Because Wilson's disease is invariably fatal if untreated and because effective treatment resolves most problems and allows prolonged survival, every patient with Wilson's disease must begin uninterrupted lifelong therapy. A low copper diet is most important during the first year of therapy, with avoidance of such foods as shellfish, nuts, mushrooms, legumes, and organ meats such as liver. The mainstay of therapy is chelation of copper and the drug D-penicillamine is usually started first. Dosing of 250-500 mg/day is escalated in 250-mg increments every 4-7 days to a total of 1-1.5 g/day in divided doses given 1 hour before or 2 hours after meals. The drug chelates hepatic copper and allows rapid urinary excretion. Although most patients tolerate D-penicillamine, it often has hypersensitivity-type side effects, some of which are too serious to allow its continued use. In such cases another effective chelating agent, trientine, can be used. A third orally active chelating agent, tetrathiomolybdate, is being studied and may be available soon.

Oral zinc therapy has also been demonstrated as effective in lowering copper stores. Zinc works by inducing enterocyte metallothionein, which sequesters dietary copper, preventing absorption and promoting elimination as the enterocyte sloughs into the intestinal lumen. Although zinc was originally promoted only as maintenance therapy after successful chelation, it has also been effective for initial therapy in asymptomatic patients and is better tolerated than D-penicillamine. Zinc acetate 50 mg 3 times daily, and taken away from meals is the most popular form and may have slightly less gastric irritation that the gluconate or sulfate salts. Some patients, including the young girl presented, have too much dyspepsia and cannot tolerate zinc. Sometimes giving the doses with meals improves tolerance, but higher doses may be required to control copper. Adding oral zinc to chelation therapy is also being studied.

Monitoring Wilson's disease patients on therapy includes routine checking of liver function and injury tests, CBC, and checking for recurrence of neurologic and psychiatric symptoms. Although determining the total serum copper and calculation of the "nonceruloplasmin-bound copper" is not particularly helpful in making the diagnosis of Wilson's disease, it may be helpful in monitoring therapy. Total copper in mg/dL (reference range 60-190) minus 3 times the ceruloplasmin (in mg/dL) estimates the nonceruloplasmin copper and is <15 mg/dL in normals and in successfully treated Wilson's patients. Annual 24-hour urines for copper should be performed. Patients on chelation therapy should be excreting 200-500 mg/day (3-8 mmol/day) and if on zinc therapy, urinary copper excretion should be <75 mg/day (1.2 mmol/day).

Liver transplantation has been performed in a number of Wilson's disease patients, usually for fulminant liver failure. Transplantation is also indicated in patients who do not respond to chelation therapy or who cannot be managed with oral chelation therapy because of either noncompliance or drug sensitivities. The fact that liver transplantation completely resolves copper accumulation is further evidence that the defect of Wilson's disease is primarily one of hepatic excretion.

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