Exchangeable and Relative Exchangeable Copper as an Alternative to 24-Hour Urinary Copper in Wilson's Disease Monitoring

Comparison of Serum Exchangeable and Relative Exchangeable Copper Levels With Clinical Parameters and Multiparametric Liver MRI Findings in Patients With Wilson's Disease

Serum exchangeable copper (EC) and relative exchangeable copper (REC) are blood tests developed to improve the assessment of copper levels in patients with Wilson's disease. EC measures the fraction of copper in the blood that is not bound to ceruloplasmin and reflects copper accumulation in the body. REC represents the proportion of this exchangeable copper relative to total serum copper. Previous studies have shown that EC and REC are more accurate than traditional copper tests for diagnosing Wilson's disease. This study aimed to evaluate the relationship between EC/REC and routine copper measurements in patients with Wilson's disease during follow-up, to assess their potential value in disease monitoring.

Study Overview

• Status: Completed
• Conditions: Wilson's Disease

Detailed Description

Wilson's disease (WD) is an inherited disorder of copper metabolism caused by mutations in the ATP7B gene and transmitted in an autosomal recessive manner. The disease leads to progressive copper accumulation in multiple organs, particularly the liver and brain, resulting in a wide spectrum of clinical manifestations, including hepatic, neurological, and psychiatric involvement.

Accurate monitoring of copper levels is essential for evaluating treatment response and adjusting therapy in patients with WD. In routine clinical practice, copper status is commonly assessed using 24-hour urinary copper excretion and non-ceruloplasmin-bound copper. However, these traditional measurements have important limitations. Collection of 24-hour urine samples is cumbersome and prone to errors, and interpretation may be challenging in patients with renal dysfunction or neurological involvement.

Total serum copper reflects both ceruloplasmin-bound and non-ceruloplasmin-bound copper. In WD, despite increased total body copper, serum ceruloplasmin levels are reduced, leading to low ceruloplasmin-bound copper concentrations. As a result, total serum copper measurements may not reliably reflect copper overload. Non-ceruloplasmin-bound copper is calculated indirectly by subtracting ceruloplasmin-bound copper from total serum copper and depends on accurate ceruloplasmin measurement. Immunological assays may overestimate ceruloplasmin levels, resulting in unreliable or even negative calculated values.

Serum exchangeable copper (EC) and relative exchangeable copper (REC) have been developed to address these limitations. EC represents the directly measured fraction of serum copper that is not bound to ceruloplasmin and is thought to better reflect bioavailable and tissue copper accumulation. REC is calculated as the ratio of EC to total serum copper. Previous studies have shown that EC and REC are more sensitive and specific than conventional copper tests and have been validated for the diagnosis of WD. However, their role as biomarkers in the follow-up and management of patients with WD has not been fully established.

The aim of this study was to evaluate the relationship between EC and REC and routine copper measurements in adult patients with Wilson's disease during follow-up, in order to assess their potential utility in monitoring copper status.

• Study Type: Observational
• Enrollment (Actual): 81

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Sıhhıye
    • Ankara, Sıhhıye, Turkey (Türkiye), 06100
      • Hacettepe Üniversitesi İç Hastalıkları Anabilim Dalı

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consisted of adult patients with Wilson's disease who were followed at the gastroenterology and neurology outpatient clinics of a tertiary university hospital. A control population was selected from adult patients presenting with dyspepsia at the same institution. Control participants were matched to patients with Wilson's disease by age and sex. All participants were recruited from the same hospital setting during the study period.

Description

Inclusion Criteria:

Wilson's Disease Group:

• Adult patients (≥18 years) diagnosed with Wilson's disease
• Followed at gastroenterology and/or neurology clinics
• Clinically stable at the time of study inclusion
• Provided written informed consent

Control Group:

• Adult patients (≥18 years) with dyspepsia
• No known diagnosis of Wilson's disease or other disorders of copper metabolism
• Age- and sex-matched to patients with Wilson's disease
• Provided written informed consent

Exclusion Criteria:

(Applied to both groups unless otherwise specified)

• Acute liver-related disease or complications, including:
• Acute liver failure
• Acute-on-chronic liver failure
• Spontaneous bacterial peritonitis
• Hepatic encephalopathy
• Hepatorenal syndrome
• Presence of diseases affecting copper metabolism other than Wilson's disease, including: Menkes disease, Malnutrition, Malabsorption syndromes
• Inability or unwillingness to provide informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Wilson's Disease Patients; Adult patients diagnosed with Wilson's disease who were followed at gastroenterology and neurology clinics. Participants underwent clinical evaluation and routine laboratory assessments, including serum exchangeable copper, relative exchangeable copper, total serum copper, and 24-hour urinary copper excretion. No study-specific intervention was assigned.
Control Group; Age- and sex-matched control participants with dyspepsia and no known disorders of copper metabolism. Participants underwent serum exchangeable copper, total serum copper, and routine blood tests. No urine samples were collected and no study-specific intervention was assigned.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation Between Serum Exchangeable Copper and 24-hour Urinary Copper Excretion in Wilson's Disease	Correlation coefficient (r) between serum exchangeable copper (EC) concentration (µmol/L), measured by inductively coupled plasma mass spectrometry (ICP-MS), and 24-hour urinary copper excretion (µg/24 h), measured by atomic absorption spectrometry, in adult patients with Wilson's disease	Day 1
Correlation Between Serum Exchangeable Copper and Total Serum Copper in Wilson's Disease and Controls	Correlation coefficient (r) between serum exchangeable copper (EC) concentration (µmol/L) and total serum copper concentration (µmol/L), both measured by inductively coupled plasma mass spectrometry (ICP-MS), in adult patients with Wilson's disease and age- and sex-matched control participants	Day 1
Assessment of Correlation Between Relative Exchangeable Copper and Urinary Copper Excretion in Wilson's Disease	Correlation coefficient (r) between relative exchangeable copper (REC, %) and 24-hour urinary copper excretion (µg/24 h), measured by atomic absorption spectrometry, in adult patients with Wilson's disease	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in serum exchangeable copper (EC) between Wilson's disease patients and controls	Comparison of serum exchangeable copper (EC) levels between adult patients with Wilson's disease and age- and sex-matched control participants.	Day 1
Difference in relative exchangeable copper (REC) between Wilson's disease patients and controls	Comparison of relative exchangeable copper (REC) levels between adult patients with Wilson's disease and age- and sex-matched control participants.	Day 1
Difference in total serum copper between Wilson's disease patients and controls	Comparison of total serum copper levels between adult patients with Wilson's disease and age- and sex-matched control participants.	Day 1
Comparison of 24-hour urinary copper excretion by Disease Phenotype in Wilson's Disease	Comparison of 24-hour urinary copper excretion (µg/day) between adult patients with hepatic involvement and those with hepatic-neurologic involvement in Wilson's disease.	Day 1
Comparison of Serum Exchangeable Copper by Disease Phenotype in Wilson's Disease	Comparison of serum exchangeable copper (EC, µmol/L) between patients with hepatic involvement and those with hepatic-neurologic involvement, in adult patients with Wilson's disease.	Day 1
Comparison of Relative Exchangeable Copper by Disease Phenotype in Wilson's Disease	Comparison of relative exchangeable copper (REC, %), between patients with hepatic involvement and those with hepatic-neurologic involvement, in adult patients with Wilson's disease.	Day 1
Comparison of Total Serum Copper by Disease Phenotype in Wilson's Disease	Comparison of total serum copper concentration (µmol/L), between patients with hepatic involvement and those with hepatic-neurologic involvement, in adult patients with Wilson's disease.	Day 1
Comparison of Copper Tests by Chelator Treatment in Wilson's Disease	Differences in 24-hour urinary copper excretion (µg/day), serum exchangeable copper (EC, µmol/L), relative exchangeable copper (REC, %), and total serum copper concentration (µmol/L) between patients treated with penicillamine and those treated with trientine, in adult patients with Wilson's disease	Day 1
Correlation of 24-Hour Urinary Copper Excretion With Ceruloplasmin and Routine Laboratory Parameters in Wilson's Disease	Correlation coefficient (r) between 24-hour urinary copper excretion (µg/day) and serum ceruloplasmin levels and selected routine laboratory parameters (including liver enzymes, bilirubin, albumin, and blood cell counts) in adult patients with Wilson's disease.	Day 1
Correlation of Serum Exchangeable Copper With Ceruloplasmin and Routine Laboratory Parameters in Wilson Disease	Correlation coefficient (r) between serum exchangeable copper (EC, µmol/L) and serum ceruloplasmin levels and selected routine laboratory parameters (including liver enzymes, bilirubin, albumin, and blood cell counts) in adult patients with Wilson's disease.	Day 1
Correlation of Relative Exchangeable Copper With Ceruloplasmin and Routine Laboratory Parameters in Wilson Disease	Correlation coefficient (r) between relative exchangeable copper (REC, %) and serum ceruloplasmin levels and selected routine laboratory parameters (including liver enzymes, bilirubin, albumin, and blood cell counts) in adult patients with Wilson's disease.	Day 1
Correlation of Total Serum Copper Concentration With Ceruloplasmin and Routine Laboratory Parameters in Wilson Disease	Correlation coefficient (r) between total serum copper concentration (µmol/L) and serum ceruloplasmin levels and selected routine laboratory parameters (including liver enzymes, bilirubin, albumin, and blood cell counts) in adult patients with Wilson's disease.	Day 1
Distribution of Urinary Copper Excretion Categories in Wilson's Disease	Proportion of adult patients with Wilson's disease classified as having low, on-target, or high 24-hour urinary copper excretion according to treatment-specific target ranges	Day 1

Collaborators and Investigators

• Sponsor: Hacettepe University

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2021
• Primary Completion (Actual): September 5, 2021
• Study Completion (Actual): September 5, 2021

Study Registration Dates

• First Submitted: February 15, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Wilson's disease; Serum Exhangeable Copper; Relative Exchangeable Copper; Total Serum Copper; 24 hour urinary copper excretion
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Digestive System Diseases; Neurodegenerative Diseases; Liver Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hepatolenticular Degeneration
• Other Study ID Numbers: 16969557-29

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared due to ethical and privacy considerations and because informed consent did not include permission for data sharing beyond the scope of the current study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No