Letter on ‘Long-Term Dynamic Changes of Alanine Aminotransferase Levels Are Associated With Liver-Related Events in Nucleos(t)ide Analogue-Treated Chronic Hepatitis B Patients in China’—Authors' Reply

Abstract

We sincerely appreciate the thoughtful comments and constructive feedback from Bilgin et al. [1] regarding our study on the prognostic significance of sex-specific alanine aminotransferase (ALT) thresholds in chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) therapy [2]. The robust design of our large-scale, dual-cohort study and the application of the latent class mixed modelling to characterise longitudinal ALT trajectories have been duly recognised. The correspondence also underscores clinically relevant implications, including the implementation of lower ALT targets and the integration of dynamic monitoring strategies, which align closely with the fundamental objectives of our investigation.

Second, we fully agree that ALT dynamics provide additional prognostic value beyond single time-point measurement. ALT levels can reflect viral replication or immune-mediated hepatocyte injury, both of which are linked to disease progression in CHB patients [3-5]. Although previous studies have shown that ALT levels at a single time-point are associated with patient outcomes [6, 7], our study further demonstrates that longitudinal ALT dynamics outperform baseline ALT levels in discriminating the risk of liver-related events (LRE). Notably, even among patients whose on-treatment ALT levels remained persistently below the conventional upper limit of normal (40 U/L), the 7-year cumulative incidence of LRE reached 8.1%. Accordingly, we proposed a pair of lower ALT thresholds (23 U/L for men and 16 U/L for women), which further stratified these patients into two risk groups, with 7-year LRE incidences of 5.5%–5.9% and 8.7%–10.8%, respectively [2]. We believe that incorporating ALT trajectories into routine monitoring may therefore enable clinicians to identify CHB patients who remain at elevated risk of LRE and facilitate more individualised follow-up and management strategies.

Third, we concur that ethnic and metabolic diversity, as well as unmeasured confounders such as alcohol use, hepatotoxic medications, and genetic predispositions, remain critical considerations for global implementation of these thresholds. ALT distributions vary significantly across populations and are influenced by sex, age, and the prevalence of metabolic syndrome prevalence [8, 9]. While our proposed cutoffs demonstrated robust prognostic value across subgroups, external validation in multiethnic cohorts and prospective designs is warranted.

In summary, we greatly appreciate the insightful interpretation of our findings and the emphasis on redefining ALT targets in CHB management by Bilgin et al. Adopting lower sex-specific ALT thresholds, together with dynamic monitoring, has the potential to refine the definition of biochemical response and enhance prognostic assessment during NA therapy. Future multi-centre, multiethnic studies will be essential to validate these findings and ultimately support more individualised and effective long-term care for CHB patients worldwide.

Ning Yu: writing – original draft. Rong Fan: writing – review and editing.

The authors declare no conflicts of interest.

This article is linked to Fan et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70195 and https://doi.org/10.1111/apt.70354.