UNASSIGNED: This study was designed to compare the effects of four meal patterns on liver steatosis, fibrosis, and biochemical factors in patients with Nonalcoholic fatty liver disease (NAFLD).
UNASSIGNED: The 12-week intervention was performed on 123 patients with NAFLD who were randomly allocated into four groups: \"3-meals\", \"skipping breakfast\", \"skipping dinner\", and \" 3 meals and 3 snacks per day.\" group. The assessment of liver steatosis, fibrosis, biochemical factors, and anthropometrical evaluation were performed at baseline and at end of the study.
UNASSIGNED: A significant improvement was found in the liver steatosis and fibrosis among the patients who consumed 3 meals, 3 snacks compared to the other groups (P < 0.001). In addition, a higher reduction was observed in serum levels of alanine amino transferase (ALT) (20.93 ± 23.37 mg/dl, P < 0.001), aspartate aminotransferase (AST) (17.15 ± 16.48 mg/dl, P < 0.001), gamma-glutamyl transferase(GGT) (13.43 ± 13.41 mg/dl; P < 0.001), and alkaline phosphatase (ALK) (47.19 ± 60.51 mg/dl; P = 0.004) in patients who consumed 3 meals, 3 snacks, while the concentration of liver enzymes in patients who consumed 3 meals increased significantly. At the end of the study, there was a significant increase in the fasting blood sugar (FBS) concentration in the \"skipping breakfast\" group (17.51 ± 38.85 mg/dl; P = 0.011) and \"3-meals\" group (17.51 ± 38.85 mg/dl, P = 0.03).
UNASSIGNED: Consuming 3 meals, 3 snack per day significantly improves disease severity and biochemical factors in NAFLD patients. Further studies are warranted.
UNASSIGNED: : IRCT20201010048982N2. Name of the registry: Urmia University of Medical Sciences. Date of registration: 2021-08-22, 1400/05/31. URL of trial registry record: https://www.irct.ir/search/result?query=IRCT20201010048982N2.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40200-023-01375-2.

Azorella compacta (A. compacta) is a shrub of the Andean Altiplano of Bolivia, Chile and Peru, consumed by local communities as a traditional medicine for several maladies such as diabetes, hepatic and inflammatory diseases. A. compacta is rich in mulinane- and azorellane-type diterpenoids. For two of these, acute hypoglycemic effects have been described, but the impact of A. compacta diterpenoids on fatty liver disease has not been investigated. Therefore, A. compacta organic fractions were prepared using petroleum ether, dichloromethane and methanol. Their content was characterized by UHPLC/MS, revealing the presence of ten diterpenoids, mainly mulinic acid, azorellanol and mulin-11,13-diene. Next, mice fed with a high-fat diet (HFD), a model of metabolic dysfunction-associated fatty liver disease (MAFLD), received one of the fractions in drinking water for two weeks. After this treatment, hepatic parameters were evaluated. The A. compacta fractions did not reduce hyperglycemia or body weight in the HFD-fed mice but increased the serum levels of hepatic transaminases (AST and ALT), reduced albumin and increased bilirubin, indicating hepatic damage, while histopathological alterations such as steatosis, inflammation and necrosis generated by the HFD were, overall, not ameliorated by the fractions. These results suggest that organic A. compacta extracts may generate hepatic complications in patients with MAFLD.

BACKGROUND: Although several epidemiological studies have identified an inverse association between healthy dietary patterns and metabolic dysfunction-associated steatotic liver disease (MASLD)/non-alcoholic fatty liver disease (NAFLD), little is known about the contribution of the food component to MASLD risk and the association between dietary patterns and severity of MASLD. This study aimed to investigate the association between healthy eating patterns and MASLD risk and severity of MASLD.
METHODS: A case-control study including 228 patients diagnosed with MASLD and 228 controls was conducted. The modified Alternate Healthy Eating Index (AHEI), Dietary Approaches to Stop Hypertension (DASH) score, and Alternative Mediterranean Diet (AMED) score were evaluated based on information collected via a validated food-frequency questionnaire. MASLD was confirmed if participants presented with ultrasound-diagnosed fatty liver diseases along with at least one of five cardiometabolic risk factors and no other discernible cause. The logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of MASLD for dietary scores.
RESULTS: Compared with participants in the lowest tertile, those in the highest tertile of AHEI had a 60% reduced risk of MASLD (OR: 0.40; 95% CI: 0.25-0.66). Similar associations were also observed for DASH and AMED, with ORs comparing extreme tertiles of 0.38 (95% CI: 0.22-0.66) and 0.46 (95% CI: 0.28-0.73), respectively. Further Stratified analysis revealed that the inverse associations between AHEI and DASH with MASLD risks were stronger among women than men, and the inverse associations between AMED and MASLD risks were more pronounced among participants with normal weight (OR: 0.22; 95% CI: 0.09-0.49). For components within the dietary score, every one-point increase in vegetable score and whole grain score within the AHEI was associated with an 11% (95% CI: 5-16%) and a 6% (95% CI: 0-12%) lower MASLD risk, respectively. Similar inverse associations with those scores were observed for the DASH and AMED.
CONCLUSIONS: Greater adherence to healthy eating patterns was associated with reduced risk of MASLD, with vegetables and whole grains predominately contributing to these associations. These findings suggested that healthy eating patterns should be recommended for the prevention of MASLD.

Branched-chain amino acids (BCAAs), as essential amino acids, engage in various physiological processes, such as protein synthesis, energy supply, and cellular signaling. The liver is a crucial site for BCAA metabolism, linking the changes in BCAA homeostasis with the pathogenesis of a variety of liver diseases and their complications. Peripheral circulating BCAA levels show complex trends in different liver diseases. This review delineates the alterations of BCAAs in conditions including non-alcoholic fatty liver disease, hepatocellular carcinoma, cirrhosis, hepatic encephalopathy, hepatitis C virus infection, and acute liver failure, as well as the potential mechanisms underlying these changes. A significant amount of clinical research has utilized BCAA supplements in the treatment of patients with cirrhosis and liver cancer. However, the efficacy of BCAA supplementation in clinical practice remains uncertain and controversial due to the heterogeneity of studies. This review delves into the complicated relationship between BCAAs and liver diseases and tries to untangle what role BCAAs play in the occurrence, development, and outcomes of liver diseases.

Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.

Background and Objectives: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine administration has been suggested to prevent glucose metabolism abnormalities and fatty liver in genetically obese ob/ob mice; however, it is not clear whether the beneficial effects of BCG are also observed in the progression of glucose intolerance induced by a high-fat diet (HFD). Therefore, the effects of BCG vaccination on changes in glucose tolerance and insulin response were investigated in HFD-fed C57BL/6 mice. Materials and Methods: We used the BCG Tokyo 172 strain to determine effects on abnormalities in glucose metabolism. For vaccination, five-week-old male mice were injected intraperitoneally with BCG and maintained on a HFD for three weeks. The mice were regularly subjected to intraperitoneal glucose tolerance and insulin tolerance tests (IGTTs and ITTs). These tests were also performed in mice transplanted with bone marrow cells from BCG-vaccinated donor mice. Results: Significant effects of BCG vaccination on blood glucose levels in the IGTTs and ITTs were observed from week 12 of the experiment. BCG vaccination significantly improved changes in fasting glucose and insulin levels, insulin resistance indexes, and glucagon-to-insulin ratios in conjunction with the HFD at the end of the experiment. Significant inhibitory effects in the IGTTs and ITTs on glucose intolerance were also observed with transplantation with bone marrow cells derived from BCG-vaccinated donor mice. Conclusions: BCG vaccination significantly delayed glucose intolerance progression, suggesting a beneficial effect of BCG on the pathogenesis of type 2 diabetes. It has also been suggested that the effects of BCG vaccination may be at least partially due to an immune memory (trained immunity) for hematopoietic stem and progenitor cells of the bone marrow.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Accumulating evidence in animal models suggests that loss of interleukin-10 (IL-10) anti-inflammatory actions might contribute to lobular inflammation, considered one of the first steps toward NASH development. However, the role of IL-10 in lobular inflammation remains poorly explored in humans. We examined mRNA and protein levels of IL-10 in liver biopsies and serum samples from morbidly obese patients, investigating the relationship between IL-10 and lobular inflammation degree. Materials and Methods: We prospectively enrolled morbidly obese patients of both sexes, assessing the lobular inflammation grade by the Brunt scoring system to categorize participants into mild (n = 7), moderate (n = 19), or severe (n = 13) lobular inflammation groups. We quantified the hepatic mRNA expression of IL-10 by quantitative polymerase chain reaction and protein IL-10 levels in liver and serum samples by Luminex Assay. We estimated statistical differences by one-way analysis of variance (ANOVA) and Tukey\'s multiple comparison test. Results: The hepatic expression of IL-10 significantly diminished in patients with severe lobular inflammation compared with the moderate lobular inflammation group (p = 0.01). The hepatic IL-10 protein levels decreased in patients with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.008 and p = 0.0008, respectively). In circulation, IL-10 also significantly decreased in subjects with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.005 and p < 0.0001, respectively). Conclusions: In liver biopsies and serum samples of morbidly obese patients, the protein levels of IL-10 progressively decrease as lobular inflammation increases, supporting the hypothesis that lobular inflammation develops because of the loss of the IL-10-mediated anti-inflammatory counterbalance.

Liver diseases, including non-alcoholic fatty liver disease (NAFLD), are a growing global health issue. Environmental exposure to toxic metals can harm the liver, increasing the risk of NAFLD. Essential elements are vital for liver health, but imbalances or deficiencies can contribute to the development of NAFLD. Therefore, understanding the interplay between toxic metals and essential elements in liver disease is important. This study aims to assess the individual and combined effects of toxic metals (lead(Pb), cadmium (Cd), mercury (Hg)), and essential elements (manganese and selenium) on the risk of liver disease. Methods: We assessed the individual and combined effects of Pb, Cd, Hg, manganese (Mn), and selenium (Se) on liver disease risk using data from the National Health and Nutrition Examination Survey between 2017 and 2018. We performed descriptive statistics and linear regression analysis and then utilized Bayesian Kernel Machine Regression (BKMR) techniques such as univariate, bivariate, and overall effect analysis. BKMR enabled the assessment of non-linear exposure-response functions and interactions between metals and essential elements. Posterior Inclusion Probabilities (PIPs) were calculated to determine the importance of each metal and essential element in contributing to liver disease. Regarding our study results, the regression analysis of liver injury biomarkers ALT, AST, ALP, GGT, total bilirubin, and the FLI-an indicator of NAFLD-with toxic metals and essential elements, adjusting for covariates such as age, sex, BMI, alcohol consumption, ethnicity, income, and smoking status, demonstrated the differential effects of these contaminants on the markers of interest. Our BKMR analysis provided further insights. For instance, the PIP results underscored Pb\'s consistent importance in contributing to liver disease (PIP = 1.000), followed by Hg (PIP = 0.9512), Cd (PIP = 0.5796), Se (PIP = 0.5572), and Mn (PIP = 0.4248). Our univariate analysis showed a positive trend with Pb, while other exposures were relatively flat. Our analysis of the single-variable effects of toxic metals and essential elements on NAFLD also revealed that Pb significantly affected the risk of NAFLD. Our bivariate analysis found a positive (toxic) trend when Pb was combined with other metals and essential elements. For the overall exposure effect of exposure to all the contaminants together, the estimated risk of NAFLD showed a steady increase from the 60th to the 75th percentile. In conclusion, our study indicates that Pb exposure, when combined with other toxic metals and essential elements, plays a significant role in bringing about adverse liver disease outcomes.

Non-alcoholic fatty liver disease (NAFLD), prevalent among conditions like obesity and diabetes, is globally significant. Existing ultrasound diagnosis methods, despite their use, often lack accuracy and precision, necessitating innovative solutions like AI. This study aims to validate an AI-enhanced quantitative ultrasound (QUS) algorithm for NAFLD severity assessment and compare its performance with Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF), a conventional diagnostic tool. A single-center cross-sectional pilot study was conducted. Liver fat content was estimated using an AI-enhanced quantitative ultrasound attenuation coefficient (QUS-AC) of Barreleye Inc. with an AI-based QUS algorithm and two conventional ultrasound techniques, FibroTouch Ultrasound Attenuation Parameter (UAP) and Canon Attenuation Imaging (ATI). The results were compared with MRI-PDFF values. The intraclass correlation coefficient (ICC) was also assessed. Significant correlation was found between the QUS-AC and the MRI-PDFF, reflected by an R value of 0.95. On other hand, ATI and UAP displayed lower correlations with MRI-PDFF, yielding R values of 0.73 and 0.51, respectively. In addition, ICC for QUS-AC was 0.983 for individual observations. On the other hand, the ICCs for ATI and UAP were 0.76 and 0.39, respectively. Our findings suggest that AC with AI-enhanced QUS could serve as a valuable tool for the non-invasive diagnosis of NAFLD.

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.