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”

Abstract

Editors,

We read with great interest the study by Fan et al. [1], which examined the significance of alanine aminotransferase (ALT) changes in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogues (NAs) from mainland China and Hong Kong. Using latent-class mixed modelling (LCMM), the authors found sex-specific optimal ALT thresholds (≤ 23 U/L for men, ≤ 16 U/L for women) that were linked to a much lower risk of liver-related events (LRE). These results challenge the traditional upper limit of normal (ULN) of 40 U/L, which comes from healthy populations and may not be the best for assessing risk in CHB [9] (Table 1).

This study stands out for its large sample size (n = 18,129), long median follow-up (53.3 months), and dual-cohort design, allowing for strong external validation. The use of LCMM to track ALT changes over time is a methodological strength, revealing different risk levels even within the “normal” ALT range. Importantly, the significant impact of the proposed thresholds persisted in high-risk groups, including patients with cirrhosis or elevated aMAP scores, and in those without fatty liver disease, highlighting the wide relevance of these findings.

The results support the growing agreement that ALT ULN values should be redefined using disease-specific and population-specific data [3-6]. Previous studies have shown that normalising ALT within 12 months of NA therapy is associated with better outcomes [7,8], and that persistently normal ALT after HBeAg seroclearance lowers the risk of hepatocellular carcinoma (HCC) [9]. However, these earlier studies often relied on single-time-point or short-term ALT measurements, while Fan et al. show the added value of long-term ALT changes.

Two main clinical implications arise. First, clinicians should think about adopting lower ALT targets in CHB treatment, adjusted by sex, as part of monitoring. Second, assessing ALT over time instead of depending on single readings may improve prognostic accuracy and help determine more personalised follow-up intervals. Incorporating these thresholds into treatment guidelines could improve how we define “biochemical response” in NA therapy.

However, there are several factors to consider before worldwide adoption. ALT distributions and metabolic conditions differ across populations, so multiethnic validation is essential. Additionally, unmeasured elements such as alcohol use, hepatotoxic drugs, and genetic factors may affect ALT levels and LRE risk. Finally, although the study primarily involved patients receiving entecavir, it is important to evaluate how applicable these thresholds are to other NAs.

In conclusion, Fan et al. [1] provide strong evidence that lower sex-specific ALT thresholds during NA therapy are linked to a reduced LRE risk in CHB. Adopting these thresholds, along with dynamic ALT monitoring, may improve long-term outcomes and lead to a significant change in CHB management.

Ersel Bilgin: writing – original draft, methodology, investigation, conceptualization, funding acquisition. Bilger Çavuş: project administration, validation, investigation, funding acquisition, methodology, writing – review and editing. Sabahattin Kaymakoğlu: project administration, supervision, formal analysis, methodology, 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.70374.