Diagnosis of Wilson's Disease
Diagnostic Approach
Wilson's disease should be suspected in any individual between ages 3 and 45 years with unexplained liver abnormalities, neurological symptoms, psychiatric disturbances, or hemolytic anemia, and diagnosis requires a combination of clinical and biochemical findings rather than reliance on any single test. 1, 2
Initial Clinical Evaluation
The diagnostic workup must include the following essential components:
- Slit-lamp examination by an experienced ophthalmologist to detect Kayser-Fleischer rings, which appear as golden-brownish pigment deposits in Descemet's membrane near the corneal limbus 2
- Serum ceruloplasmin level - values <20 mg/dL support the diagnosis, though normal levels do not exclude it 3, 4
- 24-hour urinary copper excretion - baseline values >40 μg/day (0.6 μmol/day) are suggestive 3, 1
- Serum copper levels and calculation of non-ceruloplasmin-bound (free) copper 2
- Complete blood count, liver biochemistries, and INR as baseline testing 3
Diagnostic Pitfalls and Key Distinctions
No single test is sufficient to exclude Wilson's disease. The sensitivity and specificity vary significantly by presentation:
- Kayser-Fleischer rings are present in only 50-65% of patients with predominantly hepatic presentations, though they occur in 90% of those with neurological disease 2, 5
- Serum ceruloplasmin has 98.2% sensitivity and 92.3% specificity, but 18% of patients with non-fulminant disease may have neither Kayser-Fleischer rings nor low ceruloplasmin 4, 6
- In patients presenting with liver disease alone, only 65% can be diagnosed by the typical findings of low ceruloplasmin and Kayser-Fleischer rings 5
Confirmatory Testing
When initial screening is inconclusive:
- Hepatic copper concentration >250 μg/g dry weight on liver biopsy is confirmatory 1
- ATP7B mutation analysis when diagnosis remains uncertain after clinical and biochemical testing, though mutations are detected in only 84.4% of alleles 2, 7
Special Clinical Scenarios Requiring High Suspicion
Acute liver failure presentation has distinctive features that distinguish Wilson's disease:
- Coombs-negative hemolytic anemia with intravascular hemolysis 3, 1
- Modest aminotransferase elevations (typically lower than expected for degree of liver failure) 3
- Markedly low or normal alkaline phosphatase with ratio of alkaline phosphatase to total bilirubin <2 3, 1
- Extremely elevated urinary copper (range 844-9375 μg/24h) and high non-ceruloplasmin copper (325-1743 μg/L) 6
Autoimmune hepatitis mimicry is particularly common:
- All pediatric patients presenting with autoimmune hepatitis-like features must be investigated for Wilson's disease before initiating corticosteroids 3, 1
- Adult patients with atypical autoimmune hepatitis or poor response to corticosteroid therapy require Wilson's disease evaluation 3, 1
Consider Wilson's disease in patients with nonalcoholic fatty liver disease or steatohepatitis of unclear etiology 3
Family Screening Protocol
All first-degree relatives of newly diagnosed patients must be screened as presymptomatic treatment prevents disease progression:
- History focusing on jaundice, liver disease, and subtle neurological features 3
- Physical examination 3
- Serum copper, ceruloplasmin, and liver function tests (aminotransferases, albumin, bilirubin) 3, 1
- Slit-lamp examination for Kayser-Fleischer rings 3, 1
- 24-hour urinary copper excretion 3, 1
- ATP7B mutation testing or haplotype analysis if available (most efficient screening strategy) 3
- Liver biopsy for individuals without Kayser-Fleischer rings who have subnormal ceruloplasmin and abnormal liver tests 3
Treatment Options
Initial Treatment Selection
Treatment must be initiated immediately upon diagnosis and continued lifelong, as even brief interruptions can precipitate acute liver failure. 1, 2
For presymptomatic patients identified through family screening:
- Zinc salts are preferred for children under age 3 years 1, 2
- Either zinc or chelating agents (D-penicillamine or trientine) are effective for individuals >3 years old 1
For symptomatic patients:
- D-penicillamine is first-line therapy in 93.6% of cases, with doses typically ranging from 1,000-2,000 mg/day 8, 9, 7
- Trientine hydrochloride is the alternative for patients intolerant of D-penicillamine, with dosages between 1,000-2,000 mg/day 8, 7
- Zinc salts can be used as monotherapy or maintenance therapy 1
Acute Liver Failure
Liver transplantation is the only effective treatment for acute liver failure due to Wilson's disease and these patients receive highest priority category by UNOS 3, 1
Monitoring During Treatment
Patients require monitoring at least twice yearly with the following parameters:
Target values for adequate treatment:
- For patients on chelators: 24-hour urinary copper 200-500 μg/day 1
- For patients on zinc: urinary copper excretion ≤75 μg/day 1
Critical Treatment Caveats
Neurological worsening may occur during initiation of chelation therapy, but treatment should not be permanently discontinued despite temporary symptom deterioration 9
Combination therapy with chelator plus zinc requires careful timing—chelators will bind to zinc if taken simultaneously 1
Overtreatment can cause copper deficiency, manifesting as neutropenia, anemia, and hyperferritinemia 1
Pregnancy management:
- Treatment must be maintained throughout pregnancy—interruption has resulted in acute liver failure 1, 2
- For Wilson's disease patients, limit D-penicillamine to 1 g daily during pregnancy 9
- If cesarean section is planned, reduce to 250 mg daily during the last 6 weeks and postoperatively until wound healing is complete 9
Adverse effects requiring drug discontinuation:
- Platelet count <100,000/mm³ or progressive decline in platelets or WBC over three successive measurements 9
- Proteinuria >1 g/24 hours or progressively increasing proteinuria 9
- Unexplained gross hematuria or persistent microscopic hematuria (in rheumatoid arthritis patients; risk-benefit assessment needed in Wilson's disease) 9
- Development of pemphigus, myasthenic syndrome, or Goodpasture's syndrome 9