Liver & intrahepatic bile ducts

Viral hepatitis

Herpes simplex virus hepatitis

Editor-in-Chief: Debra L. Zynger, M.D.
Raul S. Gonzalez, M.D.

Last author update: 10 December 2020
Last staff update: 29 July 2022

Copyright: 2019-2023,, Inc.

PubMed Search: Herpes simplex virus hepatitis

Raul S. Gonzalez, M.D.
Page views in 2022: 1,348
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Cite this page: Gonzalez R. Herpes simplex virus hepatitis. website. Accessed June 2nd, 2023.
Definition / general
  • Rare complication of herpes infection resulting in geographic (nonzonal) hemorrhagic necrosis that is usually fatal
  • 1% of acute liver failure (Clin Transplant 2009;23:37)
Essential features
  • Geographic (nonzonal) hemorrhagic necrosis
  • Usually pregnant women or immunocompromised patients
  • Often clinically unsuspected (Liver Transpl 2007;13:1428)
  • Often not diagnosed until autopsy due to nonspecific clinical features
  • Immunocompromised patients are most susceptible
  • Immunocompetent patients can be affected (Am J Clin Pathol 1986;85:694)
  • Risk factors include malignancy and pregnancy (mean 31 weeks) (Hum Pathol 1992;23:183)
  • Neonates can also acquire herpes congenitally (as it is one of the TORCH infections), with roughly a quarter of them at risk for developing fulminant hepatitis
  • Liver
  • HSV1 or HSV2
Clinical features
  • HSV DNA can be detected in the blood
  • 58% diagnosed at autopsy via histologic and immunohistochemical analysis of liver tissue (Liver Transpl 2007;13:1428)
  • Marked elevation of liver serum markers (AST, ALT, bilirubin, alkaline phosphatase, GGT)
  • Leukopenia
  • HSV DNA identified via PCR
Radiology images

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No liver abnormalities

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Lesions mimicking abscess

Prognostic factors
  • Rapid downhill course with acute liver failure, usually fatal (up to 81% of adults) due to massive hepatic necrosis (Clin Transplant 2009;23:37), even with rapid antiviral therapy or liver transplantation (Liver Transpl 2008;14:1498)
  • Better survival after transplantation in children (69%) than adults (38%) (J Hepatol 2011;55:1222)
  • Worse prognosis (Liver Transpl 2008;14:1498): male gender
    • Age > 40 years
    • Immunocompromised
    • ALT > 5,000 U/L
    • Platelet count < 75 x 103/L
    • Coagulopathy
    • Encephalopathy
    • Absence of antiviral therapy
Case reports
  • Empiric antiviral therapy (acyclovir)
  • Liver transplantation with lifelong acyclovir prophylaxis
Gross images

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Random lobular geographic necrosis

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Soft nodules

Microscopic (histologic) description
  • Geographic (nonzonal) hemorrhagic necrosis
  • Viable and nonviable areas distributed in a patchy, seemingly random fashion, sometimes with a clean separating border
  • Classic nuclear features of herpes infection (margination, multinucleation, molding) are seen in hepatocytes, though multinucleation is not always observed
Microscopic (histologic) images

Contributed by Yubo "Mike" Wu, D.O.
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Low-power necrosis

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Viral cytopathic effect

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HSV immunostain

Positive stains
  • HSV
Sample pathology report
  • Autopsy:
    • Widespread liver necrosis consistent with herpetic hepatitis (see comment)
    • Comment: Geographic (nonzonal) hemorrhagic necrosis of the liver is present, along with viral cytopathic effect in surviving hepatocytes. Immunohistochemistry for HSV1 is positive, confirming the diagnosis.
Differential diagnosis
  • The differential diagnosis includes other causes of hepatic necrosis and other causes of viral cytopathic effect:
    • Hypoperfusion (e.g., due to hypovolemic shock)
      • Can cause zone 3 necrosis
    • Medications that cause hepatic necrosis
      • Acetaminophen causes zone 3 necrosis
      • Unusual substances may primarily induce necrosis in other zones
    • Viral hemorrhagic fever (e.g., yellow fever)
      • Can cause zone 2 necrosis, possibly also with zone 2 necrosis
    • Disseminated intravascular coagulation and eclampsia
      • May cause zone 1 necrosis
    • Cytomegalovirus
      • Can cause prominent "owl's-eye" inclusions in hepatocytes, endothelial cells and biliary epithelium
      • Easier to detect in immunocompromised patients
      • Fulminant hepatic failure is not the typical presentation but can occur
    • Adenovirus
      • Close histologic mimicker of hepatic hepatitis
      • Causes random zones of necrosis and viral cytopathic effect
      • Involved hepatocytes have a basophilic, smudgy nucleus without any multinucleation
      • Immunohistochemistry for adenovirus can distinguish adenovirus from herpes
    • Herpes zoster virus
      • Can cause same histologic picture in liver
      • Generally only occurs in immunocompromised patients
      • HSV immunostain is negative, but VZV staining is positive
    • Measles
      • May cause multinucleation without margination or molding
      • Eosinophilic cytoplasmic inclusions may be detected
      • Necrosis would be spotty
Board review style question #1
    Herpes simplex hepatitis causes necrosis of hepatocytes in what pattern?

  1. Nonzonal necrosis
  2. Zone 1 necrosis
  3. Zone 2 necrosis
  4. Zone 3 necrosis
Board review style answer #1
A. Nonzonal necrosis

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Reference: Herpes simplex virus hepatitis
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