Liver & intrahepatic bile ducts
Drug / toxin induced hepatitis
Checkpoint inhibitor associated hepatitis
Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Topic Completed: 11 June 2020
Minor changes: 2 April 2021
Copyright: 2020-2021, PathologyOutlines.com, Inc.
PubMed Search: Checkpoint inhibitor associated hepatitis pathology
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Pathophysiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Immunohistochemistry | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Chornenkyy Y, Pezhouh MK. Checkpoint inhibitor associated hepatitis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livericpihep.html. Accessed April 19th, 2021.
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
Epidemiology
- Hepatotoxicity presents as elevations of ALT or AST and can occur at any time but typically presents after 6 - 12 weeks of therapy (J Clin Oncol 2012;30:2691)
- The rate of hepatotoxicity varies between different inhibitors
- With CTLA4 inhibitors, the incidence of all grade hepatotoxicity is 3 - 9% (J Clin Oncol 2012;30:2691)
- With PD1 inhibitors the rate is 1 - 3% (Lancet 2014;384:1109, N Engl J Med 2015;372:320, Int J Cancer 2017;141:1018)
- Combination therapies increase the risk to 11 - 20% (Stem Cell Investig 2017;4:32, N Engl J Med 2015;372:2006, J Clin Oncol 2017;35:3851)
Pathophysiology
- Caused by immune dysregulation secondary to immune therapy
Clinical features
- Mild serum aminotransferase elevations, usually self limited, occur in approximately 10 - 50% of patients (Proc Natl Acad Sci U S A 2003;100:8372, Ann Oncol 2010;21:1712, Melanoma Res 2013;23:47, Invest New Drugs 2013;31:1071)
- ALT elevations > 3 - 5 times normal (approximately 0.5 - 1.5%), usually respond to corticosteroids (N Engl J Med 2010;363:711, N Engl J Med 2012;366:2443, N Engl J Med 2015;372:2521, Nature 2014;515:558, J Clin Oncol 2017;35:2117)
- Severe cases with systemic symptoms and highly increased levels of liver function tests (ALT > 1,000 IU/L) (Invest New Drugs 2013;31:1071)
- Rare cases of fulminant hepatitis and death
Diagnosis
- 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
Laboratory
- Most common finding is asymptomatic elevation of liver function tests (AST / ALT)
Radiology description
- In severe cases with ALT > 1,000 IU/L, imaging findings were characterized by mild hepatomegaly, periportal edema and periportal lymphadenopathy (Invest New Drugs 2013;31:1071)
- Mild cases showed normal imaging findings (Invest New Drugs 2013;31:1071)
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
- 45 year old man with ipilimumab associated cholestatic hepatitis (Melanoma Res 2017;27:380)
- 48 year old man with lung adenocarcinoma and cholestatic liver injury secondary to pembrolizumab (Intern Med 2019;58:3283)
- 52 year old man with lung and liver metastasis of malignant melanoma developed fulminant hepatitis after 34 weeks of nivolumab treatment (Case Rep Oncol 2017;10:368)
- 53 year old woman with refractory immune checkpoint inhibitor hepatitis successfully treated by infliximab (JHEP Rep 2019;1:66)
- 67 year old man with pembrolizumab induced hepatitis (Pathology 2017;49:789)
- 74 year old woman with recurrent renal cell carcinoma developed nivolumab induced hepatitis (J Oncol Pharm Pract 2020;26:459)
Treatment
- Most patients respond to systemic corticosteroids (JHEP Rep 2019;1:66)
- Discontinuation of offending medication (JHEP Rep 2019;1:66)
- Infliximab can be considered as a rescue therapy (JHEP Rep 2019;1:66)
Microscopic (histologic) description
- Histologic features of both anti-CTLA4 or anti-PD1 / PDL1 associated hepatitis:
- Acute hepatitis pattern (panlobular hepatitis): perivenular infiltrate with endothelialitis (Mod Pathol 2018;31:965)
- Biliary pattern: bile ductular proliferation, mild mixed portal inflammation with little lobular necroinflammation
- Other less common features:
- Centrilobular confluent necrosis, plasmacytosis, bile duct injury, microabscesses (Mod Pathol 2018;31:965)
- Specific for anti-CTLA4 associated hepatitis: granulomatous inflammation, severe lobular necroinflammatory activity and central vein endothelialitis (Rheumatology (Oxford) 2019;58:vii17, J Hepatol 2018;68:1181, Invest New Drugs 2013;31:1071)
- Specific for anti-PD1 / PDL1 associated hepatitis: no granulomatous inflammation, infrequent central vein endothelialitis (Rheumatology (Oxford) 2019;58:vii17, J Hepatol 2018;68:1181, Invest New Drugs 2013;31:1071)
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
- 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
- Acute:
- 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
- Can be treated or untreated
- Viral hepatitis:
Additional references
- J Gastrointest Oncol 2018;9:220, LiverTox: Nivolumab [Accessed 11 June 2020], LiverTox: Pembrolizumab [Accessed 11 June 2020], LiverTox: Atezolizumab [Accessed 11 June 2020], LiverTox: Avelumab [Accessed 11 June 2020], LiverTox: Ipilimumab [Accessed 11 June 2020], LiverTox: Durvalumab [Accessed 11 June 2020]
Board review style question #1
Which of the following are typical features of checkpoint inhibitor associated hepatitis?
- Bridging fibrosis with lobular atrophy
- Macrovesicular and microvesicular steatosis
- Mallory-Denk bodies and hepatocyte ballooning
- Mild portal tract inflammation with mild lobular activity
Board review style answer #1
D. Mild portal tract inflammation with mild lobular activity
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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?
- Dense portal based plasma cell rich inflammatory infiltrates with interface activity
- Hepatocytic swelling, spotty necrosis, multiple lobular granulomata
- Macrovesicular steatosis, zone 3 ballooning, Mallory-Denk bodies
- Mild lobular and portal activity
Board review style answer #2
D. Mild lobular and portal activity
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