Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.

Wilson disease is a rare autosomal recessive disorder caused by copper accumulation, primarily affecting the liver and brain. While genetic estimates suggest a global prevalence of 13.9-15.4 per 100,000 individuals, clinical diagnoses are significantly lower, raising concerns of underdiagnosis. We aimed to investigate the presence of undiagnosed Wilson Disease in patients who underwent liver transplantation for cryptogenic liver disease at a large transplantation center. This observational study analyzed adult patients transplanted for cryptogenic liver disease at La Fe University Hospital (1991-2023). Comprehensive clinical, biochemical, and imaging assessments were used to exclude known liver diseases. ATP7B gene sequencing-including all exons, flanking introns, and the promoter region-was performed using Sanger sequencing. Variant interpretation was conducted using ClinVar, HGMD, GERP, CADD, REVEL, PolyPhen-2, and gnomAD. Among 2708 patients, 17 fulfilled the criteria for cryptogenic liver disease. Twenty-two distinct ATP7B single nucleotide variants were identified. None were classified as pathogenic. One novel variant (c.256A>C) was detected, but its pathogenicity could not be confirmed. No conclusive evidence of undiagnosed Wilson Disease was found in the cohort. Despite higher genetic prevalence estimates, this study did not identify undiagnosed Wilson Disease cases among liver transplant recipients with cryptogenic liver disease, suggesting a low prevalence of missed diagnoses in this clinical setting. Larger, multicenter studies are warranted to explore the potential underdiagnosis of Wilson Disease in broader populations.