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Key Points

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  • Disease summary:

    • Wilson disease (WD) is a disorder of hepatic copper disposition caused by mutations in the gene ATP7B, on chromosome 13, which encodes a metal-transporting P1-type ATPase, known as the Wilson ATPase. In hepatocytes the Wilson ATPase assists in moving copper across intracellular membranes, which directly contributes to production of ceruloplasmin, a ferroxidase that is functional only when copper is incorporated. Additionally, the Wilson ATPase expedites excretion of copper into bile. Accordingly, in WD serum concentrations of ceruloplasmin are low and hepatic retention of copper develops, leading to liver injury. With progression of liver disease, copper spills out of the liver and accumulates in other organs, such as the brain, eyes, renal tubules, heart, and synovial membranes. Untreated WD is a progressive degenerative disease, nearly always associated with early death.

    • WD occurs worldwide, but it is rare. The average prevalence is 30 affected persons per million population, with a corresponding carrier frequency of approximately 1 in 90. More than 500 mutations have been identified, and 80% of affected individuals are compound heterozygotes. In some populations (including Iceland, Korea, Japan, Sardinia, and the Canary Islands) where the incidence in higher, there may also be a relatively circumscribed set of mutations. In northeastern Europe, the mutation H1069Q is found as at least one of the mutations in 35% to 75% of WD patients.

  • Hereditary basis:

    • Autosomal recessive

  • Differential diagnosis (limited to principal disorders):

    • Hepatic

      • Causes of elevated serum aminotransferases: chronic hepatitis B, chronic hepatitis C, nonalcoholic fatty liver disease (NAFLD), alcoholic hepatitis, alpha-1-antitrypsin deficiency, any drug-induced liver injury

      • Fatty liver: NAFLD, alcoholic liver disease, various rare metabolic disorders

      • Acute hepatitis: acute hepatitis A, B, C, E; cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6); unknown virus(es)

      • Autoimmune hepatitis-like: autoimmune hepatitis type 1 or 2, primary sclerosing cholangitis (with an autoimmune sclerosing cholangitis pattern)

      • Cirrhosis: principal causes of cirrhosis are covered already; other rare metabolic disorders (eg, citrullinemia type 2—mainly in East Asians)

      • Gallstones: cholesterol gallstones, typically idiopathic

      • Fulminant hepatic failure presentation: highly characteristic of WD but causes of acute liver failure require attention

    • Neurologic

      • Parkinson disease

      • Choreoathetosis—other causes

      • Pseudobulbar palsy—other causes

      • Tremors—other causes

      • Dysarthria—other causes

      • Familial dysautonomia

      • Epilepsy—other causes

    • Psychiatric

      • Organic brain syndromes

      • Primary causes of neuroses

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic Criteria

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  • Genetic diagnosis: identification of two disease-causing mutations in ATP7B (80% of patients are compound heterozygotes) or identification of homozygosity for one disease-causing mutation

  • Clinical diagnosis: presence of hepatic or neurologic disorder consistent with WD + basal 24-hour urinary copper excretion greater than 0.6 μmol/d (>40 μg/d) + hepatic parenchymal copper concentration greater than 250 μg/g dry wgt

    • Serum ceruloplasmin less than 50 mg/L is highly supportive of the diagnosis; serum ceruloplasmin less than 140 mg/L is highly consistent with the diagnosis; serum ceruloplasmin greater than 140 mg/L is still compatible with the diagnosis (serum ceruloplasmin may be normal).

    • Employing greater than 0.6 ...

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