On the basis of a prospective cohort study including 137
We appreciate the comments of Dr. Bernuau et al. on our patients with onychomycosis who were given oral ketoconaprospective study of ketoconazole-induced hepatotoxicity. 1 zole, 200 mg daily, Chien et al. 1 report that among the 24 We totally agree with their concern that a risk of fulminant patients (17.5%) who developed asymptomatic elevation in hepatic failure does exist for patients using this drug. Howserum alanine aminotransferase (ALT) activity, the 17 who ever, we do have some reservations about their arguments. were followed-up adequately all normalized serum ALT First, we conducted a prospective study because retrospective within 5 to 15 weeks while continuing ketoconazole therapy. studies, particularly those based on voluntary reporting The authors conclude that ''therapy with ketoconazole may schemes, are not suitable for incidence calculations. It is be continued with caution in the absence of symptoms and/ known that the incidence of ketoconazole-induced overt or or hyperbilirubinemia, but should be discontinued if overt transient subclinical injury is much more common than the hepatitis occurs.'' estimated figures derived from retrospective reporting Two arguments make us unwilling to accept this high risk schemes. 2,3 It is likely that both overt and subclinical cases conclusion, even if we warmly support the authors' statement are under-reported, which reduces the denominator and, that ketoconazole ''was to be discontinued promptly if clinitherefore, overestimates the fatality rate. 4,5 Second, of the cal symptoms of hepatitis or hyperbilirubinemia developed.'' 1 seven patients described in the references cited by Bernuau et The first argument is that in 2 retrospectively evaluated series al., only two developed fulminant hepatitis despite stopping of patients with ketoconazole-induced hepatic injury, the ketoconazole as soon as symptoms began. 6,7 Such a catafatality rate was 1/33 2 and 3/16 3 . Thus, the benign course strophic outcome was not observed in a total of 13 patients of the 17 patients reported by Chien et al. 1 may be falsely with overt hepatitis seen in our unit, including 4 patients in reassuring.
our prospective study, 1 4 in our previous report, 8 and 5 re-The second argument is that at least 3 patients developed cent cases. More importantly, none of the 17 patients with fulminant hepatic failure after delayed discontinuation of the asymptomatic alanine transaminase (ALT) elevation develdrug. [4][5][6] In two cases, one with a fatal outcome 4 and another requiring emergency liver transplantation, 5 patients disconoped overt hepatitis despite an ALT level more than 10 times tinued ketoconazole when symptoms of hepatitis began. In the the upper limit of normal. 1 Asymptomatic hepatic injuries third case, a 38-year-old woman in whom ketoconazole was and overt hepatitis might involve different pathogenetic discontinued before jaundice, but after serum ALT had increased mechanisms, 1 representing different disease entities rather to 40 times the upper limit of normal, then developed fulminant than different stages of one disease. Therefore, the conclusion hepatic failure and died in our unit 6 (patient 1). Thus, a lifederived from the results of our prospective study is still valid. threatening risk of fulminant hepatic failure does exist, at least As stated, our recommendation is that ketoconazole may be in some patients, when ketoconazole therapy is discontinued continued with caution in the absence of symptoms and/or only when symptoms of acute hepatitis develop or even when hyperbilirubinemia. serum transaminase becomes markedly increased.
Accordingly, we endorse the statement by Lake-Bakaar et al. 3 who recommend discontinuation of the drug when serum RONG-NAN CHIEN, M.D. ALT, monitored at regular intervals, increases above three YUN-FAN LIAW, M.D. times normal.