Drug-Induced Liver Injury

Drug-Induced Liver Injury (DILI)

• DILI is an uncommon but challenging clinical problem with respect to both diagnosis and management.
• Its incidence is estimated to be 14 to 19 cases per 100,000 persons, with jaundice accompanying 30% of cases.
• DILI is responsible for 3 to 5% of hospital admissions for jaundice and is the most frequent cause of acute liver failure in most Western countries.

Pathogenesis

• The diagnosis of DILI is particularly challenging, since it is based largely on exclusion of other causes.
• The major diagnostic elements of DILI are:
  • The timing of the onset of injury after the implicated agent has been started (latency).
  • Resolution after the agent is stopped (“dechallenge”).
  • Recurrence on re-exposure (rechallenge).
  • Knowledge of the agent’s potential for hepatotoxicity (likelihood).
  • Clinical features (phenotype).

Diagnosis

• With few exceptions, there are no specific diagnostic markers for DILI.
• Special tests (liver biopsy, imaging, and testing for serologic markers) are helpful mostly in ruling out other causes of liver injury.
• Exclusion of other causes of liver injury is essential.

Types of Drug-Induced Liver Injury

• DILI is typically classified as:
  • Direct
  • Idiosyncratic
  • Indirect injury

Direct Liver Injury

• Caused by agents that are intrinsically toxic to the liver.
• The injury is common, predictable, dose-dependent, and reproducible in animal models.
• The latency period is typically short, usually with an onset within 1 to 5 days after high therapeutic or supratherapeutic doses.

Idiosyncratic Liver Injury

• Caused by agents that have little or no intrinsic toxicity and that cause liver injury only in rare cases.
• The injury is unpredictable, not dose-dependent, and not reproducible in animal models.
• Idiosyncratic liver injury is categorized as:
  • Hepatocellular
  • Cholestatic
  • Mixed (on the basis of the R ratio)

R Ratio

• Calculated by dividing the alanine aminotransferase level by the alkaline phosphatase level from the time of initial presentation.
• Hepatocellular injury is defined as an R value of more than 5.
• Cholestatic injury as a value of less than 2.
• Mixed injury as a value of 2 to 5.

Indirect Liver Injury

• Caused by the action of the drug (what it does) rather than by its toxic or idiosyncratic properties (what it is).
• Indirect injury can represent induction of a new liver condition or an exacerbation of a preexisting condition, such as:
  • Induction of immune-mediated hepatitis.
  • Worsening of hepatitis B or C or fatty liver disease.