About Wilson's Disease
Wilson's disease is an autosomal inherited metabolic defect caused by mutations in the ATP7B gene. ATP protein deficiency impairs biliary copper excretion, resulting in hepatic copper accumulation and copper toxicity. Serum copper levels tend to be lower than normal due to low levels of the plasma protein ceruloplasmin, which normally binds > 90% of serum copper. Non-ceruloplasmin serum copper ("free copper") levels increase as the disease progresses, leading to copper accumulation in other parts of the body and increased manifestation of psychiatric and neurologic symptoms over time.1
Clinical manifestations primarily involve the liver and brain
Wilson's disease may first present as hepatic disease or cirrhosis. This generally occurs in patients from the mid-to-late teens. Neurological symptoms typically appear in the early 20s, although age of onset extends from the teens to the 40s. The three major neurological symptoms -- dystonia, incoordination, and tremor -- closely resemble Parkinson's disease. About half of patients with neurological manifestations exhibit psychiatric symptoms.1
Ophthalmologic hallmark of Wilson's disease: Kayser-Fleischer rings
The Kayser-Fleischer ring is a copper deposit on the outer rim of the cornea. It is the most important diagnostic sign for identifying a patient with Wilson's disease and can only be diagnosed definitively using a slit lamp. The ring is found in 99% of such patients, with virtually all of these having neurological and psychiatric symptoms.1 The density of the ring correlates with the severity of the disease.2
A treatable disorder
Untreated Wilson's disease is a progressive and ultimately fatal condition.3 Before treatment was available, the average age of death was 30.6 years.4 But patients now benefit from chelation therapy, the mainstay of treatment today. It has proved highly effective. With the use of chelating agents, liver function usually improves in about a year, while neurologic and psychiatric symptoms usually improve between 6 and 24 months after initiating therapy. Wilson's disease requires lifelong treatment.1
Diagnosis: Tests for Wilson's Disease
| Test | Presentation in Wilson's disease | Reference range |
|---|---|---|
| Serum ceruloplasmin | Low in 85% of patients | 18 to 35 mg/dL |
| 24-hour urine copper levels | >100 µg in symptomatic patients; 60 to 100 µg in presymptomatic patients | 20-50 µg |
| Liver copper levels (based on liver biopsy) | > 200 µg dry weight of liver | 20 to 50 µg dry weight of liver |
| Kayser-Fleischer rings | Present in 99% of patients with neurologic and psychiatric symptoms; present in 30-50% of presymptomatic patients | Exist very rarely in individuals who do not have Wilson's disease |
Adapted from Brewer GJ. Wilson's disease. In: Kasper DL, Fauci AS, Longo DL, eds. Harrison's Principles of Internal Medicine. New York. 16th ed. McGraw-Hill. 2005:2313-15.
Important Safety Information
CUPRIMINE® (Penicillamine) is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe active rheumatoid arthritis unresponsive to conventional therapy. Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity. Penicillamine can cause fetal harm when administered to a pregnant woman, therefore except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated. Mothers on therapy with penicillamine should not nurse their infants. Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine. Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency. The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis. Leucopenia and thrombocytopenia have been reported to occur up to five percent of patients during penicillamine therapy. Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to t nephritic syndrome. Intrahepatic cholestasis, toxic hepatitis and obliterative bronchiolitis have been reported. Onset of new neurological symptoms has been reported, or existing neurological symptoms have worsened. Most of the various forms of pemphigus have occurred during treatment with penicillamine. Some patients may experience a drug fever sometimes accompanied with a macular cutaneous eruption. Early and late rashes have occurred. Certain patients may develop a positive antinuclear antibody (ANA) test and some of these may show a lupus erythematosus-like syndrome. Some patients may develop oral ulcerations. Hypogeusia has been reported in some patients. Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone.
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Reference: 1. Brewer GJ. Wilson's disease. In: Kasper DL, Fauci AS, Longo DL, eds. Harrison's Principles of Internal Medicine. New York. 16th ed. McGraw-Hill. 2005:2313-15. 2. Sullivan CA, Chopdar A, Shun Shin GA. Letters. Dense Kayser-Fleischer ring in a asymptomatic Wilson's disease (hepatolenticular degeneration). Br J Ophthalmol. 2002;86:114-23. 3. Parkes D. Wilson's disease. British Med J. 1984;288:1180-81. 4. Park DHR, McCabe P, Fell GS, Russell RI. Wilson's disease in Scotland. Gut. 1991;32:1541-45.
