Introduction
Sarcopenia, the progressive loss of skeletal muscle mass, is related to metabolic-dysfunction associated steatotic liver disease (MASLD) and cardiovascular damage (CVD). Genetic variants like PNPLA3, TM6SF2, and HSD17B13 influence MASLD risk. The prevalence of CVD is higher in MASLD patients, however the impact of sarcopenia on CVD in MASLD patients is undefined. Moreover, the role of genetic variants in sarcopenia and CV damage is unexplored.
Aims & Methods
To assess the impact of sarcopenia, metabolic comorbidities, and genetic variants on liver and CVD in a cohort of non-cirrhotic MASLD patients.
We enrolled 841 MASLD patients. Fibrosis was assessed by liver stiffness measurement (LSM) (LSM≥8 kPa for advanced fibrosis) and steatosis by controlled attenuation parameter (CAP) at Fibroscan (CAP>280 dB/m for severe steatosis). Sarcopenia was defined by the lowest tertile of skeletal muscle index (SMI = skeletal muscle mass/height^2) at bioimpedance analysis. CV damage markers included carotid intima-media thickness (cIMT)≥0.9 mm, carotid plaques, epicardial fat thickness (EFT) ≥5.2 mm. Increased waist circumference (WC) >102/88 cm in men/women. Genetic polymorphisms in PNPLA3, TM6SF2, and HSD17B13 were assessed in 424 patients.
Results
Mean age was 51 ys, 63% male. 43% were obese, 65% had increased WC. 50% were dyslipidemic, 25% diabetic. 24% had advanced fibrosis, 71% severe steatosis. 22% had increased cIMT, 35% had carotid plaques, 83% had increased EFT. Sarcopenia (SMI<10.35/7.75 kg/m2 in men/women) was linked to older age (54 vs 48 ys, p<0.001), lower BMI (27 vs 33.4 kg/m2, p<0.001), WC (99 vs 110 cm, p<0.001), CAP (293 vs 317 dB/m, p<0.001), and LSM (4.9 vs 6.4 kPa, p<0.001) compared to non-sarcopenic. Sarcopenic also had higher dyslipidemia (56% vs 46%, p=0.03), increased cIMT (28% vs 18%, p=0.01), and EFT (85% vs 77%, p=0.05). At adjusted multivariate analysis, sarcopenia remained associated with low BMI (OR 0.61; 95% CI 0.5-0.7, p<0.001), WC (OR 0.92; 95% CI 0.8-0.97, p=0.001), female sex (OR 2.21; 95% CI 1.2-4.0, p=0.008), and increased cIMT (OR 2.1; 95% CI 1.1-3.97). In sarcopenic, PNPLA3 CG/GG variant was linked to increased LSM (OR 1.82, 95% CI 1.1-3.1, p=0.03) but lower cIMT (OR 0.39, 95% CI 0.15-0.96, p=0.04). TM6SF2 wild-type allele was associated with increased cIMT (OR 3.4, 95% CI 1.3-5.8, p=0.004), and WC (OR 2.3, 95% CI 1.4-3.6, p=0.001). No differences were seen in HSD17B13 variant.
Analyzing different metabolic subgroups, in diabetic and hypertensive patients, prevalence of carotid plaques was higher in sarcopenic vs non-sarcopenic (56% vs 30%, p=0.04, 58% vs 20%, p<0.001). In hypertensive patients sarcopenia remained an independent risk factor for carotid plaques (OR 1.9, CI 95% 1.05-3.5, p=0.03) and high/very high CV risk (OR 3.0, CI 95% 1.2-7.2, p=0.01) in multivariate analysis adjusted for age, sex, diabetes, dyslipidemia, smoke and BMI, whereas in non-diabetic subjects for high/very high CV risk (OR 1.44, CI 95% 1.1-2.1, p=0.04).
Conclusion
MASLD patients, particularly non-obese, have a high prevalence of sarcopenia and increased subclinical CVD. Despite lower visceral adiposity, in hypertensive patients sarcopenia seems to potentiate the CVD. In sarcopenic patients, the PNPLA3 variant correlated with lower subclinical atherosclerosis, while TM6SF2 polymorphism showed a protective role against CV damage.
MASLD patients would need a prompt evaluation and treatment of sarcopenia to prevent the onset of CVD, particularly if hypertensive. Combining genetic data is required to clarify the role of sarcopenia in MASLD.
