Which pediatric patients should be screened for Wilson disease and what are the recommended first‑line screening tests?

Wilson's Disease Screening in Pediatrics

Which Pediatric Patients Require Screening

All first-degree relatives (siblings, children, and parents) of any newly diagnosed Wilson's disease patient must be screened, regardless of symptoms. 1, 2 This is the single most important screening indication, as presymptomatic treatment prevents disease manifestations entirely and ensures near-normal longevity. 2, 3

Beyond family screening, specific clinical presentations in pediatric patients mandate investigation for Wilson's disease:

Hepatic Presentations Requiring Screening

• Any child presenting with clinical features of autoimmune hepatitis must be investigated for Wilson's disease 1 - this is a Class I, Level B recommendation because these conditions are clinically and histologically indistinguishable in younger patients 1
• Children with unexplained elevation of aminotransferases or hepatomegaly 2
• Pediatric patients with clinical picture resembling acute viral hepatitis 2
• Children presenting with nonalcoholic fatty liver disease or steatohepatitis findings 1

Fulminant Hepatic Failure Pattern

• Any pediatric patient with fulminant hepatic failure plus Coombs-negative hemolytic anemia, modest aminotransferase elevations (typically <2000 IU/L), and low alkaline phosphatase (typically <40 IU/L) with alkaline phosphatase-to-bilirubin ratio <2 1 - this constellation is highly characteristic of Wilson's disease

Other Clinical Presentations

• Unexplained Coombs-negative hemolytic anemia 2
• Neuropsychiatric symptoms including tremor, dysarthria, dystonia, or "juvenile Parkinsonism" 2
• Recurrent hepatic disease with unexplained neurological symptoms 4

Age Considerations

• Wilson's disease should be suspected in any individual between ages 3 and 55 years with liver abnormalities of uncertain cause 2
• Very young children can have clinically evident liver disease from Wilson's disease 3
• Age alone should never exclude the diagnosis 2

Recommended First-Line Screening Tests

For Family Screening (First-Degree Relatives)

If molecular testing (ATP7B mutations or haplotype analysis) is available from the index patient, this is the most efficient primary screening strategy. 1, 2 This approach is now considered standard for testing asymptomatic siblings. 5, 6

When genetic testing is unavailable or as complementary testing, the comprehensive biochemical panel includes:

• Serum ceruloplasmin 1, 2
• 24-hour urinary copper excretion (basal, without penicillamine) 1, 2 - urine must be collected in copper-free containers 7
• Liver function tests including aminotransferases, albumin, conjugated and unconjugated bilirubin, and INR 1, 2
• Complete blood count 1
• Serum copper 1
• Slit-lamp examination for Kayser-Fleischer rings 1, 2

For Symptomatic Patients

The same comprehensive panel applies, with additional considerations:

• Liver biopsy with quantitative hepatic copper measurement should be performed in individuals without Kayser-Fleischer rings who have subnormal ceruloplasmin and abnormal liver tests 1, 2
• Hepatic copper concentration >250 μg/g dry weight is diagnostic 4

Penicillamine Challenge Test

• This test is only standardized and validated in pediatric patients under 18 years 7
• Primary indication: when basal 24-hour urinary copper is <100 μg/24 hours (<1.6 μmol/24 hours) in symptomatic children where Wilson's disease is still suspected 7
• Protocol: 500 mg D-penicillamine orally at hour 0 and hour 12 of 24-hour urine collection 7
• Diagnostic threshold: >1600 μg/24 hours (>25 μmol/24 hours) with 100% predictive value in symptomatic patients 7
• Specificity: 93-98% compared to other liver diseases 7

Important Caveats

• Children with autoimmune hepatitis can have elevated post-challenge urinary copper, though typically not reaching the 25 μmol/24 hour threshold 7
• Recent data suggest lowering the basal urinary copper threshold to 0.64 μmol/24 hours may eliminate need for challenge testing 7
• If initial family screening is normal, repeat screening in 2-5 years should be considered 1
• Treatment should be initiated for all individuals over 3-4 years old identified as patients by family screening 1

Newborn Screening Status

• Measurement of ceruloplasmin in dried-blood spots may promote detection, but further refinement is required before wide-scale implementation 1

The critical principle is that early diagnosis when asymptomatic results in near-normal longevity with good health, making aggressive family screening and maintaining high clinical suspicion in at-risk presentations essential. 3, 2