What are the recommended treatment options, dosing regimens, and monitoring schedule for a patient diagnosed with Wilson's disease?

Treatment and Monitoring of Wilson's Disease

For symptomatic patients with hepatic Wilson's disease, initiate treatment with a chelating agent (D-penicillamine or trientine) to rapidly remove toxic copper and prevent irreversible organ damage, while for neurological presentations, zinc or tetrathiomolybdate should be strongly preferred to avoid the 10-50% risk of neurological deterioration associated with chelators. 1, 2, 3

Treatment Selection Algorithm

Symptomatic Hepatic Disease

• Start with chelation therapy using either D-penicillamine or trientine as first-line treatment to promote rapid urinary copper excretion and prevent progression to irreversible liver damage 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, 2
• The inadequate rate of copper removal with zinc alone during the critical initial treatment phase makes it unsuitable despite its favorable safety profile 2

Neurological Presentation

• Zinc should be preferred as first-line therapy because it carries significantly lower risk of neurological deterioration compared to chelators 1, 2
• If chelators must be used, tetrathiomolybdate is preferred over D-penicillamine for acute psychosis or prominent neurologic manifestations, as it is less likely to precipitate neurologic deterioration (though it remains experimental in the United States) 3
• D-penicillamine causes neurological worsening in 10-50% of patients with neurological symptoms when used as initial therapy 2, 3

Presymptomatic/Asymptomatic Patients

• Either chelation or zinc salts can prevent disease progression, but zinc is increasingly favored due to a more favorable side-effect profile 3

Decompensated Cirrhosis

• Use combination therapy with trientine plus zinc, temporally dispersed throughout the day in four doses with 5-6 hours between administration to avoid chelator binding the zinc 4
• Typical regimen: zinc (50 mg elemental, or 25 mg elemental in children) as first and third doses; trientine (500 mg, or 10 mg/kg in children) as second and fourth doses 4
• Refer promptly to transplant center as some patients will fail medical therapy 4

Acute Liver Failure

• Liver transplantation is the only life-saving treatment 4, 1, 2, 3
• A Nazer prognostic score ≥7 predicts non-survival without transplantation 4, 3
• Plasmapheresis, exchange transfusion, or albumin dialysis may serve as temporary bridge to transplantation 4, 3

Specific Medication Dosing Regimens

D-Penicillamine

• Start at low dose (250-500 mg/day) and titrate slowly to maximum of 1000-1500 mg/day 1
• Maintenance dose: 750-1500 mg/day in 2-3 divided doses for adults 4
• Pediatric dosing: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 4
• Administer 1 hour before meals as food inhibits absorption 4
• Supplement with pyridoxine 25-50 mg/day as D-penicillamine interferes with pyridoxine action 4
• Critical warning: D-penicillamine causes severe side effects requiring discontinuation in approximately 30% of patients 1

Trientine

• Dosing: 750-1500 mg/day in 2-3 divided doses for adults 1
• Pediatric dosing: 10 mg/kg/day in divided doses 2
• Alternative dosing from FDA label: 40-50 mg/kg per day, taken 1 hour before or 2 hours after meals 5
• Administer 1 hour before or 2 hours after meals 5

Zinc Salts

• Adults and children >50 kg: 150 mg elemental zinc daily in three divided doses 1, 2, 3
• Children <50 kg: 75 mg elemental zinc daily in three divided doses 2
• Take at least 30 minutes before meals 3
• Mechanism: induces intestinal metallothionein which preferentially binds dietary copper and blocks its absorption 3

Transition to Maintenance Therapy

After 1-5 years of successful chelation, stable patients may transition to zinc monotherapy or continue reduced-dose chelator 4, 2, 3

Criteria for Transition:

• Clinically well with normal aminotransferases and hepatic synthetic function 4, 3
• Non-ceruloplasmin-bound copper within normal range 4, 3
• 24-hour urinary copper 200-500 μg/day (3-8 μmol/day) while on chelation therapy 4, 3

Monitoring Schedule and Parameters

Frequency

• During first year of treatment: every 3 months 2
• Once stable: at least twice yearly, but more frequently during symptom worsening or suspected non-compliance 2, 3

Laboratory Panel

• Liver function tests (ALT, AST, bilirubin, albumin, PT/INR) to assess hepatic function 2
• Serum copper and ceruloplasmin 3
• 24-hour urinary copper excretion 1, 2, 3

Target Laboratory Values

On Chelation Therapy:

• 24-hour urinary copper: 200-500 μg/day (3-8 μmol/day) 4, 2, 3
• Urinary copper is highest immediately after starting treatment and may exceed 1000 μg per 24 hours at that time 4

On Zinc Therapy:

• 24-hour urinary copper: <75 μg/day (1.2 μmol/day) 2, 3
• Monitor urinary zinc levels to check compliance 1

Both Therapies:

• Non-ceruloplasmin-bound copper should normalize 1, 3

Dietary Recommendations

• Avoid shellfish and liver completely 3
• Limit high-copper foods during at least the first year: nuts, chocolate, mushrooms, organ meats 1, 2, 3
• Long-term strict restriction is less critical after the first year 3
• Dietary copper restriction alone is never sufficient; pharmacologic therapy is essential 2, 3
• Check copper content of well water or water from copper pipes; flush stagnant water before use 3

Pregnancy Management

Treatment must be maintained throughout pregnancy – interruption has resulted in acute liver failure 4, 1, 3

• Reduce chelator doses by 25-50% during pregnancy, especially in the third trimester, to promote better wound healing if cesarean section is required 4, 3
• Zinc dosing remains unchanged throughout pregnancy 4
• Penicillamine, trientine, and zinc have all been associated with satisfactory maternal and fetal outcomes 4, 3
• Women taking D-penicillamine should not breast-feed as the drug is excreted into breast milk 4

Critical Pitfalls and Warnings

Never Discontinue Treatment

Treatment must never be discontinued indefinitely, even in asymptomatic patients – even brief interruptions can lead to intractable hepatic decompensation and fulminant liver failure 1, 2, 3

The only exception is successful liver transplantation, which corrects the underlying metabolic defect 3

Neurological Deterioration Risk

• If new neurological symptoms develop or existing symptoms worsen during initial chelator therapy, consider switching to zinc 2
• This risk is particularly high with D-penicillamine (10-50% of patients) 2, 3

Monitoring for Overtreatment

• Watch for signs of iatrogenic copper deficiency from overtreatment 6
• Iron deficiency may occur during chelation therapy 5

Side Effect Monitoring

• Monitor for cutaneous changes with penicillamine 3
• Monitor for psychiatric symptoms (especially depression) with all therapies 3
• D-penicillamine can cause systemic lupus erythematosus and nephrotic syndrome in 20-25% of patients 7

Adjunctive Measures

• Consider vitamin E supplementation as serum and hepatic vitamin E levels are often low in Wilson's disease 1, 2