Wilson Disease

DEFINITION

Wilson disease is an autosomal recessive inherited disorder of copper metabolism resulting in pathologic accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms and Kayser-Fleischer corneal rings. The familial nature of Wilson disease was recognized in the original description of this disease by Samuel Alexander Kinnier Wilson.

EPIDEMIOLOGY

Until very recently, Wilson disease was believed to be very rare. By a population-based approach, the incidence of Wilson disease was estimated to be at least 1:30 000-50 000 (Ireland: 17/106 live births, former East-Germany: 29) with a gene frequency of 1:90 to 1:150. However, these estimations were mostly based on adolescents or adults presenting with neurologic symptoms. More recent data however indicate that neurologic symptoms occur only in about half of Wilson disease patients.

Thus, the incidence of Wilson disease was underestimated by these studies. Furthermore, in selected populations (Jews from Uzbekistan, China) Wilson disease seems to be even more common. Among selected groups of patients Wilson disease is certainly more frequent.

About 3-6% of patients transplanted for fulminant hepatic failure and 16% of young adults with chronic active hepatitis of unknown origin have Wilson disease.

PATHOGENESIS

The basic defect in Wilson disease is the impaired biliary excretion of copper resulting in the accumulation of copper in various organs including the liver, the cornea and the brain. The consequence of copper accumulation is the development of severe hepatic and neurological disease.

Copper's unique electron structure allows these cuproenzymes to catalyze redox reactions, but causes ionic copper to be very toxic, readily participating in reactions that promote the synthesis of damaging reactive oxygen species. Copper overload particularly affects mitochondrial respiration and causes a decrease in cytochrome C activity. Damage to mitochondria is an early pathologic effect in the liver.

Damage to the liver has been shown to result in increased lipid peroxidation and abnormal mitochondrial respiration both in copper loaded dogs and in patients with Wilson disease. The mechanism(s) triggering copper-induced lipid peroxidation are unknown. However, it is conceivable that, due to hepatic copper accumulation, patients with Wilson disease are particularly sensitive to any oxidative stress.

The pathogenesis of neurologic disease is less clear. Neuronal damage is mediated by copper deposition in the brain. Copper may be directly toxic to neurons or may exert its effects by selective inhibition of brain monoamine oxidase A (MAO-A).

Copper accumulation in the brain may be secondary to liver damage, but this hypothesis is inconsistent with the clinical observation that many patients with neurologic disease have only mild liver disease, and that conversely patients with advanced liver failure have no neurologic symptoms. Further-more the preferential affection of basal ganglia cannot be explained. The discovery of the Wilson disease gene may help to better understand the pathophysiology of copper metabolism.

ATP7B is also expressed in the brain, but its function is unknown. It is conceivable that increased copper uptake into the brain is a direct result of a certain mutation resulting in specific functional alterations of cerebral ATP7B.