Wilson's Disease: Diagnosis and Treatment
Diagnostic Approach
Wilson's disease should be suspected in any patient aged 3-55 years presenting with unexplained liver abnormalities, neurologic symptoms, or psychiatric manifestations, though cases can occur from age 5 to the eighth decade. 1, 2
Key Diagnostic Tests
The diagnosis requires multiple complementary tests, as no single examination definitively confirms or excludes the disease 1:
- Slit-lamp examination for Kayser-Fleischer rings by an experienced observer (present in 50-62% of hepatic presentations, nearly all neurologic cases) 1, 2
- Serum ceruloplasmin (typically <20 mg/dL, though can be falsely elevated by inflammation, pregnancy, or estrogen) 3, 4
- 24-hour urinary copper excretion (greatly elevated, often >200 μg/day) 3, 1
- Hepatic copper concentration on liver biopsy (>250 μg/g dry weight is diagnostic; <40-50 μg/g essentially excludes Wilson's disease) 4, 1
- ATP7B mutation analysis when diagnosis remains uncertain (detects mutations in 84.4% of alleles) 3, 1, 5
- Brain MRI (shows basal ganglia abnormalities in 77.7% of patients, even before symptom onset) 1, 5
Acute Liver Failure Presentation
Acute liver failure from Wilson's disease has a distinctive pattern that requires immediate recognition, as liver transplantation is the only life-saving option. 1 Look for this characteristic constellation 3:
- Coombs-negative hemolytic anemia with intravascular hemolysis
- Modest aminotransferase elevations (typically <2000 IU/L)
- Markedly low or normal alkaline phosphatase (typically <40 IU/L)
- Alkaline phosphatase to total bilirubin ratio <2 4
- Coagulopathy unresponsive to parenteral vitamin K
- Rapid progression to renal failure
- Serum copper typically >200 μg/dL 3
- Female:male ratio of 2:1
Critical Diagnostic Pitfalls
All children with apparent autoimmune hepatitis and any adult failing to respond rapidly to corticosteroid therapy must be carefully evaluated for Wilson's disease before continuing immunosuppression. 3, 1 Patients with Wilson's disease, especially younger ones, may have clinical features and histologic findings indistinguishable from autoimmune hepatitis 3.
Kayser-Fleischer rings may be absent in up to 50% of patients with acute liver failure 3, 4, and serum ceruloplasmin has poor predictive value in acute liver failure settings 3.
Treatment
Acute Liver Failure
Liver transplantation is the only effective treatment for acute liver failure due to Wilson's disease and should be pursued immediately, with one-year survival rates of 79-87%. 1 These patients require urgent evaluation for transplantation 3.
Medical Management for Non-Acute Presentations
Lifelong treatment is mandatory and must never be discontinued, as interruption risks intractable hepatic decompensation or acute liver failure. 1, 2 Treatment must be initiated immediately upon diagnosis 4.
Initial Treatment Options
For symptomatic patients, chelating agents are the standard first-line therapy 1:
D-penicillamine is effective but may worsen neurological symptoms during initiation 4, 6
Trientine is preferred when D-penicillamine causes adverse reactions 1, 7
For presymptomatic/asymptomatic patients identified through screening 4, 1:
- Zinc is preferable for children under age 3 years 4, 1
- Either zinc or chelators are effective for older individuals 4, 1
Maintenance Therapy
After 1-5 years of chelation with clinical stability (normal aminotransferases and hepatic synthetic function), transition to 1:
- Zinc monotherapy (50 mg elemental zinc, taken at least 30 minutes before meals) 4, 1, or
- Continued reduced-dose chelator 1
Decompensated Cirrhosis
Combination therapy with chelator plus zinc, temporally separated by 5-6 hours, is recommended for decompensated cirrhosis. 1 Use zinc 50 mg elemental and trientine 500 mg as separate doses 1.
Common pitfall: Combination treatment requires careful timing to avoid having the chelator bind to zinc 4.
Monitoring During Treatment
Patients should be monitored at least twice yearly with 4:
- Liver function tests
- Indices of copper metabolism
- 24-hour urinary copper excretion
Target values 4:
- Patients on chelators: 24-hour urinary copper 200-500 μg/day
- Patients on zinc: urinary copper ≤75 μg/day
Warning: Overtreatment can lead to copper deficiency, resulting in neutropenia, anemia, and hyperferritinemia 4.
Neurologic Considerations
Neurologic evaluation and brain MRI should be performed prior to treatment in all patients with neurologic Wilson's disease. 3 Consultation with a neurologist or movement disorder specialist should be sought for patients with evident neurologic symptoms before or soon after treatment initiation 3.
Critical warning: Occasionally, neurological symptoms worsen during initiation of penicillamine therapy; despite this, the drug should not be withdrawn, as temporary interruption carries increased risk of developing sensitivity reactions upon resumption 3, 6.
Pregnancy Management
Treatment must be maintained throughout pregnancy without interruption, as discontinuation has resulted in acute liver failure. 4, 1, 6 Management during pregnancy 1, 6:
- Zinc dosage: Continue unchanged
- Chelator dosage: Reduce by 25-50%
- For penicillamine specifically: limit to 750 mg/day; reduce to 250 mg/day for last 6 weeks if cesarean section planned 6
Family Screening
All first-degree relatives of patients with Wilson's disease must be screened, as presymptomatic treatment prevents disease progression indefinitely. 4, 1, 2 Screening should include 4, 2:
- 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 for known family mutations 3
Treatment should be initiated for all individuals greater than 3 years old identified through family screening. 4