Letter: Amino Acid Imbalance Is an Independent Factor for Mortality in Patients With Liver Cirrhosis. Authors' reply

We thank the author for the careful reading of our study and for the thoughtful comments regarding the assessment of amino acid imbalance in patients with cirrhosis [1, 2]. We appreciate the opportunity to clarify the robustness and clinical relevance of our findings, particularly in the independence of amino acid imbalance and sarcopenia. First, regarding the concern about the potential influence of sarcopenia, we agree that skeletal muscle mass is an important determinant of amino acid imbalance and prognosis in patients with cirrhosis and that body mass index may inadequately reflect muscle status in the presence of fluid retention [3]. In response, we conducted additional multivariable Cox regression analyses adjusting for the skeletal muscle mass index (SMI) using the CT image at the third lumbar vertebra level [4]. After exclusion of patients with missing SMI data, the analysis was conducted in 416 patients (Table 1). In multivariable models, SMI itself was not independently associated with mortality in either model. Importantly, amino acid measures remained significantly associated with mortality even after adjustment for SMI. Specifically, a lower branched-chain amino acid to tyrosine ratio (BTR) was associated with increased mortality risk (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71–0.95; p = 0.007), while lower branched-chain amino acid (BCAA) levels (HR per 50 μmol/L increase, 0.87; 95% CI, 0.78–0.98; p = 0.016) and higher tyrosine levels (HR per 50 μmol/L increase, 1.48; 95% CI, 1.12–1.95; p = 0.005) were also associated with mortality in models including SMI. These findings indicate that the prognostic associations of BCAA, tyrosine and BTR are not fully explained by reduced skeletal muscle mass and are not simply biochemical surrogates of sarcopenia. These findings suggest that amino acid imbalance may reflect prognostically relevant metabolic processes not fully explained by skeletal muscle loss. Second, to enhance clinical relevance, we performed additional analyses by rescaling serum BCAA and tyrosine concentrations according to a 50 μmol/L increase. After adjustment of age, sex, body mass index, cirrhosis aetiology, Child–Pugh score, serum sodium, and ammonia levels, serum BCAA (HR per 50 μmol/L increase, 0.89; 95% CI, 0.80–0.98; p = 0.019) and tyrosine concentrations (HR per 50 μmol/L increase, 1.49; 95% CI, 1.16–1.93; p = 0.002) were independently associated with mortality. These rescaled estimates demonstrate that the observed associations are not only statistically significant but also have a clinically meaningful effect size. In summary, we thank the authors for their thoughtful comments, which have allowed us to further clarify the relationship between amino acid imbalance, skeletal muscle mass and mortality in patients with cirrhosis. Our additional analyses indicate that BCAA, tyrosine and BTR remain associated with mortality beyond differences in muscle mass. Together, these findings suggest that amino acid imbalance provides additional values when assessing prognosis in patients with cirrhosis. Yuki Utakata: writing – original draft, visualization, formal analysis, data curation, investigation. Takao Miwa: conceptualization, writing – review and editing, methodology, supervision. Shinji Unome: writing – review and editing, investigation. Naoya Masuda: investigation. Mikita Oi: investigation. Masashi Aiba: investigation. Kenji Imai: validation. Koji Takai: validation. Makoto Shiraki: validation. Naoki Katsumura: validation. Masahito Shimizu: writing – review and editing, supervision, project administration. This work was supported by the JSPS KAKENHI grant (grant number JP24K18908). This work was supported by the JSPS KAKENHI (Grant JP24K18908). The authors' declarations of personal and financial interests are unchanged from those in the original article [1]. The study protocol was reviewed and approved by the Institutional Review Board of the Graduate School of Medicine, Gifu University (approval number: 2025-038). Informed consent was obtained from all the participants using an opt-out method due to the retrospective nature of the study. The authors declare no conflicts of interest. This article is linked to Utakata et al papers. To view these articles, visit https://doi.org/10.1111/apt.70525 and https://doi.org/10.1111/apt.70561. The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.