Terbinafine-induced cholestatic liver disease

Copyright 0 European Association for the Study of the Liver 1996

Journal of Hepatology 1996; 24: 753-756 Printed in Denmark All rights reserved Munksgaard Copenhagen

Journal of Hepatology ISSN 0168-8278

Case Report

Terbinafine-induced George A. Lazaros’, George V. Papatheodoridis’,

cholestatic liver disease Johanna K. Delladetsima*

and Nicolaos C. Tassopoulos’

‘Liver Unit, First Department of Medicine, Western Attica General Hospital, and ‘Deparhnent of Pathology, Laikon General Hospital, Athens, Greece

Hepatobiliary disorders associated with orally administered terbinafine have rarely been reported. We describe a case of prolonged terbinafine-induced cholestatic liver disease. Extrahepatic cholestasis, viral hepatitis and autoimmune liver disorders were excluded. The histological findings of marked cholestasis without evidence of extrahepatic biliary obstruction or acute hepatitis

T

is an orally and topically active allylamine antifungal agent which appears to inhibit specifically and selectively squalene epoxidase, resulting in decreased fungal ergosterol biosynthesis and increased squalene content in fungal cells (1,2). Clinical trials have demonstrated that orally administered terbinafine is very effective in the majority of cases of cutaneous dermatophytosis and onychomycosis (l-5). Side effects appear in about 10% of patients treated with the common daily dosage of 250 mg and are usually mild, such as gastrointestinal disturbances, cutaneous symptoms or malaise (1). Hepatobiliary disorders of varying pattern and severity associated with terbinafine have rarely been reported ERESINAFINE

(677). We present an unusual case of prolonged cholestasis in a 58-year-old female treated with terbinafine for 40 days.

Case Report A 58-year-old female was referred to our Liver Unit because of deep jaundice, pruritus and anorexia. The patient had been treated with terbinafine 250 mg per

Received 8 June; revised 19 October; accepted 24 October 1995

Correspondence: Nicolaos C. Tassopoulos, First Department of Medicine, Western Attica General Hospital, 1, Dodecanissou Street, 123 51 Athens, Greece. Tel. No: (301) 5452707,6844046. Fax No: (301) 5613478,9812579.

were compatible with the diagnosis of drug induced liver disease. Biochemical parameters of liver cell damage returned to normal levels 6 months later.

Key words: Adverse effects; Antifungal; Cholestasis; Liver disease; Terbinahne.

day for dermatophyte onychomycosis. After 40 days of treatment she developed jaundice and dark urine and discontinued treatment. However, she did not seek medical advice until 18 days later. The patient underwent cholecystectomy 12 months previously, when liver function tests were normal. There was no history of other drug intake, liver disease, use of tobacco, alcohol abuse, parenteral drug abuse and blood transfusions. On admission, the patient was afebrile and physical examination revealed jaundice and mildly enlarged and tender liver, but no rash nor features of arthritis. Laboratory findings were: hematocrit: 39.3%, hemoglobin: 12.7 g/dl, white blood count: 5.3x109/l (neutrophils: 58%, lymphocytes: 32%, mononuclear cells: 6%, eosinophils: 4%), platelets: 232x109/l, prothrombin time: 12 s (control: 11.6 s), serum alanine aminotransferase (ALT): 470 IU/l (n<46), serum aspartate aminotransferase (AST): 164 IU/l (n<46), serum gamma-glutamyltransferase (GGT): 1200 IU/l (n-=31), serum 5-nucleotidase (5NU): 83 IU/l (n<9), serum alkaline phosphatase (ALP): 934 IU/l (n: 90-290) with a liver fraction of 91.2% (n<50%), total serum bilirubin: 16.7 mg/dl (conjugated: 11.1 mg/dl), serum albumin: 3.52 g/dl, y-globulins: 2.28 g/dl, immunoglobulin A: 395 mgl dl, immunoglobulin M: 307 mg/dl, immunoglobulin G: 13 19 mg/dl and serum cholesterol: 460 mg/dl. Serological markers for hepatitis A, B, and C viruses showed only evidence for past infection with 753

G.A. Lazaros et al.

Fig. 1. Bile plugs in bile canaliculi (arrows) (Hematoxylineosin x.500).

Fig. 2. Small bile duct showing slight nuclear irregularity and minimal inJammatory injltration of the epithelium (Hematoxylin-eosin x300).

hepatitis B virus (HBV) (IgM anti-HAV: negative, HBsAg: negative, IgM anti-HBc: negative, anti-HBc: positive, anti-HBs: positive, anti-HCV: negative). The presence of IgM anti-HAY HBsAg, IgM antiHBc, anti-HBc and anti-HBs were tested by a commercially available enzyme immunoassay on admission and 1 month later and of anti-HCV by a secondgeneration enzyme immunoassay on admission and 1, 3, and 6 months later. Initial serum sample was negative for HBV DNA by a double-nested polymerase chain reaction (PCR) using primers from the core region and for HCV-RNA by a double-nested PCR using primers from the 5-noncoding region. Indirect immunofluorescence for antinuclear (ANA) and antimitochondrial (AMA) antibodies, antibodies against smooth muscles (SMA) and IgM antibodies against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were negative. Moreover, IgG antibodies against CMV were found positive at the same low titer (l/40) on admission and 1 month later, while IgG antibodies against EBV were persistently negative. No antibodies against human immunodeficiency virus were detected. Repeated ultrasonography and computerized tomography of the upper abdomen revealed no abnormality. In the percutaneous liver biopsy performed 10 days after admission, the parenchyma showed marked cholestasis predominantly in acinar zone 3 characterized by bile pigment material in hepatocytes and Kupffer cells and bile plugs in bile canaliculi (Fig. 1). Portal tract inflammation was of moderate density and consisted of mononuclear cells and eosinophils. There were a few scattered necrotic hepatocytes. Single interlobular bile ducts exhibited slight degenerative changes (Fig. 2).

Serum levels of ALT, AST and bilirubin gradually decreased, while ALP and GGT levels peaked 60 days after admission. All liver tests returned to normal 6 months later (Fig. 3).

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Discussion Clinical trials have demonstrated that terbinafine is well tolerated (2-5). Side effects are more common in patients receiving griseofulvin 500 mg daily (13%) or ketoconazole 200 mg daily (13%) than in terbinafine recipients (lo%), but less common in placebo recipients (5.6%) (18). Usual side effects are mild to moderate gastrointestinal disturbances such as dyspepsia, nausea, cramping, diarrhea and burning abdominal pain (l-5), which generally appear during the first week of therapy and may be a result of druginduced delay of gastric emptying (1). Reversible loss of taste (9,lO) and skin reactions usually mild (1,4), but occasionally severe such as toxic epidermal necrolysis and erythema multiforme (ll), have also been described. Terbinafine-associated hepatotoxicity is rare and only a few cases of hepatobiliary disorders have been reported (6,7). Terbinafine is absorbed from the gastrointestinal tract in approximately 70-80% of an orally administered dose and undergoes extensive hepatic metabolism, mostly through oxidation and demethylation (1). It is strongly bound to plasma proteins and is excreted primarily in the urine (approximately 80%) and the remainder in the feces (1). The mechanism of terbinafine-induced hepatic injury remains unclear. Terbinafine binds only weakly to hepatic cytochrome P450 and does not seem to interfere with cytochrome P450 enzymes involved in drug metabolism and synthesis of steroid hormones and prostaglandins (1). There-

Terbajne-induced liver injury

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and GGT levels in a patient treated with terbinajine for

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fore, the drug is hepatotoxic, perhaps due to direct toxicity, but in a minority of patients. Moreover, general hypersensitivity reactions like fever, rash, eosinophilia, arthritis or hemolytic anemia have been detected neither in previously reported cases (6,7), nor in the present case of terbinafine-associated liver injury, suggesting that this kind of reaction is also not implicated. Thus, and taking into account the fact that hepatotoxicity has rarely been reported, an uncommon idiosyncratic effect seems to be involved. Most of the described cases with terbinafineinduced liver disease are compatible with a mixed cholestatic-hepatocellular type of injury (6,7). However, in the present case, abnormalities of liver enzymes were suggestive predominantly of a cholestatic type of injury with mild cytolysis, although higher levels of transaminases before the patient’s admission cannot be excluded. It is noteworthy that levels of ALP and GGT peaked about 80 days after discontinuation of drug; prolonged cholestasis has already been reported with other drugs such as phenothiazines (12), tricyclic antidepressants (13,14) and ajmaline (15), and has been considered as evidence for liver injury induced through an immunoallergic mechanism (14,15). Cholestasis was associated with terbinafine intake as jaundice appeared 40 days after drug administration and every other possible origin

of hepatobiliary injury was excluded. Repeated sonographic studies of the upper abdomen and an abdominal computerized tomography showed normal bile ducts. The absence of serological markers of ongoing viral hepatitis infection and the seronegativity for HBV DNA and HCV RNA by PCR excluded the diagnosis of viral hepatitis. Auto-antibodies were negative and there was no serological evidence of acute CMV and/or EBV infection. There was no history of other drug intake, alcohol abuse, parenteral drug abuse and blood transfusions. Moreover, the histologic findings of “mixed” cholestasis without evidence of extrahepatic biliary obstruction or acute hepatitis are compatible with the diagnosis of druginduced liver disease. Although our case report fulfils the criteria of drug-induced liver disease, the diagnosis would be definitely confirmed by a positive response to a rechallenge with the drug (16). However, readministration even in a small dose was not attempted because of the severity of previous liver injury and the possible idiosyncratic mechanism of action of terbinafine. In conclusion, terbinafine can induce cholestatic liver disease, and the possibility of this adverse effect must be kept in mind. Cholestasis may be prolonged and seems to resolve some months after the discontinuation of treatment. 755

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