Chapter 17 Wilson disease and related disorders

John L. Gollan, MD, PhD, FRACP, FRCP, FACP, Alexander T. Hewlett, DO, MS

Key Points

1 The Wilson disease (WD) gene is located on chromosome 13 and encodes a copper-transporting P-type adenosine triphosphatase (ATPase) protein, which is expressed primarily in the trans-Golgi network of the hepatocyte.

2 An impaired or deficient WD gene product is responsible for the lack of copper incorporation into ceruloplasmin and the defective biliary excretion of copper in WD.

3 Most patients with symptomatic WD present with hepatic or neuropsychiatric features; the principal hepatic manifestations include fulminant hepatic failure, chronic hepatitis, and cirrhosis.

4 In patients with a low serum ceruloplasmin level, the diagnosis of WD in the absence of Kayser–Fleischer rings requires determination of the hepatic copper concentration.

5 The use of DNA marker studies is limited largely to genetic screening of young family members or difficult diagnostic situations, with use of the index patient’s DNA as a reference.

6 The drug of choice for treating WD remains D-penicillamine, but alternative drugs under selected circumstances include trientine, zinc, and tetrathiomolybdate. The use of combination therapy (e.g., trientine and zinc) appears promising.

7 Liver transplantation is indicated for patients with fulminant hepatitis or decompensated cirrhosis unresponsive to therapy.

Copper Metabolism (Figs 17.1 and 17.2)

1. Dietary copper (1 to 2 mg/day) is actively transported into the proximal small intestinal epithelial cells.

2. A fraction (25% to 60%) of copper is absorbed and transferred into the portal circulation, bound to serum albumin and amino acids. The remaining intraepithelial copper is bound to metallothioneins and is subsequently excreted as intestinal epithelial cells are sloughed. No significant enterohepatic circulation of copper occurs.

3. The Menkes gene (ATP7A) product likely plays an important role in copper absorption.

4. Only a small fraction of serum albumin–bound (nonceruloplasmin) copper is normally excreted by the kidney (less than 50 μg/24 hours); most is taken up by hepatocytes.

5. In the hepatocyte, copper is complexed with and detoxified by metallothioneins or glutathione and is used as a cofactor for specific cellular enzymes, incorporated into ceruloplasmin, or excreted into bile.

6. The site of copper incorporation into ceruloplasmin may be the Golgi apparatus. The WD gene (ATP7B) product, also known as the Wilson adenosine triphosphatase (ATPase), is presumed to be responsible for copper transport in this compartment and subsequent incorporation into ceruloplasmin.

7. The delivery of copper to specific intracellular locations is mediated by small cytosolic proteins termed copper chaperones.

8. As the copper content of the hepatocyte increases, the Wilson ATPase transfers from the trans-Golgi network to a vesicular compartment adjacent to the canalicular membrane.

9. Biliary excretion of copper occurs partly through a vesicular pathway. Another, perhaps less important, route of excretion is as copper-glutathione. A third potential excretory pathway is through a specific copper transporter in the plasma membrane.

Fig. 17.1 Copper (Cu) absorption and excretion. Dietary copper (1 to 2 mg/day) is transported into the intestinal epithelial cell, with the Menkes gene product regulating absorption (25% to 60%). The remaining intraepithelial copper is bound to metallothionein and is subsequently excreted in stool as the intestinal epithelial cells are sloughed. A small amount of the absorbed copper is excreted in urine, but the majority is taken up by the hepatocyte, synthesized into ceruloplasmin, and stored in the liver or excreted in bile.

Fig. 17.2 Hepatocellular copper metabolism. Copper (Cu) is taken up by hepatocytes, where it interacts with glutathione and metallothionein. A portion of the intracellular copper is incorporated into metalloenzymes (e.g., superoxide dismutase, cytocrome cxidose), and some is transported into the trans-Golgi network by the WD gene protein (ATP7B), where it is incorporated into ceruloplasmin. It is postulated that copper is also routed from the trans-Golgi apparatus to a vesicular compartment in lysosomes for subsequent excretion in bile. Copper bound to glutathione is also excreted into the bile canaliculus through the organic anion transporter (cMOAT or MRP2) or by direct interaction with a postulated adenosine triphosphate (ATP)–dependent copper transporter.

Genetics

1. WD is an autosomal recessive disease with a gene frequency of 0.3% to 0.7%, thus accounting for a heterozygote carrier rate of slightly greater than 1 in 100. In 1985, the WD gene was shown to be linked to the red cell enzyme, esterase D, an association that established the location on chromosome 13.

2. In 1993, three different groups of investigators isolated the WD gene by using positional cloning. The gene, designated ATP7B, spans an 80-kb region of the chromosome and encodes a 7.5-kb transcript that is expressed primarily in the liver, kidney, and placenta.

3. The gene product is a 1466-amino acid protein, a member of the cation-transporting P-type ATPase subfamily, and is highly homologous to the Menkes gene (ATP7A) product and the copper-transporting ATPase (cop A) found in copper-resistant strains of Enterococcus hirae.

4. More than 269 disease-causing mutations of the WD gene have been identified to date. Most of the mutations are missense mutations. Comparatively few patients are homozygotes for the same mutation; however, most are compound heterozygotes (i.e., bearers of two different alleles).

Despite the clinical diversity of the disease, allelic heterogeneity at the ATPB7 locus does not appear to account for the marked clinical variability observed in patients.

Although one normal allele is adequate to prevent clinical disease, heterozygotes for the WD gene may demonstrate subclinical abnormalities in copper metabolism.

Pathogenesis

1. Copper toxicity plays a primary role in the pathogenesis of this disorder. Affected organs invariably exhibit elevated copper levels.

2. Maintenance of normal copper homeostasis depends on the balance between gastrointestinal absorption and biliary excretion. Intestinal copper absorption in patients with WD does not differ from that of physiologically normal or cirrhotic subjects.

3. Biliary excretion of copper is reduced in WD. Studies indicate a possible defect in the entry of copper into lysosomes, but with normal delivery of lysosomal copper to bile. Investigators have suggested that copper transport into the trans-Golgi apparatus by the WD gene product is essential for its routing and excretion through the lysosomal pathway. This process, in turn, depends on the normal recycling of the WD protein between the trans-Golgi network and the vesicular compartment.

4. Deficiency of the plasma copper protein ceruloplasmin is unlikely to have a role in the pathogenesis of WD. The low serum ceruloplasmin level in patients with WD is believed to be the result of a lack of incorporation of copper into apoceruloplasmin, which has a shorter half-life than copper-bound ceruloplasmin.

5. Excess copper appears to exhibit toxicity by the generation of free radicals, which result in lipid peroxidation, depletion of antioxidants, and polymerization of Cu-thionein leading to necrosis and apoptosis. Morphologic abnormalities from oxidant damage have been identified, particularly in mitochondria (i.e., enlargement, dilatation of cristae, and crystalline deposits).

6. Pathologic copper deposition in the basal ganglia of the brain, particularly in the caudate nucleus and the putamen, results in the neurologic and psychiatric manifestations of the disease, whereas excessive deposition in Descemet’s membrane of the cornea gives rise to Kayser–Fleischer rings.

Clinical Features

Patients with WD may be asymptomatic, although most present with hepatic or neurologic manifestations. Clinical symptoms are rarely observed before age 5 years, and most untreated patients become symptomatic by the age of 40 years. In a large series, the initial clinical manifestations were hepatic in 42%, neurologic in 34%, psychiatric in 10%, and hematologic in 12%. A few patients present with WD when they are more than 40 years old, and they normally present with neurologic symptoms that are commonly overlooked. Less commonly, patients present with renal, skeletal, cardiac, ophthalmologic, endocrinologic, or dermatologic symptoms.

Hepatic

Hepatic manifestations tend to occur at a younger age (mean, 10 to 12 years) than neurologic manifestations. Three major patterns may occur: cirrhosis, chronic hepatitis, or fulminant hepatic failure:

1. Cirrhosis

This often occurs early in the course; symptoms may be minimal or absent, with nearly normal liver biochemical tests.

Later, the patient has an insidious, but relentless, progression to cirrhosis with liver failure.

The association of WD with hepatocellular cancer was once considered rare, although several reports have appeared.

2. Chronic hepatitis

Young patients may present with features that are indistinguishable from viral or autoimmune chronic hepatitis.

Less than 5% of patients with chronic hepatitis who are less than 35 years old will have WD as the cause, and 5% to 30% of patients with WD present with features of chronic hepatitis.

Modest elevation of serum aminotransferase levels in the presence of severe hepatocellular necrosis and inflammation is a distinctive feature of Wilsonian chronic hepatitis.

The diagnosis may be difficult, because almost 50% of these patients have no evidence of Kayser–Fleischer rings and lack neurologic manifestations of the disease. Moreover, patients with severe hepatic inflammation may have normal serum ceruloplasmin levels.

The prognosis for treated patients is good even if they have developed cirrhosis.

3. Fulminant hepatic failure

Patients tend to be young, and the clinical picture may be indistinguishable from that of viral-induced massive hepatic necrosis.

Characteristic clinical features include intravascular hemolysis, splenomegaly, Kayser–Fleischer rings, and a fulminant course; patients rarely survive longer than days to weeks unless liver transplantation is performed.

Serum aminotransferases are mildly to moderately elevated, with marked elevation of the serum bilirubin, a low serum alkaline phosphatase level, and evidence of Coombs-negative hemolytic anemia. Serum ceruloplasmin may be in the normal range; however, 24-hour urinary copper and free serum copper levels are usually elevated.

Liver biopsy, if performed (in all likelihood through the transjugular route), will document an elevated hepatic copper content and usually the presence of cirrhosis.

Neurologic

1. This involvement tends to occur in the second to third decades of life.

2. Kayser–Fleischer rings are almost invariably present on ophthalmologic (slit lamp) examination.

3. Common early symptoms are dysarthria, clumsiness, tremor, drooling, gait disturbance, masklike facies, and deterioration of handwriting.

4. Rigidity with overt parkinsonian features, flexion contractures, grand mal seizures, and spasticity are seen less often and in the later stages of the disease.

5. Cognitive ability usually remains normal regardless of severe neurologic impairment.

6. Neurologic symptoms may improve markedly with treatment, although residual deficits are common despite adequate chelation therapy.

7. Three subgroups have been defined by clinical and magnetic resonance imaging (MRI) findings:

In a subgroup of patients with bradykinesia, rigidity, and cognitive impairment, MRI shows dilatation of the third ventricle.

A second group is characterized by ataxia, tremor, and reduced functional capacity; MRI reveals focal thalamic lesions.

A third subgroup exhibits dyskinesia, dysarthria, and an organic personality syndrome; MRI shows focal lesions in the putamen and globus pallidus.

Psychiatric

1. One third of all patients with WD may present with psychiatric symptoms; patients may be mistakenly diagnosed with a progressive psychiatric illness.

2. Psychiatric symptoms are present in virtually all neurologically affected patients, and the severity tends to parallel that of the neurologic abnormalities.

3. Early symptoms in teenagers may be limited to subtle behavioral changes and deterioration of academic and work performance.

4. Patients present later with personality changes, lability of mood, emotionalism, impulsive and antisocial behavior, depression, and increased sexual preoccupation.

5. Psychiatric symptoms usually resolve with chelation therapy.

Ophthalmologic

1. Kayser–Fleischer rings

This golden brown or greenish discoloration in the limbic area is evident initially at the superior and inferior corneal poles and eventually becomes circumferential.

Electron-dense granules rich in copper and sulfur are deposited in Descemet’s membrane.

Their presence or absence should be confirmed by an ophthalmologist with slit lamp examination.

They occur in most symptomatic patients with WD and virtually always in those with neurologic manifestations; they are often absent in asymptomatic cases and in more than 40% of patients with hepatic disease, particularly chronic hepatitis.

They are not pathognomonic of WD because they also are seen occasionally in patients with long-standing cholestasis from other causes.

The rings resolve in 80% of patients with chelation therapy over 3 to 5 years.

2. Sunflower cataracts

They are typically observed with Kayser–Fleischer rings, but less frequently.

Vision is unimpaired.

They resolve more rapidly than Kayser–Fleischer rings with treatment.

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