Wilson's disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, 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. Because a large number of inactivating mutations have been reported in the ATP7B gene, mutation screening for diagnosis is not routine, although this may be practical in the future. DNA haplotype analysis can be used to genotype siblings of an affected patient.
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, but as this storage capacity is exceeded, liver damage begins as early as three 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 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, such as the brain, leading to neurologic and psychiatric disease.
Wilson's disease may present as hepatitis, cirrhosis, or as hepatic decompensation, typically 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 blood transaminase enzymes, with or without jaundice, and then spontaneously regress. Hepatitis often reoccurs, 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 occur 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.
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 difficulties focusing on tasks, but cognition is not usually grossly impaired. Sensory abnormalities and muscular weakness are not features of the disease.
A history of behavioral disturbances, with onset in the five years before diagnosis, is present in half of patients with neurologic disease. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition.
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 increased urinary excretion of phosphates, amino acids, glucose, or urates may occur; however, a full-blown Fanconi 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 360-1. 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. 360-1) can only be diagnosed definitively 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.
Table 360-1 Useful Tests for Wilson's Disease
| Save Table
Table 360-1 Useful Tests for Wilson's Disease
|Test||Usefulnessa||Normal Value||Heterozygous Carriers||Wilson's disease|
|Serum ceruloplasmin||+||180–350 mg/L (18–35 μg/dL)||Low in 20%||Low in 90%|
Present in 99% + if neurologic or psychiatric symptoms present
Present in 30–50% in hepatic presentation and presymptomatic state
|24-h urine Cu||+++||0.3–0.8 μmol (20–50 μg)||Normal to 1.3 μmol (80 μg)|
>1.6 μmol (>100 μg) in symptomatic patients
0.9 to >1.6 μmol (60 to >100 μg) in presymptomatic patients
|Liver Cu||++++||0.3–0.8 μmol/g (20–50 μg per g tissue)||Normal to 2.0 μmol (125 μg)||>3.1 μmol (>200 μg) (obstructive liver disease can cause false-positive results)|
|Haplotype analysis||++++ (Siblings only)||0 Matches||1 Match||2 Matches|
A Kayser-Fleischer ring. Although ...
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