Acute and clinically relevant drug-induced liver injury: a population based case-control study


Francisco J. de Abajo, Head, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Medicines Agency, Madrid, Spain. E-mail:


Aims  To provide quantitative information about the absolute and relative risks of acute and clinically relevant drug-induced liver injury.

Methods  We performed a population-based case-control study using the UK-based General Practice Research Database as the source of information. A total of 1636792 persons subjects aged 5–75 years old registered in the database from 1 January, 1994 to 31 December, 1999 were followed-up for a total of 5404705 person-years. Cases were identified by an exhaustive computer search, then reviewed manually and finally validated against the clinical records. Only idiopathic cases serious enough to be referred to hospital or a consultant were selected. A total of 5000 controls were randomly sampled from the person-time of study cohort. Current users were defined if a prescription ended within 15 days of the index date, and nonusers if there was no prescription before the index date.

Results  One hundred and twenty-eight patients were considered as valid cases, being the crude incidence rate of 2.4 (95% confidence interval: 2.0, 2.8) per 100 000 person-years. The strongest associations were found with chlorpromazine (adjusted odds ratio (AOR); 95% CI = 416; 45, 3840), amoxicillin/clavulanic acid (AOR = 94.8; 27.8, 323), flucloxacillin (AOR = 17.7; 4.4, 71.0), macrolides (AOR = 6.9; 2.3, 21.0), tetracyclines (AOR = 6.2; 2.4, 15.8); metoclopramide (AOR = 6.2; 1.8, 21.3); chlorpheniramine (AOR = 9.6; 1.9, 49.7); betahistine (AOR = 15.3; 2.9, 80.7); sulphasalazine (AOR = 25.5; 6.0, 109); azathioprine (AOR = 10.5; 1.4, 76.4), diclofenac (AOR = 4.1; 1.9, 8.8) and antiepileptics (AOR = 5.1; 1.9, 13.7). A dose-effect was apparent for diclofenac, amoxicillin/clavulanic acid and flucloxacillin. The combination of two or more hepatotoxic drugs increased the risk by a factor of 6. The highest crude incidence rates were found for chlorpromazine, azathioprine, and sulfasalazine (about 1 per 1000 users).

Conclusions  Idiopathic, acute and clinically relevant liver injury, which has the use of drugs as the most probable aetiology, is a rare event in the general population. The relative risks of 40 drugs/therapeutic classes are provided, along with the crude incidence rates for 15 of them where a statistical association was found.