Treatment of Wilson's Disease
For symptomatic Wilson's disease patients, initiate treatment with a chelating agent (D-penicillamine or trientine) rather than zinc monotherapy, as zinc alone has been associated with hepatic deterioration and fatal outcomes in patients with active liver disease. 1
Initial Treatment Selection Based on Clinical Presentation
Symptomatic Hepatic Disease
- Start with D-penicillamine 750-1500 mg/day (adults) or 20 mg/kg/day (children) divided into 2-3 doses, taken 1 hour before meals. 2
- Add pyridoxine 25-50 mg/day supplementation, as D-penicillamine interferes with pyridoxine metabolism. 2
- Begin with incremental dosing (125-250 mg/day, increased by 250 mg every 4-7 days) to enhance tolerability and avoid rapid neurological deterioration. 2
- Never administer doses ≥1500 mg at once, as this can cause rapid and often irreversible neurological deterioration. 2
- Expect clinical improvement in synthetic liver function within 2-6 months, with continued recovery possible through the first year. 2
Symptomatic Neurological Disease
- Consider trientine or zinc as first-line therapy rather than D-penicillamine, as neurological worsening occurs in 10-50% of patients started on D-penicillamine, with the highest rate (13.8%) compared to other agents. 2, 1
- If using D-penicillamine, start with very low doses and increase slowly. 2
- Neurological improvement is slower than hepatic improvement and may take up to 3 years. 2
Asymptomatic/Presymptomatic Patients
- Either zinc or a chelating agent is effective for preventing disease progression. 1
- Zinc is preferable for presymptomatic children under age 3 years. 1
- For children and adults identified through family screening, treatment prevents morbidity and mortality. 2
Acute Liver Failure
- Liver transplantation is the only effective treatment for Wilson's disease presenting with acute liver failure. 1
- One-year survival following transplantation ranges from 79-87%. 1
Specific Medication Protocols
D-Penicillamine Dosing and Monitoring
- Maintenance dose: 750-1500 mg/day in adults, 20 mg/kg/day in children (rounded to nearest 250 mg), divided into 2-3 doses. 2
- Administer 1 hour before meals to maximize absorption (food reduces absorption by 50%). 2
- Target 24-hour urinary copper excretion: 3-8 µmol (200-500 µg) per day during maintenance therapy. 2
- To assess therapeutic efficiency, measure urinary copper after 2 days of D-penicillamine cessation: should be <1.6 µmol/24h (values >1.6 µmol/24h suggest non-adherence). 2
Trientine (Alternative Chelator)
- Developed specifically for patients intolerant to D-penicillamine. 2
- Administer 1 hour before or 2 hours after meals. 2
- Monitor 24-hour urinary copper excretion with same targets as D-penicillamine (3-8 µmol/day). 2
Zinc Therapy
- Adult dosing: 150 mg elemental zinc daily in three divided doses (50 mg three times daily). 1, 3
- Children <50 kg: 75 mg/day in three divided doses. 1
- Take 30 minutes before meals for optimal absorption. 3
- Target 24-hour urinary copper excretion: <1.2 µmol (<75 µg) per day. 2, 1
- Zinc acetate is the FDA-approved formulation, though organic forms (zinc orotate, zinc gluconate, zinc histidinate) offer better gastrointestinal tolerability. 3, 4
- Do not use zinc monotherapy for symptomatic liver disease due to risk of hepatic deterioration. 1
- Gastric irritation is the most common side effect, but overall side effects are minimal. 1
Monitoring Requirements
Frequency
- Monitor at least twice yearly, more frequently during initial treatment phase. 1
- During first year with D-penicillamine: monitor every 2 weeks initially, then monthly. 2
Laboratory Parameters
- Complete blood count with platelets (watch for thrombocytopenia, neutropenia, or aplasia requiring immediate discontinuation). 2, 5
- Liver function tests and synthetic function indices. 1
- 24-hour urinary copper excretion. 2, 1
- Serum ceruloplasmin (may decrease after treatment initiation). 2
- Non-ceruloplasmin-bound copper (should normalize with effective treatment). 2
- Urinalysis for proteinuria and hematuria (early signs of membranous glomerulopathy). 5
- Liver function tests every 6 months (every 3 months during first year for Wilson's disease). 5
Treatment Efficacy Markers
- Maintained clinical and laboratory improvement is the most important sign of efficacy. 2
- Normalization of non-ceruloplasmin-bound copper concentration indicates effective treatment. 2
Critical Side Effects and Management
D-Penicillamine Toxicity (30% discontinuation rate)
Early reactions (first 1-3 weeks): 2
- Fever, cutaneous eruptions, lymphadenopathy
- Neutropenia or thrombocytopenia
- Proteinuria
Severe reactions requiring immediate discontinuation: 2, 5
- Severe thrombocytopenia or bone marrow aplasia
- Nephrotoxicity (proteinuria >1 g/24h or progressive proteinuria)
- Unexplained gross hematuria or persistent microscopic hematuria
- Goodpasture syndrome (hemoptysis with pulmonary infiltrates)
Late reactions: 2
- Lupus-like syndrome
- Elastosis perforans serpiginosa
- Pemphigus (requires high-dose corticosteroids)
- Myasthenia gravis (ptosis and diplopia are early signs)
- Obliterative bronchiolitis
Zinc Therapy Complications
- Excessive zinc can cause severe copper deficiency (neutropenia, anemia, hyperferritinemia) even when treating hypercupremia. 3
- If serum copper falls below 90 µg/dL, reduce zinc or add copper supplementation at a zinc-to-copper ratio of 8:1 to 15:1. 3
- Monitor both serum copper and zinc levels with CRP every 3 months. 3
Special Clinical Situations
Pregnancy
- Treatment must be maintained throughout pregnancy; interruption has resulted in acute liver failure. 1, 5
- For D-penicillamine: limit daily dose to 750 mg during pregnancy; reduce to 250 mg for last 6 weeks if cesarean section planned. 5
- For zinc: maintain dosage without change during pregnancy. 1
- Chelator doses should be reduced by 25-50% during the last trimester. 1
Combination Therapy
- When combining chelator plus zinc, separate doses by 5-6 hours to prevent the chelator from binding to zinc. 1
Dietary Management
- Avoid high-copper foods (shellfish, nuts, chocolate, mushrooms, organ meats) especially during the first year of treatment. 2, 1
- Dietary management alone is never adequate as sole therapy. 2, 1
- Check well water or water from copper pipes for copper content. 2
Common Pitfalls
Non-Compliance
- Failure to comply with lifelong therapy leads to significant liver disease progression and liver failure within 1-12 months. 2
- Rapid re-administration after prolonged cessation may evoke irreversible neurological signs. 2
Overtreatment
- Overtreatment with penicillamine can lead to reversible sideroblastic anemia and hepatic siderosis. 2
- Copper deficiency from excessive treatment causes neutropenia, anemia, and hyperferritinemia. 1