Studies have
shown that EUS is a useful and minimally invasive tool
for the diagnostic evaluation of idiopathic pancreatitis
and in case of negative EUS examination relapses of
pancreatitis are infrequent. 5,6 EUS may also help in
Therapeutic EUS
zz Drainage of pancreatic fluid collections
zz Biliary and pancreatic duct drainage in cases of failed ERCP
zz Transmural gallbladder drainage
zz EUS-guided celiac plexus neurolysis/blockade
zz Drainage of mediastinal and intra-abdominal abscesses and
collections
zz EUS-guided vascular interventions
zz EUS-guided palliative oncological interventions
zz EUS-guided gastrojejunostomy
29-01-2021 14:56:55

Fig. 1: EUS: gallbladder sludge in idiopathic acute pancreatitis
diagnosing uncommon causes for AP such as pancreatico-
biliary ascariasis and parathyroid adenomas.
Diagnosis of Chronic Pancreatitis
EUS has unique capability of demonstrating subtle
structural alterations in the pancreatic parenchyma as
well as ducts even before conventional imaging modalities
demonstrate any abnormality (Fig. 2).7 The conventional
imaging modalities like computed tomography (CT) and
magnetic resonance cholangiopancreatography (MRCP)
can pick up advanced morphological changes of chronic
pancreatitis (CP) only, and therefore they have very low
sensitivity for diagnosis of early CP. EUS by demonstrating
early parenchymal and ductal changes can help in early
diagnosis of CP. In patients with presumed acute recurrent
pancreatitis, EUS can help in excluding underlying CP.
However, EUS is not a panacea for diagnosis of CP.
Being a highly sensitive imaging modality, there is a
concern for overdiagnosis of CP. To overcome these
limitations, advanced and complicated scoring systems
incorporating multiple parenchymal and ductal EUS
features have been used for diagnosis of CP. Despite
these scoring systems, concerns about interobserver
variability as well as aging, smoking, obesity, and chronic
alcohol consumption causing EUS changes in pancreas
mimicking CP persist. Therefore, EUS findings of CP
should be interpreted in an appropriate clinical context
and, if required, should be confirmed and followed up by
serial EUS examinations. Newer EUS techniques like EUS
MU-143.indd 929
Endoscopic Ultrasound for the Internist CHAPTER 143 929
Fig. 2: EUS in a patient with chronic pancreatitis. Ductal calculi
(arrow) noted
elastography that evaluate the stiffness of pancreas appear
to be promising techniques for confident diagnosis of early
CP.7 However, further studies are required to determine
their exact role in diagnosis of early CP.
EUS as a Secondary Diagnostic Modality
EUS for Submucosal Lesions
SMLs are usually asymptomatic lesions with normal
overlying mucosa detected on routine endoscopy and
require further evaluation for confirmatory diagnosis.
Endoscopy and biopsy have limited role in evaluation of
SMLs because of normal overlying mucosa. The ability of
EUS to image structures beyond GI lumen makes it ideal
modality for investigations of SMLs. EUS is an excellent
modality to differentiate extramural compression and SML
as well as determine the type and nature of SML.8-10 EUS
can help in presumptive diagnosis of SML by accurately
estimating the size, the layer of origin, the echo-pattern
and the margins of the lesion. The diagnostic accuracy of
EUS can further be enhanced by cytological or histological
analysis of specimens obtained by EUS guided FNA/fine
needle biopsy (FNB).
EUS for Unexplained Dilated Common Bile Duct
EUS transducer from duodenum closely images the
CBD, and therefore has very high diagnostic accuracy for
lower and mid CBD lesions.11-13 Isolated CBD dilatation
is commonly encountered in clinical practice because
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 930 SECTION 10 Gastroenterology
Fig. 3: EUS in dilated common bile duct (CBD). A stone noted in
lower CBD (arrow)
of wide spread use of cross-sectional imaging modalities
for patients with non-specific abdominal symptoms. In
many of these patients cross-sectional imaging modalities
like ultrasound, CT, and MRCP fail to identify the etiology
of dilated CBD and many of these patients required
endoscopic retrograde cholangiopancreatography
(ERCP) for confirming the diagnosis. ERCP is an invasive
procedure with inherent risks of serious adverse effects like
post ERCP pancreatitis. In these clinical situations EUS has
been demonstrated to be an excellent diagnostic modality
for identifying underlying etiology of unexplained CBD
dilatation (Fig. 3). More importantly, if EUS is normal,
there is extremely less likelihood of presence of any
significant underlying disease and patient therefore should
be reassured and no further follow-up is required.11-13
EUS in Pancreatic Cystic Lesions
Evaluation of patients with PCL requires a confident
differentiation of malignant, potentially malignant and
benign PCL. EUS is a useful modality for evaluation of
PCL as it can provide information about the detailed
morphology of cysts (Fig. 4) as well as enable guided FNA
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
shown to have highest sensitivity and specificity for
differentiating mucinous from non-mucinous PCL.14 Cyst
fluid molecular markers hold considerable promise for
proper evaluation of PCL. New EUS based technologies
MU-143.indd 930
Fig. 4: EUS: mucinous cystadenoma of pancreas
like contrast-enhanced EUS, EUS guided cystoscopy,
needle-based confocal laser endomicroscopy, and
through-the-needle forceps biopsy provide important
information for accurate diagnosis of PCL.
EUS for Locoregional Staging of GI Cancers
EUS can accurately define the walls of the GI tract and
thus is an accurate modality to assess the transverse
spread of malignant lesion. It can also accurately assess
the extraluminal involvement of the malignant lesion by
identifying lymph nodal as well as arterial and venous
involvement. Therefore, over last decade EUS has thus
become an important investigation for preoperative
assessment for majority of the GI cancers including
esophageal, gastric, pancreaticobiliary, as well as rectal
cancers. 18 EUS from esophagus can also evaluate the
mediastinum, and therefore EUS is an important imaging
modality for accurate staging of non-small cell lung
cancer. Combining EUS with endobronchial ultrasound
(EBUS) allows access to all mediastinal lymph node
stations, and therefore is an important staging modality
for lung cancer.18,19
EUS-guided Tissue Acquisition
Linear echoendoscope is used to perform EUS-guided
FNA with great precision in real time as the needle is
visualized in real time throughout the procedure. The
advantage of EUS-guided FNA is its ability to acquire
29-01-2021 14:56:56

Fig. 5: EUS-guided FNA from preaortic lymph node
tissue from difficult to access anatomical locations in
abdomen, retroperitoneum, mediastinum, and perirectal
spaces.20 EUS guided FNA is now routinely used in clinical
practice to acquire tissue for histological diagnosis from
pancreas, lymph nodes in mediastinum and abdomen
(Fig. 5), GI SMLs, perirectal lesions, left lobe of liver, left
adrenal, and mediastinal masses. EUS can also be used
for aspirating minimal amount of ascites and pleural
effusion.21-23 It can also be used for visualizing as well as
sampling peritoneal as well as pleural deposits in patients
with undiagnosed pleural effusion as well as ascites.21,23,24
Despite being in GI endoscopy practice for more than
a decade, EUS FNA has important limitations like false
positivity in pancreatic masses in CP and autoimmune
pancreatitis and false negativity because of technical
difficulty, marked desmoplastic background, sampling
error, or interpretative errors. Moreover, certain diseases
like lymphoma and autoimmune pancreatitis require
cote biopsy for confident diagnosis. To overcome these
limitations of EUS FNA, newer FNB needles have been
developed for use with EUS. 25,26 EUS guided FNB has
been demonstrated to provide samples with increased
cellularity along with preserved histologic architecture,
and therefore seems to be an ideal tissue acquisition
technique for histological as well as molecular testing.
Therapeutic EUS
EUS has the ability to visualize organs and lesions adjacent
to GI tract and thus provide an opportunity to target them
for various therapeutic procedures. The advantages of
MU-143.indd 931
Endoscopic Ultrasound for the Internist CHAPTER 143 931
Fig. 6: EUS-guided drainage of pancreatic pseudocyst
EUS is its ability to provide a real time imaging of the
targeted area and also, importantly, avoiding adjacent
vascular and other structures. 27 Various EUS guided
interventional procedures that are being performed
are drainage of pancreatic fluid collections, biliary
and pancreatic duct drainage in cases of failed ERCP,
transmural gallbladder drainage, celiac plexus neurolysis
(CPN)/blockade, drainage of mediastinal and intra-
abdominal abscesses and collections, various vascular
interventions, endoscopic gastrojejunostomy and is useful
for targeted chemotherapy and radiotherapy.
CPN is a procedure of chemical ablation of the celiac
plexus using absolute alcohol or phenol for relief of
intractable pain because of pancreatic cancer. It is usually
done under ultrasound, or CT guidance or surgically.
Advent of EUS guided CPN has made this procedure very
safe with rare adverse effects. Although EUS, CPN is safe
and effective, but the pain relief is usually short lasting and
patient may require repeated procedures for effective pain
relief.28
EUS guided transmural drainage of pancreatic fluid
collections including pseudocysts (Fig. 6) as well as
walled off necrosis has evolved as its treatment of choice
and is preferred over surgical as well as percutaneous
drainage.29,30 Being minimally invasive, safe, effective,
and absence of external percutaneous drainage catheter
are important advantages of EUS guided drainage of
pancreatic fluid collections. Developments of fully
covered lumen apposing metal stents (LAMS) have further
improved results of EUS guided drainage of pancreatic
29-01-2021 14:56:56
 932 SECTION 10 Gastroenterology
fluid collections. Similarly, abscesses or collections in
locations adjacent to GI tract like mediastinal, left lobe
of liver, lesser sac, and pelvic collections can be drained
under EUS guidance.27
EUS-guided transmural drainage of biliary tract and
pancreatic duct is an effective alternative to percutaneous
or surgical drainage of these ducts in patients with
failed ERCP.27 Although these procedures are effective
but are technically challenging, and therefore should be
performed only by experts in centers with radiological and
surgical back up. Similarly, EUS can be used for draining
gallbladder in cases of acute cholecystitis not responding
to antibiotics and has been shown to be safer and effective
alternative to percutaneous drainage of gallbladder with
added advantage of absence of percutaneous drain.
Advancement in accessories for EUS has led on to
exploration of unthinkable therapeutic areas. Various
palliative oncological interventions like EUS-guided
brachytherapy, fiducial marker placement, ethanol
ablation, and EUS-guided delivery of antitumor agents can
be performed and studies have shown them to be safe and
effective.27 EUS has expanded into vascular interventions
field also with various EUS guided interventions like EUS
guided glue or coil injections into gastric/ectopic varices
as well as pseudoaneurysms being safely performed.
EUS-guided intrahepatic portosystemic shunt has also
been performed as an alternative to TIPS (transjugular
intrahepatic portosystemic shunt) for the treatment of
consequences of portal hypertension. Advancement in
EUS had made it possible to perform various surgical
procedures like gastrojejunostomy safely in a minimally
invasive fashion under EUS guidance.31
Conclusion
EUS is an important investigation in the armamentarium of
an endoscopist. EUS has been shown to have a significant
impact in management of patients with various GI disorders
with significant change in both the diagnosis as well as
management. 3 The advent of EUS-guided FNA for tissue
diagnosis as well as therapeutic EUS has led on to wider
clinical applications of EUS. Locoregional staging of various
GI cancers is one of the important clinical applications of EUS
in clinical practice. 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.
MU-143.indd 932
References
1. Friedberg SR, Lachter J. Endoscopic ultrasound: current roles and
future directions. World J Gastrointest Endosc. 2017;9(10):499-505.
2. Godfrey EM, Rushbrook SM, Carroll NR, et al. Endoscopic ultrasound:
a review of current diagnostic and therapeutic applications.
Postgrad Med J. 2010;86(1016):346-53.
3. Caddy GR, Chen RY. Current clinical applications of endoscopic
ultrasound. ANZ J Surg. 2007;77(3):101-11.
4. Rana SS, Bhasin DK, Rao C, et al. Role of endoscopic ultrasound in
idiopathic acute pancreatitis with negative ultrasound, computed
tomography, and magnetic resonance cholangiopancreatography.
Ann Gastroenterol. 2012;25(2):133-7.
5. Somani P, Sunkara T, Sharma M, et al. Role of endoscopic ultrasound
in idiopathic pancreatitis. World J Gastroenterol. 2017;23(38):
6952-61.
6. Wilcox CM, Seay T, Kim H, et al. Prospective endoscopic ultrasound-
based approach to the evaluation of idiopathic pancreatitis: causes,
response to therapy, and long-term outcome. Am J Gastroenterol.
2016;111(9):1339-48.
7. Rana SS, Vilmann P. Endoscopic ultrasound features of chronic
pancreatitis: a pictorial review. Endosc Ultrasound. 2015;4(1):10-14.
8. Landi B, Palazzo L. The role of endosonography in submucosal
tumours. Best Pract Res Clin Gastroenterol. 2009;23(5):679-701.
9. Reddy Y, Willert RP. Endoscopic ultrasound: what is it and when
should it be used? Clin Med (Lond). 2009;9(6):539-43.
10. Chung IK, Hawes RH. Advantages and limitations of endoscopic
ultrasonography in the evaluation and management of
patients with gastrointestinal submucosal tumors: a review. Rev
Gastroenterol Disord. 2007;7(4):179-92.
11. De Angelis C, Marietti M, Bruno M, et al. Endoscopic ultrasound in
common bile duct dilatation with normal liver enzymes. World J
Gastrointest Endosc. 2015;7(8):799-805.
12. Holm AN, Gerke H. What should be done with a dilated bile duct?
Curr Gastroenterol Rep. 2010;12(2):150-6.
13. Rana SS, Bhasin DK, Sharma V, et al. Role of endoscopic ultrasound
in evaluation of unexplained common bile duct dilatation
on magnetic resonance cholangiopancreatography. Ann
Gastroenterol. 2013;26(1):66-70.
14. Lévy P, Rebours V. The role of endoscopic ultrasound in the diagnosis
of cystic lesions of the pancreas. Visc Med. 2018;34(3):192-6.
15. Ohno E, Hirooka Y, Kawashima H, et al. Endoscopic ultrasonography
for the evaluation of pancreatic cystic neoplasms. J Med Ultrason.
2020:47(3):401-11.
16. Pausawasdi N, Ratanachu-Ek T. Endoscopic ultrasonography
evaluation for pancreatic cysts: necessity or overkill? Dig Endosc.
2017;29(4):444-54.
17. Westerveld DR, Ponniah SA, Draganov PV, et al. Diagnostic yield
of EUS-guided through-the-needle microforceps biopsy versus
EUS-FNA of pancreatic cystic lesions: a systematic review and meta-
analysis. Endosc Int Open. 2020;8(5):656-67.
18. Lennon AM, Penman ID. Endoscopic ultrasound in cancer staging.
Brit Med Bull. 2007;84(1):81-98.
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19. Ang TL, Kwek ABE, Wang LM, et al. Diagnostic endoscopic
ultrasound: technique, current status and future directions. Gut
Liver. 2018;12(5):483-96.
20. Rana A, Rana SS. Endoscopic ultrasound-guided tissue acquisition:
techniques and challenges. J Cytol. 2019;36(1):1-7.
21. Rana SS, Bhasin DK, Srinivasan R, et al. Endoscopic ultrasound-
guided fine needle aspiration of peritoneal nodules in patients with
ascites of unknown cause. Endoscopy. 2011;43(11):1010-3.
22. Rana SS, Sharma R, Gupta R, et al. Endoscopic ultrasound-guided
transesophageal thoracentesis for minimal pleural effusion. Indian
J Gastroenterol. 2018;37(3):231-4.
23. Rana SS, Sharma R, Srinivasan R, et al. Contrast-enhanced EUS in the
evaluation of peritoneum and omentum in undiagnosed ascites.
Endosc Ultrasound. 2020;9(1):69-70.
24. Rana SS, Gupta P, Sharma RK, et al. Pleural metastasis detected
by transesophageal endoscopic ultrasonography. JGH Open.
2019;3(5):441-3.
25. DeWitt J, Cho CM, Lin J, et al. Comparison of EUS-guided tissue
acquisition using two different 19-gauge core biopsy needles: a
multicenter, prospective, randomized, and blinded study. Endosc
Int Open. 2015;3(5):471-8.
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26. Park JK, Lee KH. Present and future of endoscopic ultrasound-
guided tissue acquisition in solid pancreatic tumors. Clin Endosc.
2019;52(6):541-8.
27. Sharma V, Rana SS, Bhasin DK, et al. Endoscopic ultrasound
guided interventional procedures. World J Gastrointest Endosc.
2015;7(6):628-42.
28. Wyse JM, Sahai AV. Endoscopic ultrasound-guided management of
pain in chronic pancreatitis and pancreatic cancer: an update. Curr
Treat Options Gastroenterol. 2018;16(4):417-27.
29. Guo J, Saftoiu A, Vilmann P, et al. A multi-institutional consensus
on how to perform endoscopic ultrasound-guided peri-pancreatic
fluid collection drainage and endoscopic necrosectomy. Endosc
Ultrasound. 2017;6(5):285-91.
30. Rana SS, Sharma V, Sharma R, et al. Endoscopic ultrasound guided
transmural drainage of walled off pancreatic necrosis using a
“step–up” approach: a single centre experience. Pancreatology.
2017;17(2):203-8.
31. Braden B, Gupta V, Dietrich CF, et al. Therapeutic EUS: new tools,
new devices, new applications. Endosc Ultrasound. 2019;8(6):
370-81.
29-01-2021 14:56:56
 CHAPTER

144 Gastroesophageal Reflux

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

GERD (cough, laryngitis, asthma, and dental

Definitions3 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
Older age Pregnancy atypical:3
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
zz Water brash zz Belching zz Chronic cough
calcium channel blockers
zz Early satiety zz Asthma
„„ Protective Factors: Helicobacter pylori infection and zz Epigastric pain zz Chronic sinusitis
zz Hoarseness zz Recurrent sore throat
physical activity seem to play a protective role.
zz Globus

sensation
Pathophysiology4 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.
Other factors that contribute to acid reflux include: Diagnosis3,5-8
„„ 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.,
ischemic heart disease).
Non-acid Reflux5
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.
„„ In patients with symptoms despite acid suppression,
„„ Almost 20–40% patients continue to be symptomatic
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
Iron deficiency anemia
pancreatic secretions into stomach and esophagus.
—— 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.

MU-144.indd 935 29-01-2021 14:56:46

 936 SECTION 10 Gastroenterology

—— 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:
—— Esophageal acid exposure time (EAT)
combined with pH monitoring can reliably identify
—— Number of reflux events (events when pH
non-acid reflux.
„„ The technique uses changes in resistance to electrical
decreases to <4)
—— Nature of refluxate (acidic/neutral/alkaline)
currents to detect the presence of intraluminal liquid.
„„ An EAT of more than 6% and a total of more than 80

reflux episodes in 24 hours are considered abnormal. Treatment3,7

„„ 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

„„ Dietary changes
In patients with unproven GERD (no or LA grade
—— Avoiding fatty, spicy, large meals
A/B esophagitis)
—— Avoiding late evening snacks
Before surgery
—— Avoiding chocolate, citrus foods, caffeine,
­ Atypical presentations
—— On PPI: carbonated drinks
„„ Minimizing smoking and alcohol
­ In proven GERD (LA grade C/D esophagitis) or BE
„„ Weight reduction
> 1 cm or prior abnormal pH study
„„ Avoid NSAIDs
To establish causation of refractory symptoms

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 „„
salts, and alginate containing agents
„„ Histamine type-2 receptor antagonists (H2RA): „„
—— Better efficacy and prolonged action than antacids
—— However, tachyphylaxis (usually within 2 weeks) „„
is an issue
—— Should not be given at same time as PPI
This leads to excessive cost of therapy as well as
adverse effects
Most of the side effects are mild and self-limiting like
headache, nausea, abdominal pain, and flatulence
Recent studies, however, reveal association of PPI with
some serious adverse effects

—— 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.
„„ Endoscopic treatment
evaluation
„„ Antireflux surgery.
Side effects of PPIs
Pneumonia Vitamin B12 deficiency Recent Developments in Medical Management11
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

—— Es omeprazole strontium delaye d-releas e „„ 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)

proton-pumps in parietal cells „„ Currently, three endoluminal methods are in practice:12
—— 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 te chnique makes us e of a mo difie d

„„ C a n n ab i n o i d R e c e p t o r- a g o n i s t s : D e l t a - 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
„„ Patients suitable for endotherapy are those with: Surgical Management3,7
—— 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!
„„ Approximately half of the patients will still need anti-
reflux medications, post-surgery
„„ Further, postoperative complications like solid food
dysphagia, diarrhea, and early satiety have been
reported in 7–10% patients
„„ Surgery does not prevent progression to adeno­
carcinoma
„„ Patients who will be benefitted the most from surgery
are those with:
—— No response, non-compliance or intolerance to
medical therapy
—— Complications like refractory esophagitis, stric­
ture, and BE
—— Large hiatus hernia (>5 cm)
—— Documented acid reflux with defective anti-reflux
barrier
—— Cardiac dysfunction
—— Normal gastric emptying and esophageal motility
„„ LinxTM reflux management system:13
—— This device is in the form of a ring made by series
of titanium beads with a magnetic core connected
with titanium wires
—— This ring is placed, laparoscopically, around the
lower end of distal esophagus
—— It prevents reflux by augmenting LES
—— Short-term studies are promising with more than
90% patients reporting improvement in quality of
life
—— However, dysphagia was seen in 68% patients
Conclusion
GERD is a common gastrointestinal disorder with significant
impact on quality of life. PPIs, though mainstay of treatment,
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
CHAPTER 144 939
References
1. El-Serag HB, Sweet S, Winchester CC, et al. Update on the
epidemiology of gastrooesophageal reflux disease: a systematic
review. Gut. 2014;63(6):871-80.
2. Bhatia SJ, Reddy DN, Ghoshal UC, et al. Epidemiology and symptom
profile of gastroesophageal reflux in the Indian population: report
of the Indian Society of Gastroenterology Task Force. Indian J
Gastroenterol. 2011;30(3):118-27.
3. Hunt R, Armstrong D, Katelaris PH, et al. World Gastroenterology
Organisation Global Guidelines. Global perspective on
gastroesophageal reflux disease. J Clin G astroenterol.
2017;51(6):467-78.
4. Herregods TV, Bredenoord AJ, Smout AJ, et al. Pathophysiology of
gastroesophageal reflux disease: new understanding in a new era.
Neuro Gastro Enteral Motil. 2015;27(9):1202-13.
5. Karamanolis G, Tutuian R. Role of non-acid in patients with non-
erosive reflux disease. Ann Gastroenterol. 2013;26(2):100-3.
6. Boeckxstaens GE, Smout A. Systematic review: role of acid, weakly
acidic and weakly alkaline reflux in gastro-oesophageal reflux
disease. Aliment Pharmacol Ther. 2010;32(3):334-43.
7. Bhatia SJ, Makharia GK, Abraham P, et al. Indian consensus on
gastroesophageal reflux disease in adults: a position statement
of the Indian Society of Gastroenterology. Indian J Gastroenterol.
2019;38(5):411-40.
8. Kwiatek MA, Kahrilas K, Soper NJ, et al. Esophagogastric junction
distensibility after fundoplication assessed with a novel functional
luminal imaging probe. J Gastrointest Surg. 2010;14(2):268-76.
9. Fass R, Gasiorowska A. Refractory GERD: what is it? Curr Gastroenterol
Rep. 2008;10(3):252-7.
10. Fass R. Therapeutic options for refractory gastroesophageal reflux
disease. J Gastroenterol Hepatol. 2012;27(3):3-7.
11. Maradey-Romero C, Fass R. New and future drug development
for gastroesophageal reflux disease, J Neurogastroenterol Motil.
2014;20(1):6-16.
12. Nabi Z, Reddy DN. Endoscopic management of gastroesophageal
reflux disease: revisited. Clin Endosc. 2016;49(5):408-16.
13. Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device
for gastroesophageal reflux disease. N Engl J Med. 2013;368(21):
2039-40.
29-01-2021 14:56:47
 CHAPTER

145 Post-Infectious Irritable

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
not remember or they do not give much importance to
any such episode. The clinical syndrome, PI-IBS, denotes
persistence of abdominal discomfort, bloating, and
constipation diarrhea, which continue despite absence of
inciting pathogens. A met analysis in the past concluded
that the risk of developing PI-IBS increases sixfold after GI
infection and remains elevated for next 1–3 years.1
Epidemiology
A link between enteric infection and IBS dates back
to the Second World War when numerous cases of GI
discomfort were seen in British troupes that had earlier
suffered from enteric infection. Since then a number of
studies in various parts of the world have reported such
illnesses. The incidence or prevalence of PI-IBS, 5–32%,
in such studies tell us that it is a global phenomenon and
not related to a particular ethnic group or environment
(Box 1).2,3 The wide variation in this reported incidence
or prevalence may be because of differences in study
methodology, inclusion criteria, definition of IBS, etc.
Table 1 describes the prevalence of PI-IBS in some of these
countries. 4 The prevalence rate of PI-IBS (11.5%) does
not vary much, if we take into account the post-infection
period, that is, 3, 6, 12, 13–59, or more than 60 months.5
But initial infective organisms matter and overall, the rate

MU-145.indd 940 29-01-2021 14:56:41


TABLE 1 Prevalence of PI-IBS in different areas
Canada 14.9%
US 17.6%
Norway 54.3%
UK 14.9%
Denmark 20.9%
Germany 45.8%
France 4.5%
Italy 4.5–24.0%
Spain 11.4%
Bangladesh 16.5%
of PI-IBS was the highest after protozoa/parasitic infective
enteritis, followed by bacterial and the lowest rates were
seen with viral infection.6
Pathophysiology
IBS is a disease where diagnosis is based on clinical
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
identified in PI-IBS patients. These changes mainly alter
the integrity of intestinal epithelial barrier. It results in
paracellular permeability, which can encourage exposure
and migration of microflora or food borne antigens. This
in turn stimulates intestinal mucosal immunity, leading to
persistent intestinal microinflammation. The possibility of
inflammatory state of intestinal mucosa is substantiated by
the occurrence of infiltration of T lymphocytes, mast cells,
and enterochromaffin cells. These cells are responsible
for release of cytokines and mediators of inflammation.
In one study, increased intestinal permeability was
associated with increased stool frequency and was proved
by demonstrating increased lactulose-mannitol fractional
excretion ratio in patients, 2 years after a water borne
outbreak of gastroenteritis involving Campylobacter
jejuni and Escherichia coli. 7,8 These changes suggest
a pathophysiological model of PI-IBS and genesis of
symptoms of IBS, where symptoms start after a bout of
infection rather than its absence. An increased number of
mast cells in rectal mucosa and mucosal cellularity were
MU-145.indd 941
Post-Infectious Irritable Bowel Syndrome CHAPTER 145 941
significantly higher in patients of PI-IBS as compared to
patients of IBS, a fact confirmed by rectal-sigmoid and ileal
mucosal biopsy.
Risk Facors for Development of PI-IBS
Female sex is associated with 2.2 times higher risk.
Smoking is not considered a risk factor. Prevalent
anxiety and depression at the time of infective enteritis is
associated with PI-IBS development more often. Similarly,
somatization and neuroticism, at the time of infection,
are risk factors.6,9 Host immune status of elderly persons
protects against infection and thus lowers risk of its
development.2
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
viral gastroenteritis. The mechanism of low-hazard ratio
for viral etiology is poorly understood. It is possible that
viral enteritis is associated with less mucosal damage and
poor structural and immunological alteration.10 However,
the high incidence of PI-IBS after an attack of protozoal
enteritis (Giardiasis) merits attention as it shows the
prevalence much higher, i.e. 39–89%.11
Clinical Features
The diagnosis of IBS is always symptom based and
is mostly challenging. Similarly, there are no definite
diagnostic criteria for post-infectious IBS. The element of
“new onset IBS after an episode of acute gastroenteritis
in patients who never had IBS previously” should always
be given significance. There is strong relation between
traveler’s diarrhea (TD) and PI-IBS. Self reported TD was
associated more often than laboratory confirmed TD (1.5-
fold rise in RR).
There might be some subtle differences in PI-IBS
from IBS, which has greater stool frequency and loose
stools as compared to IBS. All different subtypes of IBS
are recognized, and the frequency is IBS-mixed, 46%,
IBS diarrhea, 39%, and IBS constipation, 15% in some
studies. 12,13 Emphasis should be laid before making a
diagnosis of PI-IBS to exclude alarm signs and checking
for preliminary investigations, that is, CBC, ESR, CRP,
stool culture, etc. in one study, PI-IBS was found to be
associated with post-infectious malabsorption syndrome
(PI-MAS), popularly known as tropical sprue. 14 Small
29-01-2021 14:56:41
 942 SECTION 10 Gastroenterology

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
^
zz Osmotic or stimulating laxatives
spontaneous remission was 27% in a year. The proportion ^
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

^
^
zz Probiotics
21–30 years and 37.5% in older population if more than 70
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

and those with history of somatization. 12 Patients with
longer history of IBS symptoms exhibited poor recovery.
Despite different pathogenesis, surprisingly, prognosis
in PI-IBS does not differ much from non PI-IBS with
recovery of one in four patients in first year. Still, it is very
encouraging to learn that over half of patients of PI-IBS
return to their preinfection state. However, it may take
years for symptoms to disappear completely.
Treatment
It is legitimate to think that traditional approach of
treatment aiming only at attenuating symptoms, must give
place to addressing new pathological targets (intestinal
permeability, microinflammation, mast cells, serotonin,
visceral hypersensitivity, etc.) However, approaches to
tackle such anomalies have not met with much success.
In a small study, treatment with prednisolone, in PI-IBS,
on presumption of immunological genesis has not shown
any benefit.15 Another RCT of an anti-inflammatory agent,
mesalazine, showed overall no benefit in IBS patients with
IBS with diarrhea, but a post hoc subgroup analysis did
suggest some response in PI-IBS.16 Furthermore, treatment
with E. coli 0147 infection with mesalazine appeared to
reduce the risk of developing PI-IBS. 17 Increased 5HT
available in small intestine in PI-IBS patients enhances
visceral hypersensitivity which can be blocked by 5HT
receptor antagonist, ondansetron. This theory encouraged
randomized trial of ondansetron in IBS with diarrhea,
which showed relief of symptoms, particularly urgency.18
SIBO is seen in rats of PI-IBS after campylobacter
infection. A recent study in India suggested that PI-
flatulence
^
Recommended in a few patients based on individual clinical profile
SSRIs, selective serotonin reuptake inhibitors.
Source: Adapted from Tripathi BK, Soni A. Irritable bowel syndrome in
patient management. In: Arulrhaj S (Ed). Medicine Update. New Delhi:
Jaypee Brothers Medical Publishers; 2020. pp. 633-7.
IBS might overlap with tropical sprue in which SIBO
is common. 14 Rifaximin is a locally acting antibiotic,
which targets SIBO, has shown benefit in IBS-D patients.
Bile salt malabsorption may develop following acute
gastroenteritis. Several studies have demonstrated that PI-
IBS can respond to cholecystokinin. However, intolerance
to this drug discourages its use.19
Despite all these novel and experimental therapies,
treatment of PI-IBS is frequently symptom directed and
matches closely with treatment of IBS. Table 2 summarizes
measures, which help treating patients of PI-IBS.
Diet
Many patients describe a chronological link between
onset and worsening of symptoms with a particular food.
However, in majority of patients there is no compelling
data to recommend an exclusion diet. The knowledge of
enhanced intestinal permeability may suggest food allergy
on the premise of penetration of food antigens and their
contact with immunocompetent cells. Possible exclusion
of such items by patients may be helpful rarely.20 A low
fiber diet with soluble fiber will help to some extent. The
consumption of poorly absorbed fermentable oligo-,
di-, mono-saccharide and polyols (FODMAPs) may be
a trigger for symptoms too. FODMAPs and insoluble

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 Post-Infectious Irritable Bowel Syndrome CHAPTER 145 943

TABLE 3 FODMAP (high and low dietary sources)

role in diseases like IBS, IBD, chronic constipation,
etc. In one study role of FMT was studied in recurrent
High FODMAP foods Low FODMAP foods Clostridium difficile infection (CDI) by Mattila et al.22 In
Vegetables Asparagus, onions, Alfalfa, bean sprouts, this study, symptoms resolved in all patients who did not
garlic, sugar, peas, green beans, capsicum, have strain 027 CDI during the first three months Out of 36
beetroot, cabbage, carrot, fresh herbs,
cauliflower, celery, sweet cucumber, lettuce, patients who had 027 infection, 32 (89.7%) had a favorable
corn, and mushrooms tomato, and zucchini response. Unfortunately rest four patients had history of
Fruits Apples, apricots, Banana, blueberries, long standing diarrheal disease with comorbidities did
figs, pears, mango, strawberries, cherries, not improve and died. However, no human trial of FMT
watermelon, peaches, kiwi, orange, grapes, and
is available in PI-IBS but success in other areas offers
and plums melon
legitimacy for using this therapy and conducting a large
Grains Rye, wheat containing Gluten-free bread, oats,
breads, wheat-based gluten-free pasta, rice, trial.
cereals with dried fruit, and quinoa
wheat pasta, and barley
Conclusion
Meat Meats, fish, and chicken
Dairy Cow’s milk, custard, and Lactose-free milk and Post-infectious IBS represents a frequently occurring new
ice cream yoghurt clinical entity which has led to better understanding of
Alternatives Legumes/pulses, Tofu, almonds
the factors involved in pathophysiology of IBS. ROME IV
cashews, and pistachios (<10 nuts) and pumpkin recognizes post-infectious IBS, a multidimensional clinical
seeds chronic inflammation triggered by enteric infection. Present
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
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