Use of zinc-copper metabolic interactions in the treatment of Wilson's disease.

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Abstract
Zinc acetate is becoming a well-established therapy for the treatment of Wilson''s disease. It is excellent for maintenance therapy and for the treatment of the presymptomatic patients. Current evidence suggests that it will also be excellent for the treatment of the pregnant patient. Zinc acts by inducing intestinal cell metallothionein, which binds copper with high affinity, blocking its absorption, and causing its excretion in the stool. We have shown that zinc, even in doses as low as 25 mg daily, negatively affects copper balance. Zinc in doses of 50 mg three times daily, with all doses separated from food, controls the abnormal positive copper balance, blocks uptake of orally administered 64Cu, controls urine and plasma copper, prevents the reaccumulation of hepatic copper, and prevents the development or progression of symptoms of copper toxicosis in Wilson''s disease patients. Zinc acetate will probably be licensed in the near future for the treatment of Wilson''s disease. We recommend that physicians use urine and plasma copper, and urine zinc, as primary monitoring tools. In contrast to the confortable situation with maintenance therapy, the initial treatment of acutely ill Wilson''s disease patients is not well worked out. Patients with neurological disease often get worse initially on penicillamine, and zinc acts more slowly than is ideal. We have initiated studies of tetrathiomolybdate for this purpose. Studies of biliary secretions of normal subjects suggest that they excrete regulatory (excess) copper packaged in a protease-resistant ceruloplasmin fragment. This fragment is missing in Wilson''s disease bile. The gene for Wilson''s disease is on chromosome 13, close to the retinoblastoma locus. A retinoblastoma probe is very useful for assisting in diagnosis of siblings, and in identifying relatives who are gene carriers.