Etiology

Wilson disease is an autosomal-recessive genetic disease caused by mutations in the ATP7B gene. More than 700 causative mutations have been discovered, such that in most countries, most patients are compound heterozygotes.[1][2][4]​​​​[11] The gene product of ATP7B is involved in transport and excretion of excess copper in the bile and subsequent elimination in the stool. The ATP7B gene is located on the short arm of chromosome 13.[4]

Pathophysiology

Copper is an essential metal that serves as a cofactor for enzymes involved in multiple cellular processes. It is absorbed through the enterocytes of the duodenum and the proximal small intestine. The copper is then transported via albumin through the portal system and removed from the circulation by the liver. The liver utilizes copper for certain metabolic processes and incorporates copper into the blood copper transport protein ceruloplasmin. Dietary consumption of copper usually exceeds metabolic demand.[12] Excess copper is secreted into bile. Most copper is removed from the body by feces, with a small amount removed by the kidneys.

ATP7B loads copper onto apoceruloplasmin to create ceruloplasmin and transports excess copper into bile.[13] Loss of ATP7B function leads to lack of copper incorporation into ceruloplasmin, and copper cannot be transported into the bile and excreted in the feces. Apoceruloplasmin has a shorter half-life than ceruloplasmin, leading to the low ceruloplasmin levels seen in patients with Wilson disease.[14] Ultimately copper accumulation exceeds the liver's storage capacity and copper is released into the blood. This copper is not bound to ceruloplasmin so accumulates more readily in the tissues, particularly the brain, kidneys, and cornea.[4] High levels of free copper probably cause toxicity by oxidant damage, which can affect the mitochondria, peroxisomes, microtubules, DNA, and plasma membranes.[15] The result is cell injury, inflammation, and cell death.

Liver inflammation and cell injury results in hepatitis. With continued exposure to high levels of copper, fibrosis and eventually cirrhosis can occur. Clinically this progresses to end-stage liver disease and hepatic failure if the patient is not treated.

The basal ganglia and areas of the brain that coordinate movement are most sensitive to copper accumulation. Occasionally white matter is also affected.[16] Copper toxicity results in inflammation, neuronal injury, and neuronal death. Inflammatory areas are seen as an increased signal on MRI of the brain. Later, MRI may show volume loss.[16]

It is difficult to determine a clear link between gene mutation and clinical phenotype for patients with Wilson disease. Patients can present with liver disease, neurologic disease, or psychiatric disease, with potential overlap and variable timing of presentation.[17]

Classification

Phenotypic classification of Wilson disease[6]

Hepatic presentation

  • H1: Acute hepatic Wilson disease: acutely occurring jaundice in a previously apparently healthy person, either due to a hepatitis-like illness or to Coombs-negative hemolytic disease, or a combination of both. May progress to liver failure necessitating emergency liver transplant.

  • H2: Chronic hepatic Wilson disease: any type of chronic liver disease, with or without symptoms. May lead to or present as decompensated cirrhosis. Diagnosis is based on standard biochemical, and/or radiologic, or biopsy evidence.

  • Hepatic presentation classification requires the exclusion of neurologic symptoms by a detailed clinical neurologic exam at the time of diagnosis.

Neurologic presentation

  • Patients in whom neurologic and/or psychiatric symptoms are present at diagnosis.

  • N1: associated with symptomatic liver disease. Usually patients have cirrhosis at the time of diagnosis of neurologic Wilson disease. Chronic liver disease may predate the occurrence of neurologic symptoms by many years, or be diagnosed during the diagnostic workup of a neurologically asymptomatic patient.

  • N2: not associated with symptomatic liver disease. Documentation of the absence of marked liver disease requires a liver biopsy.

  • NX: presence/absence of liver disease not investigated.

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