Dr. Malathi Sathiyasekaran, MD, DCH, DM*
Consultant Pediatric Gastroenterologist, KKCTH, SMF and Apollo Hospitals, Chennai.*
Viral hepatitis is the most common cause of liver disease in children. Several viruses can cause hepatitis and the two common presentations are acute and chronic hepatitis. The important early and late complications are acute liver failure, cirrhosis and hepatocellular carcinoma depending on the aetiology. In India, 80% of acute viral hepatitis in children are due to hepatitis A, E or B virus occurring either singly or as co-infection. In 10% of cases Non A to E or non A to G virus such as Coxsackie, CMV, herpes simplex, dengue, Epstein Barr, measles, parvovirus B19, human herpes virus 6, lassa, yellow fever, adenovirus and Echovirus could be the etiological agent. Chronic hepatitis is usually due to hepatitis B, C and D. Knowledge of the aetiology is very crucial especially in those requiring liver transplantation.
Management of Acute Viral Hepatitis
Most of the children with acute viral hepatitis (AVH) will recover spontaneously and require only supportive treatment. During the period of acute illness, the child should avoid undue physical exercise, take adequate calories in the form of nutritious diet, avoid hepatotoxic drugs and constipation. The role of herbal hepatotrophic drugs is controversial. It is of utmost importance to avoid unnecessary medication to children with acute hepatitis, unless the drug is essential and its mechanism of action is well understood. All children with acute hepatitis do not require hospitalization unless there is persistent vomiting, fever, abdominal distension, altered sensorium or gastrointestinal bleed. Older children and adolescents may present with significant and prolonged cholestasis or hyperbilirubinemia. Cholestasis can be treated with ursodeoxycholic acid 10-15 mg/kg/day. Very rarely steroids may be required for the management of severe cholestasis in Hepatitis viral infection.(1) Fluid retention in the form of ascites may be a presentation in some children with AVH and this can be treated with a short course of spironolactone. In the presence of spontaneous bacterial peritonitis antibiotics such as third generation cephalosporin should be prescribed. Fever during AVH should be treated with tepid sponging and paracetamol administered at half the dose, when necessary, NSAIDS should be strictly avoided. If the child is on anticonvulsants such as sodium valproate or phenytoin, it can be switched over to phenobarbitone and if on Antitubercular therapy Rifampicin, Isoniazid and Pyrazinamide should be stopped and ethambutol continued with streptomycin or quinolones. Water-soluble vitamins may be prescribed during acute hepatitis.
Specific therapy
  1. Hepatitis A: Since the majority (>95%) of children with acute hepatitis A recover without any sequelae, no specific antiviral therapy is recommended.
  2. Hepatitis E: Isolated Hepatitis E infection in children is usually mild and does not require any specific treatment. Co-infections with A or B may increase morbidity. No antiviral therapy is recommended.
  3. Hepatitis B: In acute hepatitis B, no antiviral therapy is advised. The incidence of chronicity is inversely proportional to the age of acquisition of the viral infection and in older children only 5% will progress to chronic hepatitis B. There are no drugs available to prevent the progression of acute to chronic hepatitis. These children should be followed up for 6 months to monitor spontaneous clearance of HBsAg.
  4. Hepatitis C: Sporadic acute hepatitis C is not common in children. Acute hepatitis C is not common in children. Acute hepatitis C in comparison to hepatitis B has a higher chance (50-60%) of progression to chronicity and hence it is necessary to consider treatment. Children and adolescents with acute hepatitis C either post-transfusion or following IV drug abuse should be monitored closely for 12 weeks to establish spontaneous seroconversion. Those who have persistent viremia i.e. HCV RNA positive for 12 weeks after the infection are the candidates for treatment with interferon (IFN).(2) Since the genotype plays a major role in the prognosis and therapeutic response, it should be tested before therapy.

    The current recommendation in adults is to initiate treatment with IFN alpha or PEG IFN as early as possible in asymptomatic patients infected with HCV genotype1, while treatment may be delayed in icteric individuals with significant symptoms. Treatment can also be safely delayed in patients with genotype 2 and 3 disease because these individuals clear acute hepatitis C more often than those with genotype 1 and treatment success in chronic HCV is much better. A shorter duration of therapy (12 weeks), compared to that required for the treatment of chronic hepatitis has been suggested.(3)
  5. Hepatitis D: Acute hepatitis can occur only as a co-infection with Type B virus. The incidence of acute liver failure in this type of co-infection is as high as 20%, treatment is only supportive and liver transplant may be required.
  6. Hepatitis F: In a proportion of fulminant A to E hepatitis, electron microscopy has shown small particles resembling bunya or toga virus. These viruses can re-infect the transplanted livers and can produce a hemorrhagic fever like illness. The role of these viruses and its treatment is yet to be established.
  7. Hepatitis G: The prevalence of hepatitis G in children is not known. In a study of children with liver transplant, 30% had hepatitis G without evidence of chronic hepatitis. No treatment is available.
Non A to G hepatitis
Non A - E or non A - G hepatitis can present as a severe form of acute hepatitis without spontaneous recovery and is a common cause of acute liver failure in US and UK. The management is further complicated by the associated bone marrow suppression and aplastic anemia. Parvovirus 19 has been identified in some children with ALF and bone marrow failure.
  1. Measles virus: Measles presenting with anicteric hepatitis is an atypical manifestation of the illness and usually results in spontaneous recovery. Measles virus can trigger autoimmune hepatitis 1 within 3 months of the infection.(4)
  2. Parvovirus B19: Human parvovirus B19 can present with hepatic dysfunction, elevated transaminases and acute liver failure with or without aplastic anemia. Treatment is only supportive.
  3. Herpes Simplex 1 and 2 viruses: HSV hepatitis is usually rare beyond the neonatal period unless the child is immuno compromised. Acyclovir 10-20 mg/kg per dose every 8 hours is the drug of choice for disseminated HSV infection with best results if treatment is initiated on the first day of illness. Liver transplant is indicated in acute liver failure.
  4. Cytomegalovirus:Cytomegalovirus infection usually occurs in neonates presenting as prolonged cholestasis of newborn and later may progress to cirrhosis. If diagnosis is confirmed by PCR then ganciclovir 7.5 mg/kg twice a day for 2 weeks followed by 10 mg/kg three times a week for 3 months is administered.
  5. Epstein Barr virus:EB virus is a herpes virus causing infectious mononucleosis. In childhood, the infection is usually mild. In adolescence, elevated transaminases up to 5 times normal may be detected in 80% of individuals but the hepatitis is usually mild and recovers completely. Treatment is supportive, a combination of intravenous Acyclovir and Prednisolone may improve fever and pharyngeal symptoms in those with fulminant disease.(5) EBV-related post transplantation lymphoproliferative disease is treated by immunosuppression and high dose acyclovir.
  6. Human herpes virus 6: Liver dysfunction in association with HHV6 virus infection which includes an infectious mononucleosis like syndrome, hepatitis or acute liver failure. No antiviral therapy is required unless the child is immunosuppressed, Acyclovir, Ganciclovir, Famciclovir and cidofovir are all effective against herpes viruses.
  7. Varicella Zoster:VZ virus causing liver disease is unusual except in immunosuppressed children with HIV infection or post transplant recipients. These children are treated with intravenous Acyclovir and Famciclovir.
  8. Human Immunodeficiency Virus:Infants with HIV hepatitis may manifest with cholestasis and later present with chronic hepatitis. Liver involvement in HIV infected individuals is indicative or a poor prognosis. Highly Active Anti-Retroviral Therapy (HAART) using a combination of two nucleoside reverse transcriptase inhibitor with a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor has dramatically changed the outlook of management.
  9. Dengue Virus: Hepatitis with hepatomegaly, elevated transaminases especially SGOT/ALT is part of the multi-organ involvement in dengue fever. The elevated transaminases could also be a presentation of ischemic hepatitis. The management is only supportive with fluid therapy.
  10. Yellow Fever Virus: Yellow fever can have a subclinical presentation or result in a fatal disease. In those who survive the illness the hepatocellular regeneration is rapid and post-necrotic fibrosis does not occur. Treatment is only supportive.
  11. Lassa fever: The liver is the main target organ and Lassa virus hepatitis can present with hepatocellular inflammation, necrosis or recover early with regeneration. Ribavirin may be effective for Lassa virus infection.
  12. Other viruses: Echo virus, coxsackie and adeno virus may present in neonates and infants with acute liver failure. Treatment is only supportive.
Management of Chronic Hepatitis Virus
The two viruses which commonly cause chronic hepatitis are hepatitis B and C. In some children who have received multiple transfusions, both the viruses may coexist and in HIV patients hepatitis B or C virus may be present along with HIV changing the management protocol.

Chronic hepatitis B

The critical issue in the treatment of childhood chronic HBV infection is the selection of patients. In chronic HBV, three phases of infection are recognized before viral clearance occurs namely the immune tolerant, immune clearance (or immune active) and inactive phase. The immunotolerant phase, which occurs in those infected early in life, is characterized by the presence of hepatitis B e antigen (HBeAg), high serum HBV DNA levels (> 10⁵ copies/mL), and persistently normal alanine aminotransferase (ALT) levels. The immunotolerant phase is followed by an immune clearance phase, also called "chronic hepatitis B," with elevated serum ALT levels, high HBV DNA levels, and features of chronic hepatitis on liver biopsy and is the phase which responds to therapy. The third phase, the inactive HBsAg carrier state, is heralded by clearance of HBeAg and development of anti-HBe, so-called "HBeAg seroconversion", and characterized by serum HBV DNA 10⁴ copies/mL, normal ALT levels, and minimal activity on liver biopsy. However, some patients develop viral mutations in the immune clearance phase that do not produce or down regulate HBeAg secretion but continue to replicate at high levels. This form of chronic HBV infection is referred to as HBeAg-negative chronic hepatitis B, and is associated with more severe liver disease than HBeAg-positive chronic hepatitis B⁶.

The aim of treatment in children is to stop ongoing viral replication, reduce transmission and prevent or minimize liver damage. The goal of treatment is to achieve seroconversion to anti HBe with normalization of transaminases level and ideally subsequent loss of HBsAg. In children as in adults, the success of treatment is based on seroconversion to anti-HBe and rarely to anti-Hbs. The current status of treatment options for children with chronic hepatitis B are interferon and lamivudine.

Interferon: Interferon alpha (IFN a) is an approved therapy in children with chronic HBV infection. The criteria for IFN selection are children more than 2 years of age with chronic hepatitis B in the immune clearance phase characterized by HBsAg and HBeAg positivity, significant HBV DNA, transaminases more than twice normal and activity on liver biopsy. The efficacy of IFN in children in clearing HBeAg varies between 30-40% but is much lower (8%) in children with infection due to vertical transmission.

Predictors of IFN response: The predictors of IFN response are active hepatitis on histology, low HBV DNA levels (<1000 pg/ml), high serum aminotransferases (> 2 times upper limit of normal), short duration of disease and horizontal transmission.

Dose and duration: IFN a is given (5 mU/m²) subcutaneously 3 times a week for 6 months (24 weeks) in HBeAg positive children and for 48 weeks in HBeAg negative children.(7)

Adverse effects: Children tolerate the drug well, but flu-like symptoms, bone marrow suppression, spontaneous bacterial peritonitis have been reported. Neutropenia and thrombocytopenia though significant are rate. Hypothyroidism, pancreatitis, depression, fatigue and hearing loss are reported but less than in adults. IFN can be given before sleep to reduce the side effects and a dose of paracetamol given 45 minutes before the injection.

Monitoring of children: Children should be monitored frequently both clinically and biochemically. They should be evaluated clinically every week for the first 2 months, then every month till treatment is completed. During evaluation SGPT and hemogram are checked, HBeAg can be done once in 3 months and HBV DNA at the start and end of treatment.

Lamivudine: Lamivudine is an oral pyrimidine analogue which gets incorporated into viral DNA and competitively inhibits viral reverse transcriptase.

Efficacy and adverse effects: It reduces the viral HBV load very effectively but the disadvantage is a rebound viral replication as soon as the drug is withdrawn. Jonas has also shown that 6 months after a 52 week therapy only 17% continued to be HBV DNA and HBeAg negative compare to 13% on placebo⁸. Another problem is the occurrence of YMDD mutant in 19% at the end of one year of therapy and on continuing therapy for one more year the incidence of mutation increased to 64%.8 The lamivudine withdrawal flare noted in adults has not been reported in children. Lamivudine can be prescribed in decompensated liver disease.

Dose and duration of therapy: The recommended dose is 3 mg/kg/day (maximum 100 mg). The duration of therapy is till HBeAg disappears from the serum, anti HBe appears or if neither occurs HBV DNA becomes persistently undetectable. The role of lamivudine as monotherapy in the management of chronic hepatitis B has not given encouraging results.

Combination therapy IFN with Lamivudine: Combo-therapy with different timing of lamivudine and IFN has not given better virological response than IFN alone.

Treatment of children in the immuno tolerant phase: The well accepted recommendation is to treat those children in the immuno clearance phase i.e. they should have elevated transaminases and active hepatitis. This recommendation was probably based on the fact that effective drugs were not available to treat the other phases. In children with chronic hepatitis B, a large number are seen in the immune tolerance phase and a treatment strategy is desirable for this group. Recently a trial with Lamivudine for 8 weeks followed by IFN for 44 weeks has been studied in this group and has shown satisfactory results.(9)

Pegylated interferon: The newer pegylated interferon with the IFN linked to a polyethylene glycol moiety has some advantages over the standard interferon. It has a longer duration of action and hence a weekly dose is sufficient. In children with chronic hepatitis B the present recommendation is to administer standard IFN.

Newer nucleoside analogues - Adefovir dipivoxil: Adefovir is a synthetic acyclic adenine nucleotide analogue and is a potent inhibitor of HBV reverse transcriptase of the wild type HBV and lamivudine resistant mutants. In adults this drug shows good histological, biochemical and virological improvement and has been the saving drug in lamivudine resistance. It can be used as combo therapy along with lamivudine. The incidence of resistance after 3 years of therapy is around 4%. The dose in adults is 10 mg per day. Final reports in children are yet to be published.

Entecavir: Entecavir a guanosine analogue is a potent and selective inhibitor of HBV DNA. In naïve patients entecavir has a better histologic, virologic and biochemical improvement in comparison to lamivudine. The dose in adults is 0.5 mg/day. The drug has not been recommended for children less than 16 years.

Chronic hepatitis C

Children with chronic HCV infection are usually asymptomatic. Those who are HCV RNA positive show a very low rate of spontaneous clearance and though uncommon may progress to cirrhosis and end stage liver disease necessitating treatment of children who are HCV RNA positive.

The aims of treatment are to eradicate HCV infection (loss of HCV RNA in peripheral blood), prevent progression of liver inflammation and fibrosis, normalize liver function and improve quality of life.

Criteria for treatment: Children who are anti HCV positive, HCV RNA positive with or without elevated transaminases should be considered for treatment. Liver biopsy is not always essential.

Drug/dosage and duration of therapy: Current treatment options are IFN or PEG IFN with Ribavirin. In children with chronic HCV infection, IFN 3mU/m2 thrice a week with Ribavirin 15 mg/kg/day is given for 6 months for genotype 2 and 3. The response to therapy is 70%. In genotype 1, the response is 40% with the duration of therapy being 48 weeks.(10) In adults the response to therapy for chronic HCV has improved remarkably with Peg IFN and ribavirin especially in non HCV infection. Data in children with chronic HCV infection treated with combination therapy of Peg IFN Ribavirin is sparse.
Several viruses can cause hepatitis in children, the common ones being the hepatotrophic viruses hepatitis A, B, C and E. Acute viral hepatitis is usually self limiting and antivirals are prescribed only for the herpes group of infections. Chronic hepatitis B and C require treatment with monotherapy or a combination of antivirals and immuno modulating drugs to curtail the progression of the disease and improve the quality of life.
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  5. Anderson JP, Clinical aspects of Epstein Barr virus infection. Scand J Infect Dis 1991;80(Suppl):90-104.
  6. Lok AS, McMahon B. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
  7. Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999;29:163-170.
  8. Jonas MM, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706-1713.
  9. Mieli-Vergani G, Vergani D. Treatment of hepatitis B virus in children: why, whom, how?. Indian J Gastroenterol 2006;25:121-124.
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