Pediatric Liver Disease in India

Abbreviations

CLD

chronic liver disease

EHPVO

extrahepatic portal venous obstruction

HAV

hepatitis A virus

HEV

hepatitis E virus

ICC

Indian childhood cirrhosis

LT

liver transplant

MLD

metabolic liver disease

NAFLD

nonalcoholic fatty liver disease

NCPF

noncirrhotic portal fibrosis

WD

Wilson’s disease

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In India, liver diseases were recognized and documented by the healers of Ayurvedic medicine thousands of years ago, even before the birth of Hippocrates. Sushruta (sixth century BCE) and Charaka (first century BCE) were acclaimed for their detailed medicosurgical treatises on liver diseases. The entrance of allopathy into India, a land of traditional medicine, was a breakthrough in medical practice. Over the past five decades there has been a paradigm shift in etiology, diagnosis, and management of pediatric liver diseases in India. This shift probably parallels the economic growth, increase in gross domestic product, and improved living standards in India. Liver diseases that were unique to the Indian subcontinent such as Indian childhood cirrhosis (ICC) have disappeared, infectious and tropical diseases are on a declining trend, whereas metabolic liver diseases (MLDs) are increasingly being diagnosed and newer global lifestyle disease such as fatty liver is on the rise.

Originally described in 1887 as “infantile cirrhosis” by B.C. Sen from Kolkata, and later termed ICC, it classically presents in the age group of 1 to 3 years with liver failure and excess copper on liver histology and is associated with high mortality. ¹ Historically, ICC was synonymous with chronic liver disease (CLD) in India, but by the 1980s, there was a steep decline when copper cooking utensils were replaced by stainless steel. Although genetics and environmental factors have been implicated as causes, the etiology, however, is still elusive. ²

Hepatobiliary infections caused by viruses, bacteria, protozoa, and helminths have been a perpetual and disturbing problem. Viral hepatitis is still endemic in India, and around 291 outbreaks have been reported between 2011 and 2013 by the Centre for Disease Control. ³ Hepatitis A virus (HAV) is the most common cause of sporadic acute viral hepatitis, whereas nearly all the major epidemics have been caused by hepatitis E virus (HEV). ⁴ Although the overall seroprevalence of antibodies to HAV is >80% to 90%, there has been a recent change in epidemiology with primary infection happening in the older age group because of improved living conditions. ⁴ Superadded infection with HAV or HEV unmasks quiescent or undiagnosed underlying CLD, resulting in acute decompensation, and presents as acute liver failure or acute‐on‐chronic liver failure. With regard to hepatitis B and C infection, India is ranked as a moderately prevalent country among Asian countries. The government is actively striving toward preventing blood‐borne transmission by mandatory antenatal screening for hepatitis B and C, universal immunization of hepatitis B vaccine, and standardized screening for all blood transfusion products. Amoebic liver abscess and hydatid cysts caused by entamoeba histolytica and echinococcus granulosis, respectively, have been widely reported from India, while biliary ascariasis is more endemic in the Kashmir valley. ⁵

Wilson’s disease (WD) is the most common cause of MLDs in India, but so far the prevalence in the general population is not known. ⁶ Several novel new genetic mutations for WD have been identified in India, which hinder the genetic diagnosis. Penicillamine is freely available at government hospitals, but switching over to trientine in case of a penicillamine‐related complication is not feasible in many because of the high cost. The wide availability of tandem mass spectroscopy and genetic testing has assisted in early identification of several MLDs. The high mortality (64%) and neurological sequelae (70%) in a cohort of 123 children with urea cycle defects is an eye‐opener for the need for early diagnosis and prompt therapy in MLDs. ⁷ There are no published data on the metabolic profile of all infants who present to the neonatal unit with suspected sepsis and succumb, because an underlying metabolic disorder is always possible. Progressive familial intrahepatic cholestasis has been reported as case series from several centers in India, indicating its wide prevalence across India. Although the majority of MLDs seen in the West are reported from India, mutation for alpha‐1‐antitrypsin deficiency is rare.

A study of 517 children with grade 2 or higher esophageal varices at a single center in north India showed that extrahepatic portal venous obstruction (EHPVO) is the most common cause of portal hypertension (54 %) followed by cirrhosis (39%). ⁸ EHPVO is idiopathic in 70% of children. Noncirrhotic portal fibrosis (NCPF) is a disease of uncertain etiology and an important cause of noncirrhotic portal hypertension as seen in older children. Microangiopathy of terminal branches of the portal vein resulting in occlusion and portal hypertension is the underlying pathology of NCPF. ⁹ Several centers in India have reported a decrease in incidence of NCPF, probably because of alteration of environmental factors.

Late referral of neonatal cholestasis (infants older than 60 days) has decreased from 49% in 2005 to 29% in 2017 as a result of regular health education. ¹⁰ Our latest care pathway for infants younger than 3 months with pale stools and high gamma‐glutamyl transferase cholestasis without dysmorphic features is to perform a preoperative cholangiogram followed by Kasai portoenterostomy (if needed), thus skipping preoperative liver biopsy. This avoids unnecessary surgical delay because only a few specialized centers have on‐site histopathologists competent in reporting pediatric liver pathology.

The prevalence of severe undernutrition‐associated fatty liver has declined, whereas overweight with nonalcoholic fatty liver disease (NAFLD) is on the rise. In a cross‐sectional study done on school children aged 5 to 10 years, 19% of normal‐weight children and 37% of overweight children had NAFLD. ¹¹ The estimated prevalence rate of overweight children in India by 2030 is 17.5%, while the target set by the World Health Organization and United Nations Children’s Emergency Fund is less than 3%. ¹² This clearly shows the need for a huge effort to combat this problem at individual and community levels.

Liver transplantation in India mainly depends on live donation because deceased donation rate is low, and centralized organ allocation system is not available in many states. Although the first successful pediatrics liver transplant (LT) in India was done in 1998, it was followed by a relatively low number of pediatric LTs over the next 10 years. The reasons being lack of awareness, unaffordability, and accessibility to proper treatment by the population. With visible success and improved survival after LT, the number of LTs started to increase in the beginning of the last decade, although the total number of pediatric LTs still remains less than 150 per year despite the projected need for 3000 per year. ¹³ Although affordability is an issue, few of the states in India are providing financial assistance to individuals with poor socioeconomic background for LT.

Over the years we have traversed a long way in understanding the etiopathogenesis and management of various pediatric liver diseases in India. However, we still need a multipronged approach for optimal outcome. Primordial prevention of communicable disease and lifestyle disease by school health education and community awareness programs, secondary prevention by sensitizing practicing pediatricians on early diagnosis of common pediatric liver problems, and tertiary prevention by early referral to dedicated tertiary liver hospitals would help in decreasing the disease load and improve the outcomes.