Drug-Related Acute Hepatitis

Sanjay Kakar, MD

Key Facts

Etiology/Pathogenesis

2 chief mechanisms: Intrinsic and idiosyncratic
- Idiosyncratic is the most common in children
Herbal and botanical drugs are important but often overlooked cause of hepatotoxicity

Clinical Issues

Classified into hepatitic, cholestatic, or mixed based on pattern of enzyme elevation
DILI with autoimmune markers can be indistinguishable from de novo AIH
Symptomatic and biochemical improvement in most cases on withdrawal of drug
- Minority of cases progress to chronic hepatitis and, rarely, cirrhosis
- Jaundice, high AST levels, and preexisting chronic liver disease are adverse prognostic factors

Microscopic Pathology

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 is specific

Top Differential Diagnoses

Inflammation-predominant pattern: Acute viral hepatitis, autoimmune hepatitis, Wilson disease
Necrosis-predominant pattern: Herpes/adenoviral hepatitis, ischemic necrosis, acute venous outflow obstruction

The inflammation-predominant pattern of drug-related acute hepatitis features dense lymphoplasmacytic infiltrate and interface hepatocellular injury.

Numerous plasma cells

can be seen in drug-induced liver injury and do not necessarily indicate autoimmune hepatitis.

ETIOLOGY/PATHOGENESIS

2 Chief Mechanisms

Intrinsic hepatotoxicity
- Predictable, dose-dependent hepatocellular damage by drug or its metabolite
  - Industrial, household, or environmental toxins
- Typical histological feature is necrosis with negligible inflammation
Idiosyncratic hepatoxicity
- Majority of adverse drug reactions fall in this category; antimicrobial and central nervous system drugs are the most common offending agents in children
- Further classified into metabolic and immunological categories
  - Metabolic: Drug is metabolized into toxic metabolite in predisposed individuals
  - Immunological: “Drug allergy” or hypersensitivity following sensitization to drug
- Typical histological feature is 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
Contaminants in herbal supplements, including heavy metals such as arsenic, cadmium, lead, or mercury, can also lead to liver toxicity

CLINICAL ISSUES

Presentation

Laboratory Tests

Measurement of serum levels of drug or its metabolite can be helpful in diagnosis (e.g., acetaminophen toxicity)
Antinuclear &/or anti-smooth muscle antibodies may be present
Transaminase elevations may be marked