What is the diagnosis and treatment approach for a patient suspected of having Wilson disease?

Wilson Disease: Diagnosis and Treatment

Diagnostic Approach

Wilson disease should be suspected in any patient aged 3-45 years presenting with unexplained liver abnormalities, neurologic symptoms (dystonia, tremor, dysarthria), or psychiatric manifestations, though cases can occur from age 5 to the eighth decade. 1

Key Diagnostic Tests

No single test definitively confirms or excludes Wilson disease—diagnosis requires multiple complementary examinations 1:

• Slit-lamp examination for Kayser-Fleischer rings (must be performed by an experienced observer): Present in 50-62% of hepatic presentations and nearly all neurologic cases 2, 1
• Serum ceruloplasmin: Typically <20 mg/dL, though can be falsely elevated by inflammation, pregnancy, or estrogen 3
• 24-hour urinary copper excretion: Greatly elevated, often >200 μg/day 2
• Liver biopsy with hepatic copper quantification: Diagnostic if >250 μg/g dry weight; normal values (<40-50 μg/g) essentially exclude Wilson disease 1, 3
• ATP7B mutation analysis: Detects mutations in 84.4% of alleles when diagnosis remains uncertain after clinical and biochemical testing 2, 1
• Brain MRI: Shows basal ganglia abnormalities (hyperintensity on T2) in 77.7% of patients, even before symptom onset 2, 1

Critical Diagnostic Pitfalls

Acute liver failure presentation has a distinctive pattern that distinguishes it from other causes 2:

• Coombs-negative hemolytic anemia with intravascular hemolysis
• Modest aminotransferase elevations (typically <2000 IU/L)—this modest elevation often leads clinicians to underestimate disease severity 2
• Markedly low or normal alkaline phosphatase (typically <40 IU/L)
• Coagulopathy unresponsive to vitamin K
• Rapid progression to renal failure
• Female:male ratio of 2:1

Autoimmune hepatitis mimicry is common, particularly in children and young adults 2. All children with apparent autoimmune hepatitis and any adult failing to respond rapidly to corticosteroids must be carefully evaluated for Wilson disease before continuing immunosuppression. 2

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Treatment Strategy

Lifelong treatment is mandatory and must never be discontinued—interruption risks intractable hepatic decompensation or acute liver failure. 1, 3

Treatment by Clinical Presentation

Acute Liver Failure

Liver transplantation is the only effective life-saving option and should be pursued immediately, with one-year survival rates of 79-87%. 1 While awaiting transplantation, plasmapheresis, hemofiltration, or albumin dialysis may stabilize patients and protect kidneys from copper-mediated damage 2.

Decompensated Cirrhosis

Combination therapy with chelator plus zinc, temporally separated by 5-6 hours, is recommended. 2, 1 Typical regimen:

• Zinc 50 mg elemental (25 mg in children) as doses 1 and 3
• Trientine 500 mg (10 mg/kg in children) as doses 2 and 4
• Separation prevents chelator from binding zinc and canceling efficacy of either agent 2
• Patients should be referred to transplant center promptly as some may fail medical therapy 2

Symptomatic Patients (Hepatic or Neurologic)

Initial treatment with chelating agents is standard, with trientine preferred over D-penicillamine when neurologic symptoms are present. 1, 4

• Trientine causes fewer side effects and less initial neurological worsening compared to D-penicillamine 5
• D-penicillamine carries significant risk of serious permanent neurological worsening in neurologically presenting patients 6
• Neurologic evaluation and brain MRI should be performed prior to treatment in all patients with neurologic symptoms 2

Presymptomatic/Asymptomatic Patients

Treatment prevents disease progression indefinitely when started early. 1

• Zinc is preferable for children under age 3 years 2, 1
• Either zinc or chelators are effective for older individuals 1

Maintenance Therapy

After 1-5 years of chelation with clinical stability (normal aminotransferases, hepatic synthetic function, 24-hour urinary copper 200-500 μg/day), patients may transition to:

• Zinc monotherapy (preferred—more selective, fewer side effects) 2
• Reduced-dose chelator 2

Treatment must never be terminated indefinitely—discontinuation risks intractable hepatic decompensation. 2

Pregnancy Management

Treatment must be maintained throughout pregnancy without interruption, as discontinuation has resulted in acute liver failure. 2, 1, 3

• Zinc dosage: Continue unchanged throughout pregnancy 2
• Chelator dosage: Reduce by 25-50% during pregnancy, especially last trimester 2
• D-penicillamine: Limit to 750 mg/day; reduce to 250 mg/day for last 6 weeks if cesarean section planned 3

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Family Screening

All first-degree relatives must be screened, as presymptomatic treatment prevents disease progression. 1, 7 Screening should include:

• History and physical examination
• Serum ceruloplasmin and copper levels
• Liver function tests
• Slit-lamp examination for Kayser-Fleischer rings
• ATP7B haplotype analysis or mutation testing 2, 1

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Monitoring and Common Pitfalls

Patients should be monitored at least twice yearly with liver function tests, indices of copper metabolism, and 24-hour urinary copper excretion 8.

Target values:

• On chelators: 24-hour urinary copper 200-500 μg/day 8
• On zinc: urinary copper ≤75 μg/day 8

Critical pitfalls to avoid:

• Overtreatment can lead to copper deficiency causing neutropenia, anemia, and hyperferritinemia 8
• Neurological worsening may occur during initiation of D-penicillamine—do not withdraw drug despite this, as interruption increases risk of sensitivity reactions upon resumption 3
• Combination therapy timing: Chelator and zinc must be separated by 5-6 hours to avoid binding 8