Drug Induced Liver Injury: Mechanisms, Diagnosis, and Clinical Management

Abstract

Similarly to other chemicals such as alcohol and solvents, drugs can injure the liver. A body of evidence suggests that mechanisms for drug induced liver injury (DILI) may follow a three-step cascade of events: drugs or their metabolites cause cell stress directly or through reactive oxygen species (ROS) during drug oxidation via cytochrome P450, impair mitochondrial functions, trigger immune reactions, and impair mitochondrial functions that would initiate apoptosis or necrosis leading to cell death. Clinically, toxicity DILI commonly refers to the idiosyncratic toxicity that occurs at therapeutic doses, affects a few susceptible individuals, and is not predictable. Conversely, intrinsic toxicity is dose dependent and thus predictable in individuals given an overdose of certain drugs such as acetaminophen. The diagnosis of DILI is based on timing of the events and the exclusion of alternative causes, and both require a quantitative scoring causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method), resulting in causality levels of highly probable, probable, possible, unlikely or excluded. For DILI characterization, only cases with a highly probable or probable causality grading should be used. Beside the product information, DILI databases and review articles should be consulted to help identify the offending drugs. Cessation of the suspected drug and symptomatic treatment commonly lead to a favorable outcome. N-acetylcysteine is the best treatment to prevent aggravation of DILI due to overdosed acetaminophen. In rare instances, DILI progresses in few days or weeks to acute liver failure requiring liver transplantation.

Self Study

1.1 Questions

• 1. Which statement is true?

  • (a) RUCAM is the worldwide most commonly used causality assessment method to establish or dismiss the diagnosis of DILI.

  • (b) Pathogenesis of idiosyncratic DILI is best studied with animal models.

  • (c) Idiosyncratic DILI is not foreseeable and not preventable.

  • (d) Patients with idiosyncratic DILI may profit from a variety of antidotes.

• 2. Which statement/statements is/are true?

  • (a) For the diagnosis of DILI, many alternative causes have to be excluded, since previous DILI cases often were not DILI but had to be attributed to other causes.

  • (b) To describe the liver injury signature, a liver histology is required.

  • (c) RUCAM represents an objective, quantitative diagnostic algorithm that uses defined key elements with individual scores.

1.2 Answers

• 1. Which statement is true?

  • (a) CORRECT: The worldwide preferred method is RUCAM, which is highly appreciated by regulatory agencies, large clinical centers, pharmaceutical manufacturers and authors of DILI case reports. RUCAM received an update in 2016, and this updated version should be used for future DILI cases.

  • (b) Human idiosyncratic DILI is not reproducible in animal models, which are therefore not suitable for characterizing this toxic liver disease in humans.

  • (c) CORRECT: Since idiosyncratic DILI is not predictable, patients under a drug therapy should be advised to carefully watch out for possible clinical signs

  • (d) such as dark-colored urine, itching, jaundice, and abdominal pain.

  • (e) No antidotes are available for idiosyncratic DILI, N-Acetylcysteine is an antidote only available for intrinsic DILI by overdosed acetaminophen.

• 2. Which statement/statements is/are true?

  • (a) CORRECT: Alternative causes are a problem in DILI cases and can be found by using RUCAM for general case evaluation and specific causality assessment.

  • (b) DILI signature is based on serum activities of ALT and ALP rather than on liver histology obtained through invasive liver biopsy. ALT and ALP values clearly define DILI signature as hepatocellular liver injury or as cholestatic/mixed liver injury.

  • (c) CORRECT: RUCAM is the preferred tool to assess causality of suspected DILI cases and cannot be replaced by any global introspection approach, which is, by definition, a subjective tool, lacking definition, transparency, and scoring system, and may lead to questionable results and conclusions.