What is the treatment for Wilson's disease (hepatolenticular degeneration)?

Treatment of Wilson Disease

Symptomatic patients with hepatic Wilson disease should be treated with a chelating agent (D-penicillamine or trientine) as first-line therapy, while symptomatic patients with neurological presentation may be treated with zinc to avoid neurological deterioration, and all patients with fulminant hepatic failure require immediate liver transplantation. 1

Initial Treatment Strategy by Clinical Presentation

Hepatic Presentation (Symptomatic)

• Start with a chelating agent (D-penicillamine or trientine) immediately 2, 1, 3
• 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
• The risk of inadequate copper removal with zinc alone outweighs its safety advantages during the critical initial treatment phase 1

Neurological Presentation (Symptomatic)

• Zinc may be considered as first-line therapy because it carries lower risk of neurological deterioration compared to chelators 1, 4
• Penicillamine carries a 10-50% risk of worsening neurological symptoms during initial treatment 1, 3
• If chelators are used and neurological symptoms worsen during the first month, consider switching to zinc 1
• Tetrathiomolybdate (experimental, not commercially available in the US) shows promise with no worsening of neurological symptoms and rapid reduction in circulating copper during the first 8 weeks 2, 4

Presymptomatic/Asymptomatic Patients

• Either a chelating agent (D-penicillamine) or zinc is effective in preventing disease symptoms or progression 2
• Treatment approach for presymptomatic children under age 3 years has not been determined 2

Fulminant Hepatic Failure

• Liver transplantation is the only life-saving treatment and must be performed urgently 2, 1
• Nazer prognostic score (serum bilirubin + AST + PT prolongation) ≥7 predicts non-survival without transplantation 2
• Bridge to transplantation with plasmapheresis, exchange transfusion, hemofiltration, or albumin dialysis (MARS device) to protect kidneys from copper-mediated tubular damage 2
• One-year survival following liver transplantation ranges from 79% to 87% 2

Specific Medication Dosing and Administration

D-Penicillamine 2, 3

• Start with incremental dosing: 250-500 mg/day, increased by 250 mg every 4-7 days to maximum 1,000-1,500 mg/day in 2-4 divided doses 2
• Maintenance dose: 750-1,000 mg/day in 2 divided doses 2
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 2
• Administer 1 hour before or 2 hours after meals (food inhibits absorption; closer proximity acceptable if it ensures compliance) 2
• Mandatory pyridoxine supplementation: 25-50 mg daily 2

Trientine 2, 5

• Adult dosing: 750-1,500 mg/day in 2-3 divided doses; 750-1,000 mg for maintenance 2
• Pediatric dosing: 10 mg/kg/day in divided doses 1, or 20 mg/kg/day rounded to nearest 250 mg in 2-3 divided doses 2
• Administer 1 hour before or 2 hours after meals 2
• Storage warning: Tablets are not stable at high ambient temperatures - problematic for patients traveling to warm climates 2

Zinc 2, 6

• Pediatric <50 kg: 75 mg elemental zinc daily in 3 divided doses, 30 minutes before meals 1
• Pediatric ≥50 kg and adults: 150 mg elemental zinc daily in 3 divided doses 1
• Must be separated from food and beverages (except water) by at least 1 hour to prevent decreased zinc uptake 6
• Mechanism: Induces enterocyte metallothionein which binds copper and prevents absorption; bound copper is lost in stool with enterocyte desquamation 2, 6

Maintenance Therapy Transition

After 1-5 years of successful chelator therapy, stable patients may transition to zinc monotherapy 2, 1

Criteria for Transition 2, 1

• Clinically well with no symptoms
• Normal serum aminotransferases (ALT, AST)
• Normal hepatic synthetic function (albumin, PT/INR)
• Non-ceruloplasmin-bound copper in normal range
• 24-hour urinary copper repeatedly 200-500 μg/day (3-8 μmol/day) on chelator treatment

Advantages of Zinc for Maintenance 2

• More selective for removing copper than penicillamine or trientine
• Associated with fewer side effects
• Adequate studies on optimal timing of changeover are not available 2

Monitoring Requirements

Initial Treatment Phase (First Year) 1

• Monitor every 3 months during first year 1
• Liver function tests: ALT, AST, bilirubin, albumin, PT/INR 1
• 24-hour urinary copper excretion 2, 1
• Non-ceruloplasmin-bound copper concentration 2

Stable Maintenance Phase 1

• Monitor at least twice yearly once stable 1
• Same laboratory parameters as initial phase 1

Target Urinary Copper Values 2, 1

• On chelator therapy: 200-500 μg/day (3-8 μmol/day) 2, 1
• On zinc therapy: <75 μg/day (1.2 μmol/day) 1

Dietary Modifications

Avoid high-copper foods during at least the first year of treatment: shellfish, nuts, chocolate, mushrooms, organ meats 2, 1, 3

• Daily diet should contain no more than 1-2 mg copper 3
• Exclude cereals and dietary supplements enriched with copper 3
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper 3
• Flush copper pipes of stagnant water before using for cooking or consumption 2
• Dietary management alone is never sufficient as sole therapy 2, 1
• Consider vitamin E supplementation as serum and hepatic vitamin E levels are often low in Wilson disease 1, 4

Critical Warnings and Pitfalls

Never Discontinue Treatment 2, 1, 4

• Treatment must never be terminated indefinitely - even brief interruptions can lead to intractable hepatic decompensation and death 2, 1
• Interruption of treatment during pregnancy has resulted in fulminant hepatic failure 2
• Patients who discontinue treatment risk development of intractable hepatic decompensation 2

Neurological Worsening with Chelators 1, 3

• Neurological symptoms may worsen in 10-50% of patients during initial chelator therapy 1, 3
• Despite worsening, do not withdraw penicillamine - temporary interruption increases risk of sensitivity reaction upon resumption 3
• If symptoms continue to worsen for one month, consider short courses of 2,3-dimercaprol (BAL) while continuing penicillamine 3

Penicillamine Side Effects 2

• Early reactions (first month): hypersensitivity (rash, fever), leukopenia, thrombocytopenia, lymphadenopathy
• Late reactions: lupus-like syndrome, Goodpasture syndrome, severe bone marrow toxicity, nephrotoxicity, myasthenia gravis, polymyositis, loss of taste
• Serum ceruloplasmin tends to decrease after initiation of penicillamine treatment 2

Special Populations

Pregnancy 2

• Treatment must be maintained throughout pregnancy - interruption has resulted in fulminant hepatic failure 2
• Both chelating agents (penicillamine and trientine) and zinc salts have been associated with satisfactory outcomes 2
• Reduce chelator dosage by 25-50% during pregnancy, especially last trimester, to promote better wound healing if cesarean section is performed 2
• Zinc dosage maintained throughout without change 2

Adolescents and Psychiatric Patients 7

• Poor compliance is a major problem in adolescents and patients with psychiatric disorders 7
• Transition "training" should start before planned transfer from pediatric to adult care, preferably in early adolescence 7

Prognosis with Treatment

• Noticeable improvement may not occur for 1-3 months after starting treatment 3
• Long-term survival in Wilson disease patients is similar to the general population if disease is diagnosed early and correctly treated 7
• Patients with longer delay from diagnosis to therapy and those presenting with neurological/psychiatric symptoms have worse quality of life 7
• Treatment of asymptomatic patients for over 30 years shows symptoms and signs can be prevented indefinitely with continued daily treatment 3