• 
  

  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

    
    

  
  

Diagnostic Criteria

• 
  

  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 μmol/d (>40 μg/d) as the threshold for diagnosing Wilson disease is more effective diagnostically than the previous customary value of 1.6 μmol/d (100 μg/d), which fails to identify 20% to 25% of patients. The diagnostic effectiveness of greater than 0.6 μmol/d (>40 μg/d) is particularly evident with pediatric patients.

    
    
  • 
    

    Hepatic parenchymal copper measurement greater than 100 μg/g dry wgt is consistent with the diagnosis; hepatic parenchymal copper concentration greater than 70 μg/g dry wgt warrants further investigation; liver biopsy may be dangerous in patients with hepatic decompensation (coagulopathy and/or thrombocytopenia) and carries a 1/10,000 mortality rate overall; lack of facilities for performing the biopsy or for analyzing parenchymal copper content may also militate against obtaining this diagnostic information.

    
    
  • 
    

    Histologic findings on liver biopsy may also contribute to making the diagnosis of Wilson disease. These findings may include steatosis, glycogenated nuclei in hepatocytes, focal hepatocellular necrosis, fibrosis, or cirrhosis. Transmission electron microscopy may reveal changes in mitochondrial structure (variable shape and size, dilated tips of the mitochondrial cristae, dark bodies in the matrix) which are almost exclusively found with Wilson disease. Stainable copper is not a reliable diagnostic feature because it is a late finding and can also be found with severe cholestasis.

    
    
  • 
    

    Evidence of Kayser-Fleischer rings by slit-lamp examination by a competent specialist (present in ~60% of adults with hepatic Wilson disease and in ~90%-95% of adults with neurologic Wilson disease) is highly supportive of the diagnosis—note that Kayser-Fleischer rings may be present in various sorts of severe cholestatic liver disease.

    
    
  • 
    

    24-hour urinary excretion after D-penicillamine challenge has been validated only in children. Contrary to the initial report, its diagnostic reliability is only moderate (not invariable).

    
    
  • 
    

    Head MR may reveal characteristic findings of WD, namely, the “face of the giant panda” in the midbrain on T2-weighted images. Basal ganglia abnormalities (high-signal intensity on T2, low-signal intensity on T1) may also be detected. Similar head MR findings may be found in other neurologic disorders including Leigh disease, hypoxic-ischemic encephalopathy, methanol poisoning, certain types of encephalitis, and extrapontine myelinolysis due to osmotic disequilibrium syndrome. MR is preferred to computerized tomography (CT).

    
    
  • 
    

    Incorporation of radioactive copper into ceruloplasmin is no longer utilized; incorporation of a nonradioactive isotope of copper into ceruloplasmin is unreliable as a diagnostic test.

And the absence of

• 
  

  Definitive diagnosis of any hepatic, neurologic, or psychiatric disease in the extended differential diagnosis.

Comment: Note that the rare patient has been found who has both Wilson disease and autoimmune hepatitis, as well as a few patients with acute viral hepatitis superimposed on Wilson disease; also note that some patients with both nonalcoholic fatty liver disease and Wilson disease are bound to exist on a statistical basis; note that excluding all possible non-Wilsonian neurologic and psychiatric disorders may be extremely difficult.

Clinical Characteristics

WD is clinically pleiomorphic (Table 73-1). It can present principally as hepatic, neurologic, or psychiatric disease. The usual age range for clinical presentation is 5 to 45 years; younger individuals tend to have hepatic disease. WD mainly with a neurologic presentation has been newly diagnosed in older adults. Differentiation from other chronic liver disorders in young adults, such as autoimmune hepatitis, is important because treatment is different. Particularly in adults, differentiation from relatively benign neurologic problems, such as familial tremor, is critically important. Subtle presentations include episodes of self-limited jaundice due to transient hemolysis (not liver disease) and an obstetric history of repeated spontaneous abortions (Table 73-2).