Hepatitis is inflammation of the liver, which can have a variety of etiologies.
Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis resolve spontaneously, but some progress to chronic hepatitis.
Common Causes of Hepatitis
Common causes of hepatitis include:
Specific hepatitis viruses
Metabolic dysfunction-associated steatotic liver disease (MASLD) [previously called nonalcoholic fatty liver disease (NAFLD)]
Medications (eg, isoniazid)
At least 5 specific viruses appear to be responsible for hepatitis (see table ). Other unidentified viruses probably also cause acute viral hepatitis.
Less Common Causes of Hepatitis
Less common causes of hepatitis include autoimmune disorders, genetic liver disorders, other viral infections (eg, infectious mononucleosis, yellow fever, cytomegalovirus infection), and leptospirosis.
Parasitic infections (eg, schistosomiasis, malaria, amebiasis), pyogenic infections, and abscesses that affect the liver are not considered hepatitis. Liver involvement with tuberculosis (TB) and other granulomatous infiltrations is sometimes called granulomatous hepatitis, but the clinical, biochemical, and histologic features differ from those of the diffuse liver involvement in hepatitis caused by hepatitis viruses, alcohol, and medications.
Various systemic infections and other illnesses may produce small focal areas of hepatic inflammation or necrosis. This nonspecific reactive hepatitis can cause minor liver function abnormalities but is usually asymptomatic.
Some types of infectious and noninfectious liver inflammation are summarized in table .
Selected Infections With Liver Involvement
Disease or Organism | Manifestations |
|---|---|
Viruses | |
In neonates: Hepatomegaly, jaundice, congenital defects In adults: Mononucleosis-like illness with hepatitis; may occur posttransfusion | |
Epstein-Barr virus infections | Elevated liver tests in approximately 80%; jaundice in approximately 10%* Acute hepatitis, sometimes severe in young adults |
SARS-CoV-2 infection (COVID-19)† | Mild aminotransferase elevation Direct infection by virus contributes to hepatic impairment Correlates with disease severity but can occur in asymptomatic infection as well |
Anicteric hepatitis, usually in immunocompromised patients (but can also occur in immunocompetent patients) Fever in most; rash in < 50% ‡ Acute hepatitis, often severe | |
Jaundice, systemic toxicity, bleeding Liver necrosis with little inflammatory reaction | |
Other | Hepatic infection occasionally due to echovirus or coxsackievirus infections, varicella, rubella, or rubeola |
Bacteria | |
Granulomatous reaction of liver with progressive necrotizing abscesses | |
Pyogenic abscess § | Serious infection acquired via portal pyemia, cholangitis, or hematogenous or direct spread; due to various organisms, especially gram-negative and anaerobic Illness and toxicity, yet only mild liver dysfunction |
Hepatic involvement (common, usually subclinical) with granulomatous infiltration; jaundice (rare) Disproportionately increased alkaline phosphatase | |
Other | Minor focal hepatitis in numerous systemic infections (common, usually subclinical) |
Fungi | |
Granulomas in liver and spleen (usually subclinical) that heal with calcification | |
Other | Granulomatous infiltration sometimes occurring in cryptococcosis, coccidioidomycosis, blastomycosis, or other infections |
Protozoa | |
Important disease, often without obvious dysentery Usually a large single abscess with liquefaction Systemic illness, tender hepatomegaly, surprisingly mild liver dysfunction | |
A common cause of hepatosplenomegaly, as well as mild bilirubin and liver test abnormalities, in endemic areas Jaundice absent or mild unless active hemolysis is present | |
Transplacental infection In neonates: Jaundice, central nervous system (CNS) and other systemic manifestations | |
Infiltration of reticuloendothelial system by parasite, hepatosplenomegaly | |
Helminths | |
Biliary obstruction by adult worms, parenchymal granulomas caused by larvae | |
Biliary tract infestation, cholangitis, stones, cholangiocarcinoma | |
One or more hydatid cysts, which usually have a calcified rim and may be large but which often are asymptomatic and do not disrupt liver function Can rupture into the peritoneum or biliary tract | |
Acute: Tender hepatomegaly, fever, eosinophilia Chronic: Biliary fibrosis, cholangitis | |
Periportal granulomatous reaction to ova with progressive hepatosplenomegaly, pipestem fibrosis, portal hypertension, and varices Hepatocellular function preserved; not true cirrhosis | |
Visceral larva migrans syndrome Hepatomegaly with granulomas, eosinophilia | |
Spirochetes | |
Acute fever, syncope, exhaustion, jaundice, bleeding, renal injury Liver necrosis (often mild despite severe jaundice) | |
Congenital: Neonatal hepatosplenomegaly, fibrosis Acquired: Variable hepatitis in secondary stage, gummas with irregular scarring in tertiary stage | |
Borrelia infection Systemic symptoms, hepatomegaly, sometimes jaundice | |
* Leonardsson H, Hreinsson JP, Löve A, et al. Hepatitis due to Epstein-Barr virus and cytomegalovirus: clinical features and outcomes. Scand J Gastroenterol. 2017;52(8):893-897. doi:10.1080/00365521.2017.1319972 †Wang Y, Liu S, Zhao J: SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 73(4):807-816, 2020. ‡ Norvell JP, Blei AT, Jovanovic BD, Levitsky J. Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases. Liver Transpl. 2007;13(10):1428-1434. doi:10.1002/lt.21250 § Differentiate from amebiasis with serologic tests for amebas and direct percutaneous abscess aspiration. | |
Immune Checkpoint Inhibitor Hepatitis
Immune checkpoint inhibitor (ICI) hepatitis is an immune-related adverse event caused by immune activation from checkpoint blockade therapies such as programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1), and (cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) inhibitors, which are frequently used in cancer therapy (1). Reported incidence ranges from 1 to 15%, or higher on some combination regimens (2).
ICI hepatitis most often presents as an asymptomatic rise in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) on routine laboratory monitoring, although some patients can develop more severe liver injury with hyperbilirubinemia, jaundice, or, rarely, acute liver failure. The pattern is usually hepatocellular, but mixed or cholestatic injury can also occur.
Because there is no single diagnostic test, evaluation focuses on excluding alternative causes such as viral hepatitis, hepatic metastases, biliary obstruction, ischemic injury, and other drug-induced liver injury. In some cases, liver biopsy may help clarify the diagnosis and characterize the pattern of inflammation.
Management depends on grade of injury and generally includes holding immunotherapy, close laboratory follow-up, and glucocorticoids for more significant hepatitis, with second-line immunosuppression such as mycophenolate mofetil for steroid-refractory cases (1, 2). Early recognition is important, as most patients improve with prompt treatment, though decisions about resumption of ICI therapy require an individualized assessment of oncologic benefit vs risk of recurrence.
Immune checkpoint inhibitor hepatitis references
1. Dougan M, Wang Y, Rubio-Tapia A, et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Front Pharmacol. 2023;13:1077468. Published 2023 Jan 9. doi:10.3389/fphar.2022.1077468
Drug Information for the Topic
