Potential Hepatotoxicity of Penicillamine Treatment in Three Patients with Wilson's Disease

To the Editor: Wilson's disease is an inherited disorder of copper metabolism resulting in a failure of biliary copper excretion. The accumulating copper causes cell damage, primarily in the liver and brain. The basis for the treatment of patients with Wilson's disease is to eliminate the copper burden. Initially, British anti-Lewisite (BAL) was used to increase urinary copper excretion but was impractical for long-term use because of necessary painful injections and side effects (1). In 1956 Walshe introduced penicillamine as an effective treatment of Wilson's disease. Penicillamine causes highly effective urinary copper excretion by reductive chelation (2). Well-known side effects include initial worsening of neurologic symptoms, which are irreversible in some cases, and symptoms of hypersensitivity, such as fever, rash, hives, and adenopathy after penicillamine treatment are described. There is also a risk of bone marrow depression, proteinuria, or other idiosyncratic reactions in the first few weeks of penicillamine administration. Long-term adverse effects such as autoimmune disorders and abnormalities in collagen metabolism have also been described (3,4). Despite these side effects, penicillamine still represents the drug of first choice for the treatment of Wilson's disease. Alternative treatments are triethylene tetramine (trientine) and zinc, which causes a competitive inhibition of copper absorption resulting in a mild negative copper balance. Reports of penicillamine hepatotoxicity in therapy of Wilson's disease are rare. Menara et al. (5) reported penicillamine hepatotoxicity in 2 of 10 patients with Wilson's disease. We report 3 of 50 patients with Wilson's disease treated with penicillamine at our institution, in whom liver enzyme serum levels became elevated during penicillamine treatment. Two of the patients were 7-year-old twins. After diagnosis of Wilson's disease in September 1995, penicillamine was the initial treatment. Penicillamine therapy was discontinued when liver enzyme serum levels increased after 6 weeks of therapy, and only a slight and incomplete normalization of the initially enlarged liver size was noted. After an interval of 4 months without therapy, a second attempt with penicillamine was undertaken, starting with a low dosage of only 2.5 mg/kg, which was increased stepwise to a maximum of 6.5 mg/kg. Liver enzyme serum levels increased again from alanine aminotransferase (ALT) 4.73 μmol/l (normal range, 0.16-0.70 μmol/l), aspartate aminotransferase (AST) 2.28 μmol/l (normal range 0.17-0.73 μmol/l), γ-glutamyltransferase (GGT) 1.26 μmol/l (normal range, 0.08-0.55 μmol/l) without therapy, to ALT 9.14 μmol/l, AST 6.88 μmol/l, and GGT 1.76 μmol/l in the first patient after treatment with penicillamine, and from ALT 4.01 μmol/l, AST 2.32 μmol/l, GGT 0.96 μmol/l in the second patient to ALT 8.34 μmol/l, AST 3.93 μmol/l, GGT 2.02 μmol/l during penicillamine administration. The treatment of these two patients was changed to zinc sulfate and later to zinc orotate, which resulted in reduction and, finally, normalization in liver enzyme serum levels during a period of 6 months. Other adverse effects apart from elevated serum transaminases were not observed. The third patient was treated initially with penicillamine after the diagnosis had been established in November 1994. In spite of treatment with an adequate dosage of penicillamine for 3 years, elevated liver enzyme serum levels slightly decreased but remained moderately elevated. Other reasons for increased liver enzyme serum levels, such as infections, were excluded. After the treatment was changed to zinc, the serum levels for ALT, AST, and GGT declined to levels within the normal range during a period of 7 months. In conclusion, elevated liver enzyme serum levels in three patients with Wilson's disease, during treatment with penicillamine, could reflect hepatotoxicity of penicillamine. If the hepatotoxicity to the penicillamine treatment were based on a genetic disorder, as in the case of the twins, it would not have been cleared to date. Hepatotoxic changes seem to be reversible on cessation of penicillamine treatment. Jens Deutscher Wieland Kiess *Gunter Scheerschmidt Helmut Willgerodt Children's Hospital; University of Leipzig; Leipzig, Germany; *Children's Hospital; Erfurt, Germany