Key Facts

Wilson disease is a rare but treatable cause of liver disease and neuropsychiatric illness. Early diagnosis is critical as untreated disease is fatal. It should be considered in any young person with unexplained liver or neurological disease.

Epidemiology

Prevalence ~1 in 30,000 (carrier frequency ~1 in 90). Present worldwide with higher prevalence in consanguineous populations. Typically presents between ages 3-40 (mean ~17 years). Equal sex distribution.

Aetiology

Mutations in ATP7B gene (>600 identified) cause defective hepatocyte copper transport. ATP7B normally: (1) incorporates copper into caeruloplasmin (for blood transport), and (2) excretes excess copper into bile.

Pathophysiology

Defective ATP7B → impaired biliary copper excretion + impaired caeruloplasmin synthesis → progressive copper accumulation in hepatocytes → hepatic injury → copper spills into bloodstream → deposits in brain (basal ganglia), cornea (KF rings), kidneys, and red blood cells. Free copper generates hydroxyl radicals causing oxidative damage. Hepatic manifestations range from asymptomatic transaminitis to fulminant failure. Neurological manifestations result from copper deposition in the lenticular nucleus (putamen, globus pallidus) and other basal ganglia.

Hepatic Presentation (more common in children)

• Asymptomatic transaminitis
• Chronic hepatitis
• Cirrhosis (may present with decompensation)
• Fulminant liver failure: Coombs-negative haemolytic anaemia + acute liver failure (pathognomonic combination)

Neurological Presentation (more common in adolescents/adults)

• Tremor (wingbeat tremor — arms abducted, elbows flexed)
• Dysarthria
• Dystonia, rigidity
• Parkinsonism (bradykinesia, rigidity)
• Drooling, dysphagia
• Gait abnormality

Psychiatric Presentation

• Behavioural changes, personality change
• Depression, anxiety
• Psychosis (rare)
• Cognitive decline, poor school performance

Other

• KF rings (golden-brown corneal rings — slit lamp)
• Renal tubular acidosis (Fanconi syndrome)
• Arthropathy, osteoporosis
• Cardiomyopathy (rare)
• Sunflower cataracts

Red Flags

• Acute liver failure + Coombs-negative haemolysis in young patient (fulminant Wilson)
• Any unexplained liver disease age <40
• Neurological symptoms + liver disease in young person

Bloods

• Serum caeruloplasmin: low (<0.2 g/L) in >85% (but can be normal in acute phase reaction; low in other conditions too)
• Serum copper: often low (bound to low caeruloplasmin) but FREE (non-caeruloplasmin-bound) copper is HIGH — calculated or measured directly
• 24-hour urinary copper: raised (>0.6 μmol/24h; >1.6 strongly suggestive)
• LFTs: variable; ALT may be raised; ALP characteristically LOW in fulminant Wilson (ALP:bilirubin ratio <4 suggests Wilson)
• FBC: Coombs-negative haemolytic anaemia (fulminant)
• Coagulation: raised INR
• Direct antiglobulin test (DAT/Coombs): NEGATIVE in Wilson haemolysis

Imaging

• Slit-lamp examination: KF rings (must be performed by ophthalmologist)
• MRI brain: basal ganglia signal changes ("face of the giant panda" sign in midbrain — T2 hyperintensity in tegmentum); caudate/putamen T2 changes
• USS abdomen: liver assessment

Special Tests

• Liver biopsy: hepatic copper quantification (>250 μg/g dry weight diagnostic); histology shows steatosis, chronic hepatitis, cirrhosis; copper staining (rhodanine/orcein)
• Leipzig scoring system: combines caeruloplasmin + KF rings + urinary copper + hepatic copper + neurological symptoms + mutations; ≥4 = diagnostic
• ATP7B genetic testing: >600 mutations described; confirms diagnosis
• Penicillamine challenge test: 500 mg penicillamine; measure 24h urine copper (>25 μmol/24h suggestive — mainly used in children)
• Family screening: all siblings of confirmed cases — serum copper, caeruloplasmin, 24h urine copper, genotyping

Non-pharmacological

• Dietary: avoid high-copper foods (shellfish, liver, chocolate, nuts, mushrooms) — especially during initial decoppering
• Lifelong treatment: emphasise compliance — disease recurs/progresses if treatment stopped
• Family screening: all first-degree relatives

Pharmacological

• Chelation therapy (initial decoppering):
  • D-penicillamine: 1.5-2 g/day in 2-4 divided doses (take on empty stomach); monitor FBC, U&Es, urinalysis (proteinuria); side effects: rash, bone marrow suppression, lupus-like syndrome, nephrotic syndrome, worsening of neurological symptoms in 10-50%
  • Trientine: 1.2-2.4 g/day in 2-3 divided doses; better tolerated; preferred if penicillamine intolerant or as first-line in neurological Wilson (less neurological worsening)
• Maintenance therapy:
  • Lower-dose chelation (penicillamine 0.75-1 g/day or trientine 0.9-1.5 g/day)
  • OR zinc acetate/sulphate: 150 mg elemental zinc/day in 3 divided doses; blocks intestinal copper absorption; well tolerated; can be used alone for maintenance or in presymptomatic patients
• Fulminant Wilson disease: emergency liver transplantation (medical treatment cannot reverse acute decompensation rapidly enough)
• Ammonium tetrathiomolybdate: emerging therapy for neurological Wilson (reduces neurological deterioration risk); not yet widely available

Surgical/Interventional

• Liver transplantation: curative (replaces defective ATP7B); indicated for: fulminant Wilson disease, decompensated cirrhosis unresponsive to medical therapy; corrects the metabolic defect — post-transplant, no further chelation needed; 5-year survival >85%

Referral Criteria

• All confirmed Wilson disease to hepatology (specialist centre)
• Neurology if neurological/psychiatric features
• Ophthalmology for slit-lamp KF ring assessment
• Emergency transplant centre for fulminant Wilson
• Genetics for family screening

With early diagnosis and lifelong treatment, prognosis is excellent (normal life expectancy). Without treatment, Wilson disease is fatal (progressive liver failure, neurological deterioration). Hepatic damage may partially reverse with treatment. Neurological symptoms improve in ~50-70% with treatment but may worsen transiently when starting penicillamine (~10-50%). Fulminant Wilson disease without transplant has near 100% mortality. Post-transplant 5-year survival >85%.

Leipzig Diagnostic Scoring System

Wilson vs Haemochromatosis