Muscle Quality as a Potential Diagnostic Marker of Advanced Liver Fibrosis in Patients with Non-alcoholic Fatty Liver Disease.

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

Survey of Dietary Habits and Physical Activity in Japanese Patients with Non-Obese Non-Alcoholic Fatty Liver Disease.

The incidence of non-obese non-alcoholic fatty liver disease (NAFLD), characterized by the presence of a fatty liver in individuals with a normal body mass index, is on the rise globally. Effective management strategies, including lifestyle interventions such as diet and exercise therapy, are urgently needed to address this growing public health concern. The aim of this study was to investigate the association between non-obese NAFLD, dietary habits, and physical activity levels. By elucidating these relationships, this research may contribute to the development of evidence-based recommendations for the management of non-obese NAFLD. The study had a single-center retrospective cross-sectional design and compared clinical data and dietary and physical activity habits between patients with and without non-obese NAFLD. Logistic regression analysis was utilized to investigate the relationship between food intake frequency and the development of NAFLD. Among the 455 patients who visited the clinic during the study period, 169 were selected for analysis, including 74 with non-obese NAFLD and 95 without NAFLD. The non-obese NAFLD group showed a less-frequent consumption of fish and fish products as well as olive oil and canola/rapeseed oil, while they showed more frequent consumption of pastries and cake, snack foods and fried sweets, candy and caramels, salty foods, and pickles compared to the non-NAFLD group. Logistic regression analysis revealed that NAFLD was significantly associated with the consumption of fish, fish products, and pickles at least four times a week. The physical activity level was lower and the exercise frequency was lower in patients with non-obese NAFLD compared to those without NAFLD. The results of this study suggest that a low consumption of fish and fish products and high consumption of pickles may be associated with a higher risk of non-obese NAFLD. Moreover, dietary habits and physical activity status should be taken into consideration for the management of patients with non-obese NAFLD. It is important to develop effective management strategies, such as dietary and exercise interventions, to prevent and treat NAFLD in this patient population.

Hepatic Niemann-Pick C1-Like 1 exacerbates non-alcoholic fatty liver disease by re-absorbing specific biliary oxysterols.

BACKGROUND: Dietary oxysterols are believed to be associated with the progression of non-alcoholic fatty liver disease (NAFLD). However, the molecular basis of the association between dietary oxysterols and NAFLD is poorly understood. We hypothesized that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver, would regulate hepatic oxysterol levels and affects NAFLD progression. METHODS AND RESULTS: Considering the species differences in hepatic NPC1L1 expression, we used liver-specific NPC1L1 transgenic (NPC1L1Tg) mice as a human model and demonstrated that oxysterol-rich heated cholesterol exacerbated high-fat diet-induced steatosis, an early stage of NAFLD, in a hepatic NPC1L1-dependent manner. Analyses of hepatic and biliary oxysterol levels in NPC1L1Tg mice and in vitro oxysterol uptake assays with NPC1L1-overexpressing cells revealed that NPC1L1 can uptake some, but not all, oxysterols and suppress their biliary excretion. Furthermore, in vitro and in vivo analyses revealed that 22(R)-hydroxycholesterol (22R-OHC) and 25-hydroxycholesterol (25-OHC), which are NPC1L1 substrates, were primarily involved in steatosis progression, via the activation of liver X receptor α and retinoid-related orphan receptor γ, respectively. Consistent with these results, examination of clinical specimens revealed that among the 14 major oxysterols analyzed, plasma concentrations of 22R-OHC and 25-OHC were significantly positively correlated with hepatic fat accumulation in humans. CONCLUSIONS: Among the major dietary oxysterols, 22R-OHC and 25-OHC are particularly potent in promoting the progression of hepatic steatosis in a hepatic NPC1L1-dependent manner.

Relationships of Dietary Habits and Physical Activity Status with Non-Alcoholic Fatty Liver Disease Featuring Advanced Fibrosis.

(1) Aim: Hepatic fibrosis is a prognostic factor for disease progression in non-alcoholic fatty liver disease (NAFLD). We aimed to determine the relationships between diet, physical activity, and the progression of liver fibrosis. (2) Methods: The 349 participants were categorized by their FibroScan-aspartate aminotransferase score, and they completed a questionnaire regarding their diet and physical activity. (3) Results: There were 233 patients in the negative-on-screening group, 78 in the gray zone group, and 38 in the positive-on-screening group. The frequencies of consumption of soybeans and soybean products and of light-colored vegetables were lower in the positive group; whereas the frequencies of consumption of snack food and fried sweets, jelly and pudding, fried food, and butter, lard, and beef tallow were higher. The odds ratios for the fibrosis progression in patients who consumed fried food ≥4 times/week was 2.21. The positive group also showed lower physical activity level (PAL) and exercise (Ex, metabolic equivalents for tasks (METs)/hour/week). The patients who undertook Ex at >7.5 had an odds ratio of 0.21 for the fibrosis progression. (4) Conclusion: High consumption of fried food and low Ex are risk factors for the fibrosis progression in NAFLD.

Clinical and anthropometric characteristics of non-obese non-alcoholic fatty liver disease subjects in Japan.

AIM: The underlying mechanism of non-obese non-alcoholic fatty liver disease (NAFLD) has not been fully elucidated. We classified patients with NAFLD by sex and body mass index and compared their clinical features to clarify the background pathophysiology of non-obese NAFLD. METHODS: A total of 404 patients with NAFLD were divided according to their body mass index (<25 [non-obese], 25 to <30 [obese], and ≥30 [severe obese]), and were further compared with 253 patients without obesity and NAFLD (non-NAFLD). RESULTS: The proportion of the individuals with non-obese NAFLD was 25.7% in men and 27.6% in women. The male and female non-obese NAFLD groups had lower skeletal muscle mass and muscle strength than the obese NAFLD groups. The visceral fat area, although low, was ≥100 cm2 in 59.3% of men and 43.8% of women. An increase in liver fat accumulation, hepatic fibrosis, homeostasis model assessment of insulin resistance, and leptin levels was modest in the non-obese NAFLD group compared with a marked increase in the obese NAFLD groups. The muscle mass of the non-obese NAFLD group was similar to that of the non-NAFLD group, but muscle steatosis was particularly common among women. Multivariate analysis revealed that the factors contributing to increased liver fat accumulation in the non-obese NAFLD group were visceral fat area, HbA1c, myostatin, and leptin. CONCLUSIONS: In patients with non-obese NAFLD, a sex difference was observed in the clinical features. In addition to increased visceral fat, decreased muscle mass and muscle strength, muscle atrophy (presarcopenia), and impaired glucose tolerance were considered to be important pathophysiological factors.

Urinary Levels of Titin-N Fragment, a Skeletal Muscle Damage Marker, are Increased in Subjects with Nonalcoholic Fatty Liver Disease.

Sarcopenia is a pathological condition affecting the development and progression of NAFLD. Urinary levels of titin-N fragment, a biomarker reflecting muscle damage, were measured in NAFLD subjects, and analyzed in a retrospective manner for possible correlations with NAFLD pathophysiology to assess their clinical relevance. This study enrolled 153 NAFLD subjects and 100 subjects without NAFLD, obesity or diabetes mellitus (non-NAFLD). NAFLD subjects had more decreased knee extension strength. NAFLD subjects had greater subcutaneous fat thickness and echo intensity (brightness) of the rectus femoris muscle on ultrasound images; higher levels of the intra- and extra-myocellular lipids (IMCL, EMCL) using 1H-MRS. Urinary titin-N fragment levels were increased with increasing age but not different between males and females. NAFLD subjects had higher titin-N fragment levels than non-NAFLD subjects. The levels were negatively correlated with skeletal muscle mass and knee extension strength and positively correlated with muscle echo intensity, EMCL, and liver fibrosis scores (NAFLD fibrosis score, FIB-4 index). Multivariate analysis revealed that factors affecting the levels were skeletal mass index, leg skeletal muscle mass, liver stiffness, and NAFLD fibrosis score. Urinary levels of titin-N fragment reflected skeletal muscle deterioration and functional decline, and was closely associated with hepatic pathological conditions in NAFLD subjects.

Progressive reduction in skeletal muscle mass to visceral fat area ratio is associated with a worsening of the hepatic conditions of non-alcoholic fatty liver disease.

Background: Deceased muscle mass combined with increased visceral fat mass is reportedly linked to a higher risk of worsening the hepatic conditions of non-alcoholic fatty liver disease (NAFLD). Objective: The aim of this study was conducted in a retrospective manner to investigate whether longitudinal changes in skeletal muscle mass to visceral fat area ratio (SV ratio), an index of sarcopenic obesity, are influential on the hepatic conditions and pathophysiology of NAFLD during the clinical course. Design: The association of SV ratio with hepatic conditions and pathophysiology was evaluated longitudinally for 2-5.5 years (median 4.1 years) in 92 patients with NAFLD (36 men and 56 women; 17-78 years). The subjects were divided into three groups according to the change in their SV ratio: improved, stable, or worsened, and the changes in parameters associated with NAFLD were compared among the groups. Results: In the group with a worsened SV ratio, visceral fat area increased (122±30-138±30 cm2; mean ± SD), whereas total muscle mass decreased (26.5±6.1-25.9±5.9 kg), which was especially noticeable in the lower extremities (14.8±3.3-14.3±3.1 kg). In accordance with the change of body composition, transient elastography showed higher levels of liver stiffness (7.7±5.4-9.0±6.0 kPa) and fat accumulation (265±43-293±48 dB/m). There were also higher levels of fasting plasma glucose (115±29-126±40 mg/dL) and HbA1c (6.0±1.1-6.3±1.0%). In contrast, deterioration in these parameters did not occur in the groups with improved or stable SV ratios. Conclusion: Collectively, a progressive reduction in skeletal muscle mass accompanied by an increase in visceral fat mass during the clinical course of NAFLD is associated with a worsening of the hepatic conditions, fat accumulation and progression of fibrosis.

Whole-body vibration for patients with nonalcoholic fatty liver disease: a 6-month prospective study.

Physical exercise has demonstrated benefits for managing nonalcoholic fatty liver disease (NAFLD). However, in daily life maintaining exercise without help may be difficult. A whole-body vibration device (WBV) has been recently introduced as an exercise modality that may be suitable for patients who have difficulty engaging in exercise. We tested WBV in patients with NAFLD and estimated its effectiveness. We studied the effects of a 6-month WBV program on hepatic steatosis and its underlying pathophysiology in 25 patients with NAFLD. Seventeen patients with NAFLD were designated as a control group. After WBV exercise, body weight in the study group decreased by only 2.5% compared with the control group. However, we found significant increases in muscle area (+2.6%) and strength (+20.5%) and decreases in fat mass (-6.8%). The hepatic (-9.9%) and visceral (-6.2%) fat content also significantly decreased (P < 0.05). There was substantial lowering of hepatic stiffness (-15.7%), along with improvements in the levels of inflammatory markers; tumor necrosis factor alpha (-50.9%), adiponectin (+12.0%), ferritin (-33.2%), and high-sensitivity C-reactive protein (-43.0%) (P < 0.05). These results suggest that WBV is an exercise option for patients with NAFLD that is effective, efficient, and convenient.