To evaluate the incidence, severity, and course of
ketoconazole-associated hepatic injury, 211 patients with
onychomycosis were randomized by a ratio of 2:1 to receive either
ketoconazole (137 patients) or
griseofulvin (74 patients). All of them were seronegative for
hepatitis B surface antigen (
HBsAg) and anti-hepatitis C virus (HCV) and had no biochemical abnormality before
therapy. The two groups were comparable in age, sex, and pretherapy liver biochemical tests. Liver biochemical tests were followed up biweekly for 3 months, and then at monthly intervals during the remaining course of
therapy. No biochemical abnormality or hepatic injury was found in patients during
griseofulvin treatment. Of the patients treated with
ketoconazole, 24 (17.5%; 95% confidence interval [CI], 11.1% to 23.9%) showed asymptomatic
transaminase elevation.
Ketoconazole was discontinued immediately after overt
hepatitis developed in another 4 patients (2.9%; 95% CI, 0.1% to 5.7%) who did not succumb to hepatic decompensation. The abnormal biochemical changes in patients with overt
hepatitis returned to normal after discontinuing
ketoconazole. Elderly patients were more prone to develop overt
hepatitis. In patients with asymptomatic liver injury, the abnormal biochemical changes gradually returned to normal despite continuing
ketoconazole therapy. The results of this cohort study suggest that
ketoconazole-induced overt
hepatitis is more common than previously believed and that transient subclinical injury is much more common than overt
hepatitis.
Therapy with
ketoconazole may be continued with caution in the absence of symptoms and/or
hyperbilirubinemia, but should be discontinued if overt
hepatitis occurs.