Non-ceruloplasmin copper and urinary copper in clinically stable Wilson disease: Alignment with recommended targets

Abstract

Background and AimsWilson disease (WD) is caused by accumulation of copper primarily in liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) 200-500 μg/24h and serum non-ceruloplasmin bound copper (NCC) 50-150 μg/L. We compared NCC measured by two novel assays and UCE from clinically stable WD patients on D-penicillamine therapy with these recommendations. MethodsThis is a secondary analysis of data from the Chelate Trial (NCT03539952) that enrolled physician selected clinically stable WD patients on D-penicillamine maintenance therapy with unaltered dose for at least four months. We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange HPLC protein speciation followed by copper determination with ICP-MS or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n=75). ResultsIn 76 WD patients with 21.3±14.3 average treatment-years, NCC-Sp (Mean±SD: 56.6±26.2 μg/L) and NCC-Ex (Mean±SD: 57.9±24.7 μg/L) were within the 50-150 μg/L target in 61% and 54%, respectively, below in the remaining. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 μg/L, NCC-Ex: 41-71 μg/L). NCC-Ex positively correlated with NCC-Sp (r2=0.66, P<0.001) but with systematic deviation. UCE was outside the 200-500 μg/24H target in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected. ConclusionClinically stable WD patients on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD. Impact and implicationsChelator treatment of patients with Wilson Disease (WD) is currently guided by measurements of non-ceruloplasmin bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex) while UCE values were above recommended target range in 49%. Common wisdom would suggest overtreatment in these cases but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology. Clinical trial number(NCT03539952)