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 |Favorite Table|Download (.pdf)
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 in this case, the brownish ring rimming the cornea is clearly visible to the naked eye, confirmation is usually by slit-lamp examination.
Urine copper is an important diagnostic tool, but it 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 are in an intermediate range between 0.9 and 1.6 μmol (60 and 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.
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 and rarely causes Kayser-Fleischer rings.
Treatment: Wilson's Disease
Recommended anticopper treatments are listed in Table 360-2. Penicillamine was previously the primary anticopper treatment but now plays a minor role because of its toxicity and because it often worsens existing neurologic disease if used as initial therapy. If penicillamine is given, it should always be accompanied by 25 mg/d of pyridoxine. Trientine is a less toxic chelator and is supplanting penicillamine when a chelator is indicated.
Table 360-2 Recommended Anticopper Drugs for Wilson's Disease |Favorite Table|Download (.pdf)
Table 360-2 Recommended Anticopper Drugs for Wilson's Disease
|Disease Status||First Choice||Second Choice|
|Hepatitis or cirrhosis without decompensation||Zinca||Trientine|
|Mild||Trientineb and zinc||Penicillamineb and zinc|
|Moderate||Trientine and zinc||Hepatic transplantation|
|Severe||Hepatic transplantation||Trientine and zinc|
|Initial neurologic/psychiatric||Tetrathiomolybdatec and zinc||Zinc|
For patients with hepatitis or cirrhosis, but without evidence of hepatic decompensation or neurologic/psychiatric symptoms, zinc is the therapy of choice, although some advocate therapy with trientine. Zinc has proven efficacy in Wilson's disease and is essentially nontoxic. It produces a negative copper balance by blocking intestinal absorption of copper, and it induces hepatic metallothionein synthesis, which sequesters additional toxic copper. All presymptomatic patients should be treated prophylactically, because the disease is close to 100% penetrant.
The first step in evaluating patients presenting with hepatic decompensation is to establish disease severity, which can be estimated using the Nazer prognostic index (Table 360-3). Patients with scores < 7 can usually be managed with medical therapy. Patients with scores > 9 should be considered immediately for liver transplantation, and those with scores between 7 and 9 require clinical judgment as to whether to recommend transplantation or medical therapy. A combination of trientine and zinc has been used to treat patients with Nazer scores as high as 9, but such patients should be watched carefully for indications of hepatic deterioration, which mandates transplantation.
Table 360-3 Prognostic Index of Nazer |Favorite Table|Download (.pdf)
Table 360-3 Prognostic Index of Nazer
|Score (in Points)|
|Laboratory Measurement||Normal Value||0||1||2||3||4|
|Serum bilirubina||0.2–1.2 μg/dL||<5.8||5.8–8.8||8.8–11.7||11.7–17.5||>17.5|
|Serum aspartate transferase (AST)||10–35 IU/L||<100||100–150||151–200||201–300||>300|
|Prolongation of prothrombin time (seconds)||—||<4||4–8||9–12||13–20||>20|
For initial medical therapy of patients with hepatic decompensation, a chelator (trientine is preferred) plus zinc is recommended (Table 360-2). Zinc should not, however, be ingested simultaneously with trientine, because it will chelate zinc and form therapeutically ineffective complexes; administration of the two drugs should be separated by at least one hour.
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 and trientine should be avoided because they each have a high risk of worsening the neurologic condition. Until tetrathiomolybdate is commercially available, zinc therapy is recommended. Although it is relatively slow-acting, zinc itself does not cause neurologic worsening. Although hepatic transplantation may improve neurologic symptoms, it does so only by removing copper, which can be done more safely and inexpensively with anticopper drugs. Pregnant patients should be treated with zinc or trientine throughout pregnancy, but without tight copper control, because copper deficiency can be teratogenic.
Anticopper therapy must be lifelong. With treatment, liver function usually recovers after about a year, although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve after 6 to 24 months of treatment.
Monitoring Anticopper Therapy
When first using trientine or penicillamine, 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 a month, then at twice-weekly intervals for two to three months, then at monthly intervals for three or four months, and at four- to six-month intervals thereafter.
The anticopper effects of trientine and penicillamine can be monitored by following 24-h “free” serum copper. Changes in urine copper 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 (μg/dL) of ceruloplasmin contributes 0.5 μmol/L (3 μg/dL) of serum copper. The normal free copper value is 1.6–2.4 μmol/L (10–15 μg/dL), and it is often as high as 7.9 μmol/L (50 μg/dL) in untreated Wilson's disease. With treatment, free copper should be <3.9 μmol/L (<25 μg/dL).
Zinc treatment does not require blood or urine monitoring for toxicity. Its only significant side effect is gastric burning or nausea in ˜10% of patients, usually with the first morning dose. This can be mitigated by taking the first dose an hour after breakfast or taking the zinc 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 to 0.8 μmol (20 to 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.