From the AGA Journals

Augmentin implicated in drug-induced liver injury



The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

Source: American Gastroenterological Association

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

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