Liver & intrahepatic bile ducts

Drug / toxin induced hepatitis

Checkpoint inhibitor associated hepatitis

Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Yevgen Chornenkyy, M.D., M.Sc.
Maryam Kherad Pezhouh, M.D., M.Sc.

Last author update: 11 June 2020
Last staff update: 11 June 2021

Copyright: 2020-2024,, Inc.

PubMed Search: Checkpoint inhibitor associated hepatitis pathology

Yevgen Chornenkyy, M.D., M.Sc.
Maryam Kherad Pezhouh, M.D., M.Sc.
Page views in 2023: 1,285
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Cite this page: Chornenkyy Y, Pezhouh MK. Checkpoint inhibitor associated hepatitis. website. Accessed April 14th, 2024.
Definition / general
  • Immune related adverse event secondary to immune checkpoint inhibitors such as anti-PD1 (nivolumab, pembrolizumab), anti-PDL1 (atezolizumab, avelumab, darvalumab) and anti-CTLA4 medications (ipilimumab and tremelimumab)
Essential features
  • Incidence varies; CTLA4 inhibitors are slightly more hepatotoxic than PD1 inhibitors; combination therapy increases risk
  • Presents as mild acute hepatitis pattern of injury (panlobular hepatitis), perivenular infiltrate with endothelialitis, biliary pattern with bile ductular proliferation, mixed portal inflammation with little lobular necroinflammation
ICD coding
  • ICD-10: K71.6 - Toxic liver disease with hepatitis, not elsewhere classified
  • Caused by immune dysregulation secondary to immune therapy
Clinical features
  • Elevation of liver function tests with history of immune therapy medication use, along with characteristic biopsy related changes and excluding other causes of liver injury
  • Most common finding is asymptomatic elevation of liver function tests (AST / ALT)
Radiology description
Prognostic factors
  • Normalization of liver function tests and response to steroids after discontinuation of checkpoint inhibitors; however, disease can still progress histologically even when liver function tests normalize (JHEP Rep 2019;1:66)
Case reports
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Yevgen Chornenkyy, M.D., M.Sc. and Maryam Kherad Pezhouh, M.D., M.Sc.

Nivolumab: lobular inflammation

Nivolumab: portal inflammation

Pembrolizumab: lobular inflammation

Pembrolizumab: portal inflammation

Immunohistochemistry & special stains
  • Large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and CD4+ T cells are fewer in checkpoint inhibitor induced liver injury than in autoimmune hepatitis or drug induced liver injury (Mod Pathol 2018;31:965)
  • Anti-PD1 / L1 hepatitis: similar proportions of CD4+ and CD8+ infiltrates in portal tracts, with CD8+ cells dominating lobular infiltrates
  • Anti-CTLA4 hepatitis: predominance of CD8+ cells in portal tracts and lobules
Sample pathology report
  • Liver, biopsy:
    • Liver with moderate portal and lobular lymphocyte infiltrate with mild bile duct injury, most consistent with medication associated injury (see comment)
    • Comment: Patient history of advanced melanoma status posttreatment with nivolumab and negative viral and autoimmune serologies are noted. The majority of the portal tracts and lobules are involved by moderate lymphocytes with scattered eosinophils and plasma cells with focal bile duct injury. Overall, the findings are most consistent with immune therapy associated liver injury.
Differential diagnosis
  • Other causes of immune mediated hepatitis include:
    • Viral hepatitis:
      • Acute:
        • Lobular disarray with diffuse lobular inflammation, hepatocyte swelling, necrosis and regeneration
        • Lobular inflammation generally exceeds portal inflammation
      • Chronic:
        • Predominantly portal or periportal hepatitis with varying degrees of parenchymal inflammation, hepatocellular injury and fibrosis
    • Graft versus host disease:
      • Bile duct epithelial cell damage is key distinguishing feature differentiating GVHD from other types of hepatic injury
      • Endotheliitis can also be present
    • Autoimmune hepatitis:
      • Can be treated or untreated
        • If treated, the biopsy may be normal or contain mild chronic hepatitis without specific histological features
        • If untreated, the biopsy can contain chronic hepatitis with plasma rich inflammation and interface activity
Board review style question #1
Which of the following are typical features of checkpoint inhibitor associated hepatitis?

  1. Bridging fibrosis with lobular atrophy
  2. Macrovesicular and microvesicular steatosis
  3. Mallory-Denk bodies and hepatocyte ballooning
  4. Mild portal tract inflammation with mild lobular activity
Board review style answer #1
D. Mild portal tract inflammation with mild lobular activity

Comment Here

Reference: Checkpoint inhibitor associated hepatitis
Board review style question #2

A 67 year old man with a history of autoimmune hepatitis completed 6 cycles of pembrolizumab therapy for metastatic melanoma. He began developing abdominal pain and jaundice, with ALT > 1,000 IU/L. He underwent a liver biopsy and findings are shown above. Which of the following findings favors checkpoint inhibitor hepatitis over autoimmune hepatitis?

  1. Dense portal based plasma cell rich inflammatory infiltrates with interface activity
  2. Hepatocytic swelling, spotty necrosis, multiple lobular granulomata
  3. Macrovesicular steatosis, zone 3 ballooning, Mallory-Denk bodies
  4. Mild lobular and portal activity
Board review style answer #2
D. Mild lobular and portal activity

Comment Here

Reference: Checkpoint inhibitor associated hepatitis
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