Real-World Analysis Identifies Meds Tied to Higher Risk of Liver Injury

— Case reports may not be as reliable, researchers say

A computer rendering of a liver under a red umbrella.

Real-world data can be used to identify the most potentially hepatotoxic medications based on incidence rates of severe acute liver injury among patients without pre-existing liver or biliary disease, according to a series of cohort studies.

Of 194 suspected hepatotoxic medications, 17 dispensed in VA outpatient settings came with rates of severe acute liver injury at 5.0 or more events per 10,000 person-years, 11 of which were not included in the highest hepatotoxicity category by case reports, reported Vincent Lo Re III, MD, MSCE, of the University of Pennsylvania's Perelman School of Medicine in Philadelphia, and colleagues in .

"We identified multiple medications that are significantly higher or lower risk than previously suggested by case-based analyses," Lo Re told app.

"We were not surprised by our findings," he added. "Case reports place the onus on the practitioner to publish the clinical findings from the case, which undoubtedly leads to underreporting. Case reports may also vary in the quality of the data and do not rely on standard definitions of acute liver injury."

Seven of the 17 medications -- stavudine, erlotinib (Tarceva), lenalidomide (Revlimid) or thalidomide, chlorpromazine, metronidazole, prochlorperazine (Compazine), and isoniazid -- were found to be the most hepatotoxic, with rates of 10.0 or more hospitalizations for severe acute liver injury per 10,000 person-years. The highest rate was observed with the HIV nucleoside reverse transcriptase inhibitor stavudine, at 86.4 events per 10,000 person-years.

The other 10 medications -- moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin -- had rates between 5.0 and 9.9 events per 10,000 person-years.

Antimicrobial medications, particularly antifungal medications and older antiretroviral drugs, represented 64% of those with the highest rates of severe acute liver injury.

After adjusting for diabetes, obesity, hyperlipidemia, and polypharmacy, rates of severe acute liver injury remained similar.

Aside from the 11 of 17 medications with the highest incidence of hepatotoxicity not being included in , a database of drug-induced liver injury case reports, seven medications in the study that had lower incidences of severe acute liver injury -- fewer than 1.0 event per 10,000 person-years -- were included in the highest risk category in LiverTox, noted Grace Zhang, MD, and Jessica Rubin, MD, MPH, of the University of California San Francisco, in an .

"What explains this difference in findings between the present study and LiverTox?" they asked. "Despite its undisputable value, the ability of LiverTox to capture the true incidence of drug-related hepatotoxic effects is limited because of its reliance on published case reports."

Lo Re and colleagues also pointed out that "categorizing hepatotoxic drugs using case reports does not consider the number of individuals exposed and may not accurately reflect incidence of severe ALI [acute liver injury]."

Another notable finding from the study was that statins, frequently thought to be linked to adverse hepatic effects, were in the lowest risk category for severe acute liver injury.

"Their hepatic adverse effects have long been feared by practitioners and patients alike," Zhang and Rubin wrote. "LiverTox has designated nearly all statins as category A [high] risk medications," but the database "fails to consider the denominator -- the nearly 100 million patients in the U.S. ... prescribed statins each year."

The study has important implications for clinical care, Lo Re and colleagues stressed, noting that there is currently no systematic approach to classifying drug-induced hepatotoxicity.

"Patients initiating a medication with a high rate of severe acute liver injury might require closer monitoring of liver-related laboratory tests to detect evolving hepatic dysfunction earlier, which might improve prognosis," Lo Re explained. "Moreover, within electronic health record systems, automated messages could alert clinicians ordering a medication with a high rate of severe acute liver injury to the potential risk of this outcome and to consider laboratory monitoring."

For this study, the researchers evaluated 194 medications used in the VA health system that had four or more published case reports of hepatotoxicity. They retrospectively analyzed VA electronic health record data for nearly 8 million people without pre-existing liver or biliary disease who began outpatient treatment with a medication suspected of causing hepatotoxicity from October 2000 through September 2021; 55% were taking multiple medications. Most (92.5%) were men, and the mean age across the medication cohorts was 64.4 years.

Lo Re and team identified 1,739 hospitalizations for severe acute liver injury, defined by either inpatient alanine aminotransferase level greater than 120 U/L plus a total bilirubin level greater than 2.0 mg/dL, or an international normalized ratio of 1.5 or higher plus a total bilirubin level greater than 2.0 mg/dL, recorded within the first 2 days of admission. Of these patients, 27.2% died within 180 days of hospitalization, and five patients underwent a liver transplant.

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    Katherine Kahn is a staff writer at app, covering the infectious diseases beat. She has been a medical writer for over 15 years.


The study was funded by grants from the National Cancer Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases.

Lo Re reported receiving personal fees from Entasis Therapeutics and Urovant Sciences. Several other co-authors reported multiple ties to industry.

Zhang and Rubin reported no conflicts of interest.

Primary Source

JAMA Internal Medicine

Torgersen J, et al "Severe acute liver injury after hepatotoxic medication initiation in real-world data" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.1836.

Secondary Source

JAMA Internal Medicine

Zhang GY, Rubin JB "Rethinking drug-induced liver injury -- a new era of pharmacovigilance" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.1833.