Drug, Herbal and Dietary Supplement Induced Liver Injury

Publication Date: July 26, 2022
Last Updated: August 30, 2022

DILI classification

Guidance statements

  • Clinicians should be familiar with the three main types of hepatotoxicity when evaluating patients with suspected DILI.
  • Direct hepatotoxins such as APAP can cause liver injury in nearly all exposed individuals once a threshold dose or duration of use is exceeded.
  • Idiosyncratic DILI is largely independent of the dose and duration of medication use and characterized by a low incidence and variable drug latency and clinical and histological features.
  • Idiosyncratic DILI is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolite(s).
  • Indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations that arise from the biological action of the drug on the liver and/ or host immune system.

Epidemiology of idiosyncratic DILI

Guidance statements

  • The estimated annual incidence of idiosyncratic DILI in the general population is low (14–19/100,000) but higher in exposure-based studies using electronic medical record data (33–40/100,000).
  • Antimicrobials, central nervous system agents, and anti-inflammatory agents are the most commonly implicated agents in the DILI series worldwide. However, HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries as well.
  • The daily dose of a medication, its lipophilicity, and extent of hepatic metabolism influence the risk of causing DILI when comparing medications.
  • Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility. However, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin-clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline).
  • Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs. However, the role of alcohol, tobacco, and diet in DILI susceptibility is not established.
  • Patients with pre-existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti-TB therapy). In addition, subjects with pre-existing liver disease are at increased risk of poor outcomes with a DILI episode.
  • A polymorphism in PTPN22 is a genetic risk factor across multiple drugs and major ethnic groups. Various HLA alleles have also been associated with increased susceptibility to individual drugs, but the clinical utility of HLA testing in DILI diagnosis has yet to be determined.

Overview

Title

Drug, Herbal and Dietary Supplement Induced Liver Injury

Authoring Organization

American Association for the Study of Liver Diseases