Wilson's Disease

Wilson disease, which is also known as hepatolenticular degeneration, is quite a rare inherited systemic disorder of copper metabolism. In patients with this disease, copper initially accumulates in the liver itself. When the liver's storage capacity is eventually exceeded, copper is then released from the liver and begins to collect in other organs of the body, such as the brain, eyes, and kidneys.

Symptoms

Although abnormal copper accumulation may begin at birth, the symptoms of Wilson disease may not become apparent until late childhood or adolescence. In all patients, copper initially accumulates in the liver. This may cause acute or chronic inflammation of the liver (hepatitis) or severe liver disease due to a progressive loss of standard liver function (cirrhosis). The degree of liver involvement is variable and may range from mild elevations of certain liver enzymes to complete liver damage. Associated symptoms may include fatigue, loss of appetite (anorexia), weight loss, generalized weakness, fluid accumulation in the abdomen (ascites) and abdominal swelling, or yellowish discoloration of the skin and the eyes (jaundice). Other findings may also include enlargement of the liver (hepatomegaly), spleen (splenomegaly), or both (hepatosplenomegaly). In general, the younger the age at symptom onset, the greater the degree of liver involvement. In patients with Wilson disease, neurologic symptoms seem to be predominant after age twenty.

Many individuals with Wilson's disease experience symptoms associated with damage to the nervous system. These standard symptoms usually become apparent during the second decade of life or, in some patients, during the third decade; however, these have been known to appear as late as age 50. Neurologic abnormalities rarely occur in patients younger than age ten. These neurologic symptoms may include tremor of the head, arms, or legs/ generalized, impaired muscle tone/ and sustained muscle contractions.

These produce abnormal postures, twisting, and repetitive movements (dystonia); and slowness of movements (bradykinesia), particularly those of the tongue, lips, and jaw. Patients may also sometimes experience clumsiness, difficulty with balance, and impaired coordination of voluntary movements, such as walking (ataxia), or slowness of finger movements. Tremor or trembling may also be present in one hand or leg and gradually progress to involve all four limbs. Speech may become slurred or slowed (dysarthria) and patients may inadvertently "drop" the ends of words. The voice may also have a hoarse quality (whispering dysphonia). In some patients, swallowing may become increasingly difficult (dysphagia).

Causes

Wilson disease is a genetic disorder that is thought to affect 0.00001% of people worldwide. The disorder is sometimes due to abnormal changes (mutations) in a gene that is inherited as an autosomal recessive trait. The disease gene responsible for Wilson disease, typically known as the ATP7B gene, is located on the long arm (q) of chromosome 13 (13q14.3). The protein regulated by this gene plays a important role in the transport of copper (copper-transporting ATPase). Recessively transmitted disorders may be fully expressed in individuals who inherit 2 copies of the disease gene (homozygotes), one from the mother and one from the father. Brothers or sisters of those diagnosed with Wilson disease have a one in four chance of inheriting both copies of the disease gene and thus developing the disease. Those who inherit a single copy of the disease gene (heterozygotes) are carriers of the disease trait and may then transmit a single copy of the disease gene to their children. It is estimated that as many as one in 90 to 100 individuals is a carrier for Wilson disease. Genetic testing for Wilson disease is not yet possible. However, in families with known, mutations of the gene, haplotype analysis may be useful in determining proper carrier status.

Diagnosis

Diagnosis of Wilson disease may involve one or more of the following laboratory tests, findings, or procedures:
* Unusually low serum ceruloplasmin levels. (However, ceruloplasmin levels may be normal in up to 10 percent of individuals with Wilson disease.)
* Urinary copper excretion test with findings of greater than 100mg.
* confirmation of the presence of Kayser-Fleischer rings. In individuals with brown eyes, a special examination of the eyes known as a slit lamp examination may be necessary to confirm the presence of these rings. They are present in most individuals with Wilson disease and are closely associated with neurologic and psychiatric symptoms and findings.
* Serum copper levels of less than 80µg/dl
* Demonstration of increased levels of copper in the liver of greater than 250µg/g dry weight. Tissue samples for testing are obtained through a surgical biopsy of the liver.

Treatment

The goal of drug therapy in individuals with Wilson disease is to remove the excess copper from the body and prevent ongoing copper accumulation and deposition. Therefore, drug therapy must be continued through and through life. Inadequate treatment or disruption of drug therapy may result in life-threatening complications or irreversible organ damage.

The initial approach in treating Wilson disease is the removal of excessive copper with chelating agents. The most common agent used for this purpose is D-penicillamine. This drug binds to copper and forms a stable compound that is then released in urine. D-penicillamine depletes pyridoxine or Vitamin B6 from the body. Therefore, dietary supplementation with pyridoxine is most required. The side effects of D-penicillamine range from minor disturbances to severe or life-threatening complications, such as aplastic anemia, immune complex nephritis, systemic lupus erythematosus, or myasthenia gravis. In some individuals, neurologic symptoms may worsen during penicillamine therapy.

In patients with Wilson disease, ongoing maintenance therapy usually involves use of zinc acetate, which blocks the absorption of copper in the intestines and promotes the elimination of copper is in the stool. Zinc acetate then stimulates the production of the compound metallothionein, which has a high affinity for binding copper. Therefore, copper is not absorbed through the intestine nor passed on to the liver or other organs of the body.

Copper is present in small amounts in most foods. Patients with Wilson disease must avoid all copper-rich foods such as cocoa, chocolate, liver, mushrooms, nuts, and shellfish and ensure that their copper intake restricted to less than 1/mg per day.