Advancing the Prognostic Utility of Free Testosterone in Advanced Chronic Liver Disease: Key Methodological Considerations

We read with great interest the study by Sogbe et al. which elegantly demonstrates that low free testosterone (FT) outperforms total testosterone as an independent predictor of mortality in men with advanced chronic liver disease (AdvCLD) [1]. While fully acknowledging its merits, we would like to offer some constructive suggestions to further enhance the impact of this research. First, testosterone levels are subject to physiological fluctuations and are significantly influenced by short-term factors such as nutritional status, acute illness or infection [2]. Thus, a single baseline measurement may not accurately reflect a patient's true hormonal status. In unstable advanced liver disease, this may result in the misclassification of patients, including the misinterpretation of transient testosterone declines as persistent hypogonadism. We recommend serial measurements during follow-up (e.g., every 3–6 months). Analysing these with time-dependent covariates in survival models would more precisely elucidate how dynamic FT changes relate to long-term outcomes. Second, residual confounding may persist despite adjustment for the Model for End-Stage Liver Disease-Sodium score. Systemic inflammation and malnutrition are strong drivers of frailty and mortality in advanced liver disease [3]. This is particularly relevant as the authors themselves note that chronic inflammation, a hallmark of AdvCLD, can suppress the hypothalamic–pituitary–gonadal axis via cytokines, leading to central hypogonadism [1]. If not adequately controlled for, these confounders could lead to the overestimation of FT's independent prognostic value. Future studies should systematically account for inflammatory markers and detailed nutritional status to better isolate the specific effect of hypogonadism on outcomes. Finally, the observed moderate positive correlation between serum albumin and FT suggests it is possible that the Vermeulen formula was applied using the fixed albumin constant (43 g/L) [4]. However, substantial differences exist between this fixed value and the actual albumin levels in the study cohort (2.9 ± 0.5 vs. 3.4 ± 0.6 g/dL). Notably, Vermeulen et al. specifically recommended using actual albumin concentrations for patients with marked plasma protein abnormalities [4]. Although this methodological limitation likely has minimal impact on the study's primary conclusions, we still recommend using actual albumin levels for FT calculation in patients with AdvCLD, who characteristically exhibit prevalent hypoalbuminemia. This adjustment would yield more accurate FT estimates that better reflect true hypogonadism by reducing interference from liver disease-related hypoalbuminemia, thereby strengthening FT's validity as an independent prognostic marker and providing a more reliable basis for identifying candidates for testosterone replacement therapy. Mingjing Xu: writing – original draft. Xiyan Jin and Hangyuan Wu: writing – review and editing. Wenzong Zhu: supervision. All the authors have read and approved the final version of the manuscript. The authors have nothing to report. This work was supported by the Startup Fund for Scientific Research of Wenzhou Science and Technology Bureau, grant number Y20180212. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Sogbe et al. papers. To view this article, visit https://doi.org/10.1111/liv.70393. The authors have nothing to report.