Biomarkers for treatment monitoring and prognostication of disorders of hepatic copper metabolism

Abstract: Wilson disease (WD) is an inherited disorder of copper metabolism present in 1:30,000 due to reduced biliary copper excretion and pathologic copper accumulation in the liver and later in extrahepatic sites. Despite 60-years of available medical therapy, there are unmet needs and a significant burden of disease

(disability, liver transplant or death) due to late diagnosis, treatment non-adherence and issues with monitoring. Given its rarity and wide-ranging phenotype, we created a WD patient registry and biospecimen repository sponsored by the Wilson Disease Association, a patient advocacy organization, to study the natural history of

WD and search for biomarkers. In collaboration with the Regional Laboratory for Metal Analysis (Surrey, UK) directed by Dr. Harrington, an innovative method was developed for testing blood samples for “bioavailable” or non-ceruloplasmin bound copper measured accurately (ANCC) to determine a patient’s “copper status”. We

aim to establish ranges for ANCC for patients with WD in different phases of treatment by showing that ANCC is elevated in untreated patients and with treatment failure or non-adherence, and that ANCC decreases with treatment. We will test whether ANCC is a biomarker for treatment target and prognostic indicator

for treatment outcome for WD by correlating ANCC with patient clinical outcomes. This will help determine whether ANCC is useful for guiding treatment and for patient prognostication, or whether a matrix of biochemical and clinical measures is needed. We also plan exploratory studies to determine if urinary

copper excretion measured after treatment interruption for patients on different therapies for their WD correlates with ANCC, as this alternative measurement may be a cost-effective option superior to currently used on-treatment 24 h urine copper studies for managing WD therapy. WD is managed most frequently by

liver specialists given frequent injury to the liver in this disorder, but multidisciplinary care of patients is important given the extrahepatic features of the disease that impact a patient’s quality of life. Having a biomarker such as ANCC for clinical use as a surrogate for the state of a WD patient’s disease would be

extremely useful and help to avoid treatment errors when treatment dosing or choice of therapy is based on 24 h urine copper excretion results alone due to confounders for this measurement. With respect to future clinical studies for WD, as it is no longer acceptable to use survival alone as a study endpoint, we must define

clinically meaningful endpoints, optimize treatments to achieve best clinical outcomes and enhance patient quality of life, and evaluate cost effectiveness of current and future therapies. Benefits of these studies outside of WD will be the bettering of our understanding of human copper metabolism and establishment of useful

assays for assessing copper status and their expected ranges in health and disease. With recent discoveries of the critical role that copper plays in cell metabolism and cell survival, furthering our ability to measure “copper status” using potential biomarkers like ANCC have an even larger importance beyond WD.