Referral-spectrum Effect in Hypercupriuric Referrals for Suspected Wilson Disease: Diagnostic Implications for Ceruloplasmin and 24-hour Urinary Copper Excretion.

Background and Aims: In contemporary practice, elevated 24-hour urinary copper excretion (24-h UCE) often triggers referral for suspected Wilson disease (WD). In this hypercupriuric referral setting, interpretation of 24-h UCE may be distorted by spectrum effects. In this study, we aimed to compare conventional copper biomarkers in hypercupriuric referrals and evaluate whether a Leipzig-aligned ceruloplasmin (Cp) framework could provide a clinically useful triage approach. Methods: We retrospectively studied consecutive, untreated patients evaluated for suspected WD with hypercupriuria between February 2017 and February 2025. The final diagnosis was established using a prespecified Leipzig-based algorithm, with Results: Among 541 untreated hypercupriuric patients, 65 had WD and 476 had adjudicated non-WD liver disease. Cp outperformed 24-h UCE for diagnosing WD (AUROC, 0.988 vs. 0.762). The optimal Cp cutoff was 0.15 g/L, with 90.8% sensitivity and 97.7% specificity. Cp < 0.10 g/L defined a high-probability zone with 98.0% WD prevalence, whereas Cp > 0.20 g/L defined a low-probability zone with 0.5% WD prevalence. Among non-WD controls, higher urinary copper was independently associated with higher bilirubin, prolonged international normalized ratio, and lower albumin. Conclusions: In hypercupriuric referrals for suspected WD, Cp retained strong diagnostic performance and outperformed 24-h UCE. A Leipzig-aligned Cp three-zone framework may support probability-based triage in contemporary referral practice.