Wilson Disease and Related Disorders

Key Points

1
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by disease-specific defects in the ATP7B gene that encodes a copper-transporting P-type adenosine triphosphatase (ATPase) expressed primarily in the trans-Golgi network of hepatocytes.
2
Loss of ATP7B function is responsible for defective biliary excretion of copper by liver cells that leads to pathologic accumulation of hepatic copper and secondary organ injury as well as defective copper incorporation into ceruloplasmin, which is a phenotypic marker in most patients with WD.
3
Most patients with symptomatic WD present clinically in the second or third decades of life with hepatic disease and in the third or fourth decades with neuropsychiatric features; however, patients have been diagnosed even into the eighth decade of life.
4
Liver disease due to WD ranges from asymptomatic to chronic hepatitis, cirrhosis, and even acute liver failure (ALF).
5
The diagnosis of WD requires a combination of clinical signs and biochemical testing or detection of two disease-specific mutations of ATP7B by molecular testing.
6
Family screening of first-degree relatives is mandatory, and genetic screening for the ATP7B mutation with use of the index patient’s DNA as a reference should be performed if possible.
7
Initial treatment of symptomatic patients with WD should be with copper chelation therapy: D-penicillamine or trientine; maintenance therapy or treatment of asymptomatic patients may be with a chelating agent or zinc salts, which induce a blockade of copper absorption.
8
Liver transplantation (LT) is indicated for patients with WD and ALF or decompensated cirrhosis unresponsive to medical therapy.

Copper Metabolism ( Figs. 19.1 and 19.2 )

1.
Approximately 1 to 2 mg of dietary copper is absorbed by the proximal small intestinal epithelial cells daily. The copper transporter CTR1 is responsible for copper uptake by intestinal epithelial cells, and the Menkes disease protein ATP7A participates in copper transfer from epithelial cells into the circulation.
2.
Copper that is transferred into the portal circulation is bound to serum albumin and amino acids. The remaining intraepithelial copper is mostly bound to the endogenous chelating peptide metallothionein and is subsequently excreted as intestinal epithelial cells are sloughed. No significant enterohepatic circulation of copper occurs.
3.
Only a small fraction of circulating copper (<50 μg/24 hours) is normally excreted by the kidney; most is taken up by hepatocytes, and excess is excreted into bile.
4.
In the hepatocyte, copper is complexed with and detoxified by metallothionein or glutathione and is used as a cofactor for specific cellular enzymes, incorporated into ceruloplasmin that is excreted into the circulation, or excreted into bile.
5.
The site of hepatocellular copper incorporation into ceruloplasmin is the trans-Golgi apparatus. ATP7B is presumed to be responsible for copper transport in this compartment and subsequent incorporation into ceruloplasmin.
6.
The delivery of cytosolic copper to specific intracellular locations is mediated by small proteins termed copper chaperones.
7.
Relocation of ATP7B from the trans-Golgi network to a vesicular compartment adjacent to the canalicular membrane in response to increased hepatocellular copper content facilitates canalicular and biliary copper excretion. A secondary route for biliary copper excretion of hepatocellular copper is via transport of copper-glutathione. In addition, some intracellular copper transports back across the hepatocyte basolateral plasma membrane into the circulation.

Genetics

1.
WD is an autosomal recessive disease with an incidence of 1/20,000 to 30,000 in most populations. Gene frequency for WD is estimated to be 0.3% to 0.7%, thus accounting for a heterozygote carrier rate of slightly >1 in 150 to 200.
2.
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. In 1993, three different groups of investigators identified the WD gene as encoding a copper-transporting ATPase designated ATP7B. This gene spans an 80-kb region of the chromosome that encodes a 7.5-kb transcript expressed primarily in the liver, with some smaller amount of expression in kidney and placenta.
3.
ATP7B is a 1466-amino acid protein that is a member of the cation-transporting P-type ATPase subfamily that is highly preserved in evolution. ATP7B 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.
Over 600 disease-causing mutations of the WD gene have been identified to date. Most of the mutations are missense mutations. Comparatively few patients are homozygous for the same mutation; however, most are compound heterozygotes (i.e., bearers of different mutations on each allele).
5.
Despite the clinical diversity of WD, allelic heterogeneity at the ATPB7 locus does not appear to account for the marked phenotypic and clinical variability observed in patients.
6.
Although one normal ATP7B allele is adequate to prevent clinical disease, heterozygotes with one mutation of the WD gene may demonstrate subclinical abnormalities in copper metabolism such as a mild elevation in liver copper above normal levels and, in 20%, a reduced level of circulating ceruloplasmin.

Pathogenesis

1.
Maintenance of normal copper homeostasis depends on a balance between gastrointestinal absorption and biliary excretion. Intestinal copper absorption in patients with WD does not differ from that of nonaffected individuals.
2.
Biliary excretion of copper is reduced in WD due to defective or absent ATP7B function, which may cause defective entry of cytosolic copper into the vesicular component of the excretory pathway to bile.
3.
Reduced biliary copper excretion in WD leads to pathologic hepatocellular copper accumulation via free radical–induced oxidative injury to lipids, proteins, and nucleic acids; depletion of antioxidants; and polymerization of copper-metallothionein. Therefore, copper-induced injury leads to hepatocellular necrosis and apoptosis. Morphologic abnormalities from oxidant damage have been identified, particularly in mitochondria (i.e., enlargement, dilatation of cristae, and crystalline deposits).
4.
Hepatic copper accumulation and hepatocellular injury lead to increased circulating nonceruloplasmin-bound copper, which is responsible for extrahepatic copper accumulation. Copper toxicity plays a primary role in the pathogenesis of extrahepatic manifestations of WD. Affected organs, in particular the central nervous system, invariably exhibit elevated copper levels.
5.
Pathologic copper deposition in the brain, mostly in the caudate nucleus and the putamen of the basal ganglia, results in the neurologic and psychiatric manifestations of the disease. Excessive deposition of copper in the Descemet membrane of the cornea gives rise to Kayser-Fleischer (KF) rings and rarely sunflower cataracts.
6.
Deficiency of the plasma copper protein ceruloplasmin does not have a role in the pathogenesis of WD. The low serum ceruloplasmin level in patients with WD is the result of reduced incorporation of copper into the ceruloplasmin peptide without copper (aceruloplasmin), which has a shorter half-life than copper-bound ceruloplasmin (holoceruloplasmin).

Clinical Features

1.
Patients may be asymptomatic, although most present with hepatic or neurologic manifestations. Less commonly, patients present with renal, skeletal, cardiac, ophthalmologic, endocrinologic, or dermatologic symptoms.
2.
Clinical symptoms are rarely observed before age 3 to 5 years, and most untreated patients become symptomatic by the age of 40 years. Hepatic symptoms usually are present in the second or third decade of life, and neurologic in the third and fourth decades.
3.
In a large series, the initial clinical manifestations were hepatic in 42%, neurologic in 34%, psychiatric in 10%, and hematologic in 12%. Fewer patients presented with WD after 50 years of age; the oldest reported siblings presented at 70 and 72 years of age.

Hepatic

1.
Hepatic manifestations tend to occur at a younger age (mean, 10 to 12 years) than neurologic manifestations. The rate of progression of liver disease is variable in WD patients. Patients with asymptomatic disease typically have abnormalities of liver biochemical tests that correlate histologically with hepatic steatosis and inflammation. Young patients may present with features that are indistinguishable from chronic viral or autoimmune hepatitis.
2.
Ongoing inflammation leads to progression of fibrosis and eventual cirrhosis with progressive hepatic insufficiency and liver failure. Complications of portal hypertension become evident with advancing cirrhosis.
3.
ALF develops in a minority of patients (see discussion later in chapter).
4.
Hepatocellular carcinoma, once considered rare, has been reported in patients with WD.
5.
Treated patients have a good prognosis even if they have developed cirrhosis. Treatment may even permit regression of fibrosis in some cases. Discontinuation of treatment leads to disease progression and development of ALF or progressive liver failure.

Acute Liver Failure

1.
Patients tend to be young, in their second decade of life, and the clinical picture may be indistinguishable from that of viral-induced massive hepatic necrosis. This same clinical picture may also appear in patients who discontinue therapy for WD.
2.
Although serum aminotransferase levels are only mildly to moderately elevated, there is marked elevation of the serum bilirubin, a low serum alkaline phosphatase level, and evidence of Coombs-negative hemolytic anemia. Serum ceruloplasmin levels are poorly predictive of WD in the acute setting; however, 24-hour urinary copper and circulating copper levels are markedly elevated.
3.
Characteristic clinical features include coagulopathy, nonimmune hemolysis, splenomegaly, KF rings, and a fulminant course; patients rarely survive longer than days to weeks unless LT is performed. Only rare patients may be rescued with medical therapy alone.
4.
Liver biopsy, if performed (generally via a transjugular route due to coagulopathy), demonstrates an elevated hepatic copper content and usually advanced fibrosis or cirrhosis with severe hepatocellular injury. Apoptosis and necrosis may be apparent.

Neurologic

1.
Neurologic involvement tends to occur in the third to fourth decades of life. The diagnosis of WD is often delayed for 1 to 2 years in patients in whom neurologic features predominate.
2.
Common early neurologic symptoms are dysarthria, clumsiness, tremor, drooling, gait disturbance, masklike facies, and deterioration of handwriting.
3.
Rigidity with overt Parkinsonian features, flexion contractures, and spasticity are seen less often and in the later stages of the disease. Athetosis (involuntary writhing movements) or a more severe movement disorder may be present. Rarely, generalized seizures may occur.
4.
Autonomic dysfunction may be present, most commonly in association with other advanced neurologic findings.
5.
Cognitive ability usually remains normal but may be impaired in patients with severe neurologic impairment.
6.
Neurologic symptoms may improve markedly with medical treatment or after LT, although residual deficits are common, especially in those with long-standing symptoms before the onset of therapy.
7.
Magnetic resonance imaging (MRI) shows focal lesions in the putamen and globus pallidus, and in some cases additional lesions in the pons and brainstem.

Psychiatric

1.
Of all patients with WD, one third may present with psychiatric symptoms. Patients may be mistakenly diagnosed with a progressive psychiatric illness, thereby delaying a diagnosis of WD and increasing the odds of concurrent neurologic or progressive hepatic disease.
2.
Early symptoms in teenagers may be limited to subtle behavioral changes and deterioration of academic and work performance.
3.
Patients may present later with personality changes, lability of mood, emotionalism, impulsive and antisocial behavior, depression, and increased sexual preoccupation. Frank psychosis may occur.
4.
Psychiatric symptoms may resolve with medical therapy or after LT.

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