What is the initial treatment for Wilson's disease?

Initial Treatment for Wilson's Disease

For symptomatic patients with hepatic Wilson's disease, initiate treatment with a chelating agent (D-penicillamine or trientine) as first-line therapy; for neurological presentations, consider zinc as first-line therapy due to lower risk of neurological worsening. 1, 2

Treatment Selection Based on Clinical Presentation

Hepatic Disease (Symptomatic)

• Start with a chelating agent (D-penicillamine or trientine) as these promote rapid urinary copper excretion and are most effective for symptomatic liver disease 3, 1
• Never use zinc monotherapy in symptomatic hepatic disease—documented cases of hepatic deterioration and fatal outcomes have occurred when zinc was used as sole initial therapy 3, 1, 2
• The risk of inadequate copper removal with zinc alone outweighs its safety advantages during the critical initial treatment phase for hepatic presentations 2

Neurological Disease (Symptomatic)

• Zinc may be preferred as first-line therapy because it carries significantly lower risk of neurological deterioration compared to chelators 3, 1, 2
• D-penicillamine causes neurological worsening in 10-50% of patients with neurological symptoms when used as initial therapy 3, 2
• Trientine causes neurological worsening much less commonly than penicillamine but still carries some risk 3
• If chelators are used and neurological symptoms worsen, switch to zinc immediately 2

Presymptomatic/Asymptomatic Patients

• Either zinc or a chelating agent is effective in preventing disease symptoms or progression 1
• Zinc appears preferable for presymptomatic children under age 3 years 1
• Treatment must be initiated even in asymptomatic patients to prevent irreversible organ damage 3

Specific Medication Dosing and Administration

D-Penicillamine

• Start low and titrate slowly: Begin with 250-500 mg/day, increase by 250 mg increments every 4-7 days to maximum 1000-1500 mg/day in 2-4 divided doses 3, 4
• Never exceed 1500 mg/day—higher doses can cause rapid and often irreversible neurological deterioration 3, 4
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 3, 4
• Administration: Take 1 hour before or 2 hours after meals (food reduces absorption by 50%) 3, 4
• Required supplementation: Pyridoxine 25-50 mg/day (D-penicillamine interferes with pyridoxine action) 3, 4

Trientine

• Adult dosing: 750-1500 mg/day in 2-3 divided doses, with 750-1000 mg used for maintenance 3
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 3
• Administration: 1 hour before or 2 hours after meals 3
• Trientine tablets are unstable at high ambient temperatures—warn patients traveling to warm climates 3

Zinc Acetate

• Adults and children >50 kg: 150 mg elemental zinc daily in three divided doses 1, 2
• Children <50 kg: 75 mg elemental zinc daily in three divided doses 1, 2
• Administration: 30 minutes before meals to maximize absorption 4, 2
• If combining with chelators: Separate dosing by 5-6 hours to avoid the chelator binding to zinc 1, 4

Monitoring Treatment Efficacy

On Chelator Therapy

• Target 24-hour urinary copper excretion: 200-500 μg/day (3-8 μmol/day) during maintenance 3, 1
• Initially after starting treatment, urinary copper may exceed 1000 μg/24h 3
• Values <200 μg/day may indicate non-adherence or overtreatment 3
• Monitor non-ceruloplasmin-bound copper—should normalize with effective treatment 3

On Zinc Therapy

• Target 24-hour urinary copper excretion: <75 μg/day (1.2 μmol/day) 1, 2
• Monitor urinary zinc levels to check compliance 4
• Check serum zinc and alkaline phosphatase periodically 4

Frequency of Monitoring

• At least twice yearly once stable, but more frequently during initial treatment phase 1, 2
• Every 3 months during first year of treatment 2
• Include liver function tests (ALT, AST, bilirubin, albumin, PT/INR) at each visit 2

Critical Pitfalls and Warnings

Side Effects Requiring Immediate Action

• D-penicillamine causes severe side effects requiring discontinuation in approximately 30% of patients 3
• Early reactions (first 1-3 weeks): fever, rash, lymphadenopathy, neutropenia, thrombocytopenia, proteinuria 3
• Severe bone marrow toxicity or nephrotoxicity requires immediate discontinuation 3
• Monitor regularly for proteinuria, hematuria, and CBC abnormalities 4

Treatment Adherence

• Treatment must never be discontinued indefinitely—even brief interruptions can lead to intractable hepatic decompensation and liver failure within 1-12 months 3, 2
• Non-compliance is detectable by elevated urinary copper (>1.6 μmol/24h after 2 days off D-penicillamine) and elevated non-ceruloplasmin-bound copper 3

Overtreatment Risk

• Can lead to copper deficiency causing neutropenia, anemia, hyperferritinemia, and reversible sideroblastic anemia 3, 1
• Indicated by very low non-ceruloplasmin-bound copper (<5 μg/dL) 3

Special Situations

Acute Liver Failure

• Liver transplantation is the only effective treatment for acute liver failure due to Wilson's disease 1, 2
• One-year survival following transplantation ranges from 79-87% 1

Pregnancy

• Treatment must be maintained throughout pregnancy—interruption has resulted in acute liver failure 1
• Zinc dosage maintained without change during pregnancy 1
• Chelator dosages should be reduced by 25-50% during last trimester 1

Adjunctive Measures

• Avoid high-copper foods (shellfish, nuts, chocolate, mushrooms, organ meats) especially during first year 1, 2
• Dietary management alone is never sufficient as sole therapy 1, 2
• Consider vitamin E supplementation as serum and hepatic vitamin E levels are often low in Wilson's disease 1, 2