Etiology, intervention duration, and standardization in sarcopenia management for liver cirrhosis: current challenges and future directions
We sincerely thank Drs. Zhang and Qiu for their thoughtful commentary on our article titled “Effects of exercise and nutrition in improving sarcopenia in liver cirrhosis patients: a systematic review and meta-analysis” (1). We are grateful for the opportunity to further engage in scholarly dialogue to clarify and enrich the discussion surrounding sarcopenia management in liver cirrhosis (LC).
On etiology and disease severity stratification
We acknowledge the importance of stratifying cirrhosis patients based on etiological factors (viral, alcoholic, or metabolic) and disease severity, such as the Child-Pugh classification. These subgroups exhibit varying pathophysiological mechanisms that can influence response to interventions. For instance, patients with alcoholic cirrhosis may present with higher baseline levels of muscle catabolism and micronutrient deficiency compared to those with viral hepatitis, while those with metabolic dysfunction-associated steatotic liver disease [MASLD, formerly known as metabolic associated fatty liver disease (MAFLD)] often exhibit insulin resistance and chronic low-grade inflammation that further complicate sarcopenia.
Although we fully agree with the suggestion, our ability to perform subgroup analyses was constrained by the insufficient subgroup-specific data reported in the included randomized controlled trials (RCTs). Most studies failed to consistently report etiology-specific baseline characteristics or stratified outcomes. Nevertheless, we emphasized in our discussion that the one study including patients with Child-Pugh class B/C (2) demonstrated attenuated improvements in muscle indices, possibly reflecting the greater disease burden in advanced cirrhosis. Future RCTs should be encouraged to report stratified data to enable more nuanced meta-analyses that reflect the heterogeneity of LC populations.
Duration of interventions and long-term outcomes
The commentary rightly highlights that many included studies featured relatively short intervention periods (typically 8–12 weeks), which may be insufficient to capture meaningful changes in muscle mass and functional capacity. Our meta-analysis observed that the only study with a 12-month intervention (3) demonstrated significant improvements in skeletal muscle index (SMI) and reduced sarcopenia prevalence, emphasizing the value of longer-term strategies.
We conclude that sustained interventions extending beyond 6 or 12 months are likely necessary to observe enduring effects on muscle physiology, especially in a population with progressive chronic liver disease. Additionally, longer durations allow for evaluation of the sustainability of adherence and the long-term safety profile of exercise and nutritional regimens.
Heterogeneity and standardization of interventions
The commentary also notes the substantial variability in exercise type, intensity, frequency, and the composition of nutritional interventions. Indeed, the interventions ranged from resistance training and aerobic activity to step-count goals, while nutritional support included protein, branched-chain amino acids (BCAAs), vitamin D, β-hydroxy-β-methyl butyric acid (HMB), and even non-alcoholic beer.
We acknowledged this heterogeneity as a limitation and attempted to reduce bias through subgroup and sensitivity analyses when feasible. Unfortunately, the absence of standardized protocols across trials complicates efforts to synthesize definitive recommendations. Moreover, adherence data—critical to interpreting real-world feasibility and effectiveness—were often lacking or not reported. We strongly agree with the authors’ recommendation to develop standardized yet flexible intervention frameworks, ideally adaptable to individual patient conditions such as ascites, fatigue, or hepatic encephalopathy. Adherence-enhancing strategies—such as patient education, taste optimization of supplements, and supervised exercise sessions—deserve integration into future trials.
Integration of psychosocial and quality-of-life metrics
Our study focused primarily on objective physiological outcomes (e.g., SMI, albumin, handgrip strength) in the current study. While this allowed for more consistent data pooling, we recognize the importance of incorporating patient-reported outcomes, including fatigue levels, depression/anxiety symptoms, and quality of life (QoL).
The focus of this paper was on physical indicators. However, we also agree that psychological factors are particularly pertinent to cirrhotic patients, many of whom experience social isolation, functional limitations, and financial constraints that can impact participation and outcomes. Further research in this area is warranted. A more holistic approach—including instruments such as the Short Form 36-Item Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), or liver disease-specific QoL scales—would enhance the ecological validity of future studies. Additionally, the inclusion of psychosocial variables could inform the development of supportive interventions that address both physical and emotional domains of sarcopenia care.
Diagnostic criteria and measurement standardization
We fully agree with the concern regarding inconsistent diagnostic criteria for sarcopenia across studies. Although we adopted definitions aligning with international consensus groups such as European Working Group on Sarcopenia in Older People (EWGSOP) and Asian Working Group for Sarcopenia (AWGS), the included studies varied in their use of SMI, handgrip strength, walking speed, and functional tests, with differing thresholds and measurement tools. This inconsistency hinders meta-analytical comparisons and may contribute to variability in reported effect sizes. Establishing and adhering to a universal set of diagnostic criteria—ideally endorsed by hepatology societies—would significantly improve the comparability and reproducibility of sarcopenia research in cirrhotic populations.
Additional reflections and future directions
We would like to emphasize several points raised in our discussion that resonate with the concerns of the commentary authors:
- Sarcopenia and liver frailty are interconnected conditions that require multidisciplinary assessment and intervention. Tools such as the Liver Frailty Index (LFI), which incorporates static balance and lower limb strength, may serve as complementary endpoints to SMI or handgrip strength.
- The bidirectional relationship between sarcopenia and MASLD suggests a shared pathophysiology involving insulin resistance and inflammatory cytokines. Therefore, therapeutic interventions should ideally address both muscle health and metabolic regulation simultaneously.
- Although our meta-analysis did not find statistically significant improvements in all sarcopenia-related variables, the clinical significance of maintaining or slightly improving physical function in this population—especially without adverse effects—is not to be underestimated.
Conclusions
Stratified, long-term, standardized, and patient-centered trials are essential to advancing evidence-based care for sarcopenia in LC. We remain committed to multidisciplinary collaboration in optimizing sarcopenia interventions.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.
Funding: None.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-340/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Hsu HC, Chow LH, Chen YL, et al. Effects of exercise and nutrition in improving sarcopenia in liver cirrhosis patients: a systematic review and meta-analysis. Hepatobiliary Surg Nutr 2025;14:33-48. [Crossref] [PubMed]
- Chen LK, Woo J, Assantachai P, et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc 2020;21:300-307.e2. [Crossref] [PubMed]
- Okubo H, Ando H, Nakadera E, et al. Levocarnitine Supplementation Suppresses Lenvatinib-Related Sarcopenia in Hepatocellular Carcinoma Patients: Results of a Propensity Score Analysis. Nutrients 2021;13:4428. [Crossref] [PubMed]
