Rate and clinical predictors of skeletal muscle loss in patients with cirrhosis

Abstract

Background

Skeletal muscle mass predicts outcomes in cirrhosis and represents a therapeutic target. However, the natural rate of muscle change in this population remains poorly defined.

Objective

We characterised longitudinal skeletal muscle change and its association with clinical outcomes in cirrhosis.

Design

This cohort study enrolled ambulatory adults with cirrhosis awaiting liver transplantation at a tertiary centre who underwent at least two abdominal CT scans between February 2015 and January 2021. Skeletal muscle index (SMI) at L3 was quantified and normalised for height. Annualised percent change in SMI (ΔSMI/year%) was calculated. The primary outcome was waitlist mortality, defined as death or delisting for being too ill for transplantation.

Results

Among 364 patients (median age 62 years; 68% male; model for end-stage liver disease-sodium (MELD-Na) 12), the median (IQR) ΔSMI/year% was −1.6% (−7.4 to +3.7). Rapid muscle loss (RML) was defined as the worst quartile of ΔSMI/year% (< −7.4%; n=91). Independent predictors of RML included ascites (OR 1.77, 95% CI 1.00 to 3.12) and higher MELD-Na (OR 1.06, 95% CI 1.00 to 1.13). Cumulative waitlist mortality was significantly higher in patients with RML than in those without RML at 12 months (32% vs 10%) and 24 months (75% vs 27%) (log-rank p<0.001). RML independently predicted waitlist mortality in adjusted Cox models (HR 3.43–3.52).

Conclusion

Patients with cirrhosis had a median skeletal muscle loss of 1.6%/year. In this cohort, RML independently predicted waitlist mortality and was associated with ascites and MELD-Na. These data could inform effect-size estimates for future trials targeting sarcopenia in cirrhosis with low-to-moderate MELD-Na.

INTRODUCTION

Sarcopenia, defined as the progressive loss of skeletal muscle mass, is highly prevalent among patients with cirrhosis, affecting 30%–70% of this population.¹ Its pathogenesis is multifactorial, driven by a combination of malnutrition, liver-related metabolic disturbances, systemic inflammation, hormonal dysregulation and reduced physical activity, as well as social and environmental influences.² Crucially, sarcopenia is a well-established prognostic marker in patients with cirrhosis, independently associated with adverse outcomes such as hepatic decompensation,³ infection,⁴ prolonged hospitalisation,⁵ impaired quality of life⁶ and increased mortality both before and after liver transplantation (LT).^{7 8}

Sarcopenia is increasingly recognised as a potentially important therapeutic target in the cirrhotic population. However, to effectively assess the efficacy of interventions targeting sarcopenia, a thorough understanding of the natural history and trajectory of skeletal muscle change is essential. Existing studies in this critical area are limited by small sample sizes^9–12 and a predominant focus on Asian cohorts,^10–15 which restricts the generalisability of their findings to broader global populations. Consequently, the expected rate of skeletal muscle change and the factors influencing its trajectory in patients with cirrhosis remain poorly characterised.

Therefore, this study primarily aimed: (1) to quantify the rate of skeletal muscle change over time; (2) to identify the clinical predictors of rapid muscle loss (RML); and (3) to evaluate the prognostic significance of these changes for waitlist mortality among ambulatory patients with cirrhosis awaiting LT.

METHODS

Study design and patient selection

Adult patients with cirrhosis awaiting LT in the ambulatory setting at the University of California, San Francisco, were prospectively enrolled into the Functional Assessment in Liver Transplantation (FrAILT) Study. This substudy included participants enrolled between 1 February 2015 and 31 January 2021, who had at least two abdominal CT scans performed in the ambulatory setting: one obtained within 6 months of study enrolment and another within 6 months of the study endpoint. Patients lacking a follow-up CT scan or those with suboptimal image quality on either baseline or follow-up CT were excluded. CT scans were considered suboptimal if the third lumbar vertebra (L3) level was incompletely visualised or if unilateral skeletal muscle truncation at the L3 level precluded accurate quantification of total skeletal muscle area (SMA). Sociodemographic and clinical characteristics, including age, sex, race, body mass index (BMI), aetiology of cirrhosis, comorbidities, ascites, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC) and model for end-stage liver disease-sodium (MELD-Na) scores, were extracted from the electronic medical record by trained study personnel. All participants provided written informed consent. The study was approved by the Institutional Review Board at the University of California, San Francisco (IRB number: 22-36799), and conducted in accordance with the principles of the Declarations of Helsinki and Istanbul.

Assessment of skeletal muscle index (SMI)

Body composition was assessed using abdominal CT scans obtained during liver transplant evaluation. Cross-sectional SMA was quantified at the L3 level using a post-processing workstation (GE Advanced Workstation 4.6, Volume Viewer software; GE Healthcare, Waukesha, WI, USA). Muscles included the psoas, erector spinae, multifidus, quadratus lumborum, rectus abdominis, transversus abdominis and internal and external obliques. Skeletal muscle tissue was delineated using standard Hounsfield unit (HU) thresholds of −29 to +150.¹⁶ Muscle area (cm²) was derived by summing the pixels within the defined HU range and multiplying by pixel surface area. All CT images were analysed by a single trained radiologist blinded to clinical outcomes. SMA values were normalised by height squared (m²) to derive the SMI (cm²/m²). The annualised percent change in SMI (ΔSMI/year%) was calculated as:

$$\text{ΔSMI}/\mathrm{y}\mathrm{e}\mathrm{a}\mathrm{r}\text{\%}=\frac{\left(\text{last}\text{SMI}-\text{baseline}\text{SMI}\right)}{\text{baseline}\text{SMI}}\times \frac{100}{\text{interval}\text{between}\text{CT}\text{scans}\text{in}\text{years}}$$

RML was defined as the worst quartile of ΔSMI/year% loss within the study cohort.

Clinical assessment and follow-up

Ascites and HE were identified via manual review of physician notes and physical examinations conducted at the time of patient enrolment. Ascites was classified as mild to moderate if controlled with diuretics, or as severe/refractory if management required large-volume paracentesis at least once per month or transjugular intrahepatic portosystemic shunt placement. Patients were followed prospectively until a terminal waitlist event occurred or, for those without such an event, until 31 January 2021. Clinical outcomes included death, removal from the waitlist due to medical unfitness for transplantation, LT (from living or deceased donors), waitlist deferral or inactivation due to psychosocial factors or continued active waitlist status.

Study outcome

The primary outcome of this study was waitlist mortality, defined as a composite endpoint encompassing both death and delisting due to being too ill for LT.

Definitions

Sarcopenia was identified using previously validated sex-specific thresholds of SMI—<50 cm²/m² for men and <39 cm²/m² for women—according to the American Association for the Study of Liver Diseases guidelines.^{2 7} Frailty was assessed using the Liver Frailty Index (LFI), a standardised composite measure incorporating grip strength, chair stands and balance testing in cirrhosis; patients were classified as robust if LFI <3.2 and frail if LFI >4.4, based on established cutoffs.¹⁷ The severity of cirrhosis was evaluated using the MELD-Na score.¹⁸

Statistical analysis

Continuous variables were expressed as medians (IQR) and compared using the Mann–Whitney U test. Categorical variables were presented as counts (percentages) and compared using the Pearson χ² test or Fisher’s exact test when appropriate. Waitlist survival was defined as the time from study enrolment to death or delisting for being too ill for transplant. Patients were censored at the date of transplantation, delisting for non-medical reasons or the last date of clinical follow-up. Kaplan–Meier curves were used to estimate cumulative incidence of waitlist mortality and differences were compared using the log-rank test. Predictors of waitlist mortality were examined using Cox proportional-hazards regression, and predictors of RML were evaluated using logistic regression. Candidate variables with p<0.10 in univariable analyses, as well as established clinical prognostic factors, were included in multivariable models. Statistical significance was defined as a two-sided p<0.05. Analyses were conducted using Stata V.15.1 (StataCorp, College Station, TX, USA).

Patient and public involvement

Patients or the public were not involved in the design, conduct, reporting or dissemination of this research.

RESULTS

Patient characteristics

A total of 670 patients with cirrhosis enrolled in the FrAILT study between 1 February 2015 and 31 January 2021, with available baseline CT data, were screened for eligibility (figure 1). Through the rigorous screening process, we excluded 28 patients with suboptimal baseline imaging quality, 264 patients lacking follow-up CT and 14 patients with suboptimal follow-up imaging quality. Consequently, 364 patients with adequate baseline and follow-up CT scans were finally included in the analysis.

Figure 1.

Study flow diagram for participant selection. Among 670 patients with cirrhosis screened from the FrAILT study (2015–2021), 28 were excluded for suboptimal baseline CT quality, 264 for lack of follow-up CT and 14 for suboptimal follow-up CT quality. A total of 364 patients with adequate baseline and follow-up CT scans were included in the final analysis. CT, computed tomography; FrAILT, Functional Assessment in Liver Transplantation.

Baseline characteristics of all enrolled patients, and stratified by the presence or absence of RML, are summarised in table 1. Overall, the median age was 62 years (IQR 56–66), 68% of the cohort were male, 51% identified as non-Hispanic White and the median BMI was 27.8 kg/m² (IQR 24.9–31.5). The most common aetiology of cirrhosis was hepatitis C virus (HCV) infection (47%), followed by alcohol-associated liver disease (18%), metabolic dysfunction-associated steatotic liver disease/steatohepatitis (16%) and hepatitis B virus (HBV) infection (10%). Hypertension (43%) and diabetes mellitus (35%) were the most prevalent comorbidities, followed by coronary artery disease (7%) and cerebrovascular accident (1%). Ascites was present in 51% of patients (39% mild/moderate; 12% severe/refractory), HE in 41%, and HCC in 71%. The median MELD-Na score was 12 (IQR 9–15). At baseline, 13% of patients met criteria for frailty (LFI >4.4) and 40% met criteria for sarcopenia.

Table 1.

Baseline characteristics stratified by rapid muscle loss status

	Overall n=364	ΔSMI/year%		P value
		Rapid muscle loss (worst quartile) n=91	No rapid muscle loss (all others) n=273
Age (years)	62 (56–66)	60 (56–65)	62 (56–66)	0.39
Sex (male)	247 (68)	60 (66)	187 (69)	0.65
Race
Non-Hispanic White	184 (51)	47 (52)	137 (50)	0.048
Hispanic white	103 (28)	29 (32)	74 (27)
Asian	59 (16)	9 (10)	50 (18)
Black	16 (4)	4 (4)	12 (4)
Native American	2 (1)	2 (2)	0 (0)
BMI (kg/m2)	27.8 (24.9–31.5)	27.7 (24.6–31.3)	27.8 (24.9–31.6)	0.82
Aetiology				0.48
HCV	171 (47)	43 (47)	128 (47)
Alcohol-associated	65 (18)	16 (18)	49 (18)
MASLD/MASH	58 (16)	17 (19)	41 (15)
HBV	35 (10)	6 (7)	29 (11)
AIH/PBC/PSC	19 (5)	7 (8)	12 (4)
Others	16 (4)	2 (2)	14 (5)
Hypertension	157 (43)	36 (40)	121 (44)	0.43
Diabetes mellitus	126 (35)	27 (30)	99 (36)	0.25
Coronary artery disease	24 (7)	3 (3)	21 (8)	0.14
CVA	5 (1)	1 (1)	4 (1)	0.80
Ascites (any)	184 (51)	58 (64)	126 (46)	0.004
Mild/moderate	141 (39)	42 (46)	99 (36)
Severe/refractory	43 (12)	16 (18)	27 (10)
Hepatic encephalopathy	150 (41)	44 (48)	106 (39)	0.11
HCC	258 (71)	62 (68)	196 (72)	0.51
MELD-Na	12 (9–15)	13 (11–16)	12 (8–15)	0.003
Frailty (LFI>4.4)	49 (13)	15 (16)	34 (12)	0.32
LFI at baseline	3.6 (3.2–4.1)	3.7 (3.2—4.2)	3.6 (3.2–4.1)	0.51
Sarcopenia
Overall	147 (40)	23 (25)	124 (45)	0.001
Men	108 (44)	19 (32)	89 (48)	0.03
Women	39 (33)	4 (13)	35 (41)	0.01
SMI at baseline (cm2/m2)
Overall	49 (43–55)	51 (45–57)	49 (42–53)	0.12
Men	51 (46–56)	54 (47–59)	50 (46–55)	0.08
Women	43 (38–49)	47 (41–49)	42 (36–49)	0.046
SMI at last follow-up (cm2/m2)
Overall	48 (42–53)	45 (38–52)	49 (44–53)	0.001
Men	50 (45–55)	48 (41–54)	50 (46–55)	0.01
Women	42 (37–49)	42 (36–45)	42 (38–49)	0.07
ΔSMI/year%
Overall	−1.6 (−7.4 to +3.7)	−16.0 (−29.3 to −10.1)	+0.7 (−2.6 to +5.5)	< 0.001
Men	−1.6 (−7.1 to +3.6)	−15.3 (−25.2 to −10.2)	+0.3 (−2.7 to +5.2)	< 0.001
Women	−1.3 (−7.7 to +4.5)	−17.7 (−43.1 to −10.1)	+1.2 (−2.4 to +7.1)	< 0.001
CT follow-up (months)	10 (6–18)	6 (4–10)	11 (7–21)	< 0.001

Values are number (%) or median (IQR).

AIH, autoimmune hepatitis; BMI, body mass index; CT, computed tomography; CVA, cerebrovascular accident; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LFI, liver frailty index; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MELD-Na, model for end-stage liver disease-sodium; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SMI, skeletal muscle index.

The median time between the first and last CT scans was 10 months (IQR 6–18). The overall annualised percent change in SMI (ΔSMI/year%) was −1.6% (−7.4 to +3.7), with a slightly more pronounced decline in men (−1.6% (−7.1 to +3.6)) than in women (−1.3% (−7.7 to +4.5)). Although most patients lost muscle over the observation period, a substantial subset maintained or gained muscle mass; median ΔSMI/year% ranged from −16.0% in the worst quartile to +11.3% in the best quartile (online supplemental figure 1). The cohort was stratified into RML (annual SMI loss greater than 7.4%; ie, ΔSMI/year% <−7.4%; n=91) and non-RML (annual SMI loss of 7.4% or less; ie, ΔSMI/year% ≥ −7.4%; n=273) subgroups. Compared with non-RML patients, those with RML had a higher prevalence of ascites (64% vs 46%; p=0.004), higher median MELD-Na (13 vs 12; p=0.003) and lower prevalence of sarcopenia (25% vs 45%; p=0.001). Longitudinal LFI change tracked directionally with RML status—worsening was more frequent (38% vs 22%) and improvement less frequent (17% vs 26%) in the RML than the non-RML group—though the overall distribution of LFI trajectories did not differ significantly (p=0.10). When the cohort was instead stratified by muscle gain status (best quartile of ΔSMI/year%, ie, ≥ +3.7%, vs all others), patients in the best quartile had a higher prevalence of baseline sarcopenia (55% vs 35%; p=0.001; online supplemental table 1), suggesting greater potential for recovery of skeletal muscle mass during follow-up.

Factors associated with RML

In univariable logistic regression analysis, the presence of ascites (OR 2.05, 95% CI 1.26 to 3.34; p=0.004) and higher MELD-Na (per 1-point increase: OR 1.07, 95% CI 1.02 to 1.12; p=0.004) were significantly associated with RML. In the multivariable model adjusting for age, sex, HCC, HE and LFI, both ascites (OR 1.77, 95% CI 1.00 to 3.12; p=0.05) and MELD-Na (per 1-point increase: OR 1.06, 95% CI 1.00 to 1.13; p=0.05) remained independent predictors of RML (table 2).

Table 2.

Univariable and multivariable logistic regression for predictors of rapid muscle loss

	Univariable analysis			Multivariable analysis
	OR	95% CI	P value	OR	95% CI	P value
Age (year)	0.99	0.96 to 1.02	0.42	1.00	0.97 to 1.03	0.81
Sex (male)	0.89	0.54 to 1.47	0.65	1.00	0.59 to 1.70	0.98
Hepatocellular carcinoma	0.84	0.50 to 1.40	0.51	1.49	0.77 to 2.87	0.24
Hepatic encephalopathy	1.47	0.91 to 2.38	0.11	1.07	0.61 to 1.86	0.82
Liver frailty index	1.14	0.83 to 1.58	0.42	0.97	0.68 to 1.39	0.87
Ascites	2.05	1.26 to 3.34	0.004	1.77	1.00 to 3.12	0.05
MELD-Na (per 1 point)	1.07	1.02 to 1.12	0.004	1.06	1.00 to 1.13	0.05

MELD-Na, model for end-stage liver disease-sodium.

Clinical outcomes

During a median follow-up of 13 months (IQR 8–20) in the overall population, 91 (25%) patients died or were delisted for being too ill for LT, 209 (57%) underwent LT, 41 (11%) were deferred or inactivated due to psychosocial reasons and 23 (6%) were still waiting at the end of follow-up. A total of 34 (37%) patients with RML and 57 (21%) of those without RML experienced death or delisting due to being too ill for LT during a median observation period of 10 months (IQR 7–13) and 14 months (IQR 9–23), respectively (table 3). The cumulative incidence of waitlist mortality was significantly higher among patients with RML at 12 months (32% vs 10%; p<0.001) and 24 months (75% vs 27%; p<0.001) compared with non-RML patients (figure 2). By 24 months, of the 91 patients with RML, 34 had died or been delisted and 47 had undergone LT and were censored; the small number consequently remaining at risk contributed to the high cumulative incidence estimate at this time point. RML remained significantly associated with cumulative incidence of waitlist mortality at 24 months compared with those without RML, even when stratified by sex: 64% vs 31% in men (p=0.01) and 100% vs 20% in women (p=0.001).

Table 3.

Clinical outcomes according to rapid muscle loss status

	Overall n=364	ΔSMI/year%		P value
		Rapid muscle loss (worst quartile) n=91	No rapid muscle loss (all others) n=273
Outcomes				0.001
Death or delisting	91 (25)	34 (37)	57 (21)
Transplant	209 (57)	50 (55)	159 (58)
Deferred or inactivated	41 (11)	7 (8)	34 (12)
Waiting	23 (6)	0 (0)	23 (8)
Follow-up (months)	13 (8–20)	10 (7–13)	14 (9–23)	< 0.001

SMI, skeletal muscle index.

Figure 2.

Cumulative incidence of waitlist mortality stratified by rapid muscle loss (RML) status. Waitlist mortality was higher in patients with RML than non-RML patients at 12 months (32% vs 10%) and 24 months (75% vs 27%) (log-rank p<0.001).

Factors predicting waitlist mortality

In univariable Cox regression analysis, RML was significantly associated with an elevated risk of waitlist mortality (HR 3.28, 95% CI 2.11 to 5.12; p<0.001). This association persisted robustly in the multivariable setting. In model 1, after adjusting for age, sex, ascites, HE, MELD-Na, LFI and baseline SMI, RML emerged as the sole independent predictor of waitlist mortality (HR 3.43, 95% CI 2.16 to 5.46; p<0.001). Consistent with these findings, RML also demonstrated strong predictive capacity for waitlist mortality in model 2, following adjustment for age, sex, ascites, HE, MELD-Na, LFI and sarcopenia (HR 3.52, 95% CI 2.20 to 5.65; p<0.001) (table 4).

Table 4.

Univariable and multivariable Cox regression for predictors of waitlist mortality

	Univariable analysis			Multivariable analysis (model 1) *			Multivariable analysis (model 2) *
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Age (year)	1.01	0.98 to 1.03	0.62	1.01	0.98 to 1.04	0.51	1.01	0.98 to 1.04	0.45
Sex (male)	0.89	0.58 to 1.38	0.62	0.99	0.61 to 1.61	0.98	0.84	0.53 to 1.31	0.44
Ascites	1.23	0.81 to 1.88	0.33	0.97	0.60 to 1.56	0.90	0.99	0.61 to 1.59	0.96
Hepatic encephalopathy	1.41	0.93 to 2.14	0.11	1.32	0.81 to 2.15	0.27	1.33	0.81 to 2.16	0.26
MELD-Na (per 1 point)	1.04	0.99 to 1.08	0.09	1.01	0.96 to 1.06	0.64	1.01	0.96 to 1.06	0.62
Liver frailty index	1.13	0.83 to 1.53	0.44	0.96	0.69 to 1.32	0.79	0.95	0.69 to 1.31	0.77
SMI at baseline (cm2/m2)	0.99	0.97 to 1.01	0.38	0.98	0.96 to 1.01	0.21	—	—	NA
Sarcopenia	1.11	0.73 to 1.71	0.62	—	—	NA	1.39	0.88 to 2.18	0.16
ΔSMI/year%
All others	Ref	—	—	Ref	—	—	Ref	—	—
Rapid muscle loss	3.28	2.11 to 5.12	< 0.001	3.43	2.16 to 5.46	< 0.001	3.52	2.20 to 5.65	< 0.001

^*Model 1 incorporated all clinically significant parameters into the multivariable analysis, except sarcopenia. Model 2 incorporated all clinically significant parameters into the multivariable analysis, except baseline SMI.

MELD-Na, model for end-stage liver disease-sodium; SMI, skeletal muscle index.

DISCUSSION

In this predominantly low-to-moderate MELD-Na cohort, RML (the worst quartile of ΔSMI/year% loss) is a strong and independent predictor of waitlist mortality, beyond MELD-Na and traditional clinical factors. Patients with ascites and higher MELD-Na are at greater risk for accelerated skeletal muscle loss. To the best of our knowledge, this is one of the largest US cohorts to examine the association between longitudinal changes in skeletal muscle mass and clinical outcomes in patients with cirrhosis awaiting LT.

In the general population, age-related skeletal muscle loss typically becomes apparent only after the fourth decade of life. For context, a prior CT-based study of healthy adults reported a decline in L3 SMI of approximately −0.4%/year in men and −0.2%/year in women aged 41 years or older.¹⁹ As that reference cohort was younger and leaner than the present population, these values are best regarded as a broad qualitative benchmark rather than a direct comparison. Nevertheless, the median loss observed in our cirrhotic cohort (−1.6%/year in men and −1.3%/year in women) was several-fold greater, consistent with the catabolic milieu of cirrhosis. This observation is also consistent with the emerging concept that cirrhosis represents a state of accelerated biological ageing, in which mitochondrial dysfunction and cellular senescence contribute to progressive physiological decline.²⁰ Progressive liver failure and portal hypertension cause inflammation, hyperammonaemia, hormonal imbalance, malnutrition and reduced physical activity, which together accelerate protein breakdown and impair muscle synthesis.²¹ In addition, cirrhosis shifts energy metabolism towards early fasting and increased amino acid use for gluconeogenesis, promoting further muscle loss.²²

CT-based assessment at the L3 level is among the most accurate methods for quantifying skeletal muscle in patients with cirrhosis, although its use for longitudinal monitoring is constrained by cost, radiation exposure and reliance on clinically indicated imaging.^{2 23} Several previous studies showed that the rate of change in SMA or SMI, as assessed by serial CT imaging, independently predicts cirrhosis-related complications,¹³ hepatic decompensation¹⁴ and mortality.^{10–12 14 15} However, these studies have been conducted predominantly in Asian cohorts,^10–15 limiting their generalisability to broader populations, particularly in the Western hemisphere. The only study performed in a US cohort similarly found that the rate of muscle loss independently predicted survival in cirrhosis;⁹ however, its small sample size limits the strength of its conclusions. Building on this limited evidence, the present study—using one of the largest US cohorts—demonstrates that a greater annualised rate of muscle loss independently predicts waitlist mortality beyond MELD-Na and traditional clinical factors, thereby establishing the prognostic value of dynamic muscle change at a scale not previously available. This reflects the ongoing metabolic and clinical deterioration that drives prognosis in cirrhosis.

In this study, the presence of ascites and a higher MELD-Na score emerged as independent predictors of RML after adjustment for age, sex, HCC, HE and LFI in multivariable analysis. Both factors reflect hepatic decompensation and systemic derangements, which plausibly accelerate skeletal muscle mass decline in cirrhosis; however, given a 75th-percentile MELD-Na of 15, the present cohort did not substantially capture patients with advanced disease. Ascites denotes the onset of hepatic decompensation, characterised by pronounced portal hypertension, splanchnic vasodilation, diminished oral intake secondary to early satiety and abdominal distension, and elevated resting energy expenditure, which collectively foster a sustained negative nitrogen balance and progressive skeletal muscle catabolism.^{24 25} In parallel, a higher MELD-Na value incorporates kidney dysfunction and hyponatraemia—surrogate markers of circulatory dysfunction, inflammation and ammonia retention—each contributing to muscle breakdown via activation of myostatin, ubiquitin–proteasome and autophagy pathways.^{26 27} Together, these factors create an environment of reduced anabolic drive, increased catabolism and metabolic stress, thereby making ascites and elevated MELD-Na not only markers of poor prognosis but also mechanistically credible predictors of accelerated muscle loss.

Our findings indicate that men exhibited a slightly more pronounced decline in ΔSMI/year% compared with women in the cirrhotic population, a pattern consistent with prior reports.¹⁵ Men generally have higher baseline muscle mass and greater dependence on anabolic hormones, such as testosterone, which decline sharply with liver dysfunction. Hypogonadism—highly prevalent in advanced cirrhosis—leads to decreased protein synthesis and increased myostatin expression, accelerating muscle catabolism in men.²¹ In contrast, women may be partially protected by oestrogen’s anti-inflammatory and anti-oxidative effects, which may slow muscle wasting despite lower absolute muscle mass.²⁸ Additionally, differences in fat distribution and metabolic substrate utilisation between sexes influence energy homeostasis: women preferentially oxidise lipids, whereas men rely more on amino acid catabolism during fasting or stress, leading to greater skeletal muscle loss when metabolic reserve is challenged.²⁹

Developing effective strategies to slow, halt or reverse skeletal muscle loss (sarcopenia) in patients with cirrhosis remains a significant unmet clinical need. Although several interventions—such as ensuring adequate calorie and protein intake,^{2 23} late-evening nutritional supplements,³⁰ nocturnal nasogastric feeding,³¹ testosterone replacement³² and resistance training^{2 23}—have been proposed or investigated to treat sarcopenia, there is a clear necessity for further development and rigorous evaluation. Crucially, to rationally design and test the efficacy of such interventional studies, a thorough understanding of the natural rate of skeletal muscle change in the cirrhotic population is essential. The findings of the present study directly address this critical gap and may provide a foundation for the design of future interventional clinical trials. For such trials, L3 CT remains the best-validated endpoint for muscle mass, although muscle ultrasound may offer a more accessible, repeatable alternative once its longitudinal data become available.³³ In our cohort, longitudinal LFI change was only directionally concordant with RML status and did not reach significance, suggesting bedside frailty testing captures only part of the skeletal-muscle signal detected by serial CT.

A key strength of this study is the prospective, systematic ascertainment of baseline clinical characteristics and waitlist outcomes within the FrAILT cohort, which reduces information bias and confounding. However, we acknowledge several limitations. First, although participants were prospectively enrolled in the FrAILT study, the present body-composition analysis was a secondary substudy based on clinically indicated CT scans rather than protocolised imaging. Consequently, many screened patients were excluded because follow-up CT imaging was unavailable. This approach enriched the cohort for patients with HCC (71% vs ≈43% in the broader FrAILT cohort),³⁴ who undergo more frequent surveillance imaging and often receive transplantation priority through non-biological exception points, resulting in a lower median MELD-Na (12 vs ≈18).³⁴ This HCC enrichment likely contributed to the higher proportion of HCV (47% vs ≈36% in the broader FrAILT cohort),³⁴ substantially exceeding the 4%–5% reported among contemporary LT recipients in the USA and Europe in the direct-acting antiviral era.^{35 36} These cohort characteristics may also have attenuated the prognostic value of baseline sarcopenia measures for waitlist mortality. Accordingly, our findings should be interpreted within the context of a predominantly low-to-moderate MELD-Na, HCC-enriched, HCV-predominant cohort and extrapolation to patients with very high MELD-Na should be undertaken with caution. Second, this single-centre study enrolled outpatients awaiting transplantation, over half of whom were non-Hispanic White, limiting generalisability across racial populations. Third, longitudinal dietary and physical activity data were not systematically captured; HE was defined by clinical history and/or lactulose/rifaximin use rather than standardised West Haven grading; and cause-specific mortality and delisting were not formally adjudicated, precluding aetiology-specific analyses of waitlist dropout. Finally, because skeletal muscle was assessed at only two time points, we could not characterise the temporal trajectory of muscle loss, nor fully exclude that very short inter-scan intervals amplified annualised estimates in some patients.

In conclusion, patients with cirrhosis experience a substantially greater annualised loss of CT-quantified SMI compared with healthy individuals. Among those awaiting LT, RML—associated with ascites and higher MELD-Na—independently predicted waitlist mortality beyond traditional clinical factors in this predominantly low-to-moderate MELD-Na cohort. This suggests a potential role for dynamic muscle assessment in waitlist risk stratification, which merits prospective evaluation using protocolised serial imaging. Our data could help inform effect size calculations for future clinical trials evaluating interventions targeting sarcopenia in patients with cirrhosis and low-to-moderate MELD-Na scores.

Supplementary Material

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WHAT IS ALREADY KNOWN ON THIS TOPIC

• Sarcopenia is a well-established prognostic marker in cirrhosis and is increasingly viewed as a modifiable therapeutic target.

• However, the natural rate of skeletal muscle change in cirrhosis is poorly defined, with prior data limited by small sample sizes and predominantly Asian cohorts.

WHAT THIS STUDY ADDS

• In one of the largest US cohorts to date, the median skeletal muscle loss in cirrhosis was 1.6%/year, several-fold greater than in the general population.

• Rapid muscle loss independently predicted waitlist mortality beyond traditional clinical factors in this predominantly low-to-moderate model for end-stage liver disease-sodium (MELD-Na) cohort, identifying the rate of muscle change as a distinct prognostic marker.

• Ascites and higher MELD-Na were independent predictors of rapid muscle loss.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These data could help inform effect-size estimation and trial design for future interventions targeting skeletal muscle in cirrhosis with low-to-moderate MELD-Na.

Data availability statement

Data are available upon reasonable request.