What is the treatment for Wilson's disease?

Treatment of Wilson's Disease

Wilson's disease requires lifelong pharmacological treatment with either chelating agents (D-penicillamine or trientine) or zinc salts, with the choice determined by disease presentation: chelators for symptomatic hepatic disease, while zinc may be preferred for neurological presentations or maintenance therapy. 1, 2

Initial Treatment Selection Based on Clinical Presentation

Symptomatic Hepatic Disease

• Initiate a chelating agent (D-penicillamine or trientine) as first-line therapy for any patient presenting with symptomatic liver disease. 1, 3, 2
• Zinc monotherapy is absolutely contraindicated in symptomatic hepatic disease—documented cases of hepatic deterioration and fatal outcomes have occurred when zinc was used as sole initial therapy. 3, 2
• The inadequate copper removal rate with zinc alone during active hepatic disease creates unacceptable risk during the critical initial treatment phase. 3

Neurological or Neuropsychiatric Presentation

• Zinc may be considered as first-line therapy for patients with neurological symptoms, as it carries substantially lower risk of neurological deterioration compared to chelators. 3, 2
• Chelating agents remain acceptable alternatives, but penicillamine carries a 10-50% risk of worsening neurological symptoms during initial treatment. 3, 4
• If neurological symptoms develop or worsen during initial chelator therapy, switch to zinc. 3

Asymptomatic/Presymptomatic Patients

• Either zinc or a chelating agent effectively prevents disease symptoms or progression. 2
• Zinc appears preferable for presymptomatic children under age 3 years. 2

Specific Medication Regimens

D-Penicillamine 1, 4

• Mechanism: Promotes urinary copper excretion and induces metallothionein. 1
• Adult dosing: 750-1500 mg/day in 2-3 divided doses for maintenance. 1
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses. 1
• Administration: Take 1 hour before meals (food inhibits absorption). 1
• Required supplementation: Pyridoxine 25-50 mg/day, as penicillamine interferes with pyridoxine action. 1
• Critical warning: Neurological symptoms may worsen initially in 10-50% of patients—do not discontinue despite this, as temporary interruption increases sensitivity reaction risk upon resumption. 4, 3

Trientine 1

• Mechanism: Chelates copper by forming stable complex with four constituent nitrogens in planar ring. 1
• Adult dosing: 750-1500 mg/day in 2-3 divided doses (750-1000 mg for maintenance). 1
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses. 1, 3
• Advantages: Neurological worsening much less common than with penicillamine; fewer side effects overall. 1
• Indicated especially for: Patients intolerant of penicillamine, history of renal disease, severe thrombocytopenia, or autoimmune tendency. 1
• Important interaction: Do not co-administer with iron—the trientine-iron complex is toxic. 1

Zinc Salts 2, 5

• Mechanism: Induces enterocyte metallothionein which binds copper and prevents intestinal absorption. 2
• Adult dosing (>50 kg): 150 mg elemental zinc daily in 3 divided doses. 3, 2
• Pediatric dosing (<50 kg): 75 mg elemental zinc daily in 3 divided doses. 3, 2
• Administration: Take 30 minutes before meals. 3
• FDA indication: Approved for maintenance treatment after initial chelation therapy. 5
• Side effects: Minimal—gastric irritation most common. 2

Treatment Monitoring Protocol

Frequency 3, 2

• During first year: Every 3 months. 3
• Once stable: At least twice yearly, more frequently during dose adjustments. 3, 2

Laboratory Parameters 3, 2

• Liver function tests: ALT, AST, bilirubin, albumin, PT/INR to assess hepatic function. 3
• 24-hour urinary copper excretion targets:
  • On chelator therapy: 200-500 μg/day (3-8 μmol/day). 1, 3, 2
  • On zinc therapy: <75 μg/day (1.2 μmol/day). 3, 2
  • Values <200 μg/day on chelators indicate either non-adherence (with elevated non-ceruloplasmin copper) or overtreatment (with very low non-ceruloplasmin copper <5 μg/dL). 1
• Non-ceruloplasmin bound copper: Should normalize with effective treatment. 1

Additional Monitoring 4

• Complete blood count: Monitor for leukopenia, thrombocytopenia (requires immediate cessation if progressive decline). 4
• Urinalysis: Check for proteinuria/hematuria (warning signs of membranous glomerulopathy). 4
• Liver function tests every 6 months (every 3 months during first year in Wilson's disease). 4

Adjunctive Dietary Measures

Copper Restriction 3, 2, 4

• Avoid high-copper foods during at least the first year: Shellfish, nuts, chocolate, mushrooms, organ meats. 3, 2
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper. 4
• Critical caveat: Dietary management alone is never sufficient as sole therapy. 3, 2

Vitamin E Supplementation 3, 2

• Consider vitamin E as adjunctive treatment—serum and hepatic vitamin E levels are often low in Wilson's disease. 3, 2

Transition to Maintenance Therapy

Criteria for Transition 3

• After 1-5 years of successful chelator therapy, stable patients may transition to zinc monotherapy or continue reduced-dose chelator. 3
• Required criteria: Clinically well, normal liver enzymes and synthetic function, normal non-ceruloplasmin-bound copper, appropriate urinary copper excretion on treatment. 3

Special Clinical Situations

Pregnancy 2, 4

• Treatment must be maintained throughout pregnancy—interruption has resulted in acute liver failure. 2, 4
• Zinc dosage maintained without change during pregnancy. 2
• Chelator dosages should be reduced by 25-50% during last trimester. 2
• For penicillamine specifically: Limit to 750 mg/day during pregnancy; reduce to 250 mg/day for last 6 weeks if cesarean section planned. 4

Acute Liver Failure 3, 2, 4

• Liver transplantation is the only effective treatment for acute liver failure due to Wilson's disease. 3, 2
• One-year survival following transplantation: 79-87%. 2
• Transplantation also indicated for decompensated cirrhosis unresponsive to medical therapy. 2

Critical Pitfalls and Warnings

Treatment Adherence 3, 2

• Treatment must never be discontinued indefinitely—even brief interruptions can lead to intractable hepatic decompensation or fulminant hepatic failure. 3, 2
• Interruptions for even a few days have been followed by sensitivity reactions after reinstitution. 4
• Poor compliance is a major problem, particularly in adolescents and patients with psychiatric disorders. 6

Combination Therapy Timing 2

• If using chelator plus zinc, maintain 5-6 hours between doses to prevent the chelator from binding to zinc. 2

Overtreatment Recognition 1, 2

• Copper deficiency from overtreatment can cause neutropenia, anemia, hyperferritinemia, and reversible sideroblastic anemia. 1, 2
• Indicated by very low non-ceruloplasmin copper (<5 μg/dL) and urinary copper <200 μg/day. 1

Serious Adverse Effects Requiring Immediate Cessation 4

• Progressive decline in platelet count or WBC (even within normal range). 4
• Development of Goodpasture's syndrome (abnormal urinary findings with hemoptysis and pulmonary infiltrates). 4
• Pemphigus (various forms, usually late complication). 4
• Myasthenic syndrome symptoms (ptosis, diplopia, extraocular muscle weakness). 4