Wilson Disease

Autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene, encoding a hepatocyte copper transporter responsible for biliary copper excretion and incorporation of copper into ceruloplasmin.

Impaired function leads to progressive copper accumulation, initially in the liver and subsequently, once hepatic storage capacity is exceeded, in the brain (particularly the basal ganglia), cornea, and other tissues.

Onset is typically in childhood to early adulthood, though presentation can occur at any age.

Hepatic presentation is most common in younger patients and ranges from asymptomatic transaminase elevation, through chronic hepatitis and cirrhosis, to acute liver failure, the latter often accompanied by a characteristic Coombs negative hemolytic anemia from copper induced red cell damage, a distinctive and diagnostically useful clue.

Neurological presentation, more common in slightly older patients, includes tremor, dysarthria, dystonia, parkinsonism, and gait disturbance.

Psychiatric presentation includes personality change, depression, and, less commonly, psychosis, and can precede or accompany other features.

Kayser-Fleischer rings (golden brown copper deposition in Descemet's membrane at the corneal limbus, visible on slit lamp examination) are present in nearly all patients with neurological involvement, though in a smaller proportion of those with hepatic disease alone.

• Serum ceruloplasmin is typically low, though it is an acute phase reactant and can be falsely normal in the context of active inflammation, so a normal level does not exclude the diagnosis.

• 24 hour urinary copper excretion is elevated and is a key diagnostic and monitoring test.

• Slit lamp examination for Kayser-Fleischer rings should be performed in all suspected cases.

• Liver biopsy with quantitative hepatic copper content is the most sensitive test and may be needed when other results are equivocal.

• Genetic testing for ATP7B mutations confirms the diagnosis and is particularly useful for screening first degree relatives once an index case is identified.

• MRI brain in patients with neurological features characteristically shows basal ganglia signal change, though this supports rather than establishes the diagnosis.

Copper chelation therapy is the mainstay of treatment:

• Penicillamine, the traditional first-line agent, requires pyridoxine supplementation to prevent deficiency and carries a range of side effects including bone marrow suppression, proteinuria, and, notably, a risk of paradoxical neurological worsening on initiation.

• Trientine is an alternative chelator with a more favorable side effect profile and is increasingly preferred, particularly for patients with neurological presentation given the lower risk of initial worsening.

• Zinc salts work by a different mechanism, inducing metallothionein in enterocytes to block intestinal copper absorption, and are used for maintenance therapy after initial chelation, or as first-line treatment in presymptomatic or minimally symptomatic patients identified through family screening.

Dietary copper restriction (avoiding shellfish, organ meats, nuts, chocolate, and mushrooms) is a reasonable adjunct, though not sufficient alone. Liver transplantation is curative for the underlying metabolic defect (since the transplanted liver has normal ATP7B function) and is indicated for acute liver failure or decompensated cirrhosis unresponsive to medical therapy.

Lifelong treatment and monitoring is required even after neurological or hepatic improvement, given the risk of relapse on treatment discontinuation.