Wilson's disease

Wilson's disease or hepatolenticular degeneration is an autosomal recessive hereditary disease, with an incidence of about 1 in 30,000 in most parts of the world and a male preponderance. Its main feature is accumulation of copper in tissues, which manifests itself with neurological symptoms and liver disease. The estimated heterozygous carrier rate is about 1 in 100, meaning that 1 in 100 people are unaffected carriers of this mutation.

Signs and symptoms
Symptoms usually appear around the ages of 10 to 21 years, but sometimes not until the age of 30, and in rare instances at age 50 and even beyond. Presentation before 5 years of age is extremely rare, despite the biochemical defect being present at birth.

The age of presentation seems to correlate with the organ system involved. About half (40–50%) of patients first present with hepatic symptoms and half (40–50%) with neurologic symptoms. The average age for hepatic symptoms is 10–14 years, compared with 19–22 years for neurologic symptoms. Patients rarely present after age 40.

The main features are liver and neuropsychiatric problems. Chronic active hepatitis, culminating in cirrhosis is the most common hepatic presentation, but some patients present with fulminant liver failure (which is characterised by remarkably low alkaline phosphatase and often high bilirubin levels compared to similar disease states ) and a surprisingly rare incidence of hepatocellular carcinoma. Neuropsychiatric phenomena are early dementia, mood disorders or psychosis and signs of asterixis (a flapping tremor of the hands) and parkinsonism (including ataxia, dyskinesia, and rigidity).

Adjunctive features are renal (renal tubular acidosis, kidney stones), ophthalmic (Kayser-Fleischer rings, sunflower cataracts), cardiac (cardiomyopathy, cardiac arrhythmias) and dermal (hidradenitis suppurativa). Hemolysis (anemia due to destruction of red blood cells) is usually present only in severe cases.

Diagnosis
A suppressed level of ceruloplasmin is present in over 80% of patients, and this is commonly performed as a screening test in patients with liver problems. A more accurate measurement is the direct testing for copper levels in a 24h specimen of urine, in the blood or in the sample obtained by liver biopsy. The average concentration of hepatic copper may reach 20 times normal levels, whilst plasma ceruloplasmin levels are typically less than 30% of normal.

An eye exam would detect the Kayser-Fleischer ring, although its absence does not rule out Wilson's and it may be missed on cursory examination. This sign is characterised by brown rings around the cornea in the eye that result from copper deposition in Descemet's membrane of the cornea. Wilson's disease is also associated with sunflower cataracts, brown or green pigmentation of the anterior and posterior lens capsule.

Pathophysiology
The Wilson disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta but has also been found in the heart, brain, and lung, albeit at much lower levels. The gene codes for a P-type ATPase that transports copper into bile and incorporates it into ceruloplasmin.

The mutant form of ATP7B expressed in people with Wilson's disease inhibits the release of copper into bile. As the excretion of copper from the body is thus impaired, the copper builds up in the liver and injures liver tissue. Eventually, the damage causes the liver to release the copper directly into the bloodstream, which carries the copper throughout the body. The copper buildup leads to damage in the kidneys, brain, and eyes, presumably by generation of reactive oxygen species and binding to neuromelanin. If not treated, Wilson's disease can cause severe brain damage, liver failure, and death.

Copper deposits in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus), result in cell death, producing symptoms akin to Parkinson's disease.

Treatment
The disease is treated with lifelong use of chelating agents such as D-penicillamine or trientine hydrochloride, drugs that help remove copper from tissue. Patients will also need to take vitamin B6 and follow a low-copper diet, which means avoiding mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.

Taking extra zinc may be helpful in blocking the intestines' absorption of copper. Zinc acetate is an agent utilized to inhibit copper absorption in patients with Wilson's disease. It blocks the intestinal absorption of the metal both from the diet and endogenous secretions. It also acts by producing metallothionein, a protein that binds with copper to prevent its release into the blood, and facilitates elimination via the stool.

Liver transplantation is effective in patients with fulminant Wilson disease that does not respond to the usual treatment. Because the primary defect resides within the liver, transplantation is curative, but as it is only undertaken in severely ill patients the prognosis is still mediocre.

Epidemiology
In Western populations the incidence is around 1 per 30,000, with a carrier rate of 1 in 100. The gene frequency is much higher in Hispanics, especially in Central America, and in El Salvador, the incidence is 1 in 186. In Usulután Department, El Salvador it has been reported that 1 in 4 persons carry the disease.

History
The disease bears the name of the British physician Dr Samuel Alexander Kinnier Wilson (1878-1937), a neurologist who described the condition in 1912. Dr J.N. Cumings made the link with copper accumulation in 1948. The first effective chelation agent, penicillamine, was discovered in 1956 by Dr John Walshe. The genetic basis was elucidated in the 1980s and 1990s by several research groups.