What is the recommended treatment for Wilson's disease?

Treatment of Wilson's Disease

Symptomatic patients with hepatic manifestations should be treated with a chelating agent (D-penicillamine or trientine) as first-line therapy, while zinc is appropriate for presymptomatic patients, maintenance therapy after initial chelation, and may be preferred for patients with neurological symptoms. 1, 2

Initial Treatment Strategy by Clinical Presentation

Symptomatic Hepatic Disease

• Chelating agents (D-penicillamine or trientine) are mandatory for initial treatment of symptomatic hepatic Wilson's disease 1, 2
• Zinc monotherapy is contraindicated in symptomatic hepatic disease due to documented cases of hepatic deterioration and fatal outcomes when used as sole initial therapy 2, 3
• The risk of inadequate copper removal with zinc alone outweighs its safety advantages during the critical initial treatment phase 3

Neurological Presentation

• Zinc may be considered as first-line therapy for patients with neurological symptoms, as it carries lower risk of neurological deterioration compared to chelators 2, 3
• D-penicillamine causes neurological worsening in 10-50% of patients with neurological symptoms when used as initial therapy 2, 3
• If neurological symptoms develop or worsen during initial chelator therapy, switching to zinc should be considered 3

Presymptomatic/Asymptomatic Patients

• Either zinc or a chelating agent is effective in preventing disease symptoms or progression 1, 2
• Zinc appears preferable for presymptomatic children under age 3 years 2

Fulminant Hepatic Failure

• Liver transplantation is the only life-saving treatment for acute liver failure due to Wilson's disease 1, 2, 3
• One-year survival following liver transplantation ranges from 79-87% 2

Specific Medication Regimens

D-Penicillamine

• Maintenance dose: 750-1500 mg/day in two or three divided doses for adults 1
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg in divided doses 1
• Must be administered 1 hour before or 2 hours after meals 1, 4
• Supplemental pyridoxine (25-50 mg/day) should be provided as penicillamine interferes with pyridoxine action 1

Trientine

• Adult dosing: typically similar to penicillamine dosing 1
• Pediatric dosing: 10 mg/kg/day in divided doses 3
• Should be administered 1 hour before or 2 hours after meals 1
• Tablets are not stable at high ambient temperatures, which is problematic for patients traveling to warm climates 1

Zinc

• Adults and children >50 kg: 150 mg elemental zinc daily in three divided doses 2, 3
• Children <50 kg: 75 mg/day in three divided doses 2, 3
• Should be taken 30 minutes before meals to maximize absorption 2
• Mechanism: induces enterocyte metallothionein which binds copper and prevents its absorption from the gastrointestinal tract 1, 2
• Also blocks reabsorption of endogenously secreted copper in saliva and gastric secretions, creating negative copper balance 1
• Side effects are minimal, with gastric irritation being most common (approximately 10% of patients) 5
• FDA-approved for maintenance treatment of patients initially treated with a chelating agent 6

Monitoring Treatment Adequacy

Frequency

• At least twice yearly once stable, but more frequently during initial treatment phase 2, 3
• During first year of treatment, monitoring every 3 months is recommended 3

Laboratory Parameters

• For patients on chelators: 24-hour urinary copper excretion should be 200-500 μg/day (3-8 μmol/day) 1, 2, 3
• For patients on zinc: urinary copper excretion should be <75 μg/day (1.2 μmol/day) 1, 2, 3
• Liver function tests (ALT, AST, bilirubin, albumin, PT/INR) to assess hepatic function 3
• Non-ceruloplasmin-bound copper should normalize with effective treatment 1
• Urinary zinc excretion may be measured periodically to check compliance 1

Transition to Maintenance Therapy

• After 1-5 years of successful chelator therapy, stable patients may transition to zinc monotherapy 1, 2, 3
• Criteria for transition include: clinically well status, normal liver enzymes and synthetic function, normal non-ceruloplasmin-bound copper, and appropriate urinary copper excretion on treatment 1, 3
• Advantages of long-term zinc treatment include greater selectivity for copper removal and fewer side effects compared to chelators 1

Dietary Modifications

• Foods with very high copper concentrations should be avoided, at least in the first year: shellfish, nuts, chocolate, mushrooms, and organ meats 1, 2, 3
• Dietary management alone is never sufficient as sole therapy 1, 3
• Well water or water from copper pipes should be checked for copper content 1
• Flush stagnant water from copper pipes before using for cooking or consumption 1

Adjunctive Treatment

• Vitamin E may have a role as adjunctive treatment, as serum and hepatic vitamin E levels are often low in Wilson's disease 1, 2, 3
• No rigorous studies have been conducted on vitamin E supplementation 1

Special Populations

Pregnancy

• Treatment must be maintained throughout pregnancy - interruption has resulted in acute liver failure 2
• Zinc dosage is maintained without change during pregnancy 2
• Chelating agent dosages should be reduced by 25-50% during the last trimester 2

Critical Pitfalls and Warnings

Never Discontinue Treatment

• Treatment must never be terminated indefinitely - even brief interruptions can lead to intractable hepatic decompensation 1, 2, 3
• Patients who discontinue treatment altogether risk development of fatal hepatic decompensation 1

Combination Therapy Timing

• If combining chelator with zinc, doses must be separated by 5-6 hours to avoid having the chelator bind to zinc 2

Overtreatment Risk

• Overtreatment can lead to copper deficiency, resulting in neutropenia, anemia, and hyperferritinemia 2
• This is particularly important to avoid in children because copper is required for growth 5

Compliance Monitoring

• Non-compliance with treatment can lead to hepatic deterioration 2
• Regular monitoring with 24-hour urine copper and zinc measurements is essential 5