What is Wilson's disease?

Wilson's Disease: A Genetic Copper Metabolism Disorder

Wilson's disease is an inherited autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, resulting in defective biliary excretion of copper and its toxic accumulation primarily in the liver and brain. 1

Genetic Basis and Epidemiology

• The disease results from mutations in the ATP7B gene, which encodes a copper-transporting P-type ATPase responsible for copper excretion into bile and incorporation into ceruloplasmin 1
• More than 500 distinct mutations have been described, with approximately 380 confirmed to cause disease 1
• The gene frequency is 1 in 90-150, with disease incidence as high as 1 in 30,000 1
• The disease follows autosomal recessive inheritance, meaning both parents must be carriers for offspring to be affected 2

Pathophysiology

Normal copper homeostasis is maintained exclusively through biliary excretion; when ATP7B protein is absent or dysfunctional, copper accumulates in hepatocytes until storage capacity is exceeded, then releases into bloodstream and deposits in extrahepatic organs. 1, 3

• Copper initially accumulates in the liver from early childhood, causing cytological changes before clinical symptoms appear 4
• Once hepatic storage capacity is exceeded, copper enters circulation and deposits in brain (causing neuropsychiatric symptoms), cornea (Kayser-Fleischer rings), kidneys, bones, and other organs 1, 5
• The toxic copper generates reactive oxygen species (ROS) through Haber-Weiss and Fenton reactions, leading to copper-dependent cell death (cuproptosis) 6
• Failure to incorporate copper into ceruloplasmin results in low serum ceruloplasmin levels in most patients 1, 7

Clinical Presentation

Wilson's disease can present at any age from 3 years to the eighth decade, though most patients present between ages 5 and 35. 1, 8

Hepatic Manifestations (40% of presentations)

• Asymptomatic hepatomegaly or isolated splenomegaly 8
• Persistently elevated aminotransferases (AST, ALT) found incidentally 8
• Acute hepatitis-like presentation 8
• Autoimmune hepatitis-like syndrome, especially in children or adults not responding to conventional therapy 8, 1
• Fatty liver on histology 8
• Cirrhosis (compensated or decompensated) 1, 8
• Acute liver failure with Coombs-negative hemolytic anemia and acute renal failure 8, 7

Neurological Manifestations (35% of presentations)

• Tremor with characteristic "wing-beating" appearance 8, 9
• Dysarthria (slurred speech) and drooling as early symptoms 8, 9
• Dystonia (focal, segmental, or severe) 8, 9
• Lack of motor coordination and ataxia 8, 6
• Deteriorating handwriting including micrographia 8
• Parkinson-like symptoms ("juvenile Parkinsonism") with bradykinesia, bradyphrenia, and hypomimia 8, 9
• Pseudobulbar palsy with dysphagia 8

Psychiatric Manifestations (10% of presentations)

• Behavioral changes, particularly in children and adolescents 8, 4
• Declining school performance 8
• Personality changes, impulsiveness, labile mood 8, 4
• Depression, anxiety, or frank psychosis 8, 4
• Psychiatric symptoms can precede somatic disorders by years, with diagnostic delays up to 12 years reported 4

Ophthalmologic Findings

• Kayser-Fleischer rings (golden-brownish pigment deposits in Descemet's membrane at the corneal limbus) are present in 90% of patients with neurological manifestations but only 50-62% with primarily hepatic disease 1, 8
• Slit-lamp examination by an experienced observer is required for detection 8, 7
• Kayser-Fleischer rings are usually absent in children presenting with liver disease 8

Other Manifestations

• Hemolysis (acute episodes, recurrent, or chronic low-grade) often with undetectable serum haptoglobin 8, 6
• Renal abnormalities including aminoaciduria and nephrolithiasis 8
• Premature osteoporosis and arthritis 8, 6
• Cardiomyopathy and cardiac arrhythmias 8, 6
• Pancreatitis 8
• Menstrual irregularities, infertility, or repeated miscarriages 8

Diagnostic Approach

The diagnosis requires a combination of clinical features, biochemical parameters, and ophthalmologic examination, as no single test is definitive. 1, 10

When to Suspect Wilson's Disease

• Any individual aged 3-55 years with unexplained liver disease 8, 10
• Unexplained liver disease combined with neurological or neuropsychiatric disorders 8
• Hemolysis of unclear etiology, especially Coombs-negative 8, 6
• Movement disorders, particularly if accompanied by liver abnormalities 8
• Apparent autoimmune hepatitis not responding to conventional therapy 8, 1
• Children with declining school performance or behavioral changes attributed to puberty 8

Diagnostic Testing

• Serum ceruloplasmin <20 mg/dL (though 18% of non-fulminant patients may have normal levels) 1, 10
• Slit-lamp examination for Kayser-Fleischer rings 8, 7
• Hepatic copper concentration >250 μg/g dry weight provides critical diagnostic information 1, 7
• 24-hour urinary copper excretion (normal <40-50 μg/24h; in fulminant failure: 844-9375 μg/24h) 1, 10
• Non-ceruloplasmin-bound copper (free copper) calculation 10
• Brain MRI showing hyperintensity on T2 imaging in basal ganglia 1, 9
• Genetic testing by whole-gene sequencing when diagnosis is difficult to establish 1, 2

Common Diagnostic Pitfalls

• Failing to consider Wilson's disease in patients over 40 years (5 of 30 patients in one series were over 40) 10
• Misdiagnosing neuropsychiatric symptoms as primary psychiatric disorders 4
• Assuming normal ceruloplasmin excludes the diagnosis 10
• Overlooking the diagnosis in children with isolated behavioral changes 8

Treatment Principles

Treatment has two objectives: minimize dietary copper intake to <1-2 mg/day and promote excretion/detoxification of excess tissue copper through chelation therapy. 7

Dietary Modifications

• Exclude chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals 7
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper 7

Pharmacologic Treatment

First-line treatment for symptomatic patients is copper chelation with D-penicillamine, though trientine and zinc acetate are alternatives. 7, 3, 5

• D-penicillamine: Chelates copper to facilitate urinary excretion; noticeable improvement may not occur for 1-3 months 7
• Trientine hydrochloride: Alternative chelator for patients intolerant to penicillamine; dosage 1,000-2,000 mg/day 5
• Zinc acetate: Blocks intestinal copper absorption by inducing metallothionein in enterocytes; dosage 50 mg three times daily, separated from food by at least one hour 3

Important Treatment Considerations

• Neurological symptoms may temporarily worsen during initiation of penicillamine therapy, but the drug should not be withdrawn 7
• Temporary interruption carries increased risk of developing sensitivity reactions upon resumption 7
• Early chelation therapy improves prognosis and can produce marked neurological improvement, fading of Kayser-Fleischer rings, and amelioration of hepatic dysfunction 7, 5
• Liver transplantation is indicated for end-stage liver disease with untreatable complications or acute liver failure, and is curative by replacing the hepatic gene mutation 6, 11

Prognosis

• Without treatment, Wilson's disease is uniformly fatal 1, 7, 6
• With appropriate treatment, life is prolonged and clinical improvement occurs in most patients 7, 5
• In one study comparing treated versus untreated patients, all 13 treated patients were alive at follow-up (mean 4.1 years), while 9 of 12 untreated patients died of hepatic disease (mean 2.7 years without therapy) 5