Chapter 408: Wilson’s Disease

Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, which encodes a membrane-bound, copper-transporting ATPase. Clinical manifestations are caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make this diagnosis early.

The frequency of Wilson’s disease in most populations is about 1 in 30,000–40,000, and the frequency of carriers of ATP7B mutations is ~1%. Siblings of a diagnosed patient have a 1 in 4 risk of Wilson’s disease, whereas children of an affected patient have about a 1 in 200 risk. Although a large number of inactivating mutations have been reported in the ATP7B gene, mutation screening for diagnosis is now available, and a definitive diagnosis can be obtained in 50–75% of patients, depending on the population. DNA haplotype analysis can be used to genotype siblings of an affected patient. A rare multisystem disorder of copper metabolism with features of both Menke’s and Wilson’s diseases has been reported. It is termed the MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia) syndrome and is caused by mutations in the AP1S1 gene, which encodes an adaptor protein necessary for intracellular trafficking of copper pump proteins ATP7A (Menke’s disease) and ATP7B (Wilson’s disease).

ATP7B protein deficiency impairs biliary copper excretion, resulting in positive copper balance, hepatic copper accumulation, and copper toxicity from oxidant damage. Excess hepatic copper is initially bound to metallothionein; liver damage begins as this storage capacity is exceeded, sometimes by 3 years of age. Defective copper incorporation into apoceruloplasmin leads to excess catabolism and low blood levels of ceruloplasmin. Serum copper levels are usually lower than normal because of low blood levels of ceruloplasmin, which normally binds >90% of serum copper. As the disease progresses, nonceruloplasmin serum copper (“free” copper) levels increase, resulting in copper buildup in other parts of the body (e.g., in the brain, with consequent neurologic and psychiatric disease).

Hepatic Features

Wilson’s disease may present as hepatitis, cirrhosis, or hepatic decompensation. Patients typically present in the mid- to late teenage years in Western countries, although the age of presentation is quite broad and extends into the fifth decade of life. An episode of hepatitis may occur—with elevated serum aminotransferase levels, with or without jaundice—and then spontaneously regress. Hepatitis often recurs, and most of these patients eventually develop cirrhosis. Hepatic decompensation is associated with elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites, peripheral edema, and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may develop because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson’s disease a likely diagnosis.

Neurologic Features

The neurologic manifestations of Wilson’s disease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. MRI and CT scans reveal damage in the basal ganglia and occasionally in the pons, medulla, thalamus, cerebellum, and subcortical areas. The three main movement disorders include dystonia, incoordination, and tremor. Dysarthria and dysphagia are common. In some patients, the clinical picture closely resembles that of Parkinson’s disease. Dystonia can involve any part of the body and eventually leads to grotesque positions of the limbs, neck, and trunk. Autonomic disturbances may include orthostatic hypotension and sweating abnormalities as well as bowel, bladder, and sexual dysfunction. Memory loss, migraine-type headaches, and seizures may occur. Patients have difficulty focusing on tasks, but cognition usually is not grossly impaired. Sensory abnormalities and muscular weakness are not features of the disease.

Psychiatric Features

Half of patients with neurologic disease have a history of behavioral disturbances with onset in the 5 years before diagnosis. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition.

Other Manifestations

Some female patients have repeated spontaneous abortions, and most become amenorrheic prior to diagnosis. Cholelithiasis and nephrolithiasis occur with increased frequency. Some patients have osteoarthritis, particularly of the knee. Microscopic hematuria is common, and levels of urinary excretion of phosphates, amino acids, glucose, or urates may increase; however, a full-blown Fanconi’s syndrome is rare. Sunflower cataracts and Kayser-Fleischer rings (copper deposits in the outer rim of the cornea) may be seen. Electrocardiographic and other cardiac abnormalities have been reported but are not common.

Diagnostic tests for Wilson’s disease are listed in Table 408-1. Serum ceruloplasmin levels should not be used for definitive diagnosis, because they are normal in up to 10% of affected patients and are reduced in 20% of carriers. Kayser-Fleischer rings (Fig. 408-1) can be definitively diagnosed only by an ophthalmologist using a slit lamp. They are present in >99% of patients with neurologic/psychiatric forms of the disease and have been described very rarely in the absence of Wilson’s disease. Kayser-Fleischer rings are present in only ~30–50% of patients diagnosed in the hepatic or presymptomatic state; thus, the absence of rings does not exclude the diagnosis.

Urine copper measurement is an important diagnostic tool, but urine must be collected carefully to avoid contamination. Symptomatic patients invariably have urine copper levels >1.6 μmol (>100 μg) per 24 h. Heterozygotes have values <1.3 μmol (<80 μg) per 24 h. About half of presymptomatic patients who are ultimately affected have diagnostically elevated urine copper values, but the other half have levels that are in an intermediate range between 0.9 and 1.6 μmol (60–100 μg) per 24 h. Because heterozygotes may have values up to 1.3 μmol (80 μg) per 24 h, patients in this range may require a liver biopsy for definitive diagnosis.

Testing for mutations in ATP7B can be done and is recommended for a definitive diagnosis. Several hundred inactivating mutations have been described and genetic testing laboratories can now make a definitive diagnosis in about 50–75% of patients, depending on the population.

The gold standard for diagnosis remains liver biopsy with quantitative copper assays. Affected patients have values >3.1 μmol/g (>200 μg/g [dry weight] of liver). Copper stains are not reliable. False-positive results can occur with long-standing obstructive liver disease, which can elevate hepatic and urine copper concentrations and rarely causes Kayser-Fleischer rings.

When trientine or penicillamine is first used, it is necessary to monitor for drug toxicity, particularly bone marrow suppression and proteinuria. Complete blood counts, standard biochemical profiles, and a urinalysis should be performed at weekly intervals for 1 month, then at twice-weekly intervals for 2 or 3 months, then at monthly intervals for 3 or 4 months, and at 4- to 6-month intervals thereafter.

The anticopper effects of trientine and penicillamine can be monitored by following “free” serum copper levels. Changes in urine copper levels are more difficult to interpret because excretion reflects the effect of the drug as well as body loading with copper. Free serum copper is calculated by subtracting the ceruloplasmin copper from the total serum copper. Each 10 mg/L (1 mg/dL) of ceruloplasmin contributes 0.5 μmol/L (3 μg/dL) of serum copper. The normal serum-free copper value is 1.6–2.4 μmol/L (10–15 μg/dL); the level is often as high as 7.9 μmol/L (50 μg/dL) in untreated Wilson’s disease. With treatment, the serum-free copper should be <3.9 μmol/L (<25 μg/dL).

Zinc treatment does not require monitoring of blood or urine for toxicity. Its only significant side effect is gastric burning or nausea in ~10% of patients, usually with the first morning dose. This effect can be mitigated if the first dose is taken an hour after breakfast or if zinc is taken with a small amount of protein. Because zinc mainly affects stool copper, 24-h urine copper can be used to reflect body loading. The typical value in untreated symptomatic patients is >3.1 μmol (>200 μg) per 24 h. This level should decrease during the first 1–2 years of therapy to <2.0 μmol (<125 μg) per 24 h. A normal value (0.3–0.8 μmol [20–50 μg]) is rarely reached during the first decade of therapy and should raise concern about overtreatment (copper deficiency), the first sign of which is anemia and/or leukopenia.

The age of onset of clinical disease may be considerably younger in India and the Far East; in these regions, onset often occurs in children at only 5 or 6 years of age. The incidence of the disease may be increased in certain populations as a result of founder effects. For example, in Sardinia, the incidence may be 1 in 3000. In countries where penicillamine, trientine, and zinc acetate (as Galzin) are not available or are unaffordable, zinc salts such as gluconate or sulfate provide an alternative treatment option.