Wilson's disease is a rare inherited disorder of copper metabolism, resulting in the toxic accumulation of copper in the liver, brain, and other organs. Individuals with Wilson's disease have mutations in the ATP7B gene, which encodes a membrane-bound copper-transporting adenosine triphosphatase (ATPase). Deficiency of this protein impairs copper excretion into the bile and copper incorporation into ceruloplasmin, leading to its rapid degradation.
Clinical Features
Clinical manifestations typically appear in the mid- to late-teen years but may occur later. Hepatic disease may present as hepatitis, cirrhosis, or hepatic decompensation. In other pts, neurologic or psychiatric disturbances are the first clinical sign and are always accompanied by Kayser-Fleischer rings (corneal deposits of copper). Dystonia, incoordination, or tremor may be present, and dysarthria and dysphagia are common. Autonomic disturbances also may be present. Microscopic hematuria is common. In about 5% of pts, the first manifestation may be primary or secondary amenorrhea or repeated spontaneous abortions.
Diagnosis
Serum ceruloplasmin levels are often low but may be normal in up to 10% of pts. Urine copper levels are elevated. The “gold standard” for diagnosis is an elevated copper level on liver biopsy. The disorder can be caused by a large number of different mutations but genetic testing, if available, can confirm the diagnosis in the majority of pts.
| TREATMENT | ||
Wilson's DiseaseHepatitis or cirrhosis without decompensation should be treated with zinc acetate (50-mg elemental Zn PO three times a day). Zinc is effective by blocking intestinal copper absorption and inducing metallothionein, which sequesters copper in a nontoxic complex. For pts with hepatic decompensation, the chelator trientene (500 mg PO twice a day) plus zinc (separated by at least 1 h to avoid zinc chelation in the intestinal lumen) is recommended, although liver transplantation should be considered for severe hepatic decompensation. For initial neurologic therapy, trientine and zinc are recommended for 8 weeks, followed by therapy with zinc alone. For initial neurologic therapy, tetrathiomolybdate is emerging as the drug of choice because of its rapid control of free copper, preservation of neurologic function, and low toxicity. Penicillamine is no longer first-line therapy. Zinc treatment does not require monitoring for toxicity, and 24-h urine copper can be followed for a therapeutic response. Trientine may induce bone marrow suppression and proteinuria. With chelation therapy, measuring free serum copper levels (adjusting total serum copper for ceruloplasmin copper) rather than urine copper is used to monitor therapeutic response. Anticopper therapy must be lifelong. |
Section 13. Endocrinology and Metabolism