VIRAL HEPATITIS

Acute hepatitis is a clinical syndrome of heterogeneous etiology (Table 15.6), characterized by abrupt onset of clinical jaundice and/or laboratory evidence of hepatic dysfunction, e.g.

Viral hepatitis refers to primary infection of the liver due to heterogeneous group of specific hepatotropic viruses, designated as A-G. Hepatitis due to other viruses, e.g. CMV, HSV, EBV, etc. is generally excluded from this terminology.

While liver pathology in all hepatotropic viral infections is nearly similar during acute stage (centrilolobular necrosis and periportal infiltration without destruction of normal architecture); route of infection, severity/ duration of disease and later course differs significantly (Table 15.7).

TABLE 15.6: Common causes of acute hepatitis

• Infective:

- Hepatotropic viruses: HAV, HBV, HCV, HEV

- Other viruses: CMV, EBV, dengue

- Bacterial: Septicemia, enteric fever, leptospirosis

- Others: Amoebiasis, malaria, brucellosis

• Drugs and Toxins:

- Drug-induced: INH, Rifampicin, Valproate

- Poisoning: Paracetamol, pesticides

• Metabolic:

- Reye syndrome

- Others: Wilson disease*

• Others:

- Autoimmune hepatitis*

- Budd-Chiari syndrome

- Acute cholestatic syndromes

*Acute manifestation of chronic disease

Hepatitis A (HAV) is the commonest cause of viral hepatitis in children, though clinical disease is mild, self­limiting and generally benign. Complications, e.g. acute liver failure or chronic liver disease are extremely rare. Epidemiology: HAV is excreted in stools of a clinical or subclinical case and transmitted via feco-oral route by ingestion of contaminated water/food.

High-risk factors: Focal outbreaks are common in summer and rainy season, specially in unsanitary slums with contaminated water supply.

Clinical manifestations: Incubation period varies from 15 to 45 days. HAV infection is relatively mild in children than in adults and presents as anicteric or icteric disease.

Anicteric hepatitis accounts for gt;80% of HAV infections, presenting as low-grade fever, vomiting, diarrhea, mild tender hepatomegaly and borderline liver function tests abnormalities for 1-2 weeks.

Icteric hepatitis indicates more severe hepatic injury, with appearance of jaundice after few days of prodromal symptoms and more moderate hepatomegaly. Symptoms tend to improve once the jaundice sets in, which lasts for 2-3 weeks. Mild pruritis is common, specially in recovery phase.

TABLE 15.7: Common hepatotropic viral infections

Ent: Enteral; Prnt: Pareteral; Pnt: Perinatal; NS: Non-specific; NTdA: Nucleos(t)ide analogues; DAA: Direct acting antivirals

Diagnosis may be confirmed by presence of anti-HAV IgM antibodies in second week.

Liver function tests are indicated as base-line para­meter, though serial testing is unnecessary in clinically improving case. Serum alkaline phosphatase may be elevated in recovery phase due to transient cholestasis.

Presence of bile salts and pigments in urine is a simple screening method in hepatitis, tested by Hay's sulfur test and Fouchet test respectively (Ch 21.2).

D/D includes other causes of acute hepatitis (Table 15.6), closest being HEV and drug-induced hepatitis. Treatment: HAV hepatitis is self-limiting, without specific therapy except nutritious high carbohydrate diet and avoidance of excessive fat. Complications, e.g. fulminant hepatic failure are extremely rare, except in cases with pre-existing liver disease (lt;1%). Some cases may develop prolonged cholestasis waxing and waning course but with eventually complete recovery.

Prevention of HAV depends on:

• Public health measures, i.e. improvement of sanitation and potable water supply. Patients are contagious from 2 weeks before to about a week after the onset of jaundice.

• Personal protection, i.e. use of boiled or UV exposed water, specially during epidemics,

• Active immunization with either two doses of inactivated HAV vaccine in second year of life at 6-18 months interval or a single dose of Live HAV vaccine at 12 months of age. While not yet included in National Immunization schedule, IAP recommends HAV immunization to all children, specially those with—(a) chronic liver disease, or (b) institutionalized care, e.g. orphanages.

Catch-up immunization is recommended till 10 years, while pre-vaccination screening for HAV antibodies is advised before vaccination in older children (gt;10 years) due to substantial chance of natural infection and immunity by this age.

• Post-exposure prophylaxis is indicated in household contacts within 10 days of exposure, preferably with initiation of HAV vaccination.

Hepatitis B (HBV), though less common than HAV, is an important health problem due to higher risk of late complications, e.g. chronic liver disease, cirrhosis and hepatocellular carcinoma. India is in the intermediate risk zone of HBV prevalence, with chronic carrier rate of ~3-4%.

Epidemiology: HBV, also referred as Dane particle, is a DNA virus containing many antigens, most important being a surface antigen (HbsAg), a core antigen (HbcAg) and a non-structural antigen (HbeAg).

Persons with chronic HBV infection are primary reservoir of infection. Children are usually infected from mothers (perinatal/vertical transmission), though horizontal transmission via parenteral route, i.e. transfusions, accidental needle pricks, drug abuse or sexual contact is not uncommon.

Risk of perinatal transmission is highest when mother is both HbsAg and HbeAg positive (70-90%), than in HbeAg negative mothers (25%), if HB vaccine with/without immunoglobulins (HBIG) is not given within 24 hours. Clinical spectrum: Perinatal HBV infections are gene­rally asymptomatic in childhood, despite potential risk for future liver disease. A symptomatic case presents after an incubation period of 50-180 days, with:

• Non-specific prodrome, e.g. lethargy, anorexia and malaise

• Icterus in lt;25% cases, lasting for ~ 4 weeks,

• Extra-hepatic manifestations of probable immune etio­logy, e.g. arthralgia/arthritis, rash or papular acroder­matitis (Gianotti-Crosti syndrome), glomerulonephritis and aplastic anemia, for 2-3 weeks.

Unless complicated by fulminant liver failure, acute episode lasts for 4-6 weeks.

Complications: HBV infection is associated with considerable early and late morbidity, including (a) acute fulminant liver failure in 30%, (b) chronic liver disease, including cirrhosis in 40% and (c) hepatocellular carcinoma in lt;5-10%. Except acute liver failure, other complications may develop even in asymptomatic cases or carriers.

Infections acquired before 5 years of age are more likely to become chronic carriers-defined as HbsAg positivity beyond 6 months. Risk of chronic carrier state after HBV infection is gt;90% in perinatally infection versus 5% in adults infections.

Diagnosis is serological and various markers are used to define chronicity and infectivity of the infection (Fig. 15.1).

HBsAg is the first serological marker to appear after infection, present in almost all infected children. Clinical significance of other seromarkers includes:

• Persistence of HBsAg indicates a carrier state or chronic infection, while its disappearance within 3-6 months indicates resolution of infection.

• Presence of HBeAg indicates high infectivity and HBeAg positive mothers are more likely to transfer infection to their baby.

• Anti-HBcAg is the most useful marker to differentiate HBV immunized vs infected children. While anti- HBsAg is present in both, anti-HBcAg is positive only in natural infection.

• Presence of anti HBeAg antibodies indicates lesser risk of infectivity.

Fig. 15.1: Natural course and sero-markers in HBV infection.

Treatment of acute HBV infection is entirely supportive, including monitoring for acute hepatic failure. For treatment of chronic HBV infection, see Ch 15.8.

Prevention of HBV revolves around pre-and post­exposure immunization as well as strict screening of transfusion products.

• Infants born to HbsAg positive mothers should receive HB vaccine as well as HBIG (0.5 ml each, at different sites) as early as possible, preferably within 12 hours of birth, followed by HB vaccine after 1 and 6 months (or three doses as in NIS/IAP schedule). Efficacy of perinatal HBV prophylaxis is 90-95%.

However, all children should be re-screened after 1 year for HBsAg as well as anti-HbsAg. While presence of anti-HbsAg indicates that the baby is immune, HbsAg positivity without anti-HbsAg indicates infection without immunity and probability of progressive liver disease.

• Routine immunization with four doses are given in national immunization schedule at birth as stand­alone vaccine and 6, 10 and 14 weeks as pentavalent vaccine. HB vaccine is specially indicated in children with hemolytic anemia or haemophilia on multiple transfusions. Catch-up immunization in older unimmunized children or adults is indicated with three-dose 0,1, 6 months schedule.

Hepatitis C (HCV) is an emerging transfusion-related infection, which has already infected ~ 3% of world population. Exact incidence in India is not known due to limited diagnostic facilities, though HCV screening for all blood products is compulsory here since 1998.

Epidemiology: HCV infection in children is almost always transmitted via infected blood transfusion. Perinatal risk of transmission from viremic mothers is only ~ 5%. Clinical spectrum is milder than HBV disease. Most cases are asymptomatic in early stage and clinical jaundice is seen in lt;25%. However, 20-50% cases progress to develop chronic liver disease, cirrhosis and hepatocellular carcinoma after many years. Chronic infection may also be associated with small vessel vasculitis and extrahepatic manifestations in adults.

Diagnosis of acute HCV disease is possible with HCV- PCR (RNA) assay after 2 months of age/exposure while serological tests turn positive only after 3-4 months of clinical illness. HCV-RNA should be repeated at ~3 years of age in children with positive serological tests to confirm chronicity of infection.

Treatment aims to clear viremia, improve liver histology and reduce the risk of chronic liver disease. Genotyping of virus is important before therapy as response may vary.

All children gt;3 years of age with HCV, irrespective of the genotype, must be treated with a fixed-dose combination of directly acting antivirals (DAA) including Sofosbuvir with Velpatasvir, for 12 weeks. Other DAAs or inter- feron/pegylated interferon therapy may be used in children with selected genotypes, including combination therapy in non-responders.

Sequential estimation of HCV-RNA is essential to monitor the therapeutic response.

Prevention: No vaccine is available against HCV and screening of donor blood remains the most effective preventive intervention.

Hepatitis D (HDV) is considered a defective RNA virus, which depends entirely on HBV for its replication. HDV infection may be either a co-infection with HBV or a super-infection, leading to acute exacerbation of chronic HBV infection. Chronic liver disease is more common, when both infection co-exist. HDV has not been isolated and diagnosis depends on detecting specific IgM antibodies.

Hepatitis E (HEV), like HAV, is a fecooral infection through contaminated water, more common in adults than children. Clinical presentation is limited to acute liver disease, which is more severe in adults, specially pregnant women. Pediatric infections are usually mild and sub-clinical. Chronic sequelae are unknown. Diagnosis rests on presence of anti-HEV IgM antibodies and treatment is symptomatic.

Hepatitis G (HGV): Advances in the molecular technology lead to identification of two newer hepatic viruses-hepatitis GB virus (HGBV-C) and hepatitis G virus (HGV). Present evidence suggests that both of them are close variants of same species, transmitted through blood transfusions or organ transplants. No serological test is presently available for diagnosis and clinical spectrum or management is yet to be defined.

15.5