Diagnostic Accuracy of Exchangeable Copper for Grading the Severity of Wilson Disease

Wilson disease (WD) diagnosis remains challenging due to variable biomarker performance across clinical presentations. Exchangeable copper (CuEXC) directly quantifies non-ceruloplasmin-bound copper (NCC), the pathogenic copper fraction. We assessed the diagnostic accuracy of CuEXC across WD phenotypes and its utility for evaluating disease severity. In this prospective study (NCT05231876) at the French National Reference Center for WD, we enrolled 158 treatment-naïve patients (48% female; mean age 20 ± 14 years; 44% ≤ 18 years) referred between 2009 and 2025. Clinical presentations included asymptomatic (n = 11), hepatic (n = 87), and neurologic (n = 60). CuEXC was measured at diagnosis and compared against ceruloplasmin, total copper, relative exchangeable copper (REC), and 24-h urinary copper using ROC analysis. Seven patients with hemolytic anemia uniformly associated with acute liver failure had extreme CuEXC elevations (median 11.0 μmol/L) and were excluded from ROC analyses. CuEXC increased stepwise across phenotypes (0.8, 1.6, and 2.9 μmol/L; p < 0.001). CuEXC distinguished advanced from mild-to-moderate liver disease (AUC 0.86; 95% CI, 0.82-0.89; optimal threshold 1.8 μmol/L: sensitivity 83%, specificity 87%) and differentiated neurologic from hepatic presentations (AUC 0.87; 95% CI, 0.80-0.93; optimal threshold 2.07 μmol/L: sensitivity 88%, specificity 81%; pragmatic cutoff 2.0 μmol/L: sensitivity 91%, specificity 80%). Performance was consistent across age groups. CuEXC outperformed other biomarkers in head-to-head comparisons. After excluding hemolysis, CuEXC ≥ 1.8 μmol/L supports screening for advanced liver disease, even without clinical or laboratory liver abnormalities. CuEXC ≥ 2.0 μmol/L warrants expedited neurologic assessment and may help distinguish neuro Wilson from hepatic encephalopathy. CuEXC enhances early risk stratification for timely intervention in WD.