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.

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.

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

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.

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.