Clinical Determinants of Delayed Diagnosis in Wilson's Disease: Misdiagnosis Patterns, Phenotypes, and Impact on...

Diagnostic delay in Wilson's disease (WD) remains common because of marked phenotypic heterogeneity. Although neuropsychiatric presentations are known to delay recognition, quantitative evidence linking delayed diagnosis to transplant-free survival is limited, particularly in mixed hepatic-neurologic phenotypes. We aimed to characterize diagnostic delay and misdiagnosis, identify associated phenotypes, and evaluate the independent association of delayed diagnosis with transplant-free survival.

We retrospectively analyzed data from 150 patients with definite WD at a tertiary referral center over 10 years. Diagnostic delay was categorized as early (≤3 months), intermediate (>3 to ≤12 months), or delayed (>12 months). Presenting phenotypes were classified as hepatic, neurologic, psychiatric, or mixed. Patients who underwent urgent liver transplantation at index presentation were excluded from survival analyses. Transplant-free survival, defined as delayed liver transplantation or death, was assessed using Kaplan-Meier analysis and Cox regression adjusted for cirrhosis at diagnosis.

Overall, 92 patients (61.3%) had documented misdiagnosis or prolonged delay. The median diagnostic delay was longer in neuropsychiatric than in isolated hepatic presentations (24 vs. 8 months), with mixed presentations showing an intermediate delay (18 months). Kaplan-Meier analysis across the three delay categories showed stepwise worsening of transplant-free survival: 100% in patients diagnosed within 3 months, intermediate in those diagnosed after >3 to ≤12 months, and lowest in those diagnosed after >12 months (log-rank P = 0.030). Thirteen post-diagnosis composite events occurred. In a multivariable analysis adjusted for cirrhosis at diagnosis, a delay >12 months independently predicted delayed liver transplantation or death (hazard ratio, 4.5; 95% confidence interval, 1.1-18.0; P = 0.036).

Diagnostic delay in WD remains frequent and is strongly influenced by presenting phenotype. Neuropsychiatric and mixed presentations are particularly vulnerable to delayed recognition, and prolonged delay is independently associated with poorer transplant-free survival. Earlier recognition, cross-disciplinary awareness, and systematic family screening may improve outcomes.