What is the recommended treatment for Wilson's disease?

Treatment of Wilson's Disease

Symptomatic patients with Wilson's disease require initial treatment with a chelating agent—either D-penicillamine or trientine—to rapidly remove toxic copper and prevent irreversible organ damage. 1

Initial Treatment Strategy by Clinical Presentation

Symptomatic Patients (Hepatic or Neuropsychiatric Manifestations)

• Start with chelation therapy using D-penicillamine or trientine to enhance urinary copper excretion and rapidly control free (non-ceruloplasmin-bound) copper that causes acute cytotoxic effects 1, 2, 3
• D-penicillamine dosing: 15-25 mg/kg daily, administered at least 1 hour before or 2 hours after meals 2, 4
• Trientine dosing: 40-50 mg/kg daily, administered 1 hour before or 2 hours after meals 1, 4
• Critical caveat: Neurological symptoms may worsen in 10-50% of patients during early chelation therapy 5

Neuropsychiatric Presentations Requiring Special Consideration

• For patients presenting with acute psychosis or prominent neurological symptoms, tetrathiomolybdate may be preferable as it appears less likely to cause neurological deterioration during initial treatment, though it remains experimental in the United States 1, 5
• Atypical antipsychotics (risperidone 2 mg/day or olanzapine 7.5-10 mg/day) should be used adjunctively if needed, avoiding typical antipsychotics due to extrapyramidal side effect risk 5

Presymptomatic/Asymptomatic Patients (Identified Through Family Screening)

• Either chelation therapy (D-penicillamine or trientine) OR zinc salts are effective for preventing disease symptoms or progression 1
• Zinc is increasingly favored for presymptomatic patients due to fewer side effects 1
• Optimal treatment for presymptomatic children under age 3 years has not been determined 1

Fulminant Hepatic Failure

• Liver transplantation is the only life-saving option for patients with fulminant hepatic failure 1
• Nazer prognostic score ≥7 (based on bilirubin, AST, and PT prolongation) indicates patients will not survive without transplantation 1
• Plasmapheresis, exchange transfusion, or albumin dialysis may temporarily stabilize patients as a bridge to transplantation 1

Maintenance Therapy Transition

After 1-5 years of successful chelation therapy, stable patients may be transitioned to zinc maintenance therapy 1, 6

Criteria for Transition to Zinc:

• Clinically well with normal serum aminotransferases and hepatic synthetic function 1
• Nonceruloplasmin-bound copper concentration in normal range 1
• 24-hour urinary copper repeatedly 200-500 μg (3-8 μmol) per day on chelation treatment 1, 5

Zinc Maintenance Dosing:

• 150 mg elemental zinc daily divided into three doses for adults >50 kg 7
• Must be taken at least 30 minutes before meals for optimal absorption 7
• Zinc works by inducing intestinal metallothionein, which preferentially binds dietary copper and prevents absorption 1, 7

Monitoring Treatment Efficacy

Target Laboratory Values:

• On chelation therapy: 24-hour urinary copper 200-500 μg/day (3-8 μmol/day) 1, 5
• On zinc therapy: 24-hour urinary copper <75 μg/day (1.2 μmol/day) 1, 5
• Nonceruloplasmin-bound copper should normalize with effective treatment 1, 3

Monitoring Frequency:

• Minimum twice yearly for stable patients 1
• More frequent monitoring during initial treatment phase, symptom worsening, or suspected noncompliance 1
• Laboratory testing should include liver biochemistries, hepatic synthetic function, serum copper, ceruloplasmin, and 24-hour urinary copper 1

Dietary Modifications

Only two foods require strict avoidance: shellfish and liver 8, 9

• Other high-copper foods (nuts, chocolate, mushrooms, organ meats) should be avoided during the first year of treatment but are less critical long-term 1
• Dietary copper restriction alone is insufficient as therapy—medical management is far more important than strict dietary limitations 1, 8, 9
• Check copper content of well water or water from copper pipes; flush stagnant water before use 1

Critical Treatment Principles

Lifelong Therapy is Mandatory:

• Treatment must never be discontinued indefinitely, even in asymptomatic patients 1, 5
• Discontinuation risks intractable hepatic decompensation and fulminant hepatic failure 1, 5
• The only exception is successful liver transplantation, which corrects the metabolic defect 1

Pregnancy Management:

• Continue treatment throughout pregnancy—interruption has resulted in fulminant hepatic failure 1
• Reduce chelator doses by 25-50% during pregnancy, especially in the third trimester, to promote wound healing if cesarean section is needed 1
• Both penicillamine, trientine, and zinc have been associated with satisfactory maternal and fetal outcomes 1

Side Effect Management:

• D-penicillamine causes serious side effects (SLE, nephrotic syndrome) in 20-25% of patients 4
• Switch to trientine if D-penicillamine must be withdrawn due to side effects 4
• Monitor for cutaneous changes with penicillamine and psychiatric symptoms (especially depression) with all therapies 1

Liver Transplantation Indications

• Fulminant hepatic failure (absolute indication) 1
• Decompensated liver disease unresponsive to medical therapy 1
• Not recommended as primary treatment for isolated neurologic disease, as medical therapy usually stabilizes liver disease and transplant outcomes for neurologic symptoms are inconsistent 1, 5