What is the treatment for Wilson's disease?

Treatment of Wilson Disease

For symptomatic Wilson disease patients, initiate treatment immediately with a chelating agent (D-penicillamine or trientine) if presenting with hepatic disease, or consider zinc as first-line for neurological presentations to avoid worsening symptoms. 1, 2

Initial Treatment Selection Based on Presentation

Hepatic Presentation

• Start with a chelating agent (D-penicillamine or trientine) as first-line therapy for any patient presenting with liver disease symptoms 1
• Never use zinc monotherapy as initial treatment in symptomatic hepatic disease - documented cases of hepatic deterioration and fatal outcomes have occurred when zinc was used alone 2
• D-penicillamine dosing: 750-1500 mg/day in adults (divided into 2-3 doses), or 20 mg/kg/day in children rounded to nearest 250 mg 1
• Trientine dosing: 10 mg/kg/day in children, given in divided doses 1, 2
• Administer chelators 1 hour before meals since food inhibits absorption 1
• Add pyridoxine supplementation (25-50 mg/day) when using D-penicillamine, as it interferes with pyridoxine action 1

Neurological/Psychiatric Presentation

• Zinc may be preferred 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 1, 2, 4
• If chelators are used and neurological symptoms worsen during the first month, consider switching to zinc 2
• Tetrathiomolybdate (experimental, not commercially available in US) shows promise with no worsening of neurological symptoms and rapid reduction in circulating copper 1, 3

Asymptomatic/Presymptomatic Patients

• Either chelating agent or zinc is effective in preventing disease symptoms or progression 1
• Treatment prevents symptoms indefinitely if continued daily 1

Zinc Therapy Dosing

• Children <50 kg: 75 mg elemental zinc daily in three divided doses, 30 minutes before meals 2
• Children >50 kg and adults: 150 mg elemental zinc daily in three divided doses 2, 5
• Zinc is FDA-approved for maintenance treatment after initial chelation therapy 5

Special Clinical Scenarios

Acute Liver Failure

• Liver transplantation is the only life-saving treatment for Wilson disease presenting as acute liver failure 1
• Nazer prognostic score (bilirubin + AST + PT prolongation): score ≥7 predicts non-survival without transplant 1
• Bridge to transplant with plasmapheresis, hemofiltration, or albumin dialysis (MARS device) to protect kidneys from copper-mediated damage 1

Decompensated Cirrhosis

• Combination therapy: zinc (50 mg elemental) as doses 1 and 3, plus trientine (500 mg) as doses 2 and 4, separated by 5-6 hours to prevent chelator from binding zinc 1
• This intensive induction regimen is investigational but has supportive data 1
• Refer promptly to transplant center as some patients fail medical therapy 1
• Transition to monotherapy after 3-6 months if responding 1

Pregnancy

• Treatment must never be interrupted during pregnancy - interruption has resulted in acute liver failure and death 1, 4
• Reduce chelator dose by 25-50% during pregnancy, especially last trimester, to promote wound healing if cesarean section needed 1
• For Wilson disease specifically: limit D-penicillamine to 750 mg/day maximum; reduce to 250 mg/day for last 6 weeks if cesarean planned 4
• Zinc dosing remains unchanged throughout pregnancy 1
• Women taking D-penicillamine should not breastfeed as drug is excreted in breast milk 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, normal liver enzymes and synthetic function, normal non-ceruloplasmin-bound copper, and urinary copper 200-500 μg/day (3-8 μmol/day) on chelator treatment 1, 2
• Zinc offers more selective copper removal with fewer side effects for long-term maintenance 1, 3

Monitoring Requirements

Frequency

• At least twice yearly once stable 1, 2
• Every 3 months during first year of treatment 2
• More frequently during initial treatment phase, with worsening symptoms, suspected non-compliance, or medication side effects 1

Laboratory Parameters

• Liver function tests (ALT, AST, bilirubin, albumin, PT/INR) 2
• 24-hour urinary copper excretion targets:
  • On zinc therapy: <75 μg/day (1.2 μmol/day) 2
  • On chelator therapy: 200-500 μg/day (3-8 μmol/day) 1, 2, 3
  • May exceed 1000 μg/day immediately after starting chelation 1
• Liver function tests every 6 months for duration of therapy; every 3 months during first year in Wilson disease 4
• Complete blood count to monitor for thrombocytopenia or leukopenia 4
• Urinalysis for proteinuria/hematuria (warning signs of membranous glomerulopathy) 4

Dietary Modifications

• Avoid high-copper foods during at least the first year: shellfish, nuts, chocolate, mushrooms, organ meats 1, 2, 4
• Daily diet should contain no more than 1-2 mg copper 4
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper 4
• Dietary management alone is never sufficient as sole therapy 1, 2

Adjunctive Treatments

• Consider vitamin E supplementation as serum and hepatic vitamin E levels are often low in Wilson disease 2, 3
• For acute psychosis: atypical antipsychotics preferred over typical antipsychotics (lower extrapyramidal side effect risk); use low initial doses (risperidone 2 mg/day or olanzapine 7.5-10 mg/day) 3

Critical Pitfalls and Warnings

• Treatment must never be discontinued indefinitely - even brief interruptions (a few days) can lead to intractable hepatic decompensation, sensitivity reactions upon reinitiation, or death 1, 2, 3, 4
• Do not withdraw D-penicillamine if neurological symptoms worsen initially - temporary interruption increases risk of sensitivity reaction upon resumption 4
• If neurological symptoms continue worsening for one month after starting penicillamine, consider short courses of dimercaprol (BAL) while continuing penicillamine 4
• D-penicillamine side effects requiring drug cessation: progressive platelet/WBC decline, proteinuria >1 g/24 hours, unexplained gross hematuria, Goodpasture's syndrome (hemoptysis with pulmonary infiltrates), obliterative bronchiolitis, myasthenic syndrome, pemphigus 4
• Up to 30% of patients on D-penicillamine experience adverse events leading to discontinuation 6
• Almost 25% of Wilson disease patients do not adhere to treatment, partially due to complex regimens (3 times daily, before meals) 6

Liver Transplantation Indications

• Absolute indications: acute liver failure, decompensated cirrhosis unresponsive to medical therapy 1
• One-year survival: 79-87% 1
• Transplantation corrects the hepatic metabolic defect and normalizes extrahepatic copper metabolism 1
• Not recommended as primary treatment for neurological Wilson disease - liver disease usually stabilized by medical therapy, and outcomes not always beneficial 1
• Living donor transplant possible when donor is heterozygous family member 1