What is the treatment for Wilson's disease?

Treatment of Wilson's Disease

Wilson's disease requires lifelong pharmacological treatment with chelating agents (D-penicillamine or trientine) as first-line therapy for symptomatic hepatic disease, while zinc may be used for neurological presentations, presymptomatic patients, or maintenance therapy. 1, 2

Initial Treatment Selection Based on Clinical Presentation

Symptomatic Hepatic Disease

• Initiate a chelating agent (D-penicillamine or trientine) immediately as first-line therapy for any patient presenting with liver dysfunction. 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. 1, 2
• The risk of inadequate copper removal with zinc alone outweighs its safety advantages during the critical initial treatment phase in hepatic presentations. 1

Neurological or Neuropsychiatric Presentation

• Zinc may be preferred as first-line therapy for patients with neurological symptoms, as it carries significantly lower risk of neurological deterioration compared to chelators. 1, 2
• Chelating agents remain acceptable alternatives, but penicillamine carries a 10-50% risk of worsening neurological symptoms during initial treatment. 1, 4, 5
• If neurological symptoms develop or worsen during initial chelator therapy, consider switching to zinc. 1

Presymptomatic/Asymptomatic Patients

• Either zinc or a chelating agent is effective in preventing disease symptoms or progression. 2
• Zinc appears preferable for presymptomatic children under age 3 years. 2
• Treatment prevents symptoms indefinitely if continued daily. 5

Acute Liver Failure

• Liver transplantation is the only effective life-saving treatment for Wilson's disease presenting as acute liver failure. 1, 2, 4

Specific Medication Dosing and Administration

D-Penicillamine

• Maintenance dose: 750-1500 mg/day in two or three divided doses for adults. 3
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in two or three divided doses. 3
• Administer 1 hour before meals - food inhibits absorption. 3
• Add pyridoxine supplementation (25-50 mg/day) as D-penicillamine interferes with pyridoxine action. 3
• Promotes urinary copper excretion and may induce metallothionein. 3, 5

Trientine

• Dosage: 750-1500 mg/day in two or three divided doses for adults, with 750-1000 mg used for maintenance. 3
• Pediatric dosing: 10 mg/kg/day (approximately 20 mg/kg/day rounded to nearest 250 mg) in divided doses. 3, 1
• Indicated especially in patients intolerant of penicillamine or with features suggesting potential intolerance (renal disease history, severe thrombocytopenia, autoimmune tendency). 3
• Neurological worsening appears much less common than with penicillamine. 3
• Avoid coadministration with iron as the complex is toxic. 3

Zinc

• 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
• Take 30 minutes before meals to maximize absorption. 1
• Induces enterocyte metallothionein which binds copper and prevents its absorption. 2
• Side effects are minimal, with gastric irritation being most common. 2
• FDA-approved for maintenance treatment after initial chelation therapy. 6

Monitoring Requirements and Treatment Targets

Frequency of Monitoring

• Every 3 months during the first year of treatment. 1
• At least twice yearly once stable, but more frequently during initial treatment phase. 1, 2

Laboratory Parameters

• Liver function tests (ALT, AST, bilirubin, albumin, PT/INR) to assess hepatic function. 1
• 24-hour urinary copper excretion targets:
  • On chelator therapy: 200-500 μg/day (3-8 μmol/day) indicates adequate treatment. 3, 1, 2
  • On zinc therapy: <75 μg/day (1.2 μmol/day) is the target. 1, 2
  • Values <200 μg/day on chelators may indicate nonadherence or overtreatment. 3
• Non-ceruloplasmin-bound copper should normalize with effective treatment. 3
• Urinary copper excretion is highest immediately after starting treatment and may exceed 1000 μg (16 μmol) per day initially. 3

Additional Monitoring

• Liver function tests every 6 months for duration of therapy (every 3 months during first year in Wilson's disease). 5
• Monitor for proteinuria and hematuria as warning signs of membranous glomerulopathy. 5
• Watch for neurological deterioration, especially during initial chelator therapy. 5

Transition to Maintenance Therapy

• After 1-5 years of successful chelator therapy, stable patients may transition to zinc monotherapy or continue reduced-dose chelator. 1, 2
• Criteria for transition include: clinically well, normal liver enzymes and synthetic function, normal non-ceruloplasmin-bound copper, and appropriate urinary copper excretion on treatment. 1

Adjunctive Dietary and Supportive Measures

Dietary Copper Restriction

• Avoid high-copper foods during at least the first year: shellfish, nuts, chocolate, mushrooms, organ meats, molasses, broccoli, and copper-enriched cereals. 1, 2, 5
• Daily diet should contain no more than 1-2 mg of copper. 5
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper. 5
• Dietary management alone is never sufficient as sole therapy. 1, 2

Vitamin E Supplementation

• Consider vitamin E as adjunctive treatment as serum and hepatic vitamin E levels are often low in Wilson's disease. 1, 2, 4

Critical Warnings and Pitfalls

Treatment Adherence

• Treatment must NEVER be discontinued indefinitely - even brief interruptions can lead to intractable hepatic decompensation, fulminant hepatic failure, and death. 1, 2, 4
• Temporary interruption carries increased risk of developing sensitivity reactions upon resumption of therapy. 5
• Poor compliance is a major problem, especially in adolescents and patients with psychiatric disorders. 7

Neurological Deterioration

• Neurological symptoms may worsen in 10-50% of patients during initiation of penicillamine therapy. 1, 4, 5
• Despite worsening, the drug should not be withdrawn as interruption increases sensitivity reaction risk. 5
• If symptoms continue worsening for a month, consider short courses of dimercaprol (BAL) while continuing penicillamine. 5

Overtreatment Complications

• Copper deficiency from overtreatment can result in neutropenia, anemia, hyperferritinemia, and reversible sideroblastic anemia. 3, 2
• Very low non-ceruloplasmin-bound copper (<5 μg/dL or 50 μg/L) indicates overtreatment. 3

Combination Therapy Timing

• If combining chelator plus zinc, maintain 5-6 hours between doses to avoid having the chelator bind to zinc. 2

Special Populations

Pregnancy

• Treatment must be maintained throughout pregnancy - interruption has resulted in acute liver failure and maternal death. 2, 5
• For Wilson's disease patients: limit daily penicillamine to 750 mg during pregnancy. 5
• Reduce to 250 mg for last 6 weeks if cesarean section is planned, and continue postoperatively until wound healing is complete. 5
• Zinc dosage is maintained without change during pregnancy. 2
• Reduce chelator doses by 25-50% during last trimester. 2

Transition from Pediatric to Adult Care

• Transition is a vulnerable period requiring "training" that should start before planned transfer, preferably in early adolescence. 7
• Cooperation between adult and pediatric clinics is essential. 7