Evaluating patients for drug-induced liver injury

Drug-induced liver injury (DILI) can range from asymptomatic liver enzyme elevation, the most common presentation, to acute liver failure.

DILI can occur in overdose situations or during therapeutic use, either as a result of direct or idiosyncratic hepatotoxicity. Drugs most commonly associated with DILI include antibiotics (e.g., amoxicillin–clavulanate, macrolides, fluoroquinolones, nitrofurantoin), statins, antiepileptics (e.g., phenytoin, carbamazepine) and acetaminophen. Although DILI is rarely reported with antipsychotics, a recent study found that several antipsychotics were associated with hepatotoxicity, including first-generation (e.g., perphenazine, fluphenazine, thioridazine) and second-generation antipsychotics (e.g., olanzapine, clozapine).

DILI generally occurs one to five days after exposure with direct hepatotoxicity (e.g., acetaminophen), and five to 90 days after exposure with idiosyncratic hepatotoxicity (e.g., phenytoin, amoxicillin–clavulanate). However, in patients with previous exposure, idiosyncratic hepatotoxicity can occur sooner. After drug discontinuation, liver enzyme levels decrease within days to weeks, although 10% of patients may continue to have chronic disease one
year later.

DILI is often classified as hepatocellular, cholestatic or mixed, based on patterns of enzyme elevation. In hepatocellular injury (often referred to as hepatitis), a disproportionate elevation in serum aminotransferases is observed compared with alkaline phosphatase. Conversely, in patients presenting with cholestatic injury (cholestasis), a disproportionate elevation in alkaline phosphatase compared with serum aminotransferases is seen.

Implications for pharmacists

For patients presenting with nonspecific symptoms (e.g., nausea, anorexia, fatigue, right upper quadrant pain) within three months of starting a drug, an evaluation for DILI should be done. This includes a thorough medication history, timing of symptom onset and consideration of other diagnoses, such as autoimmune hepatitis. LiverTox (https://livertox.nih.gov) is an excellent resource to consult. This websiteprovides a searchable database of more than 1,000 agents that have been associated with DILI.

Sandra Knowles, BScPhm, is a drug information pharmacist with Sunnybrook Health Sciences Centre in Toronto.

References

Kumachev A, Wu PE. Drug-induced liver injury. CMAJ 2021;193:E310. (accessed December 6, 2022).

Brennan PN, Carlidge P, Manship T, et al. Guideline review: EASL clinical practice guidelines: drug-induced liver injury (DILI). Frontline Gastroenterol 2022;13:332-6. (accessed December 6, 2022).

Zeiss R, Hafner S, Schonfeldt-Lecuona C, et al. Drug-associated liver injury related to antipsychotics: exploratory analysis of pharmacovigilance data. J Clin Psychopharmacol 2022;42:440-4.