Can terbinafine (Lamisil) give rise to an isolated increase in gamma-GT value?/nA 33-year-old fema

Fråga: "Can terbinafine (Lamisil) give rise to an isolated increase in gamma-GT value? A 33-year-old female patient has been treated with terbinafine in a dose of 250 mg daily for 10 days. At the end of treatment, a gamma-GT value of 3.97 ukat/L (reference interval: less than 0.8) was observed without any clinical manifestations of liver disease. All other "liver function tests" were normal. The patient´s gamma-GT value prior to treatment is not known. She has, however, no history of liver disease."

Sammanfattning: Clinical trials suggest an association between treatment with terbinafine and increased gamma-GT levels. The clinical significance of such an increase is unclear. Monitoring of liver values is recommended in such cases with immediate withdrawal of the drug upon deterioration. Treatment with terbinafine has been associated with liver damage although the incidence appears to be low. The most frequently reported liver injury is a mixed reaction with cholestatic dominance.

Svar: Information concerning isolated liver enzyme abnormalities under terbinafine treatment without clinical manifestation of liver disease is scarce. However, analysis of data from clinical trials revealed an association between exposure to the drug and above-normal levels of gamma-GT (1). Whether an increase in enzyme levels in asymptomatic patients heralds an incipient liver injury is unknown.

The question of liver injury as a result of treatment with terbinafine has previously been addressed in Drugline (2). At that time, a number of case reports suggested that the drug can cause a reversible toxic liver reaction. An update of the literature revealed new reported cases of liver damage attributed to terbinafine. A mixed cholestatic-hepatocellular type of hepatitis was reported in two patients treated with terbinafine (3). Complete recovery was observed in one patient while in the other elevated levels of alkaline phosphatase and gamma-GT were still present three months after cessation of treatment. Lazaros et al reported a case of terbinafine-induced liver disease with histological changes of pronounced cholestasis (4).

Another case of prolonged cholestasis was described where a liver biopsy performed after six months showed cholestasis with a reduction in the number of interlobular biliary ducts (5). However, serum bilirubin levels reverted to normal within three months. The development of hepatobiliary dysfunction during treatment with terbinafine has been estimated to occur in 1:45000- 1: 54000 of treated patients (6). The authors reported three new cases of terbinafine-associated hepatitis with features of hepatocellular necrosis (transaminase increase) as well as cholestasis (ALP elevation) (6). Two more cases were reported (7,8). In the latter, an initial worsening was observed after discontinuation of terbinafine treatment. Also, the course was unusally prolonged (normalization of enzyme values after one year) (8). In most reported cases a latency of 4-6 weeks was observed between the start of therapy and the development of liver damage, suggesting an idiosyncratic reaction rather than a direct toxic effect. Although terbinafine-associated liver damage seems to be reversible, a recent report suggests that this adverse effect can be very serious (9). Fulminant hepatic failure developed in a 48-year-old woman who took an ordinary dose of terbinafine (250 mg) daily for five days. The patient´s condition deteriorated over a period of four weeks and she had to undergo a liver tranplantation, the outcome of which was successful. The histological picture was that of extensive necrosis and almost total disappearance of hepatocytes. This case differs from those previously reported since liver injury occurred early and was characterized by severe parenchymal rather than cholestatic damage. Finally, liver damage occurred in terbinafine treated patients as a component in a hypersensitivity syndrome with multisystem involvement (10).

A search in the Swedish register of adverse drug reactions (Swedis) revealed 16 cases of liver/biliary injury where the relationship between terbinafine treatment and injury was judged as possible/probable (11). In four of these cases transaminases as well as ALP/gamma-GT were elevated.

In the present case, it is difficult to establish whether the observed level of gamma-GT (3.97) is due to treatment with terbinafine since pre-treatment levels are unknown. However, it might be prudent to discontinue the drug and monitor liver enzymes afterwards.