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  • Cited by 2
  • Print publication year: 2007
  • Online publication date: December 2009

11 - Neonatal Hepatitis and Congenital Infections

    • By Philip Rosenthal, Professor of Pediatrics and Surgery, Department of Pediatrics, University of California–San Francisco, San Francisco, California; Medical Director, Pediatric Liver Transplant Program, Department of Pediatrics, University of California–San Francisco Children's Hospital, San Francisco, California
  • Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
  • Publisher: Cambridge University Press
  • DOI:
  • pp 232-246


Neonatal hepatitis refers to a heterogeneous group of disorders that result in a somewhat similar morphologic change in the liver of an infant less than 3 months of age in response to various insults. The term neonatal hepatitis has been used at times to include all causes of cholestasis in infancy in which extrahepatic biliary obstruction is excluded. Although in the majority of cases an etiology cannot be found, specific infectious and metabolic causes have been identified that may present as neonatal hepatitis. At final diagnosis, neonatal hepatitis is responsible for approximately 40% of the cases of infants with cholestasis and is the most frequently encountered liver disorder of early infancy. Males usually predominate over females (two to one). Additionally, some familial cases have been reported, suggesting either a maternal environmental factor or autosomal recessive inheritance.

Histologically, there is a loss of the lobular architecture with preservation of the zonal distribution of portal tracts and central veins. There is ballooning degeneration of hepatocytes with fusion of hepatocyte membranes and nuclear transformation into multinucleated giant cells. These multinucleated giant cells are believed to be the response of immature hepatocytes to most forms of injury and are a nonspecific finding in neonatal liver biopsy samples. There may be abundant extramedullary hematopoiesis and variable inflammation (Figure 11.1). Cholestasis may be marked because the newborn already is in a relative state of physiologic cholestasis.

Hamilton, J R, Sass-Kortsak, A. Jaundice associated with severe bacterial infection in young infants. J Pediatr 1963;63:121–32.
Zimmerman, H J, Fang, M, Utili, R. Jaundice due to bacterial infection. Gastroenterology 1979;77:362–74.
Andres, J M, Walker, W A. Effect of Escherichia coli endotoxin on the developing rat liver. I. Giant cell induction and disruption in protein metabolism. Pediatr Res 1979;13:1290–3.
Bolder, U, Ton-Nu, H T, Schteingart, C D. Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion. Gastroenterology 1997;112:214–25.
Borges, M A G, DeBrito, T, Borges, J M G. Hepatic manifestations in bacterial infections of infants and children. Clinical features, biochemical data and morphologic hepatic changes. Acta Hepatogastroenterol 1972;19:328–44.
Lam, H S, Li, A M, Chu, W C W. Mal-positioned umbilical venous catheter causing liver abscess in a preterm infant. Biol Neonate 2005;88:54–6.
Garcia, F J, Nager, A L. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics 2002;109:846–51.
Hoarau, C, Ranivoharimina, V, Chavet-Queru, M S. Congenital syphilis: update and perspectives. Sante 1999;9:38–45.
Herman, T E. Extensive hepatic calcification secondary to fulminant neonatal syphilitic hepatitis. Pediatr Radiol 1995;25:120–2.
Kumar, R, Gupta, N, Sabharwal, A, Shalini. Congenital tuberculosis. Indian J Pediatr 2005;72:631–3.
Montoya, J G, Rosso, F. Diagnosis and management of toxoplasmosis. Clin Perinatol 2005;32:705–26.
Desmonts, G, Couvreur, J. Congenital toxoplasmosis. A prospective study of 378 pregnancies. N Engl J Med 1974;290:1110–16.
Schmidt, D R, Hogh, B, Andersen, O. Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine. Eur J Pediatr 2005;165:19–25.
Nicol, K K, Geisinger, K R. Congenital toxoplasmosis: diagnosis by exfoliative cytology. Diagn Cytopathol 1998;18:357–61.
Munro, S C, Trincado, D, Hall, B, Rawlinson, W D. Symptomatic infant characteristics of congenital cytomegalovirus disease in Australia. J Paediatr Child Health 2005;41:449–52.
Laifer, S A, Ehrlich, G D, Huff, D S. Congenital cytomegalovirus infection in offspring of liver transplant recipients. Clin Infect Dis 1995;20:52–5.
Zuppan, C W, Bui, H D, Grill, B G. Diffuse hepatic fibrosis in congenital cytomegalovirus infection. J Pediatr Gastroenterol Nutr 1986;5:489–91.
Watkins, J B, Sunaryo, F P, Berezin, S H. Hepatic manifestations of congenital and perinatal disease. Clin Perinatol 1981;8:467–80.
Weller, T H, Hanshaw, J B. Virologic and clinical observations on cytomegalic inclusion disease. N Engl J Med 1962;266:1233–44.
Snover, D C, Horwitz, C A. Liver disease in cytomegalovirus mononucleosis: a light microscopical and immunoperoxidase study of six cases. Hepatology 1984;3:408–12.
Greenfield, C, Sinickas, V, Harrison, L C. Detection of cytomegalovirus by the polymerase chain reaction. A simple, rapid and sensitive non-radioactive method. Med J Aust 1991;154:383–5.
Berenberg, W, Nankervis, G. Long-term followup of cytomegalic inclusion disease of infancy. Pediatrics 1970;46:403–10.
Dressler, S, Linder, D. Noncirrhotic portal fibrosis following neonatal cytomegalic inclusion disease. J Pediatr 1978;93:887–8.
Hanshaw, J B. Herpes virus hominis infections in the fetus and newborn. Am J Dis Child 1973;126:546–55.
Twagira, M, Hadzic, N, Smith, M. Disseminated neonatal herpes simplex virus (HSV) type 2 infection diagnosed by HSV DNA detection in blood and successfully managed by liver transplantation. Eur J Pediatr 2004;163:166–9.
Nakamura, Y, Yamamoto, S, Tanaka, S. Herpes simplex viral infection in human neonates: an immunohistochemical and electron microscopic study. Human Pathol 1985;16:1091–7.
Raga, J, Chrystal, V, Coovadia, H M. Usefulness of clinical features and liver biopsy in diagnosis of disseminated herpes simplex infection. Arch Dis Child 1984;59:820–4.
Egawa, H, Inomata, Y, Nakayama, S. Fulminant hepatic failure secondary to herpes simplex virus infection in a neonate: a case report of successful treatment with liver transplantation and perioperative acyclovir. Liver Transplant Surg 1998;4:513–15.
Schluter, W W, Reef, S E, Redd, S C. Changing epidemiology of congenital rubella syndrome in the United States. J Infect Dis 1998;178:636–41.
Monif, G R G, Asofsky, R, Sever, J L. Hepatic dysfunction in the congenital rubella syndrome. BMJ 1966;1:1086–8.
Strauss, L, Bernstein, J. Neonatal hepatitis in congenital rubella. Arch Pathol 1968;86:317–27.
Duff, P. Hepatitis in pregnancy. Semin Perinatol 1998;22:277–83.
Noble, R C, Kane, M A, Reeves, S A. Posttransfusion hepatitis A in a neonatal intensive care unit. JAMA 1984;252:2711–15.
Renge, R L, Dani, V S, Chitambar, S D, Arankalle, V A. Vertical transmission of hepatitis A. Indian J Pediatr 2002;69:535–6.
Leikin, E, Lysikiewicz, A, Garry, D, Tejani, N. Intrauterine transmission of hepatitis A virus. Obstet Gynecol 1996;88:690–1.
Poland, G A, Jacobson, R M. Prevention of hepatitis B with the hepatitis B vaccine. N Eng J Med 2004;351:2832–8.
Tang, J R, Hsu, H Y, Lin, H H. Hepatitis B surface antigenemia at birth: a long-term follow-up study. J Pediatr 1998;133:374–7.
Suskind, D L, Rosenthal, P. Chronic viral hepatitis. Adolesc Med Clinic 2004;15:145–58.
Granovsky, M O, Minkoff, H L, Tess, B H. Hepatitis C virus infection in the mothers and infants cohort study. Pediatrics 1998;102:355–9.
Kumar, R M, Shahul, S. Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol 1998;29:191–7.
Chang, M H. Chronic hepatitis virus infection in children. J Gastroenterol Hepatol 1998;13:541–8.
Realdi, G, Alberti, A, Rugge, M. Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis. Gut 1982;23:270–5.
Hasan, F, Jeffers, L J, Medina, M. Hepatitis-C associated hepatocellular carcinoma. Hepatology 1990;12:589–91.
McHutchison, J G, Gordon, S C, Schiff, E R. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485–92.
Fried, M W, Shiffman, M L, Reddy, K R. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82.
Gonzalez-Peralta, R P. Treatment of chronic hepatitis C in children. Pediatr Transplantation 2004;8:639–43.
Bortolotti, F, Iorio, R, Nebbia, G. Interferon treatment in children with chronic hepatitis C: long-lasting remission in responders, and risk for disease progression in non-responders. Dig Liver Dis 2005;37:336–41.
Kowala-Piaskowska, A, Sluzewski, W, Figlerowicz, M, Mozer-Lisewska, I. Factors influencing early virological response in children with chronic hepatitis C treated with pegylated interferon and ribavirin. Hep Res 2005;32:224–6.
Dalekos, G N, Galanakis, E, Zervou, E. Interferon-alpha treatment of children with chronic hepatitis D virus infection: the Greek experience. Hepatogastroenterology 2000;47:1072–6.
Chen, H L, Chang, M H, Lin, H H. Antibodies to E2 protein of hepatitis G virus in children: different responses according to age at infection. J Pediatr 1998;133:382–5.
Zanetti, A R, Tanzi, E, Romano, L. Multicenter trial on mother-to-infant transmission of GBV-C virus. The Lombardy Study Group on Vertical/Perinatal Hepatitis Viruses Transmission. J Med Virol 1998;54:107–12.
Woelfle, J, Berg, T, Keller, K M. Persistent hepatitis G virus infection after neonatal transfusion. J Pediatr Gastroenterol Nutr 1998;26:402–7.
Naoumov, N V, Petrova, E P, Thomas, M G. Presence of a newly described human DNA virus (TTV) in patients with liver disease. Lancet 1998;352:195–7.
Okamoto, H, Akahane, Y, Ukita, M. Fecal excretion of a nonenveloped DNA virus (TTV) associated with posttransfusion non-A-G hepatitis. J Med Virol 1998;56:128–32.
Koidl, C, Michael, B, Berg, J. Detection of transfusion transmitted virus DNA by real-time PCR. J Clin Virol 2004;29:277–81.
Abzug, M J. Prognosis for neonates with enterovirus hepatitis and coagulopathy. Pediatr Infect Dis J 2001;20:758–63.
Kawashima, H, Ryou, S, Nishimata, S. Enteroviral hepatitis in children. Pediatr Int 2004;46:130–4.
Abzug, M J. Presentation, diagnosis, and management of enterovirus infections in neonates. Paediatr Drugs 2004;6:1–10.
Pardi, D S, Romero, Y, Mertz, L E. Hepatitis-associated aplastic anemia and acute parvovirus B19 infection: a report of two cases and a review of the literature. Am J Gastroenterol 1998;93:468–70.
Granot, E, Miskin, H, Aker, M. Monoclonal anti-CD52 antibodies: a potential mode of therapy for parvovirus B19 hepatitis. Transplant Proc 2001;33:2151–3.
Tajiri, H, Tanaka-Taya, K, Ozaki, Y. Chronic hepatitis in an infant, in association with human herpesvirus-6 infection. J Pediatr 1997;131:473–5.
Landing, B H. Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst: the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 1974;4:113–39.
Steele, M I, Marshall, C M, Lloyd, R E. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 1995;21:697–702.
Tyler, K L, Sokol, R J, Oberhaus, S M. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998;27:1475–82.
Phillips, M J, Blendis, L M, Poucell, S. Syncytial giant-cell hepatitis: sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features. N Engl J Med 1991;324:455–60.
Kahn, E, Greco, M A, Daum, F. Hepatic pathology in pediatric acquired immunodeficiency syndrome. Human Pathol 1991;22:1111–19.
Poles, M A, Dieterich, D T, Schwarz, E D. Liver biopsy findings in 501 patients infected with human immunodeficiency virus (HIV). J AIDS Hum Retrovirol 1996;11:170–7.
Laxer, R M, Roberts, E A, Gross, K R. Liver disease in neonatal lupus erythematosus. J Pediatr 1990;116:238–42.
Lee, L A, Sokol, R J, Buyon, J P. Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics 2002;109:E11.
Alpert, L I, Strauss, L, Hirschhorn, K. Neonatal hepatitis and biliary atresia associated with trisomy 17–18 syndrome. N Engl J Med 1969;280:16–20.
Schwab, M, Niemeyer, C, Schwarzer, U. Down syndrome, transient myeloproliferative disorder, and infantile liver fibrosis. Med Pediatr Oncol 1998;31:159–65.
Pratt, D S. Cholestasis and cholestatic syndromes. Curr Opin Gastroenterol 2005;21:270–4.
Mil, S W, Houwen, R H, Klomp, L W. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet 2005;42:449–63.
Krantz, I D, Piccoli, D A, Spinner, N B. Alagille syndrome. J Med Genet 1997;34:152–7.
Bull, L N, Eijk, M J, Pawlikowska, L. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998;18:219–24.
Vivarelli, R, Grosso, S, Cioni, M. Pseudo-TORCH syndrome or Baraitser-Reardon syndrome: diagnostic criteria. Brain Dev 2001;23:18–23.
Sanchis, A, Cervero, L, Bataller, A. Genetic syndromes mimic congenital infections. J Pediatr 2005;146:701–5.
Knoblauch, H, Tyennstedt, C, Brueck, W. Two brothers with findings resembling congenital intrauterine infection-like syndrome (pseudo-TORCH syndrome). Am J Med Genet A 2003;120:261–5.
Hadzic, N, Portmann, B, Lewis, I, Mieli-Vergani, G. Coombs positive giant cell hepatitis-a new feature of Evans' syndrome. Arch Dis Child 1998;78:397–8.
Akylidiz, M, Karasu, Z, Arikan, C. Successful liver transplantation for giant cell hepatitis and Coombs-positive haemolytic anemia: a case report. Pediatr Transplant 2005;9:630–3.
Balistreri, W F, Grand, R, Hoofnagle, J H. Biliary atresia: current concepts and research directions. Summary of a symposium. Hepatology 1996;23:1682–92.
Bates, M D, Bucuvalas, J C, Alonso, M H. Biliary atresia: pathogenesis and treatment. Semin Liver Dis 1998;18:281–93.
Tazawa, Y, Abukawa, D, Maisawa, S. Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis. Dig Dis Sci 1998;43:392–6.
Shet, T M, Kandalkar, B M, Vora, I M. Neonatal hepatitis — an autopsy study of 14 cases. Ind J Pathol Microbiol 1998;41:77–84.
Nishinomiya, F, Abukawa, D, Takada, G. Relationships between clinical and histological profiles of non-familial idiopathic neonatal hepatitis. Acta Paediatr Jpn 1996;38:242–7.
Ruebner, B, Thaler, M M. Giant-cell transformation in infantile liver disease. In: Javitt, N B, ed. Neonatal hepatitis and biliary atresia. DHEW publication no. (NIH) 79–1296. Bethesda, MD: U.S. Department of Health, Education and Welfare, 1979: 299–314.
Park, W H, Kim, S P, Park, K K. Electron microscopic study of the liver with biliary atresia and neonatal hepatitis. J Pediatr Surg 1996;31:367–74.
Moore, L, Bourne, A J, Moore, D J. Hepatocellular carcinoma following neonatal hepatitis. Pediatr Pathol Lab Med 1997; 17:601–10.
Suita, S, Arima, T, Ishii, K. Fate of infants with neonatal hepatitis: pediatric surgeons' dilemma. J Pediatr Surg 1992;27:696–9.
Dick, M C, Mowat, A P. Hepatitis syndrome in infancy – an epidemiological survey with 10 year follow up. Arch Dis Child 1985;60:512–16.
Lee, P I, Chang, M H, Chen, D S. Prognostic implications of serum alpha-fetoprotein levels in neonatal hepatitis. J Pediatr Gastroenterol Nutr 1990;11:27–31.
Chang, M H, Hsu, H C, Lee, C Y. Neonatal hepatitis: a follow-up study. J Pediatr Gastroenterol Nutr 1987;6:203–7.
Deutsch, J, Smith, A L, Danks, D M. Long-term prognosis for babies with neonatal liver disease. Arch Dis Child 1985;60:447–51.