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Drug-Related Acute Hepatitis
Minority of cases progress to chronic hepatitis and rarely cirrhosis
Jaundice, high AST levels, and preexisting chronic liver disease are adverse prognostic factors
Microscopic
• Most medications produce inflammation-predominant pattern
• Most toxins & a few medications like acetaminophen produce necrosis-predominant pattern
• Concomitant bile duct injury, eosinophils, granulomas, perivenular necrosis, and cholestasis out of proportion to hepatocellular injury suggest DILI, but none of these are specific
Top Differential Diagnoses
• Inflammation-predominant pattern: Acute viral hepatitis, autoimmune hepatitis, Wilson disease
Portal and Interface InflammationThe inflammation-predominant pattern of drug-related acute hepatitis features dense lymphoplasmacytic infiltrate and interface hepatocellular injury.
Prominent Plasma CellsNumerous plasma cells can be seen in drug-induced liver injury and do not necessarily indicate autoimmune hepatitis.
Trichrome StainThe collagen in the portal tracts is coarse and stains darkly , while the periportal area with ductular reaction shows light staining . The latter indicates confluent necrosis rather than fibrosis.
Orcein StainThe elastic fibers are highlighted in the portal tract , while the area of confluent necrosis is negative . The combination of trichrome and elastic stains help in distinguishing confluent necrosis (acute hepatitis) from fibrosis (chronic hepatitis).
TERMINOLOGY
Abbreviations
• Drug-induced liver injury (DILI)
ETIOLOGY/PATHOGENESIS
2 Chief Mechanisms
• Intrinsic hepatotoxicity
Predictable, dose-dependent hepatocellular damage
– Industrial, household, or environmental toxins
Typically shows necrosis with negligible inflammation
• Idiosyncratic hepatotoxicity
Majority of adverse drug reactions fall in this category
Metabolic and immunological categories
– Metabolic: Drug is metabolized into toxic metabolite in predisposed individuals
– Immunological: Drug allergy or hypersensitivity following sensitization to drug
Typically shows inflammation-predominant liver injury
Herbals/Botanicals
• Important but often overlooked cause of hepatotoxicity
• Not regulated by Food and Drug Administration and hence not subject to rigorous testing
• Nearly 20% of American adults have used herbal remedies, and > 5 billion dollars are spent on these annually
• Heavy metal contaminants in these agents (arsenic, cadmium, lead, mercury) can also lead to liver toxicity
CLINICAL ISSUES
Presentation
• 3 clinical patterns
Hepatitic
– Acute hepatitis with autoimmune markers may mimic autoimmune hepatitis (AIH)
– May have features of hypersensitivity like rash, arthralgia, and peripheral eosinophilia
– Progression to chronic hepatitis with fibrosis and even cirrhosis can occur
Cholestatic
Mixed
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can be seen in drug-induced liver injury and do not necessarily indicate autoimmune hepatitis.
, while the periportal area with ductular reaction shows light staining 
. The latter indicates confluent necrosis rather than fibrosis.
, while the area of confluent necrosis is negative 
. The combination of trichrome and elastic stains help in distinguishing confluent necrosis (acute hepatitis) from fibrosis (chronic hepatitis).
