Wilson Disease: Diagnosis and Treatment
Diagnosis
Wilson disease should be suspected in any patient aged 3-45 years presenting with unexplained liver abnormalities, neurologic symptoms, or psychiatric manifestations, though cases can occur from age 5 to the eighth decade. 1
Essential Diagnostic Workup
The diagnostic approach requires multiple complementary tests, as no single examination definitively confirms or excludes the disease 2:
Slit-lamp examination for Kayser-Fleischer rings (golden-brownish corneal deposits) - present in 50-62% of hepatic presentations and nearly all neurologic cases. Must be performed by an experienced observer, as rings are not always visible by direct inspection 1, 2
Serum ceruloplasmin - decreased (<20 mg/dL) in 98.3% of patients 3, 4
24-hour urinary copper excretion - elevated (>100 μg/day) in 73% of cases, with further increase after D-penicillamine challenge in 54% 4, 2
Liver biopsy with hepatic copper quantification - copper >250 μg/g dry weight is diagnostic; normal values (<40-50 μg/g) essentially exclude Wilson disease. Intermediate values (70-250 μg/g) require further testing 2, 3
ATP7B mutation analysis - detects mutations in 84.4% of alleles and should be performed when diagnosis remains uncertain after clinical and biochemical testing 2, 4
Brain MRI - shows basal ganglia abnormalities (hyperintensity on T2) in 77.7% of patients, even before symptom onset 2, 4
Critical Diagnostic Pitfalls
Acute liver failure from Wilson disease has a distinctive pattern: Coombs-negative hemolytic anemia, modest aminotransferase elevations (typically <2000 IU/L), markedly low or normal alkaline phosphatase, coagulopathy unresponsive to vitamin K, and rapid progression to renal failure 2, 1
Autoimmune hepatitis mimicry is common - 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
Treatment Strategy
Lifelong treatment is mandatory and must never be discontinued, as interruption risks intractable hepatic decompensation or acute liver failure. 2, 1
Treatment by Clinical Presentation
Acute Liver Failure
Liver transplantation is the only effective life-saving option and should be pursued immediately. 2 Patients with Nazer prognostic score ≥7 (based on bilirubin, AST, and PT prolongation) do not survive without transplantation 2. Bridge therapies until transplant include plasmapheresis, hemofiltration, or albumin dialysis to protect kidneys from copper-mediated damage 2.
Decompensated Cirrhosis
Combination therapy with chelator plus zinc, temporally separated by 5-6 hours: 2
- 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
- This intensive induction regimen continues for 3-6 months
- Patients failing this regimen require prompt transplant referral
- Responders transition to monotherapy (zinc or chelator alone) after 3-6 months
Symptomatic Patients (Hepatic or Neurologic)
Initial treatment with chelating agents (D-penicillamine or trientine) is standard. 3 D-penicillamine was used as first choice in 93.6% of patients, though 21.1% required switching due to adverse effects 4. Trientine is preferred when D-penicillamine causes adverse reactions 2.
Common pitfall: Neurologic symptoms may worsen during the first month of chelation therapy. Despite this, treatment should not be withdrawn, as interruption increases sensitivity reaction risk upon resumption 3.
Presymptomatic/Asymptomatic Patients
Treatment prevents disease progression indefinitely. 2, 3 For children under age 3 years, zinc is preferable; for older individuals, either zinc or chelators are effective 2, 1.
Maintenance Therapy
After 1-5 years of chelation with clinical stability, patients may transition to zinc monotherapy or continue reduced-dose chelator. 2 Stable patients demonstrate normal aminotransferases, normal hepatic synthetic function, normal non-ceruloplasmin copper, and 24-hour urinary copper 200-500 μg/day on treatment 2. Zinc offers more selective copper removal with fewer side effects than chelators 2.
Pregnancy Management
Treatment must be maintained throughout pregnancy without interruption, as discontinuation has resulted in acute liver failure. 2, 1
- Zinc dosage: Continue unchanged throughout pregnancy 2
- Chelator dosage: Reduce by 25-50% during pregnancy, especially in the third trimester to promote wound healing if cesarean section is needed 2
- Breastfeeding: Women taking D-penicillamine should not breastfeed, as the drug is excreted in breast milk 2
- Outcomes: Experience with 26 live births showed adequate maternal protection and acceptable fetal outcomes, though birth defect rate was 7.7% versus 4% in general population 5
Liver Transplantation Indications
Transplantation is indicated for: 2
- All patients with acute liver failure
- Decompensated cirrhosis unresponsive to medical therapy
- One-year survival ranges 79-87%, with excellent long-term survival thereafter 2
- Transplantation corrects the hepatic metabolic defect and normalizes extrahepatic copper metabolism 2
Family Screening
All first-degree relatives must be screened, as presymptomatic treatment prevents disease progression. 1 Screening includes history, physical examination, serum ceruloplasmin and copper, liver function tests, slit-lamp examination, and ATP7B haplotype analysis or mutation testing 1.
Monitoring and Prognosis
Cirrhosis at diagnosis is the strongest predictor of death (OR 6.8) and need for liver transplantation (OR 0.07). 6 Twenty-year survival is 92% overall but only 84% for patients with cirrhosis at diagnosis, compared to 97% in age-matched healthy controls 6. Early diagnosis at a precirrhotic stage significantly improves survival and reduces transplant need 6.
Treatment response: 26% of patients fully recover, 24% improve, 35% stabilize, but 15% deteriorate despite therapy 6. Most deaths (71%) are Wilson disease-related 6.