Letter: Incremental Value and Stratified Interpretation of Dual Autoantibody Positivity in Primary Biliary Cholangitis

We read with interest the study by Liu et al. 1., which evaluated the diagnostic relevance of PBC-specific autoantibodies using liver histology as the reference standard. The finding that dual positivity for AMA/AMA-M2 and anti-gp210/sp100 was associated with the highest rate of biopsy-confirmed PBC provides valuable insight into serological interpretation. However, several aspects warrant a more cautious appraisal of the conclusions drawn. First, the association between dual antibody positivity and a more severe biochemical profile may be confounded by the uneven distribution of PBC-autoimmune hepatitis (AIH) overlap syndrome. Overlap is a distinct entity characterised by concurrent cholestatic and hepatocellular injury, hypergammaglobulinaemia and broader autoantibody reactivity 2, 3. In this study, PBC-AIH overlap was more frequent in the dual-positive group (48.6%) than in the AMA-only group (37.4%). Given that overlap syndrome is independently associated with elevations in ALP, GGT, transaminases and immunoglobulins, it is unclear whether the observed disease severity reflects the serological pattern itself or the enrichment of overlap cases. It would be informative to know whether the authors considered adjusted or subgroup analyses to assess the independent contribution of antibody profiles after accounting for overlap status. Second, while dual-positive patients demonstrated the highest diagnostic yield, the study did not assess whether anti-gp210 or anti-sp100 offer incremental diagnostic value beyond AMA or conventional biochemical markers. Since such analyses were not performed, we suggest that future studies incorporate multivariable modelling and ROC-based methods to determine whether these antibodies meaningfully improve diagnostic accuracy. Without this, the clinical utility of their combined use remains uncertain. Third, AMA and AMA-M2 were analysed as a unified category (AMAs) despite being derived from different platforms—indirect immunofluorescence versus ELISA or immunoblot—with known discordance 4, 5. This grouping may obscure assay-specific performance characteristics, particularly in diagnostically ambiguous cases. Similarly, while anti-gp210 and anti-sp100 are both considered PBC-specific ANA, they differ in sensitivity, prognostic value and platform-dependent variability 6. Evaluating these markers separately would better preserve their distinct clinical implications and support more precise diagnostic applications. In summary, Liu et al.'s study reinforces the diagnostic potential of serological patterns in PBC. Nonetheless, further work is needed to clarify the independent role of antibody combinations and to determine whether they offer additive value beyond existing diagnostic tools. Ao Gao: conceptualization, methodology, software, formal analysis, project administration. Xueying Ye: conceptualization, investigation, validation. Wenming Shao: conceptualization, methodology, validation. Yunfeng Hu: conceptualization, methodology, funding acquisition, investigation, validation, writing – review and editing, software. The authors have nothing to report. Declaration of Generative AI and AI-Assisted Technologies in the Writing Process: During the preparation of this work, the authors used ChatGPT to check grammar and spelling. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication. Guangdong Provincial Administration of Traditional Chinese Medicine Research Project Fund (Grant 20261077 to WS). The authors declare no conflicts of interest. This article is linked to Liu et al. paper. To view this article, visit https://doi/10.1111/apt.70614. The data that support the findings of this study are available from the corresponding author upon reasonable request.