Wilson's Disease

Alternative names: Inherited Copper Toxicosis.

A genetic disorder called Wilson's disease affects copper metabolism and leads to low serum and hair copper levels but high levels in the liver and brain.  This can be a serious and even fatal problem unless treated by chelating agents; BAL or penicillamine is most often used as it binds copper in the gut and carries it out.

This is an inherited liver disorder named after British neurologist Samuel Wilson.  The small intestine absorbs too much copper and the liver excretes too little of it, resulting in a copper buildup in the liver and brain.

The copper toxicosis of Wilson's disease is characterized, from birth on, by an average concentration of hepatic copper 20 times higher than normal and by deficiency of the plasma copper protein ceruloplasmin, averaging about 30% of normal.  These concentrations are diagnostic of the disease, but they are present in every infant during the first 2-3 months of life, making diagnosis before 6 months of age unreliable.  However, because clinical manifestations are never seen before the age of 5 years, studies to confirm or exclude the diagnosis in children at significant risk of Wilson's disease can be safely delayed until the second year of life.

In about 40 to 50% of patients, the first manifestations of disease occur in the liver.  The initial illness may be an episode of acute hepatitis, occasionally misdiagnosed as infectious mononucleosis.  Although the patient may be asymptomatic for years, hepatitis – acute, chronic active, or fulminant – may develop at any time.  Whether or not such an illness occurs, hepatic pathology progresses to fibrosis and ultimately to cirrhosis.

Incidence

Wilson's disease is a progressive and uniformly fatal disorder of copper metabolism that affects the 1 person in 30,000 who inherits a mutant pair of the gene ATP7B located on chromosome 13.  Symptoms never occur in heterozygous carriers, who have only one mutant gene and who appear to constitute about 1.1% of every ethnic and geographic population studied.  Onset is slow and begins between 11 and 25 years of age.

Signs and Symptoms

In about 40 to 50% of patients, the disease first affects the central nervous system (CNS).  Although copper diffuses out of the liver into the blood and then into other tissues, it has disastrous effects only on the brain.  There it can cause motor neurologic disease characterized by any combination of tremors, dystonia, dysarthria, dysphagia, chorea, drooling, open-mouthedness, and incoordination.  Sometimes, copper toxicity to the brain is first noted as grossly inappropriate behavior, sudden deterioration of schoolwork, or, rarely, psychosis indistinguishable from schizophrenia or manic-depressive illness.  As copper moves from liver to brain, some of it always deposits in Descemet's membrane of the cornea, producing gold or greenish gold Kayser-Fleischer rings or crescents.  Except for headache, sensory disturbances never occur.

In 5 to 10% of patients, Wilson's disease may first manifest as Kayser-Fleischer rings detected during a refractive eye examination; as amenorrhea or repeated miscarriages; or, because of renal copper deposits, as gross or microscopic hematuria or an abnormally low serum level of uric acid resulting from its abnormally high urinary excretion.

Diagnosis and Tests

Wilson's disease is almost certainly the diagnosis in any patient presenting with fulminant hepatitis, Coombs-negative hemolytic anemia, ceruloplasmin deficiency, and hypercupriuria.

Unless Wilson's disease is suspected, its diagnosis is often missed because of its rarity.  It should be suspected in a person under the age of 40 with any of the following:

• An otherwise unexplained hepatic, neurologic, or psychiatric disease
• Otherwise unexplained persistent, asymptomatic transaminasemia
• A sibling, parent, or cousin with Wilson's disease

• When Wilson's disease is suspected, the diagnosis generally can be unequivocally confirmed if the patient has one of the following pairs of abnormalities:

  • Deficiency of oxidase-active ceruloplasmin (< 20 mg/dL) and excess of hepatic copper (> 250 ug/gm [> 3.9 umol/gm] dry liver) accompanied by histopathologic changes compatible with Wilson's disease;
  • Deficiency of ceruloplasmin and the presence of Kayser-Fleischer rings confirmed by an ophthalmologist using a slit lamp;
  • The confirmed presence of Kayser-Fleischer rings and motor neurologic abnormalities of the kind listed above;
  • Excess of hepatic copper and abnormally low incorporation of 64Cu into ceruloplasmin, despite a normal concentration of ceruloplasmin (20 to 30 mg/dL);
  • Deficiency of ceruloplasmin and urinary excretion of space (> 100 ug or 1.6 umol) copper in 24 hours, without administration of penicillamine.

Note: The diagnosis cannot be based on ceruloplasmin deficiency alone because about 20% of heterozygous carriers of Wilson's disease have ceruloplasmin deficiency, but heterozygotes never have symptoms or signs of Wilson's disease.  Heterozygotes must not be treated.  The diagnosis cannot be based on an excess of hepatic copper alone because equally high concentrations of copper occur in primary biliary cirrhosis and other cholestatic syndromes.

Treatment and Prevention

Continual, lifelong treatment is required.

Prognosis

Regardless of the way Wilson's disease evolves, it is always fatal, generally before age 30 and usually after years of suffering, unless timely, lifelong, uninterrupted specific treatment is instituted.