Treatment of Wilson's disease: the historical background.

When considering the management of patients with Wilson's disease it is necessary to understand the basis on which present views are founded. Wilson's original description of the disease he called 'hepato-lenticular degeneration' was based on four patients he had seen and studied himself and six cases culled from the literature. He emphasized the predominantly neurological picture, and believed that the hepatic lesion did not affect the clinical outcome, even though one of his own patients actually died from variceal haemorrhage. Bramwell challenged this view when, in 1916, he suggested that some patients might present with liver failure before the nervous system became involved, a forme fruste of the disease. Despite Rumpel's observation in 1913 that excess copper was present in the liver of a patient dying of this disease, its role in pathogenesis was not established until Cumings reported in 1948 that this metal was present in excess in both brain and liver of all patients dying of Wilson's disease. Until this time the situation had been, quite simply, no pathogenesis, no treatment. In his seminal paper Cumings made the modest suggestion that removal of copper from the tissues of these patients with the recently discovered metal-binding agent then known as British antilewisite (BAL) and now marketed as Dimercaprol, might arrest the progress of this hitherto universally fatal disease. Cumings's observation was the beginning of a therapeutic revolution. In the early 1950s, both Cumings and Denny Brown published the first results of treatment with BAL and they were able to report a considerable improvement in symptoms. Unfortunately the use of BAL was associated with problems; it had to be given by painful intramuscular injection often associated with fever and leucopenia, haematuria and abscess formation. Its use was something of an ordeal for the patient, and each course of injections was followed by a lesser improvement. At some stage a sulphonic acid derivative of BAL (Unithiol, Dimival) which can be given by mouth was used in the Eastern block countries, but perhaps because of cost and lack of availability, found little favour in the West, although its use was successful in one patient. Thus, though it became clear that the course of the disease could be influenced by therapy, a search for more effective and less toxic treatments was set in train. An alternative chelating agent, EDTA, was tried but proved disappointing, as did the use of intravenous aminoacids. The finding, at this time, that caeruloplasmin was absent or deficient in most patients suggested that replacement of this protein should be the specific form of treatment. This also proved to be illusory. However, the situation was radically altered for the better when I reported that penicillamine, a degredation product of penicillin, was to be found in the -SH state in the urine of patients treated with penicillin. This aminoacid is able to mobilize large amounts of copper for excretion in the urine, in both patients and normals, when given by mouth. As a result of this observation, almost overnight, Wilson's disease became one of the few inherited metabolic disease for which there was an effective therapy. So successful did this prove that Schouwink's observation that zinc salts could block copper absorption from the gut and could be of therapeutic value passed virtually unnoticed. It was almost a decade later that Hoogenraad and his colleagues introduced this as an alternative approach to the management of patients with Wilson's disease. Furthermore, they claimed that this avoided the problems of toxicity associated with penicillamine in some patients. A decade of penicillamine usage had indeed revealed a wide spectrum of toxic reactions varying from an early urticarial rash through skin damage, marrow depression to SLE and immune complex nephritis; one or other of these reactions