Wilson disease was uniformly fatal until effective drugs were introduced, and the goal of treatment is to reverse the copper overload and then keep the body in negative copper balance for life. Treatment works either by removing copper from the body or by stopping it from being absorbed, and it must continue even when the patient feels well, because stopping it allows copper to build up again.
Chelating agents
Chelators bind copper in the circulation and increase its excretion in the urine. D-penicillamine has been the most widely used; the initial dose is 1,000–2,000 mg/day in divided doses, falling to a maintenance dose of 750–1,000 mg/day. Trientine was developed as an alternative for patients who cannot tolerate penicillamine and is now also used first-line; the initial dose is 750–1,500 mg/day and the maintenance dose 750–1,000 mg/day. Both are taken on an empty stomach, because food and antacids reduce their absorption. In patients with predominantly neurological disease, treatment is started at a low dose, such as penicillamine 250–500 mg/day, and increased slowly over weeks, because a rapid release of copper can transiently worsen neurological symptoms; this paradoxical worsening is seen in up to about a third of treated patients with a neurological presentation.
Chelation is monitored with the 24-hour urinary copper: on adequate treatment the excretion is roughly 200–500 µg per day. A value below 200 µg suggests either over-treatment with copper deficiency or poor adherence to treatment.
Zinc salts
Zinc salts work differently. They induce metallothionein in the intestinal cells, which binds dietary copper and traps it, so the copper is lost when the cells are shed instead of being absorbed. The usual dose is 50 mg of elemental zinc three times a day. Zinc acts slowly, taking several months for its full effect, so it is best suited to maintenance therapy and to patients found before symptoms appear by screening, and it is not adequate on its own for severe liver disease. Tetrathiomolybdate, which both chelates copper and blocks its absorption, is a newer agent used in some patients, particularly those with neurological disease.
Diet
A low-copper diet is advised, particularly in the first two or three years of treatment. Shellfish, nuts, chocolate, mushrooms and organ meats, especially liver, are the richest sources and should be avoided until a negative copper balance is achieved. Copper cookware and drinking water from copper plumbing are additional sources worth avoiding.
Monitoring and pregnancy
Treatment is lifelong, and monitoring aims to detect both non-adherence and over-treatment. Clinical assessment, liver tests and copper studies, principally the 24-hour urinary copper and where available exchangeable copper, are checked at intervals, every 6 to 12 months when the patient is stable. Treatment must be continued during pregnancy, with the dose adjusted, because stopping it can cause worsening neurological disease or liver failure.
Liver transplantation
Liver transplantation is reserved for Wilsonian acute liver failure, which is often fatal without it, and for decompensated liver disease that does not respond to medical therapy. Because the transplanted liver carries a working ATP7B, transplantation corrects the underlying defect and copper handling in the rest of the body returns to normal, so copper-lowering drug therapy is no longer needed afterwards. It is also considered for a few patients with severe progressive neurological disease, although its role there is not settled.
Prognosis
Untreated, Wilson disease is progressive and fatal. With adherence to treatment and regular monitoring, most patients live a normal or near-normal life expectancy. Hepatic disease often improves within the first months, whereas neurological recovery is slower and may continue over years, and a minority of patients are left with residual neurological disability. Finding and treating affected relatives before symptoms appear gives the best outcome, which is why family screening is part of management.