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Key Features

Essentials of Diagnosis

  • Elevated total and conjugated bilirubin

  • Hepatomegaly and dark urine

  • Patency of extrahepatic biliary tree

General Considerations

  • Characterized by impaired hepatocyte secretion of bile and patency of the extrahepatic biliary system

  • A specific cause can be identified in about 60% of cases

  • Infectious agents include

    • Herpes simplex virus

    • Varicella virus

    • Enteroviruses (coxsackievirus and echovirus)

    • Cytomegalovirus (CMV)

    • Rubella virus

    • Adenovirus

    • Parvovirus

    • Human herpesvirus type 6 (HHV-6)

    • Hepatitis B virus (HBV)

    • HIV

    • Treponema pallidum

    • Toxoplasma gondii

Clinical Findings

Symptoms and Signs

  • Clinical symptoms typically present in the first 2 weeks of life but may appear as late as age 2–3 months

  • Infant may have jaundice, petechiae, or rash and generally appears ill

  • Poor oral intake, poor sucking reflex, lethargy, hypotonia, and vomiting are frequent

  • Stools may be normal to pale in color but are seldom acholic

  • Dark urine stains the diaper

  • Firm hepatomegaly is present

  • Splenomegaly is variably present

  • Unusual presentations include neonatal liver failure, hypoproteinemia, anasarca (nonhemolytic hydrops), and hemorrhagic disease of the newborn.

Differential Diagnosis

  • Galactosemia

  • Hereditary fructose intolerance

  • Tyrosinemia

  • Concomitant bacteremia

  • α1-Antitrypsin deficiency

  • Cystic fibrosis

  • Bile acid synthesis defects

  • Progressive familial intrahepatic cholestasis

  • Mitochondrial respiratory chain disorders

  • Neonatal iron storage disease

  • Alagille syndrome, arthrogryposis/renal dysfunction/cholestasis (ARC) syndrome or Zellweger syndrome

  • Idiopathic neonatal hepatitis


Laboratory Findings

  • Neutropenia, thrombocytopenia, and mild hemolysis are common

  • Mixed hyperbilirubinemia, elevated aminotransferases with near-normal alkaline phosphatase, prolongation of clotting studies, mild acidosis, and elevated cord serum IgM suggest congenital infection

  • Nasopharyngeal washings, urine, stool, serum, and cerebrospinal fluid (CSF) should be cultured for virus and tested for pathogen-specific nucleic acid

  • Specific IgM antibody may be useful

  • Serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bile acids are typically elevated


  • Long-bone radiographs can show "celery stalking" in the metaphyseal regions of the humeri, femurs, and tibias

  • When indicated, computed tomography (CT) scans can identify intracranial calcifications (especially with CMV and toxoplasmosis).

  • Hepatobiliary scintigraphy shows decreased hepatic clearance of the circulating isotope with intact excretion into the gut

Diagnostic Studies

  • Careful ophthalmologic examination may be useful for diagnosis of herpes simplex virus, CMV, toxoplasmosis, and rubella.

  • Percutaneous liver biopsy shows

    • Typical inclusions of CMV in hepatocytes or bile duct epithelial cells

    • Presence of intranuclear acidophilic inclusions of herpes simplex or varicella-zoster virus

    • Presence of adenovirus basophilic intranuclear inclusions

    • Positive immunohistochemical stains for several viruses

  • Viral cultures, immunohistochemical stains, or polymerase chain reaction (PCR) testing of biopsy material may be helpful


  • Acyclovir for herpes simplex virus, varicella; ganciclovir for CMV; supportive/intravenous immunoglobulin for parvovirus; pyrimethamine and sulfadiazine ...

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