Improving the prognosis before and after liver transplantation: Is muscle a game changer?

Liver transplantation (LT) is currently the only curative treatment option for selected patients with end stage liver disease or hepatocellular carcinoma. Improving waiting list-mortality, post-transplant morbidity and mortality and refining the selection of the patients remain our current central objectives. In this field, different concepts dealing with nutrition and the muscle such as sarcopenia, malnutrition, frailty or myosteatosis have emerged as possible game changers. For more than a decade, many prospective studies have demonstrated that sarcopenia and frailty are major predictive factors of mortality in the waiting list but also after LT. Malnutrition is also a well-known risk factor for morbidity and mortality. Muscle composition is a newer concept giving insight on muscle quality which has also been shown to be linked to poorer outcomes. Each of these terms has a precise definition as well as pathophysiological mechanisms. The bidirectional liver-muscle axis makes sense in this situation. Defining the best, easy to use in clinical practice tools to assess muscle quality, quantity, and function in this specific population and developing quality prospective studies to identify interventional strategies that could improve these parameters as well as evaluate the effect on mortality are among the important challenges of today

Frailty in metabolic dysfunction-associated fatty liver disease is related to the presence of diabetes and the severity of liver fibrosis

Background and Aims: Frailty is very common in end-stage liver disease, regardless of disease etiology, and has a significant impact on clinical outcome and quality of life, due to impaired skeletal muscle function, quality and quantity. However, there are few data available on the relationship between liver and skeletal muscle, especially in patients with earlier disease stages. Our aims are to evaluate the prevalence of frailty in a prospective cohort of patients with metabolic-dysfunction associated fatty liver disease (MAFLD) according to its severity. Method: Patients with MAFLD were recruited in a prospective single-center cohort study. Epidemiological, clinical, biological and anthropometric data were collected. All patients underwent a noninvasive assessment for frailty screening, including a dominant hand grip strength test, a balance test, and the time required to do five times sit to stand to calculate the liver frailty index (LFI). The severity of MAFLD was assessed by the fatty liver index (FLI), fibrosis 4 (FIB-4) index, and by transient elastography (elasticity and controlled attenuation parameter). Results: 92 patients with MAFLD were recruited, including 44 men (47.8 %) and 44 patients with type 2 diabetes (47.8 %). Mean age was 55 years (19-78), mean BMI was 32.7 kg/m² (23.9 - 47.5) and mean HOMA-IR was 7.6 (0.5-30.1). Regarding the severity of MAFLD, the mean elasticity was 6.45 KPa (3.1 - 35) and the mean FIB-4 score was 1.33 (0.31 - 5.61). The mean FLI was 85.1 (28-100) and the mean controlled attenuation parameter (CAP) was 332.3 dB/m (207-400). Regarding frailty parameters, the mean dominant grip strength was 31 kg (8 - 62), the mean time to do five chair stands was 8.2 seconds (4.25 - 24.25), the mean balance test score was 9.9 seconds (2.1 - 10) and the mean LFI was 2.98 (1.13 - 4.71). 51 patients had an LFI score 2.67 vs 2.8 in case of FIB-4 < 1.3 (p = 0.042) (Figure). Conclusion: 44% of MAFLD patients already have a frail or pre-frail status regardless of age. This reduction of strength is associated with the presence of diabetes and the severity of MAFLD in terms of fibrosis. Further research is needed to determine the cause of this frailty and its potential impact on liver disease severity and prognosis

Are elevated systemic bile acids involved in the pathophysiology of sarcopenia and liver injury following gastric bypass?

Bariatric surgery is currently the most effective treatment for sustained weight loss in severe obesity. However, recent data describe the development of liver damage and in particular massive steatosis and cholangitis in some patients, for which certain pathophysiological mechanisms are suggested such as bacterial overgrowth, malabsorption or sarcopenia. We describe the case of a patient presenting with a new liver dysfunction 6 years after a gastric bypass. The work-up revealed sarcopenic obesity characterised by low muscle mass and low muscle function as well as elevated fasting bile acids, severe liver steatosis and cholangitis. The pathophysiology of this disease is complex and multifactorial but could include bile acid toxicity. Bile acids are increased in cases of liver steatosis, but also in cases of gastric bypass and malnutrition. In our opinion, they may contribute to the loss of muscle mass and the vicious circle observed in this situation. Treatment with enteral feeding, intravenous albumin supplementation and diuretics reversed the liver dysfunction and the patient was discharged from hospital

Exploring the impact of dietary patterns and ultra-processed food consumption on the severity of biopsy-proven steatotic liver disease

Introduction: The consumption of ultra-processed foods (UPF) has significantly increased in recent years, raising concerns due to its positive association with obesity and diabetes. However, the relationship between ultra-processed foods and the severity of steatotic liver disease (SLD) has been less studied. Nonetheless, studies have indicated that both moderate (vs. low) and high (vs. low) consumption of UPF significantly elevate the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). No study has been conducted on UPF consumption in alcohol-related liver disease (ALD). Objective: Our aim is to evaluate nutritional intake and UPF consumption in SLD. Methods: Patients with histologically confirmed hepatic steatosis (MASLD or ALD) were prospectively included, excluding those with MetALD. Anthropometric and biological data were collected. Dietary intake was assessed through a 24-hour recall, and the NOVA classification was employed to quantify ultra-processed food (UPF) consumption in grams. UPF consumption data were compared with those of the general population available in the literature (Vandevijvere et al., 2019). Finally, the severity of liver phenotype was histologically evaluated using the Beaujon score (SAF). Results: Dietary intake and consumption of ultra-processed and processed foods were assessed in 62 SLD patients (46 with MASLD and 16 with ALD). The mean age of MASLD and ALD patients was 54 and 52 years respectively (NS). MASLD patients exhibited significantly higher mean body mass index (BMI) and abdominal circumference compared to ALD patients (35 vs. 22 kg/m², p = 0.0001; 117 vs 91 cm; p = 0.0001). Biological data showed a mean GGT level of 64 U/L in MASLD patients and 590 U/L in ALD patients (p = 0.0001), a mean HDL-C level of 43 mg/dl in MASLD patients and 89 mg/dl in ALD patients (p = 0.0001), and mean triglyceride levels of 181 mg/dl in MASLD and 196 mg/dl in ALD (NS). Both MASLD and ALD patients presented a mean moderate degree of steatosis, histologically assessed as grade 2. Among the 62 histologically evaluated patients, 3 were classified as F0 (4.9%), 12 as F1 (19.7%), 28 as F2 (45.9%), 17 as F3 (27.9%), and 1 as F4 (1.6%). One patient could not be evaluated due to the biopsy's size. Although MASLD patients had a significantly higher BMI than ALD patients, the energy intake of MASLD patients was significantly lower than that of ALD patients (1806 vs. 2716 kcal/day; p = 0.0003). In terms of nutritional intake, MASLD patients consumed more fats (73 vs. 53 g/day; p = 0.050) and fibers (17 vs. 8 g/day; p = 0.0003) than ALD patients. Our results also indicate that MASLD patients consume more ultra-processed and processed foods than the general population (ultra-processed foods: 40 vs. 35% of total energy intake (TEI); processed foods: 24 vs. 13% of TEI). When alcohol consumption is considered, ALD patients consume more processed foods than MASLD patients (2628 vs. 196 g/day; p = 0.0001). No impact of UPFs on the severity of the hepatic phenotype in terms of steatosis, inflammatory activity, and fibrosis is evident. Conclusion: ALD patients consume more calories than MASLD patients, despite being significantly thinner. The difference in energy intake between patients with MASLD and those with ALD is mainly attributed to the caloric contribution of alcohol consumption, which is also responsible for the greater consumption of processed foods. Despite an increased consumption of UPF in MASLD patients compared to the general population, this dietary habit does not appear to significantly influence the severity of the hepatic phenotype. This observation underscores the multifactorial complexity of the disease

Nutrition et maladie stéatosique du foie : pas d’évidence d’un impact de la consommation d’aliments ultra-transformés sur la sévérité de l’atteinte hépatique

Introduction : La consommation d’aliments ultra-transformés (UPF) est en augmentation et a été associée au risque de maladie hépatique stéatosique d’origine métabolique (MASLD), d’obésité et de diabète de type 2. La relation entre la consommation de ces UPF et l’histologie hépatique dans la MASLD et la maladie hépatique liée à l’alcool (ALD) n’a pas encore été étudiée. Notre objectif est d’évaluer la relation entre apports nutritionnels, consommation d’UPF et marqueurs de sévérité histologique de la maladie hépatique chez des patients avec MASLD ou ALD. Méthode: Les patients avec confirmation histologique d’une MASLD ou d’une ALD ont été recrutés prospectivement. Les apports nutritionnels sont évalués par un rappel de 24h. La consommation d’UPF est mesurée via la classification NOVA. Les boissons alcoolisées fermentées sont classées comme aliments transformés. L’évaluation histologique de la maladie hépatique est réalisée via le score de Beaujon (SAF). Résultats: Soixante-deux patients (46 patients MASLD et 16 patients ALD) ont été inclus. L’âge et indice de masse corporel moyens (IMC) sont de 54 et 52 ans (ns), et 35 et 22kg/m² (p<0.05) pour les patients MASLD et ALD respectivement. Trois patients sont histologiquement stadifiés F0 (4.9%), douze F1 (19.7%), vingt-huit F2 (45.9%), dix-sept F3 (27.9%), et un F4 (1.6%). Pour les apports caloriques, les patients MASLD consomment plus de lipides (73 vs 53g/j; p = 0.05), graisses saturées (29 vs 22g/j; p = 0.02) et fibres (17 vs 8g/j; p = 0.0003) que les patients ALD mais moins de calories au total (1806 vs 2716 kcal/j; p = 0.0003). Il n’y a pas de différence d’apports protéiques ou glucidiques entre MASLD et ALD. Les patients ALD consomment plus d’aliments transformés que les patients MASLD (2628 vs. 196 g/j; p = 0.0001). Aucun lien entre la quantité d’UPF consommée et les degrés de stéatose modérée ou sévère, d’activité faible ou haute, d’absence ou de présence de fibrose hépatique n’est mise en évidence. Conclusion: Les patients ALD consomment plus de calories et d’aliments transformés que les patients MASLD malgré un IMC plus faible. La consommation d’UPF évaluée par un rappel de 24h n’a pas d’impact sur l’histologie hépatique chez les patients MASLD et ALD

The evolution of the muscle compartment from the listing to six-month post-transplantation : a longitudinal monocentric study.

Background and aims: Body composition of the cirrhotic patient plays an important role in his prognosis. Skeletal muscle mass (sarcopenia), malnutrition, frailty (liver frailty index LFI) and myosteatosis are associated with worse outcome in cirrhotic patients. The aim of this study was to determine the best muscle-related predictor of morbidity and mortality on the waiting list and after LT and to evaluate the evolution of all muscle-related parameters up to six months post-transplant. Method: This single-center prospective observational study screened adult patients who were candidates for liver transplantation from June 2021 to September 2022. Each candidate received a functional and nutritional assessment during its pre-transplant evaluation. Muscle quantity and quality were assessed using an abdominal CT scan at the third lumbar level (L3). Sarcopenia was defined as skeletal muscle mass index (SMI) <39 cm2/m2 in females and <50 cm2/m2 in males. Myosteatosis was assessed by skeletal muscle radiodensity attenuation (SM-RA), with cut-offs of SM-RA <41 HU for patients with a BMI <24.9 kg/m2 and <33 HU for patients with a BMI ≥25 kg/ m2. Frailty was defined using the Liver Frailty Index (LFI). Time-to- event analysis was performed using Kaplan-Meier method to investigate the impact of functional variables on outcome. One-year survival was determined for patients who underwent liver transplant during this period. Univariate and multivariate Cox proportional hazard regressions were computed to identify predictors of morbid- ity and mortality on the waiting list for LT. Results: 103 patients were screened, 84 were placed on the Eurotransplant LT waiting list and 49 were transplanted during the study period. The mean age was 54 years and 67.7% were males. The primary etiology of liver disease was alcohol and 38% had a hepatocellular carcinoma. The one-year patient survival probability on the waiting list was 76.9 ± 7.2%. This probability was significantly reduced in patients with myosteatosis compared with patients with higher SM-RA values (43 ± 17% vs 95 ± 4%, p < 0.001). Compared with other muscle characteristics, myosteatosis was the strongest predict- ive factor of mortality. 28 patients had a full 6-months post-LT assessment. Of those liver transplanted patients, 57.7% were frail and 40.7% had myosteatosis before LT. At 6 months post-LT, 53.8% were frail and only 25% had myosteatosis. SMI was not different before and after LT. Compared with pre-LT data, muscle density increased with a mean delta of 4.6 HU ( p = 0.06) (Figure). The 5 chairs stand test significantly improved after LT (11.6 sec vs 9.0 sec ( p = 0.013). The other parameters (handgrip, LFI, ...) remained stable. Conclusion: Myosteatosis is significantly associated with negative pre-transplant outcomes. After LT, patients improve in muscle strength but not in muscle quantity or quality evaluated by CT-scan

Frailty in MASLD patients is associated with the presence of diabetes and the degree of liver fibrosis

Introduction: Loss of muscle strength and mass has been identified as a predictive factor for mortality. It is now evident that the loss of muscle mass and function, or sarcopenia, plays also a significant role in the development and severity of advanced liver diseases. However, the links between muscle strength and the severity of the hepatic phenotype in earlier stages of steatotic diseases are still underexplored. Objective: Our aim is to assess the relationships between muscle strength, frailty, and the severity of liver disease in MASLD patients. Methods: In this prospective study, the frailty of MASLD patients was assessed using the liver frailty index (LFI), including a handgrip strength test for the dominant hand, a balance test, and the time required to perform five sit-to-stand. Forearm and quadriceps muscle strength were measured using handgrip and an isokinetic dynamometer (Cybex®). Hepatic disease severity was evaluated by transient elastography, based on the controlled attenuation parameter (CAP) and elasticity. The presence of diabetes was defined by hypoglycemic medication use. Insulin resistance was evaluated in non-diabetic patients using the HOMA-IR method. Results: 152 patients diagnosed with MASLD were included in this study. The demographic composition of the cohort demonstrated a balanced distribution between genders, with 49% females and 51% males. The mean age was 56 years (range: 19 to 78 years), and the mean body mass index (BMI) was 33 (range 22 to 60 kg/m²). There was a high prevalence of diabetes in the cohort, affecting 45% of participants. Metabolic parameters revealed a mean controlled attenuation parameter (CAP) of 328 dB/m, indicating severe hepatic steatosis. The mean liver elasticity was 8 kPa (range: 2 to 49 kPa). Among the patients assessed by transient elastography, 54 patients were classified as F0-F1 (36.5%), 48 patients as F2 (32.4%), 31 patients as F3 (20.9%), and 15 patients as F4 (10.2%). The mean handgrip strength was 39.1 kg for males and 20.3 kg for females (p = 0.0001). The mean quadriceps strength was 106.9 N-m in males and 72.9 N-m in females (p = 0.0001). Using the LFI, 51 patients (40%) were identified as robust, 70 (56%) as pre-frail, and 5 (4%) as frail. Quadriceps muscle strength was significantly lower in frail patients compared to the robust patients (mean strength: 46.7 vs. 111.8 N-m; p = 0.0036). Frailty was not associated with the degree of steatosis assessed by CAP or insulin resistance measured by HOMA-IR. However, frailty was associated with age (r = 0.4559, p = 0.0001). Besides age, the presence of diabetes was associated with increased frailty (mean LFI 3.3 vs. 2.96 in non-diabetic patients, p = 0.0122) and also higher liver elasticity (mean LFI: 2.97 in F0-F2 vs. 3.5 in F3-F4 patients; p = 0.0008). Conclusion: Frailty and decreased muscle strength are associated with the essential components of MASLD, namely the presence of type 2 diabetes and the degree of liver fibrosis. Other factors such as age and gender should also be considered. This underscores a potential liver-muscle axis in the pathogenesis of the disease

Myosteatosis in the liver transplant candidate: Is it the future prognostic marker ?

INTRODUCTION: The body composition of the cirrhotic patient plays an important role in his prognosis. Several factors such as loss of skeletal muscle mass, malnutrition, and frailty (assessed by liver frailty index LFI) are closely associated with an increased risk of mortality in the liver transplant list. Myosteatosis is defined as the pathological excess of fat within the muscle expressed as a lower mean skeletal muscle radiodensity on computed tomography. Several studies have recently observed a negative impact of myosteatosis on the outcome of cirrhotic patients as well as in the postoperative outcome of patients undergoing liver transplantation (LT). There are still questions about the impact of this myosteatosis on liver function and on muscles functionality. [...

Intramyocellular lipids are associated with insulin resistance in metabolic dysfunction-associated steatotic liver disease

Background and Aims: Insulin resistance is considered an indicator of the severity of MASLD. In this context, the role of skeletal muscle fat and its intra- or extra-myocellular localisation on insulin sensitivity remains debated. The aim of this study is to assess muscle lipid content and cellular localisation using proton-magnetic resonance spectroscopy (1H-MRS) and its relationship with insulin resistance in a cohort of MASLD subjects. Method: MASLD patients were prospectively recruited based on the co-existence of liver steatosis measured by a controlled attenuation-parameter (CAP) above 251 dB/m and at least one cardiometabolic risk factor. Type 2 diabetes was defined by the intake of hypoglycemic drugs. Insulin resistance was estimated in non-diabetic patients using the homeostatic model assessment of insulin resistance (HOMA-IR). Intra (IMCL) and extramyocellular lipids (EMCL) were measured in vivo using 1H-MRS. Single voxel 1H-MRS was performed on a 3-Tesla Signa Premier scanner (GE healthcare) on tibialis anterior (TA) and soleus using a PRESS-sequence (voxel size 10 X 10 X 15 mm3, TE=27ms, TR=1500ms, 8 averages). JMRUI software, including the AMARES algorithm was used to quantify IMCL and EMCL on non-water suppressed spectra. Results: 54 MASLD patients were included. 32 patients were male (59%), with a mean age of 54 years (range: 19-75). 27 patients were diabetic (50%). Mean BMI was 35 (range: 24-60). Mean waist circumference was 118 cm (range: 89-160). Mean CAP and liver elasticity were 342 dB/m (range: 242-400) and 14.8 kPa (range: 3.6-35). In the entire cohort, mean TA lipid content was 0.6% for IMCL (range: 0.1-1.5) and 1.8% (0.3-6.8) for EMCL (p 0.05) or for IMCL for TA between diabetic and non-diabetic patients (0.55% versus 0.7%; p > 0.05). Conclusion: The majority of skeletal muscle lipids are extramyocellular. However, IMCL but not EMCL content assessed by 1H-MRS positively correlates with insulin resistance assessed by the HOMA-IR index in non-diabetic MASLD patients. This observation is reinforced by the IMCL content in diabetic patients being significantly higher compared to non-diabetic patients. This observation highlights a link between IMCL, systemic insulin resistance and type 2 diabetes in MASLD