Wilson disease is a rare, autosomal recessive, inherited disorder affecting copper metabolism. It occurs in approximately 1 out of every 30,000 individuals and is characterized by excessive copper deposition throughout the body’s tissues, especially the liver, brain, and eyes. Hallmark features of the disease include liver disease, neurological and psychiatric problems, and Kayser-Fleischer rings.1 

Etiology

The primary cause of Wilson disease involves variants of the ATP7B gene, which is responsible for encoding ATPase 2, a protein that transports copper from the liver to other body regions.1 

Variations in the PRNP gene may also contribute to Wilson disease. The PRNP gene encodes a prion protein that appears to be implicated in the transport of copper and is found within the brain and other tissues.1

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Symptoms

Symptom onset of Wilson disease typically begins in adolescence, but they may initially appear any time between the ages of 6 and 45 years.1 

Hepatic 

The initial sign of Wilson disease is often hepatic dysfunction. While patients may present with acute hepatitis, the 3 main patterns of hepatic dysfunction consist of chronic active hepatitis, fulminant hepatic failure, and, most commonly, cirrhosis.2 

Symptoms of hepatic dysfunction include jaundice, fatigue, loss of appetite, and ascites.1 In addition to jaundice and ascites, signs and symptoms of fulminant hepatic failure include digital clubbing, spider nevi, palmar erythema, and hematemesis.2

Neurological

Asymmetric tremor, which can be resting, kinetic, or postural in nature, is the most common initial neurological symptom. Other early neurological manifestations of Wilson disease include ataxia, hypersalivation, dysarthria, clumsiness, and hypomimia.1,2 Late manifestations of Wilson disease include dystonia, spasticity, rigidity, flexion contractures, and grand mal seizures.2 

Psychiatric

Psychiatric problems associated with Wilson disease are classified into behavioral, cognitive, affective, and schizophrenic-like categories. Psychiatric signs and symptoms include depression, anxiety, mood swings, changes in personality, and impaired cognitive ability. Psychiatric presentations in a smaller percentage (10% to 20%) of patients with Wilson disease involve emotional lability, disinhibition, impulsiveness, and self-injurious behavior.1,2 

Ophthalmic

Around 90% of people with symptomatic Wilson disease, especially those with neurological symptoms, present with Kayser-Fleischer rings, greenish gold to brownish rings surrounding the irises. The rings form due to copper deposits in the Descemet membrane in the limbus of the cornea. These rings may be observed with the naked eye or using an ophthalmoscope set at +40. Slit-lamp examination or gonioscopy may be required in cases where the rings are not visible.1,2

Musculoskeletal 

Musculoskeletal manifestations of Wilson disease include arthropathy resembling premature osteoarthritis, polyarthritis, osteochondritis dissecans, chondromalacia patellae, chondrocalcinosis, osteoporosis, rickets, osteomalacia, and spontaneous fractures.2

Dermatological 

Patients with Wilson disease may present with azure lunulae, a bluish, moon-shaped discoloration of the base of the fingernails.2

Cardiac

Cardiac manifestations of Wilson disease include arrhythmias and an increase in autonomic tone.2

Hematologic/Renal 

Hematologic and renal manifestations of Wilson disease include hematuria, urolithiasis, and, in 10% to 15% of patients, Coombs-negative acute intravascular hemolysis.2

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Diagnosis

The diagnosis of Wilson disease requires a thorough physical and neurological examination as well as laboratory testing to determine serum ceruloplasmin levels and the 24-hour urinary copper excretion rate.2 

A diagnosis of Wilson disease is suspected in people with serum ceruloplasmin levels under 20 mg/dL and a 24-hour urinary copper excretion rate above 40 μg/day who have Kayser-Fleischer rings. Elevated urinary copper excretion may also manifest in other cholestatic hepatic diseases.2

A liver biopsy confirming hepatic copper concentrations above 250 μg/g of dry weight may indicate Wilson disease; however, other hepatic conditions may also present with elevated copper concentrations.2

Imaging may include magnetic resonance imaging or computed tomography scans to detect brain lesions and imaging of the abdomen to confirm ascites. Electrocardiography may also be performed to detect cardiac arrhythmias.2 

In the early stages of Wilson disease, electron microscopy may confirm the presence of copper-containing hepatocytic lysosomes, while atomic absorption spectrophotometry quantifies the amount of hepatic copper.2 

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Staging

Wilson disease progresses in 4 stages. Stage I involves initial copper accumulation at hepatic binding sites. Stage II involves the redistribution of copper inside the liver and the eventual secretion of copper into the circulatory system. Stage III involves chronic copper deposition throughout extrahepatic tissues, including the brain. Stage III can progress to fatal disease if left untreated. Stage IV requires the use of long-term chelation therapy to restore copper balance in the body.3 

Treatment

The primary treatment for Wilson disease consists of lifelong use of chelating agents including penicillamine or trientine, which may exacerbate neurological symptoms when initiated. Surgical treatments include decompression or transjugular intrahepatic shunting for uncontrolled variceal bleeding and curative liver transplantation.2

Pharmacological treatments to manage secondary symptoms involve antiepileptics for seizures; neuroleptics for psychiatric symptoms; anticholinergics, gamma-aminobutyric acid (GABA) antagonists, baclofen, or levodopa for advanced neurological symptoms such as dystonia or parkinsonism; and protein restriction and/or lactulose for hepatic encephalopathy.2 

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References

  1. Wilson disease. MedlinePlus. Updated July 11, 2022. Accessed September 9, 2022.
  2. Gilroy RK. Wilson disease: practice essentials. Medscape. Updated February 14, 2019. Accessed September 9, 2022.
  3. Gilroy RK. Wilson disease: background. Medscape. Updated February 14, 2019. Accessed September 9, 2022.

Reviewed by Kyle Habet, MD, on 9/25/2022.