What screening, diagnostic tests, and treatment are recommended for a first-degree relative of a patient with Wilson’s disease?

Screening and Management of First-Degree Relatives of Wilson's Disease Patients

All first-degree relatives of a newly diagnosed Wilson's disease patient must undergo comprehensive screening immediately, as siblings have a 25% risk of being affected and early treatment prevents all disease manifestations and ensures near-normal life expectancy. 1

Who Requires Screening

Screen all first-degree relatives including:

• Siblings (25% risk of homozygosity) 1
• Parents (to identify rare homozygous cases) 2
• Children (0.5% risk, but justified given devastating consequences if untreated) 1

The 2018 familial screening study identified 2 previously undiagnosed patients (1 mother, 1 sibling) among 50 screened family members, demonstrating that screening must extend beyond siblings to include the previous generation 2.

Screening Protocol

Primary Screening Approach

When the index patient's ATP7B mutation(s) are known, genetic testing is the most efficient and definitive primary screening method and should be performed first 3, 4. This is now considered the standard approach for asymptomatic siblings 4.

Comprehensive Biochemical and Clinical Evaluation

All first-degree relatives require the following assessment: 1, 3, 4

• History: Specifically inquire about jaundice, unexplained liver disease, tremor, dysarthria, dystonia, psychiatric symptoms, and hemolytic anemia 1, 3
• Physical examination: Assess for hepatomegaly, splenomegaly, neurological signs (tremor, rigidity, dysarthria), and psychiatric manifestations 1, 3
• Serum ceruloplasmin (typically <20 mg/dL in affected patients) 1, 3, 5
• Serum copper (total and calculated non-ceruloplasmin-bound copper) 1, 3
• 24-hour urinary copper excretion (>100 μg/24h supports diagnosis; must use copper-free containers) 1, 3, 4
• Liver function tests: ALT, AST, albumin, total and conjugated bilirubin, INR 1, 3, 4
• Complete blood count (to detect hemolytic anemia) 1, 3
• Slit-lamp examination by an experienced ophthalmologist for Kayser-Fleischer rings 1, 3, 4

Critical Diagnostic Caveat

Biochemical profiles overlap significantly between affected patients and heterozygous carriers in the ranges of ceruloplasmin 0.8-1.5 g/L, serum copper >9 μmol/L, and urinary copper <100 μg/24h 2. This overlap makes genetic testing essential to avoid subjecting heterozygous carriers to unnecessary lifelong treatment 4, 6.

Confirmatory Testing

For relatives without Kayser-Fleischer rings who have subnormal ceruloplasmin and abnormal liver function tests, proceed to liver biopsy with quantitative hepatic copper measurement 1, 3, 4. Hepatic copper concentration >250 μg/g dry weight confirms Wilson's disease 3, 4, 5.

Genetic Testing Strategy

• If index patient's mutations are identified: Screen relatives for those specific mutations 1, 4
• If mutations unknown: Perform haplotype analysis using polymorphisms surrounding ATP7B (requires DNA from both parents and index patient) 1
• Genetic testing is the only reliable method to definitively distinguish heterozygous carriers from affected homozygous/compound heterozygous siblings 1, 2, 6

Treatment Initiation

All individuals identified as affected through family screening who are older than 3-4 years must begin treatment immediately 1, 3, 4. Treatment prevents disease manifestations entirely in presymptomatic patients and provides excellent long-term prognosis 3, 4.

Treatment Options for Presymptomatic Patients

For presymptomatic or mildly affected patients, either maintenance-dose chelation or zinc therapy is effective: 1, 3

• Zinc acetate 25-50 mg three times daily (taken at least 30 minutes before meals for optimal absorption) 3, 7
• Zinc is preferable for presymptomatic children under age 3 years 3
• Maintenance-dose chelating agents (D-penicillamine 750-1500 mg/day in divided doses, or trientine) are alternatives 1, 5
• D-penicillamine requires pyridoxine supplementation 25-50 mg/day 1, 5

Monitoring During Treatment

Monitor patients at least twice yearly with: 3

• Liver function tests (ALT, AST, albumin, bilirubin)
• 24-hour urinary copper excretion
• Indices of copper metabolism (ceruloplasmin, serum copper)

Target urinary copper values: 3

• On chelators: 200-500 μg/24h
• On zinc: ≤75 μg/24h

Critical Treatment Pitfalls

• Overtreatment causes copper deficiency manifesting as neutropenia, anemia, and hyperferritinemia 3
• Treatment must never be interrupted, including during pregnancy, as interruption has resulted in acute liver failure 3
• If combining chelator plus zinc, separate administration times to prevent the chelator from binding zinc 3

Follow-Up Screening

If initial screening is normal, repeat evaluation after 2-5 years to detect late-onset disease manifestations 4.

Prognosis with Early Detection

Presymptomatic patients identified through family screening who receive continuous treatment have been followed for over 30 years with prevention of all disease symptoms and near-normal life expectancy 1, 5. The 30-year experience demonstrates that lifelong treatment prevents disease manifestations indefinitely 5.