Evaluation of novel assays of non-ceruloplasmin copper to monitor chelation treatment in patients with Wilson disease: Monitoring chelation treatment in Wilson disease.
No Thumbnail Available
All Authors
Ott, P.
Sandahl, T.
Ala, A.
Cassiman, D.
Couchonnal-Bedoya, E.
Cury, RG.
Czlonkowska, A.
Denk, G.
D'Inca, R.
Gondim, FAA.
LTHT Author
Moore, Joanna
LTHT Department
Abdominal Medicine & Surgery
Hepatology
Liver Unit
Hepatology
Liver Unit
Non Medic
Publication Date
2026
Item Type
Journal Article
Language
Subject
CHELATING AGENTS
Subject Headings
Abstract
BACKGROUND: We examined the use of two newer measures of non-ceruloplasmin bound copper (NCC) and 24-hour urinary Cu excretion (UCE) to monitor chelation therapy in clinically stable Wilson Disease (WD).
METHODS: We post-hoc analyzed data from Chelate study, in which 77 clinically stable WD patients on penicillamine (DPA) entered a 12-week screening phase after which 53 were randomized to continued DPA or same dose trientine-tetrahydrochloride (TETA4) (weeks 12-60). Data included NCC measured by protein speciation (NCC-Sp), exchangeable copper (NCC-Ex), and UCE.
RESULTS: In 32/53 patients with unchanged dose from week 1 to 60, NCC-Sp decreased from 57.9+/-21.1mcg/L to 39.6+/-16.25mcg/L (P=0.0002), while NCC-Ex decreased from 56.4+/-20.3mcg/L to 46.2+/-11.5(P=0.01), likely due to improved adherence during participation in a clinical trial. UCE dropped by ~50% after switching to TETA4 and gradually decreased in the DPA arm. Biomarker values did not reach steady state until week 60. The visit-to-visit coefficient of variance was 30% for NCC-Sp, 20% for NCC-Ex and 52% for UCE. Including all 45 patients who completed week 60, those with lower tertile values of NCC-Sp (16.3-30.9mcg/L) and NCC-Ex (18.7-43.1mcg/L) had lower and more stable AST and ALT, and higher and more stable S-Albumin and S-Protein than those with higher values. No neurological changes were noted despite these differences in NCC. Copper deficiency was not observed.
CONCLUSION: Non-ceruloplasmin by protein speciation and exchangeable copper have potential to guide chelation in WD patients on maintenance therapy. Specific target ranges should be established, and we hypothesize they may include values below normal ranges. Further studies are required to improve our understanding of the responses to dose changes and non-adherence and if standardization of sampling conditions can reduce visit-to-visit variability.
TRIAL NO: (NCT03539952) IMPACT AND IMPLICATIONS: The use of biomarkers of copper metabolism (non-ceruloplasmin and 24 hour urinary copper excretion) to monitor chelating treatment in Wilson Disease is poorly supported by data and development of newer methodologies (NCC-Ex and NCC-Sp) further supports re-evaluation in longitudinal studies. Our study suggests that in patients with stable Wilson disease, the response of NCC-Sp and NCC-Ex to a dose change may take as long as 6-12 months to achieve and with an intraindividual visit-to-visit variation coefficient of = 20-25% this will impact clinical practice and decision making (requiring serial measurements) and estimation of sample size and longevity of clinical trials. Steady state NCC-Ex and NCC-Sp below the commonly recommended 50-150 mcg/L range were associated with stable ALT, AST, S-albumin, and S-protein in contrast to values above 50 mcg/L, where ALT and AST increase and S-albumin and S-protein decreased, suggesting that future prospective studies may lead to re-evaluation and changes to ranges for treatment goals for NCC-Ex and NCC-Sp. The lack of a similar association of UCE and clinical outcome and high variation (51%) question the current use of UCE to guide dosing in WD patients with stable disease.
Journal
JHEP Reports : Innovation in Hepatology / EASL