Gastroenterology

Gastroenterology

Volume 144, Issue 7, June 2013, Pages 1419-1425.e3
Gastroenterology

Original Research
Full Report: Clinical—Liver
Incidence, Presentation, and Outcomes in Patients With Drug-Induced Liver Injury in the General Population of Iceland

https://doi.org/10.1053/j.gastro.2013.02.006Get rights and content

Background & Aims

Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a population-based cohort.

Methods

We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients.

Results

The crude annual incidence rate of DILI was 19.1 (95% confidence interval [CI], 15.4–23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8−77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2−8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24−70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4−24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205−1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184−718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20−187).

Conclusions

In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.

Section snippets

Materials and Methods

Iceland has a population of approximately 251,000 inhabitants older than age 15. All physicians in the country received a letter concerning this upcoming prospective study in January and February of 2010, stating the purpose of the study. In the letter the physicians were encouraged to report to the investigators, via e-mail, all suspected patients older than the age of 15, with liver injury suspected to be caused by drugs or herbal medicines and/or dietary supplements (HDS), with predefined

Results

During the 2-year study period a total of 96 patients, including 54 (56%) women, median age of 55 (interquartile range [IQR], 38–69 y), were identified who fulfilled the criteria for inclusion in the study. The youngest patient was 16 years old and the oldest patient was 91 years old. Overall, 110 patients originally were recorded in the study but 14 patients had to be excluded: 7 of these had nondrug causes for their liver injury, owing to polymyalgia rheumatica, Epstein–Barr hepatitis,

Incidence of DILI

The crude incidence observed in the present study, 19.1 per 100, 000 inhabitants per year, is similar although somewhat higher than in the only other published population-based study from France that showed a crude incidence of 13.9 cases per 100,000.4 There are some differences between these 2 studies that have to be taken into account. In the current study, liver injury resulting from acetaminophen was excluded whereas this was not the case in the French study.4 In fact, 1 of the 2 patients

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This article has an accompanying continuing medical education activity on page e19. Learning Objective: Upon completion of this CME exercise, successful learners will be able to summarize the incidence of drug-induced liver injury (DILI), the most common type of drugs associated with DILI and the highest risk of drugs associated with DILI as well as the prognosis of patients with jaundice owing to DILI.

Conflicts of interest The authors disclose no conflicts.

Funding Supported by a grant from the National University Hospital of Iceland Research Fund.

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