This study aimed to evaluate the association of the triglyceride-glucose index (TyG index) with body composition and laboratory parameters in individuals with chronic kidney disease (CKD) stage 3-5.

A total of 89 individuals with CKD stages 3-5 were classified into two groups based on glomerular filtration rate (GFR): the CKD stages 3 to 4 group (n = 53) and the CKD stage 5 group (n = 36). Body composition parameters, including body fat mass, lean body mass, skeletal muscle mass, and body mass index, were measured. Laboratory indices, including hemoglobin, albumin, cholesterol, and the TyG index were analyzed. The correlations between the TyG index and these parameters were analyzed using Pearson correlation, and the factors of the TyG index were analyzed using linear regression.

(1) Hemoglobin levels, lymphocyte counts, the TyG index, and low-density lipoprotein cholesterol concentrations were higher in patients with CKD stages 3 to 4 compared to those with CKD stage 5. (2) Measures of body composition, including body fat mass, lean body mass, skeletal muscle mass, and BMI were significantly higher in patients with CKD stages 3 to 4 compared to those with CKD stage 5. (3) The TyG index exhibited positive correlations with cholesterol, lymphocyte and monocyte counts, fasting blood glucose, triglycerides, low-density lipoprotein cholesterol, and BMI, while showing a negative correlation with serum creatinine levels. (4) Multivariate linear regression suggested that creatinine, blood glucose, GFR, triglycerides, low-density lipoprotein, and monocyte-lymphocyte ratio may be the influencing factors of TYG index.

TYG index was positively correlated with BMI. The TyG index, an indicator of insulin resistance, is closely linked to chronic inflammation, impaired renal function, and alterations in blood glucose and lipid profiles. These findings underscore the potential utility of the TyG index in assessing metabolic and inflammatory changes in CKD.

Skeletal muscle alterations (SMAs) are being increasingly recognized in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and appear to be associated with deleterious outcomes in these patients. However, their actual prevalence and pathophysiology remain to be elucidated.

To determine the prevalence of SMAs and to assess the significance of circulating myokines as biomarkers in patients with MASLD.

Skeletal muscle strength and muscle mass were measured in a cross-sectional study in a cohort of 62 patients fulfilling MASLD criteria, recruited from the outpatient clinics of a tertiary level hospital. The degree of fibrosis and liver steatosis was studied using abdominal ultrasound and transitional elastography. Anthropometric and metabolic characteristics as well as serum levels of different myokines were also determined in the MASLD cohort. Statistical analysis was performed comparing results according to liver fibrosis and steatosis.

No significant differences were found in both skeletal muscle strength and skeletal muscle mass in patients with MASLD between different stages of liver fibrosis. Interestingly, serum levels of fibroblast growth factor-21 (FGF21) were significantly higher in patients with MASLD with advanced hepatic fibrosis (F3-F4) than in those with lower fibrosis stages (F0-F2) (197.49 ± 198.27 pg/mL vs 95.62 ± 83.67 pg/mL; P = 0.049). In addition, patients with MASLD with severe hepatosteatosis (S3) exhibited significantly higher serum levels of irisin (1116.87 ± 1161.86 pg/mL) than those with lower grades (S1-S2) (385.21 ± 375.98 pg/mL; P = 0.001).

SMAs were uncommon in the patients with MASLD studied. Higher serum levels of irisin and FGF21 were detected in patients with advanced liver steatosis and fibrosis, respectively, with potential implications as biomarkers.

This study aimed to assess the relationship between regional body composition and metabolic dysfunction-associated fatty liver disease (MAFLD) in Chinese children.

In this study, 1399 children aged 7-14 years were included. Liver steatosis was assessed using the controlled attenuation parameter (CAP) measured through Fibroscan. MAFLD is defined as the presence of liver steatosis along with either overweight/obesity, prediabetes/diabetes, or at least two metabolic index abnormalities. Regression analyses were applied to assess the relationship between regional body composition and MAFLD in children. Subgroup analyses were performed based on sex and weight.

The participants had a mean age of 9 years, with 52.11% being boys. Among them, 134 (9.57%) were diagnosed with MAFLD, and 17 (1.22%) had severe fatty liver disease. We found an inverse correlation between the muscle percentage in each region and MAFLD, with the extremities demonstrating the most significant negative correlation (OR: 0.732; 95% CI: 0.634-0.844). Conversely, regional fat was positively associated with MAFLD, with the strongest correlation found in the upper limbs (OR: 3.104; 95% CI: 2.023-4.764). Subgroup analyses showed similar results.

The decrease in regional muscle percentage, particularly in the limbs, along with the increase in regional fat percentage, especially in the upper limbs, is associated with a higher probability of developing MAFLD in prepubertal children. Additional prospective studies are needed to strengthen and validate these findings.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is diagnosed when hepatic steatosis is proven by imaging and one of the five cardiometabolic criteria is present. The relationship between MASLD and body composition components has recently received increased research attention. However, the five cardiometabolic criteria do not include components of body composition. This study aimed to identify significant body composition factors associated with MASLD in patients undergoing health checkups.

This study included a cohort of 6599 examinees who participated in a health check-up conducted between 2022 and 2023, and their data were prospectively analyzed. The inclusion criteria were undergoing abdominal ultrasonography, alcohol consumption <30 g/day for males or <20 g/day for females, and one of the five cardiometabolic criteria.

Finally, 3864 examinees were enrolled. In total, 1133 (51.8%) males and 454 (27.1%) females had MASLD. Sarcopenia was present in only 0.62% of males and 0.66% of females with MASLD. The MASLD group had significantly lower skeletal muscle mass/weight (SMM/WT) values than the non-MASLD group. Multivariate analysis revealed that SMM/WT was independently associated with MASLD.

SMM/WT was significantly associated with MASLD. Therefore, muscle mass assessment using SMM/WT may be a potential marker for diagnosing MASLD.

Sarcopenic obesity (SO) is associated with cardiometabolic disorders and steatotic liver disease and carries major health risks. We assessed the hepatic and metabolic clinical phenotype associated with SO in patients with obesity undergoing bariatric surgery (BS). We also evaluated whether weight-loss and metabolic improvement post-surgery differ between patients with and without SO.

972 consecutive patients from a single-center BS cohort who underwent whole-body dual-energy X-ray absorptiometry (DXA) and peri-operative liver biopsy were included. SO was diagnosed using the AIM-SO score, an AI-assisted unbiased clustering algorithm based on body composition. One-year post-surgery, 862 patients were reassessed for AIM-SO score changes.

Pre-operatively, 207 (21.3 %) patients were diagnosed with SO. These patients had significantly higher prevalence of type-2 diabetes (T2D), arterial hypertension and obstructive sleep apnea (OSA) compared to patients without SO (all p ≤ 0.003). Patients with SO had more severe liver damage: higher grades of moderate/advanced steatosis (64.2 % vs. 47.3 %), steatohepatitis (44.4 % vs. 32.3 %) and advanced fibrosis (12.1 % vs. 6.0 %) (all p ≤ 0.01). One-year post-BS, 58.5 % of patients had remission of SO. Patients with persistent SO exhibited less weight-loss than those with SO remission (-23.8 kg vs. -29.1 kg, p < 0.001) and had lower rates of remission for T2D (41.9 % vs. 69.8 %), arterial hypertension (20.8 % vs. 45.3 %), and metabolic syndrome (47.6 % vs. 75.0 %) (all p ≤ 0.009).

The DXA-based AIM-SO score identifies patients with SO who are at greater risk of hepatic and cardiometabolic comorbidities, and predicts less favorable weight-loss and metabolic improvements post-BS.

The association between nonalcoholic fatty liver disease (NAFLD) and sarcopenia has been suggested. We investigated sarcopenia's impact on NAFLD severity and its relationship with cardiometabolic risk in adolescents. We conducted a retrospective study on 122 patients aged 13-18 years and diagnosed with both NAFLD and sarcopenia by laboratory tests, abdominal ultrasound (US), and multifrequency bioelectrical impedance analysis. Sarcopenia was stratified into tertiles based on the skeletal muscle-to-fat ratio (MFR), NAFLD severity was established by the US, and cardiometabolic risk was assessed by the triglyceride-glucose (TyG) index and the atherogenic index of plasma (AIP). Compared with the other patients, those in the lower MFR tertiles exhibited a greater severity of NAFLD (p < 0.001) and significantly higher TyG index and AIP. The independent effect of MFR was observed to have a negative correlation with the severity of NAFLD (p < 0.001). Based on the aforementioned results, the degree of sarcopenia can be considered as one of the risk factors of severe NAFLD and might be an indicator of cardiometabolic risk in adolescents. Weight training to reach the amount of muscle mass could be included in the treatment strategies to improve or prevent NAFLD in adolescents with sarcopenia.

Objective Myosteatosis affects the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and may be a potential therapeutic target. This study aimed to examine the effects of ipragliflozin on myosteatosis in patients with type 2 diabetes mellitus (T2D) and MASLD. Methods Patients were treated with ipragliflozin (IPR group) or a control (CTR group) for 72 weeks in a randomized trial. Changes in myosteatosis of the lumbar skeletal muscles were evaluated using computed tomography (CT). The response of myosteatosis to treatment and the baseline characteristics of the patients were analyzed. Patients 44 participants (IPR group, 23; CTR group, 21) with MASLD complicated by T2D Results Myosteatosis increased in the CTR group (n=23) but remained unchanged in the IPR group (n=21). The changes were apparent at 24 weeks (P=0.004), but were not significant after 24 weeks. A hierarchical cluster analysis was performed to identify clusters with and without improvement in myosteatosis. The clusters with decreasing intramuscular adipose tissue content (IMAC) at 48 and 72 weeks were not treated, but they had lower visceral fat area and severe liver steatosis at baseline. Improvements in glycemic control and resistance to decreasing abdominal skeletal muscle area from baseline to 24 weeks affected the decrease in IMAC at 48 and 72 weeks. Conclusion Ipragliflozin had a limited effect on skeletal muscle adiposity in patients with T2D and MASLD. Regardless of the treatment, a specific phenotype of adiposity and hepatic steatosis before treatment is associated with the long-term outcomes of myosteatosis. Maintaining skeletal muscle mass and better glycemic control during treatment are essential for the future improvement of myosteatosis.

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.

The progressive aging of the population has led to a rise in geriatric pathologies, with sarcopenia, characterized by muscle mass and function loss, becoming a crucial prognostic indicator. This study investigates sarcopenia in elderly hospitalized patients with advanced chronic liver disease (cirrhotic) and non-liver disease patients, comparing their prevalence and exploring correlations with anthropometric and biochemical factors. The cohort of 115 patients, including 50 cirrhotic and 65 non-cirrhotic individuals, exhibited significant comorbidities and a mean age of 78.4 years. Cirrhotic patients presented distinct laboratory parameters indicating liver damage. Applying European Working Group on Sarcopenia in Older People criteria, probable sarcopenia prevalence was similar in cirrhotic (62%) and non-cirrhotic (63%) patients. Stratifying probable sarcopenia into confirmed sarcopenia and dynapenia revealed no significant differences between populations. Correlation analyses demonstrated positive associations between Appendicular Skeletal Muscle Mass (ASM) and anthropometric parameters, malnutrition risk, and grip strength. In cirrhotic patients, muscle mass inversely correlated with liver damage. Odds ratio analysis highlighted the Mini Nutritional Assesment's (MNA) significant predictive capability for sarcopenia. ROC curve analysis affirmed MNA and biochemical markers' combined use, such as transferrin, albumin, total cholesterol, lymphocyte count and C-reactive protein as a strong predictor. Despite limitations, such as a small sample size, this study underscores the significance of thorough sarcopenia screening in elderly hospitalized patients, especially those with cirrhosis. Indeed, individuals with end-stage liver disease are particularly susceptible to sarcopenia. A more personalized approach utilizing tools like MNA and biochemical markers could prove beneficial. Further research is warranted to validate these findings and inform clinical interventions.

In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications.

This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100.

Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95]).

Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.

Portal hypertension is the key mechanism driving the transition from compensated to decompensated cirrhosis. In this review, the authors described the pathophysiology of portal hypertension in cirrhosis and the rationale of pharmacologic treatment of portal hypertension. We discussed both etiologic and nonetiologic treatment of portal hypertension and the specific clinical scenarios how nonselective beta-blocker can be used in patients with cirrhosis. Finally, the authors summarized the evidence for emerging alternatives for portal hypertension in patients with cirrhosis.

In recent times, sarcopenia and non-alcoholic fatty liver disease (NAFLD) have garnered widespread attention in public health. Nevertheless, the relationship between sarcopenia and NAFLD remains uncertain. This study investigated the association between NAFLD and sarcopenia in the elderly population.

In this cross-sectional study, 1099 adults aged 60 and older participated. The participants were classified based on their body composition, and the International Society of Physical and Rehabilitation Medicine's diagnostic algorithm (ISarcoPRM) was utilized to diagnose sarcopenia, while the fatty liver index was utilized to diagnose NAFLD. Binary logistic regression analysis determined the correlation between NAFLD and sarcopenia.

Of the 1099 participants, 213 (58.2 %) males and 480 (65.5 %) females were afflicted with NAFLD. After adjusting for other clinical factors, exercise was found to decrease the likelihood of NAFLD in females (but not in males) by approximately 70 % [relative risk (RR): 0.312, 95 % confidence interval (CI): 0.182-0.547]. In addition, sarcopenia was not discerned as a risk factor for NAFLD in either gender (both p > 0.05). However, obesity increased the likelihood of NAFLD in males by 27.5 (95 % CI: 10.4-73.1) and in females by 28.1 (95 % CI: 17.1-46.4), and sarcopenic obesity increased the likelihood of NAFLD by 49.5 (95 % CI: 11.1-219.1) in males and 35.5 (95 % CI: 18.5-68.2) in females (all p < 0.001).

Our study suggests that sarcopenia is not a risk factor for NAFLD in non-obese elderly subjects. However, a strong association was observed between obesity, especially sarcopenic obesity, and NAFLD. Regular physical activity seems protective for NAFLD in older females.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

Despite observational studies suggest hypotheses indicating a potential link, the precise causal connection between sarcopenia and digestive system illnesses has not been clearly defined.

We first use Linkage Disequilibrium Score Regression (LDSC) testing to determine the genetic correlation of traits associated with sarcopenia and 10 specific gastrointestinal diseases. Subsequently, we performed a set of bidirectional Mendelian Randomization (MR) analyses to gauge the genetic inclination towards sarcopenia-related traits in relation to each gastrointestinal condition, individually, across the FinnGen, UK Biobank, and other extensive collaborative consortia. The analytical outcomes were synthesized using a fixed-effects meta-analytic model. For outcomes indicating substantial causal impacts, mediation MR analyses were executed. Additionally, a battery of sensitivity analyses was conducted to evaluate the study's strength and dependability.

Our findings established a strong causal link between appendicular lean mass and gastroesophageal reflux disease (OR  =  0.8607; 95% CI: 0.8345-0.8877; p <  0.0001) and a noteworthy correlation with nonalcoholic fatty liver disease (OR  =  0.7981; 95% CI: 0.7281-0.8749; p < 0.0001), as per the meta-analysis data. We also evaluated the intermediary role of metabolic disorders in the association between appendicular lean mass and the aforementioned diseases. The intermediary effect towards gastroesophageal reflux disease is quantified as 0.0087 (95% CI, 8e-04, 0.0183), accounting for 5.9398% (95% CI, 0.5462, 12.4940%) of the overall effect. For non-alcoholic fatty liver, the intermediary impact is 0.0150 (95% CI, 0.0050, 0.0270), representing 19.7808% (95% CI, 6.5936, 35.6055%) of the total effect.

The findings posit that augmenting muscle mass may serve as a preventative strategy against gastroesophageal reflux disease and non-alcoholic fatty liver, highlighting the critical role of metabolic disorder management in reducing the risks of these sarcopenia-related conditions.

To assess changes in laboratory indices, paravertebral muscle (PVM) fat infiltration and multi b-value DWI parameters and their potential correlation with NAFLD.

This retrospective analysis included 178 patients with histopathologically confirmed NAFLD, incluiding 76 with non-alcoholic steatohepatitis (NASH). Differences in PVM fat infiltration ratio (FIR), DWI parameters, and laboratory indices were compared between two groups. The correlation between FIR and NAFLD activity score (NAS) was also analysed. Binary logistic regression was used to identify the independent risk factors for NASH. The clinical utility of PVM fat infiltration, DWI parameters, and laboratory indices for diagnosing NASH in patients with NAFLD was evaluated using receiver operating characteristic (ROC) curves.

The FIRs at the L2 and L3 levels were significantly higher in the with NASH group than those in the without NASH group. The heterogeneity index (α) and perfusion fraction (f) values at the L3 level of PVM were lower in the with NASH group. Moreover, the FIR at the L3 level was positively correlated with NAS. FIR at the L3 level was an independent risk factor for NASH along with alanine aminotransferase level. The area under the ROC curve (AUC) using L3 level PVM radiological parameters and laboratory indices for diagnosing NASH in patients with NAFLD was significantly higher than that using the degree of PVM fat infiltration, DWI parameters, or laboratory indices alone.

Radiological parameters of the PVM were correlated with NAFLD. An integrated curve combining PVM radiological parameters may help distinguish NASH from NAFLD, thereby offering novel insights into the diagnosis of NASH.

The objectives were to examine if there is a causal relationship between osteosarcopenic adiposity (OSA) syndrome (coexistence of osteopenia/osteoporosis, sarcopenia, and excess adiposity) and cardiometabolic disorders or if these disorders initiate the development of OSA and its worsening. The search was conducted in PubMed, Scopus, and Web of Science to include articles up to the end of 2023. Of n=539 articles retrieved, n=15 met the eligibility criteria. Only studies conducted in adults and with all three body composition compartments (bone, muscle/lean, adipose) measured were considered. The results revealed that several cardiometabolic disorders, namely, hypertension, dyslipidemia (elevated total and LDL-cholesterol, lower HDL-cholesterol), insulin resistance, hyperglycemia, lower serum vitamin D, and some inflammatory markers were accompanied by OSA. In most cases, the OSA phenotype was associated with worse outcomes than cases with healthy or less impaired body composition. Our initial questions about the reciprocal cause-and-effect relationships could be surmised with more certainty for the OSA and some cardiovascular risks (hypertension, dyslipidemia) and some metabolic abnormalities (several inflammatory markers). The results of this review underscore the importance of body composition in health and from a clinical perspective, all three body composition compartments should be measured by standardized technologies using regulated diagnostic criteria to identify OSA. Randomized trials and prospective studies in diverse groups of older and younger individuals are necessary to determine if the relationships between OSA and clinical endpoints are causal and reversible through intervention and to uncover the mechanisms.

Muscle-liver crosstalk plays an important role in the development and progression of non-alcoholic fatty liver disease (NAFLD). The measurement of muscle echo-intensity during ultrasonography is a real-time, non-invasive method of assessing muscle quality. In this retrospective study, we investigated the significance of poor muscle quality (namely, a greater mass of non-contractile tissue, including intramuscular fat) as a risk factor for advanced liver fibrosis and considered whether it may represent a useful tool for the diagnosis of advanced liver fibrosis.

We analyzed data from 307 patients with NAFLD (143 men and 164 women) who visited the University of Tsukuba Hospital between 2017 and 2022. The patients were stratified into the following tertiles of muscle quality according to their muscle echo-intensity on ultrasonography: modest (84.1 arbitrary units [A.U.]), intermediate (97.4 A.U.), and poor (113.6 A.U.). We then investigated the relationships between muscle quality and risk factors for advanced liver fibrosis and calculated appropriate cutoff values.

Patients with poor muscle quality showed a significant, 7.6-fold greater risk of liver fibrosis compared to those with modest muscle quality. Receiver operating characteristic curve analysis showed that muscle quality assessment was as accurate as the fibrosis-4 index and NAFLD fibrosis score in screening for liver fibrosis and superior to the assessment of muscle quantity and strength, respectively. Importantly, a muscle echo-intensity of ≥92.4 A.U. may represent a useful marker of advanced liver fibrosis.

Muscle quality may represent a useful means of identifying advanced liver fibrosis, and its assessment may become a useful screening tool in daily practice.

Sarcopenia is a progressive age-related disease that can cause a range of adverse health outcomes in older adults, and older adults with severe sarcopenia are also at increased short-term mortality risk. The aim of this study was to construct and validate a risk prediction model for sarcopenia in Chinese older adults.

This study used data from the 2015 China Health and Retirement Longitudinal Study (CHARLS), a high-quality micro-level data representative of households and individuals aged 45 years and older adults in China. The study analyzed 65 indicators, including sociodemographic indicators, health-related indicators, and biochemical indicators.

3454 older adults enrolled in the CHARLS database in 2015 were included in the final analysis. A total of 997 (28.8%) had phenotypes of sarcopenia. Multivariate logistic regression analysis showed that sex, Body Mass Index (BMI), Mean Systolic Blood Pressure (MSBP), Mean Diastolic Blood Pressure (MDBP) and pain were predictive factors for sarcopenia in older adults. These factors were used to construct a nomogram model, which showed good consistency and accuracy. The AUC value of the prediction model in the training set was 0.77 (95% CI = 0.75-0.79); the AUC value in the validation set was 0.76 (95% CI = 0.73-0.79). Hosmer-Lemeshow test values were P = 0.5041 and P = 0.2668 (both P > 0.05). Calibration curves showed significant agreement between the nomogram model and actual observations. ROC and DCA showed that the nomograms had good predictive properties.

The constructed sarcopenia risk prediction model, incorporating factors such as sex, BMI, MSBP, MDBP, and pain, demonstrates promising predictive capabilities. This model offers valuable insights for clinical practitioners, aiding in early screening and targeted interventions for sarcopenia in Chinese older adults.

Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions, progressing from mild steatosis to advanced fibrosis. Sarcopenia, characterized by decreased muscle strength and mass, shares common pathophysiological traits with NAFLD. An association exists between sarcopenia and increased NAFLD prevalence. However, data on the prevalence of sarcopenia in NAFLD and its impact on the outcomes of NAFLD remain inconsistent.

To analyze the prevalence and outcomes of sarcopenia in patients with NAFLD.

We conducted a comprehensive search for relevant studies in MEDLINE, Embase, and Scopus from their inception to June 2023. We included studies that focused on patients with NAFLD, reported the prevalence of sarcopenia as the primary outcome, and examined secondary outcomes, such as liver fibrosis and other adverse events. We also used the Newcastle-Ottawa scale for quality assessment.

Of the 29 studies included, the prevalence of sarcopenia in NAFLD varied widely (1.6% to 63.0%), with 20 studies reporting a prevalence of more than 10.0%. Substantial heterogeneity was noted in the measurement modalities for sarcopenia. Sarcopenia was associated with a higher risk of advanced fibrosis (odd ratio: 1.97, 95% confidence interval: 1.44-2.70). Increased odds were consistently observed in fibrosis assessment through biopsy, NAFLD fibrosis score/body mass index, aspartate aminotransferase to alanine aminotransferase ratio, diabetes (BARD) score, and transient elastography, whereas the fibrosis-4 score showed no such association. Sarcopenia in NAFLD was associated with a higher risk of steatohepatitis, insulin resistance, cardiovascular risks, and mortality.

This systematic review highlights the critical need for standardized diagnostic criteria and measurement methods for sarcopenia in NAFLD patients. The variability in study designs and assessment methods for sarcopenia and liver fibrosis may account for the inconsistent findings. This review demonstrates the multidimensional impact of sarcopenia on NAFLD, indicating its importance beyond liver-related events to include cardiovascular risks, mortality, and metabolic complications.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a new term for diagnosing fatty liver disease, which is considered to be a multi-systemic disease with multiple extrahepatic manifestations, including sarcopenia. The link between sarcopenia and MAFLD remains uncertain, especially among young and middle-aged adults. Thus, we examined the relationship between MAFLD and sarcopenia in young and middle-aged individuals in this study.

A total of 2214 individuals with laboratory tests, dual-energy X-ray absorptiometry and ultrasound transient elastography from NHANES 2017-2018 were selected for this study. MAFLD was diagnosed as fatty liver disease with any one of the situations: overweight/obesity, diabetes mellitus, presence of metabolic dysregulation. Sarcopenia was defined by appendicular lean mass adjusted for body mass index (BMI). Multivariable logistic regression and restricted cubic spline (RCS) model were applied to explore the relationship between MAFLD and sarcopenia, and the mediation analyses were also conducted. Moreover, subgroup analyses stratified by BMI and lifestyles were done.

The prevalence of MAFLD was 47.85%, and nearly 8.05% of participants had sarcopenia. The prevalence of sarcopenia was higher in participants with MAFLD (12.75%; 95% CI 10.18-15.31%) than in the non-MAFLD (3.73%; 95% CI 2.16-5.31%). MAFLD was significantly positively associated with sarcopenia after adjustments [OR = 2.87 (95% CI: 1.62-5.09)]. Moreover, significant positive associations were observed between liver fibrosis and sarcopenia prevalence in MAFLD patients (OR = 2.16; 95% CI 1.13-4.15). The RCS curve revealed that MAFLD was linearly associated with sarcopenia. The relationship between the MAFLD and sarcopenia were mediated by C-reactive protein (mediation proportion: 15.9%) and high-density lipoprotein cholesterol (mediation proportion: 18.9%). Subgroup analyses confirmed the association between MAFLD and sarcopenia differed in different lifestyle groups.

Both MAFLD prevalence and severity was significantly associated with sarcopenia. Thus, clinicians should advise comorbidity screening and lifestyle changes to young and middle-aged patients.

Non-alcoholic fatty liver disease (NAFLD) recently became a leading liver disease that threatens health worldwide. Low muscle strength, obesity, insulin resistance, and metabolic syndrome are recognized key factors for NAFLD. However, the impact of low muscle strength itself in different metabolic conditions has not been widely studied.

A cross-sectional analysis was performed of a sample of 5,427 participants from the 2019 Korea National Health and Nutrition Examination Survey. Relative handgrip strength (rHGS, defined as handgrip strength/body mass index) was used to assess muscle strength. The cut-off values for a low rHGS were 1.405 for men and 0.850 for women. NAFLD was diagnosed if the Hepatic Steatosis Index was >36. Participants were stratified according to insulin resistance, metabolic syndrome, and central obesity for the subgroup analyses.

Complex sample multivariate logistic regression analysis revealed a significant association between low muscle strength and NAFLD after the adjustment for other confounders (odds ratio [OR], 1.92; P<0.001). In the insulin resistance, metabolic syndrome, and central obesity subgroups, a significant association between low muscle strength and NAFLD remained (OR, 1.66-4.19 depending on subgroup; all P<0.05), whereas it did not in the no central obesity group.

This study demonstrated that low muscle strength is correlated with a risk of NAFLD. This relationship was independent of insulin resistance and metabolic syndrome but was dependent on the presence of central obesity.

This editorial comments on an article published in a recent issue of World Journal of Gastroenterology, entitled "Association of low muscle strength with metabolic dysfunction-associated fatty liver disease: A nationwide study". We focused on the association between muscle strength and the incidence of non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD), as well as the mechanisms underlying the correlation and related clinical applications. NAFLD, which is now redefined as MAFLD, is one of the most common chronic liver diseases globally with an increasing prevalence and is characterized by malnutrition, which may contribute to decreased muscle strength. Reduction of muscle strength reportedly has a pathogenesis similar to that of NAFLD/ MAFLD, including insulin resistance, inflammation, sedentary behavior, as well as insufficient vitamin D. Multiple studies have focused on the relationship between sarcopenia or muscle strength and NAFLD. However, studies investigating the relationship between muscle strength and MAFLD are limited. Owing to the shortage of specific medications for NAFLD/MAFLD treatment, early detection is essential. Furthermore, the relationship between muscle strength and NAFLD/MAFLD suggests that improvements in muscle strength may have an impact on disease prevention and may provide novel insights into treatments including dietary therapy, as well as tailored physical activity.

Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stability, affect localization, transform molecular function, and cooperate with other protein modifications. Among them, adenosine 5'-monophosphate-activated protein kinase (AMPK), serine/threonine kinase (AKT), and nuclear factor kappa-B (NF-kB) are considered the core mechanisms in steatotic liver disease. As to treatment, lifestyle changes, prescription drugs, and herbal ingredients can alleviate symptoms by influencing phosphorylation. It demonstrates the significant role of phosphorylation as a mechanism occurrence and a therapeutic target in steatotic liver disease, which could be a new star for future exploration.

With the aging of the population, sarcopenia has become more common. Studies have shown a broad association between liver disease and sarcopenia. However, this link remains unclear. Our study explored the link between NAFLD and sarcopenia and predicting the pathogenesis. To begin, we investigated the causal relationship and genetic correlation between them using MR and LDSC. Second, each GWAS was annotated by MAGMA. The annotated genes were analyzed for pleiotropy using the PLACO approach. Finally, functional analysis was conducted on the identified pleiotropic genes. We observed a significant genetic correlation between NAFLD and sarcopenia. Subsequently, we conducted gene-level pleiotropy analysis using PLACO and identified a total of 153 genes with pleiotropic effects. Functional analysis revealed enrichment of these genes in various tissues, including pancreas, liver, heart, blood, brain, and muscle, with involvement in cellular regulation, intracellular function, and antigen response. Moreover, our MR analysis provided evidence of a causal relationship between NAFLD and sarcopenia. Our study has discovered the genetic and causal relationships between NAFLD and sarcopenia, providing further insights into their pathophysiological mechanisms. The identification of pleiotropic genes also offers potential targets for future drug therapies aimed at controlling or treating NAFLD and sarcopenia.

To analyze the relationship between leg skeletal muscle mass index (LSMI) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) and the ability of LSMI to predict NAFLD.

Two hundred patients with T2DM and NAFLD treated at Changzhou Second People's Hospital Affiliated with Nanjing Medical University and the National Metabolic Management Center from June 2022 to June 2023 were divided into four LSMI quartiles. The clinical information from the four patient groups was compared, and the relationship between type 2 diabetes and LSMI and NAFLD was examined. We used receiver operating characteristic curves to determine how well the LSMI predicts NAFLD in T2DM.

The lowest quartile (Q1) had a higher prevalence of NAFLD than group Q4 (P < 0.05). LSMI was negatively associated with body mass index, LS, CAP, and other markers (P < 0.05). Receiver operating characteristic curve analysis LSMI predicted NAFLD with an ideal critical value of 0.64 and an area under the curve of 70.9%. The combined predictive value of the LSMI and the appendicular skeletal muscle mass index was more significant.

Reduced LSMI is associated with NAFLD.

Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are scarce. We aimed to explore the impact of changes in relative skeletal muscle mass on the MAFLD treatment response.

MAFLD patients undergoing magnetic resonance imaging-based proton density fat fraction for liver fat content (LFC) assessments and bioelectrical impedance analysis before and after treatment (orlistat, meal replacement, lifestyle modifications) were enrolled. Appendicular muscle mass (ASM) was adjusted by weight (ASM/W).

Overall, 256 participants were recruited and divided into two groups: with an ASM/W increase (n=166) and without an ASM/W increase (n=90). There was a great reduction in LFC in the group with an ASM/W increase (16.9% versus 8.2%, P < 0.001). However, the change in LFC in the group without an ASM/W increase showed no significant difference (12.5% versus 15.0%, P > 0.05). △ASM/W Follow-up-Baseline [odds ratio (OR)=1.48, 95% confidence interval (CI) 1.05-2.07, P = 0.024] and △total fat mass (OR=1.45, 95% CI 1.12-1.87, P = 0.004) were independent predictors for steatosis improvement (relative reduction of LFC ≥ 30%). The subgroup analysis showed that, despite without weight loss, decrease in HOMA-IR (OR=6.21, 95% CI 1.28-30.13, P=0.023), △total fat mass Baseline -Follow-up (OR=3.48, 95% CI 1.95-6.21, P <0.001 and △ASM/W Follow-up-Baseline (OR=2.13, 95% CI 1.12-4.05, P=0.022) independently predicted steatosis improvement.

ASM/W increase and loss of total fat mass benefit the resolution of liver steatosis, independent of weight loss for MAFLD.

Sarcopenia is associated with NAFLD. It is unknown if the association is explained by shared risk factors. Our study sought to investigate the association between liver fat and sarcopenia in our cohort. Liver fat was measured on CT between 2008 and 2011. We excluded heavy alcohol use and missing covariates. Muscle mass in a subset (n = 485) was measured by 24 h urinary creatinine. Physical function was defined by h strength and walking speed. Sarcopenia was defined as low muscle mass and/or low physical function. We created multivariable-adjusted regression models to evaluate cross-sectional associations between liver fat and low muscle mass, grip strength, and walking speed. The prevalence of hepatic steatosis was 30% (n = 1073; 58.1% women; mean age 65.8 ± 8.6 years). There was a significant positive association between liver fat and muscle mass in linear regression models. The association was not significant after adjusting for BMI. The odds of sarcopenia increased by 28% for each SD in liver fat (OR 1.28; 95% CI 1.02, 1.60) and persisted after accounting for confounders in multivariable-adjusted models (OR 1.30, 95% CI 1.02, 1.67). Further studies are needed to determine if there is a causal relationship between liver fat and sarcopenia and whether treatment of sarcopenia improves liver fat.

There is a lack of scoring system to predict the occurrence of cirrhosis in individuals with acute-on-chronic liver failure (ACLF) in the absence of cirrhosis. The goal of this study was to develop a psoas muscle index (PMI)-based nomogram for cirrhosis risk in non-cirrhotic patients with HBV-related ACLF. We included 274 non-cirrhotic HBV-ACLF patients who were randomly assigned to training and validation groups. Logistic analyses were performed to identify risk factors for cirrhosis. A nomogram was then constructed. The predictive performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUROC), calibration curve, and decision curve analysis (DCA). During the 360-day follow-up, 44.5% (122/274) of non-cirrhotic HBV-ACLF patients developed cirrhosis. A higher PMI at the L3 level was correlated with a decreased risk of long-term cirrhosis occurrence (OR 0.677, 95% CI 0.518-0.885, P = 0.004). The nomogram incorporating PMI, age, neutrophil-to-lymphocyte ratio (NLR), and international normalized ratio (INR), indicated satisfactory predictive performance for cirrhosis risk stratification in ACLF population. The nomograms had an AUROC of 0.812 (95% CI 0.747-0.866) and 0.824 (95% CI 0.730-0.896) in the training and validation cohorts, respectively. The calibration curves displayed excellent predictive accuracy of the nomogram in both sets. In both cohorts, the DCA verified the nomogram's clinical efficacy. In non-cirrhotic HBV-ACLF patients, a greater PMI appears to protect against long-term cirrhosis occurrence. Strong predictive performance has been demonstrated by PMI-based nomograms in assessing the likelihood of 1-year cirrhosis in those with HBV-ACLF.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

Major depressive disorder (MDD) is clinically documented to co-occur with multiple gastrointestinal disorders (GID), but the potential causal relationship between them remains unclear. We aimed to evaluate the potential causal relationship of MDD with 4 GID [gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), peptic ulcer disease (PUD), and non-alcoholic fatty liver disease (NAFLD)] using a two-sample Mendelian randomization (MR) design.

We obtained genome-wide association data for MDD from a meta-analysis (N = 480 359), and for GID from the UK Biobank (N ranges: 332 601-486 601) and FinnGen (N ranges: 187 028-218 792) among individuals of European ancestry. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses to test the hypothesis of MR. Individual study estimates were pooled using fixed-effect meta-analysis.

Meta-analyses IVW MR found evidence that genetically predicted MDD may increase the risk of GERD, IBS, PUD and NAFLD. Additionally, reverse MR found evidence of genetically predicted GERD or IBS may increase the risk of MDD.

Genetically predicted MDD may increase the risk of GERD, IBS, PUD and NAFLD. Genetically predicted GERD or IBS may increase the risk of MDD. The findings may help elucidate the mechanisms underlying the co-morbidity of MDD and GID. Focusing on GID symptoms in patients with MDD and emotional problems in patients with GID is important for the clinical management.

This study aimed to elucidate the association between total lean muscle mass and the incidence of non-alcoholic fatty liver disease (NAFLD) in the adult Korean population.

Utilizing data derived from the 18-year prospective cohort of the Korean Genome and Epidemiology Study, NAFLD was diagnosed via the hepatic steatosis index with an established cutoff value of 36. Lean muscle mass was assessed via bioelectrical impedance analysis and subsequently divided into tertiles. A generalized mixed model with a logit link was employed for repeated measures data analysis, accounting for potential confounders.

Analysis encompassed 7,794 participants yielding 49,177 measurements. The findings revealed a markedly increased incidence of NAFLD in the lower tertiles of muscle mass, specifically, tertile 1 (odds ratio [OR], 20.65; 95% confidence interval [CI], 9.66-44.11) and tertile 2 (OR, 4.57; 95% CI, 2.11-9.91), in comparison to tertile 3. Age-dependent decreases in the OR were observed within the tertile 1 group, with ORs of 10.12 at age of 40 years and 4.96 at age of 80 years. Moreover, each 1%-point increment in total muscle mass corresponded with an estimated OR of 0.87 (95% CI, 0.82-0.93) for NAFLD resolution.

The study demonstrates a significant association between total muscle mass and NAFLD prevalence among Korean adults. Given the potential endocrine role of muscle mass in NAFLD pathogenesis, interventions aimed at enhancing muscle mass might serve as an effective public health strategy for mitigating NAFLD prevalence.

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.

Sarcopenia has emerged as a significant prognostic factor in liver disease, posing a significant risk to patients in terms of morbidity and mortality. However, the evaluation of skeletal muscle mass and quality remains challenging, as cross-sectional imaging is not a suitable screening tool. In order to better include this crucial variable in the routine risk stratification of patients with chronic liver disease, there is an urgent need for simple and reliable non-invasive diagnostic tools for sarcopenia. Therefore, the use of ultrasound techniques has garnered attention as a promising alternative for detecting sarcopenia and muscle abnormalities. This narrative review aims to provide an overview of the current literature on the use of ultrasound as a diagnostic tool for sarcopenia, with particular focus on patients with cirrhosis, emphasizing its potential limitations and future prospects.

Frailty, a clinical phenotype of decreased physiological reserve, is a strong determinant of adverse health outcomes in patients with cirrhosis. The only cirrhosis-specific frailty metric is the Liver Frailty Index (LFI), which must be administered in person and may not be feasible for every clinical scenario. We sought to discover candidate serum/plasma protein biomarkers that could differentiate frail from robust patients with cirrhosis. A total of 140 adults with cirrhosis awaiting liver transplantation in the ambulatory setting with LFI assessments and available serum/plasma samples were included. We selected 70 pairs of patients on opposite ends of the frailty spectrum (LFI>4.4 for frail and LFI<3.2 for robust) who were matched by age, sex, etiology, HCC, and Model for End-Stage Liver Disease-Sodium. Twenty-five biomarkers with biologically plausible associations with frailty were analyzed using ELISA by a single laboratory. Conditional logistic regression was used to examine their association with frailty. Of the 25 biomarkers analyzed, we identified 7 proteins that were differentially expressed between frail and robust patients. We observed differences in 6 of the 7 proteins in the expected direction: (a) higher median values in frail versus robust with growth differentiation factor-15 (3682 vs. 2249 pg/mL), IL-6 (17.4 vs. 6.4 pg/mL), TNF-alpha receptor 1 (2062 vs. 1627 pg/mL), leucine-rich alpha-2 glycoprotein (44.0 vs. 38.6 μg/mL), and myostatin (4066 vs. 6006 ng/mL) and (b) lower median values in frail versus robust with alpha-2-Heremans-Schmid glycoprotein (0.11 vs. 0.13 mg/mL) and free total testosterone (1.2 vs. 2.4 ng/mL). These biomarkers represent inflammatory, musculoskeletal, and endocrine/metabolic systems, reflecting the multiple physiological derangements observed in frailty. These data lay the foundation for confirmatory work and development of a laboratory frailty index for patients with cirrhosis to improve diagnosis and prognostication.

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk.