WILSON DISEASE

Wilson disease (hepatolenticular degeneration)

Wilson disease

Wilson disease (hepatolenticular degeneration) is a rare autosomal recessive disorder that usually occurs in persons under age 40 (mean age of onset is between 12 and 23 years of age). The worldwide prevalence is about 30 per million population.

The condition is characterized by excessive deposition of copper in the liver and brain. The genetic defect, localized to chromosome 13 (ATP7B), has been shown to affect a copper-transporting adenosine triphos­phatase in the liver and leads to copper accumulation in the liver and oxidative damage of hepatic mitochondria.

Most patients are compound heterozygotes (ie, carry two different mutations). Over 500 mutations in the Wilson disease gene have been identified. The H1069Q mutation accounts for 37–63% of disease alleles in populations of Northern European descent. The major physiologic aber­ration in Wilson disease is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, espe­cially in the liver, brain, cornea, and kidney.

Symptoms & Causes

The symptoms of Wilson disease vary. Wilson disease is present at birth, but the symptoms don’t appear until the copper builds up in the liver, the brain, or other organs.

Some people do not have symptoms of Wilson disease before they are diagnosed with the disease and treated. If you do have symptoms, the symptoms may be related to your liver, nervous system and mental health, eyes, or other organs.

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Liver symptoms

People with Wilson disease may develop symptoms of hepatitis, or inflammation of the liver. In some cases, people develop these symptoms when they have acute liver failure. These symptoms may include

  • feeling tired
  • nausea and vomiting
  • poor appetite
  • pain over the liver, in the upper part of the abdomen
  • darkening of the color of urine
  • lightening of the color of stool
  • yellowish tint to the whites of the eyes and skin, called jaundice

Some people with Wilson disease have symptoms only if they develop chronic liver disease and complications from cirrhosis. These symptoms may include

  • feeling tired or weak
  • losing weight without trying
  • bloating from a buildup of fluid in the abdomen, called ascites
  • swelling of the lower legs, ankles, or feet, called edema
  • itchy skin
  • jaundice

Nervous system and mental health symptoms

People with Wilson disease may develop nervous system and mental health symptoms after copper builds up in their body. These symptoms are more common in adults but sometimes occur in children.7 Nervous system symptoms may include

  • problems with speech, swallowing, or physical coordination
  • stiff muscles
  • tremors or uncontrolled movements

Mental health symptoms may include

  • anxiety 
  • changes in mood, personality, or behavior
  • depression 
  • psychosis 

Eye symptoms

Many people with Wilson disease have Kayser-Fleischer rings, which are greenish, gold, or brownish rings around the edge of the corneas. A buildup of copper in the eyes causes Kayser-Fleischer rings. A doctor can see these rings during a special eye exam called a slit-lamp exam

Among people who have nervous system symptoms of Wilson disease, more than 9 out of 10 have Kayser-Fleischer rings. However, among people who have only liver symptoms, 5 or 6 out of 10 have Kayser-Fleischer rings.

Diagnosis

The diagnosis can be challenging, even with the use of scoring systems (eg, the Leipzig criteria), and is generally based on demonstration of increased urinary copper excre­tion (greater than 40 mcg/24 h and usually greater than 100 mcg/24 h) or low serum ceruloplasmin levels (less than 14 mg/dL [140 mg/L]; less than 5 mg/dL [50 mg/L] is diagnostic), and elevated hepatic copper concentration (greater than 210–250 mcg/g of dry liver) as well as Kay­ser-Fleischer rings, neurologic symptoms, and Coombs-negative hemolytic anemia.

However, increased urinary copper and a low serum ceruloplasmin level (by a stan­dard immunologic assay) are neither completely sensitive nor specific for Wilson disease, although an enzymatic assay for ceruloplasmin appears to be more accurate

The ratio of exchangeable copper to total copper in serum has been reported to improve diagnostic accuracy. In equivocal cases (when the serum ceruloplasmin level is normal), the diagnosis may require demonstration of a rise in urinary copper after a penicillamine challenge, although the test has been validated only in children and is rarely used now. Liver biopsy may show acute or chronic hepatitis or cirrhosis. MRI of the brain may show evidence of increased basal ganglia, brainstem, and cerebel­lar copper even early in the course of the disease. If available, molecular analysis of ATP7B mutations can be diagnostic.

Treatment

Early treatment to remove excess copper before it can produce hepatic or neurologic damage is essential.

Early in treatment, restriction of dietary copper (shellfish, organ foods, nuts, mushrooms, and chocolate) may be of value.

Oral penicillamine (0.75–2 g/day in divided doses taken 1 h before or 2 h after food) has been the drug of choice and enhances urinary excretion of chelated copper.

Oral pyridoxine, 50 mg per week, is added because penicillamine is an antimetabolite of this vitamin. If penicillamine treat­ment cannot be tolerated because of gastrointestinal intolerance, hypersensitivity, autoimmune reactions, neph­rotoxicity, or bone marrow toxicity, consider the use of trientine, 250–500 mg three times a day, a chelating agent as effective as penicillamine but with a lower rate of adverse effects.

Trientine is increasingly used as a first-line agent, although its cost has become exorbitant.

Oral zinc acetate or zinc gluconate, 50 mg three times a day, inter­feres with intestinal absorption of copper, promotes fecal copper excretion, and has been used as first-line therapy in presymptomatic or pregnant patients and those with neurologic disease and as maintenance therapy after decoppering with a chelating agent, but adverse gastroin­testinal effects often lead to discontinuation and its long-term efficacy and safety (including a risk of hepa­totoxicity) have been questioned.

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Ammonium tetrathio­molybdate, which complexes copper in the intestinal tract, has shown promise as initial therapy for neuro­logic Wilson disease.

Treatment should continue indefinitely. The doses of penicillamine and trientine should be reduced during pregnancy.

Liver transplantation is indicated for fulminant hepatitis (often after plasma exchange or dialysis with MARS as a stabilizing measure), end-stage cirrhosis (with excellent outcomes), and, in selected cases, intractable neurologic disease, although survival is lower when liver transplantation is undertaken for neurologic disease than for liver disease. All first-degree relatives, especially siblings, require screening with serum ceruloplasmin, liver biochemical tests, and slit-lamp examination or, if the causative mutation is known, with mutation analysis.

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