The triglyceride-glucose index (TyG) and triglyceride-glucose body mass index (TyG-BMI) have been identified as potential predictive factors for metabolic dysfunction-associated steatotic liver disease (MASLD). However, they do not include high density lipoprotein (HDL-C), which is closely related to lipid metabolism. Furthermore, there is a lack of comprehensive and longitudinal data to determine the cut-off points for different degrees of hepatic steatosis and liver fibrosis in MASLD. This study aimed to investigate the predictive capability of triglyceride-glucose-high density lipoprotein-body mass index (TGH-BMI) in determining hepatic steatosis and liver fibrosis in MASLD, as well as to establish the predictive cut-off points.

We analyzed the relationships of TGH-BMI (TGH-BMI = ln [TG (mg/dL) ∗FBG (mg/dL)/HDL-C (mg/dL)] ∗ BMI (kg/m2)) with different degrees of hepatic steatosis and fibrosis in 35,114 participants who underwent health check-ups. A total of 2262 subjects without MASLD were selected for the analysis of cumulative hazard of hepatic steatosis and liver fibrosis in TGH-BMI dichotomous groups over a follow-up period of 1001 days.

Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) demonstrated a consistent upward trend as TGH-BMI increased across quartile groups, as determined by One-way analysis of variance (P < 0.001). TGH-BMI and CAP, LSM exhibit distinct curve-like relationships between males and females when utilizing smoothing functions and conducting threshold effect analysis (P < 0.05). In males, prior to the inflection point at TGH-BMI = 177.733, there was a significant increase of 0.807 in CAP for every 1 unit increase in TGH-BMI (P < 0.05), after the inflection point, there was still an increase of 0.417 in CAP for every 1 unit increase in TGH-BMI (P < 0.05); There was no significant correlation between LSM and TGH-BMI before the first inflection point at TGH-BMI = 131.689 (P > 0.05) and after the second inflection point at TGH-BMI = 253.268 (P > 0.05). Between the first and the second inflection, LSM showed an increase of 0.015 for every 1 unit increase in TGH-BMI (P < 0.05). In females, before the inflection point at TGH-BMI = 94.686, there was a significant increase of 0.272 in CAP for every 1 unit increase in TGH-BMI (P < 0.05), after the inflection point, there was a notable change as CAP increased by 0.806 for every 1 unit increase in TGH-BMI (P < 0.05). There was no significant correlation between LSM and TGH-BMI before the inflection point at TGH-BMI = 118.098 (P > 0.05), after the inflection point, LSM showed an increase of 0.017 for every 1 unit increase in TGH-BMI (P < 0.05). Notably, TGH-BMI has been shown to be a strong predictor for the severity of hepatic steatosis and liver fibrosis in MASLD. The Area Under Curves (AUCs) for hepatic steatosis, moderate or above hepatic steatosis, severe hepatic steatosis and liver fibrosis in males were 0.845, 0.846, 0.882 and 0.668 respectively, the AUCs for hepatic steatosis, moderate or above hepatic steatosis, severe hepatic steatosis and liver fibrosis in females were 0.855, 0.895, 0.939 and 0.705 respectively (P < 0.05). In individuals without MASLD, the cumulative hazard of hepatic steatosis was found to be strongly associated with the dichotomy of increased TGH-BMI (TGH-BMID2: Hazard Ratio (HR) = 2.412, 95 % Confidence interval (CI): 2.0164-2.9071, P < 0.0001), while the same is true in liver fibrosis (TGH-BMID2: HR = 1.454, 95 % CI: 1.0633-1.9883, P = 0.0191).

The TGH-BMI demonstrates a strong predictive value for hepatic steatosis and liver fibrosis, with significantly different cut-off points for men and women. Therefore, it is important to consider the potential need for gender-specific cut-off points for triglyceride, glucose, high density lipoprotein and body mass index in clinical practice. In individuals without MASLD, a higher TGH-BMI is associated with an increased risk of developing MASLD in the future.

Imbalance in the gut microbiota is a key factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. The Dietary Index for Gut Microbiota (DI-GM) integrates the potential relationship between diet and gut microbiota diversity. This study aims to investigate the association between DI-GM and the risk of NAFLD and liver fibrosis, providing theoretical support for dietary intervention strategies.

This study utilized data from NHANES 2017-2020, including 6,181 eligible adult participants. The relationship between DI-GM and the risk of NAFLD and liver fibrosis was assessed using DI-GM quartiles, multivariate logistic regression, and restricted cubic spline (RCS) analysis. Subgroup analysis was performed to explore the predictive role of DI-GM in different populations. All analyses were weighted to ensure the representativeness of the results.

DI-GM was negatively associated with the risks of NAFLD and liver fibrosis. As DI-GM scores increased, the risk of NAFLD and liver fibrosis significantly decreased (52.81%, 43.16%, 40.40%, and 31.98%, p < 0.05; 17.52%, 9.04%, 7.21%, and 6.78%, p < 0.05). Multivariate logistic regression analysis revealed that, in the unadjusted model (Model 1), for each unit increase in DI-GM, the risk of NAFLD decreased by 6.9% (OR = 0.931, 95% CI: 0.886-0.979, p < 0.001), while the risk of liver fibrosis decreased by 15.6% (OR = 0.844, 95% CI: 0.757-0.941, p < 0.05). In the quartile analysis, individuals in the highest DI-GM quartile (Q4) had a 58% lower risk of NAFLD compared to those in the lowest quartile (Q1) (OR = 0.42, 95% CI: 0.219-0.806, p < 0.001). The results remained significant even after adjusting for covariates. RCS analysis showed that DI-GM had a nonlinear relationship with the risks of NAFLD and liver fibrosis, with inflection points at scores of 2 and 5, indicating enhanced protective effects.

This study reveals a negative association between DI-GM and the risk of NAFLD and liver fibrosis, highlighting the potential role of healthy dietary patterns in the prevention and management of NAFLD and liver fibrosis through gut microbiota modulation, providing a theoretical basis for dietary interventions.

To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, separately, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with a reduced risk of cirrhosis and other adverse liver outcomes among patients with type 2 diabetes.

With an active comparator, new-user approach, we conducted a cohort study using the U.K. Clinical Practice Research Datalink linked with hospital and national statistics databases. Cox proportional hazards models using propensity score fine stratification weighting were used to calculate hazard ratios (HRs) and 95% CIs for cirrhosis (primary outcome) and decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality (secondary outcomes).

In the first cohort comparing 25,516 patients starting GLP-1RAs and 186,752 starting DPP-4 inhibitors, GLP-1RAs were not associated with the incidence of cirrhosis (HR 0.90, 95% CI 0.68-1.19) or the secondary outcomes. In a separate cohort comparing 33,161 patients starting SGLT-2 inhibitors and 124,431 starting DPP-4 inhibitors, SGLT-2 inhibitors were associated with a reduced incidence of cirrhosis (HR 0.64, 95% CI 0.46-0.90), as also decompensated cirrhosis (HR 0.74, 95% CI 0.54-1.00), but not with a lower risk of hepatocellular carcinoma or liver-related mortality.

In patients with type 2 diabetes in the U.K., GLP-1RAs were not associated with a lower risk of cirrhosis compared with DPP-4 inhibitors in patients with type 2 diabetes. However, SGLT-2 inhibitors were associated with a lower risk of cirrhosis compared with DPP-4 inhibitors.

Recent studies have utilized time-restricted feeding (16/8) (TRF) and dietary approaches to stop hypertension separately to manage metabolic-associated fatty liver disease (MAFLD); however, the effectiveness of combining these two approaches has not been investigated. The objective of this study was to examine the impact of TRF in conjunction with a DASH diet on various factors related to MAFLD. A 12-week randomized controlled trial was conducted to assess the impact of TRF (16/8), along with a DASH diet, compared with a control diet based on standard meal distribution, in patients with MAFLD. An investigation was conducted to examine alterations in anthropometric indices, as well as liver parameters, serum metabolic indices, and an inflammatory marker. The TRF plus DASH diet reduced body mass index (p = 0.03), abdominal circumference (p = 0.005), controlled attenuation parameter (CAP) (p < 0.001), alanine aminotransferase (p = 0.039), and aspartate aminotransferase (0.047) compared to the control group. The levels of insulin and homeostasis model assessment of insulin resistance reduced in both groups significantly (P < 0.05). In MAFLD patients, TRF (16/8) in combination with a DASH diet is superior to a low-calorie diet in promoting obesity indices, and hepatic steatosis and fibrosis. Further long-term investigations are needed to draw definitive conclusions.

Cigarette smoke (CS), an intricate blend comprising over 4000 compounds, induces abnormal cellular reactions that harm multiple tissues. Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease (CLD), encompassing non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Recently, the term NAFLD has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), and NASH has been renamed metabolic dysfunction-associated steatohepatitis (MASH). A multitude of experiments have confirmed the association between CS and the incidence and progression of MASLD. However, the specific signaling pathways involved need to be updated with new scientific discoveries. CS exposure can disrupt lipid metabolism, induce inflammation and apoptosis, and stimulate liver fibrosis through multiple signaling pathways that promote the progression of MASLD. Currently, there is no officially approved efficacious pharmaceutical intervention in clinical practice. Therefore, lifestyle modifications have emerged as the primary therapeutic approach for managing MASLD. Smoking cessation and the application of a series of natural ingredients have been shown to ameliorate pathological changes in the liver induced by CS, potentially serving as an effective approach to decelerating MASLD development. This article aims to elucidate the specific signaling pathways through which smoking promotes MASLD, while summarizing the reversal factors identified in recent studies, thereby offering novel insights for future research on and the treatment of MASLD.

Resmetirom, the first FDA-approved drug for nonalcoholic steatohepatitis (NASH) with fibrosis in obese patients, when combined with lifestyle modifications, improves NASH resolution and reduces fibrosis by at least one stage. Low thyroid hormone (T3) levels are linked to a higher risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Epidemiological studies have confirmed the positive correlation between hypothyroidism and MASLD. Unraveling the molecular mechanisms of T3 signaling pathways in MASLD will enhance the prospects of identifying effective and specific targets. Therefore, this review discusses the significant role of thyroid hormones in the homeostasis of fat metabolism and describes the possible molecular mechanisms of thyromimetics in the treatment of MASLD.

A comprehensive search in PubMed and EMBASE was conducted using the keywords "thyromimetics and liver diseases," "thyroid hormone and liver diseases," "hypothyroidism and liver diseases," "T3, T4 and liver disease," and "resmetirom and liver disease." Relevant papers published before October 2024 were included.

T3 treatment enhances mitochondrial respiration, biogenesis, β-oxidation, and mitophagy, reducing liver lipid accumulation. However, T3 treatment causes cardiotoxicity through thyroid hormone receptor (THR)α agonistic activity. To address this, molecules with high THRβ agonistic but lower THRα activity have been developed. Besides resmetirom, other THRβ agonists like TG68, CS27109, MB07811, and KB-141 show promising results in experimental studies. These molecules upregulate THRβ target genes, activate genes for fatty acid β-oxidation in mitochondria and fatty acid breakdown in peroxisomes, downregulate the genes involved in de novo lipogenesis, reduce inflammation by downregulating NF-κB/JNK/STAT3 signaling pathways, and accelerate fibrosis resolution by downregulating the expressions of fibrosis marker genes in NASH liver tissue.

Future clinical studies should thoroughly investigate THRβ agonists, including TG68, CS27109, MB07811, and KB-141.

Cilostazol has previously been shown to reduce liver steatosis and enhance hepatic perfusion. We investigated the effects of cilostazol after major hepatectomy in a steatotic rat model. Six weeks prior to surgery, Sprague-Dawley rats were fed with a high-fructose diet. The treatment group received daily 5 mg/kg cilostazol. Seven days following the cilostazol treatment, all animals underwent 70% liver resection (PHX). Analysis of hepatic blood flow and microcirculation and immunohistochemical examinations were conducted 30 min after PHX (postoperative day [POD] 0) as well as on POD 1, POD 3 and POD 7. The weight of cilostazol-treated animals was significantly reduced compared to untreated controls after completion of the 6-week high-FRC diet. Furthermore, 41% macrovesicular steatosis was found in the control group compared to 8% in the cilostazol group. Hepatic arterial and portal venous perfusion were increased in the cilostazol group on POD 7. Lower liver enzyme release was found postoperatively in cilostazol-treated animals. Moreover, apoptosis and neutrophil infiltration were reduced after cilostazol treatment. Proliferation of hepatocytes and liver regeneration after PHX were significantly increased in the cilostazol group. Consequently, cilostazol should be evaluated as a novel strategy to reduce the rate of liver failure after PHX in steatotic liver.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear.

To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components.

The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models.

In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model.

We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.

Circular RNAs (circRNAs) play an important role in regulating inflammation and oxidative stress during the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanism is unclear. This study aimed to determine the role of mmu_circ_0009303 in MASLD. We used a bioinformatics approach to identify potential targets and established an in vitro model of MASLD. Oil red O staining, cell transfection and dual-luciferase reporter assay were used to determine the role of mmu_circ_0009303. The results indicated that the mmu_circ_0009303 expression was significantly increased in the MASLD model both in vitro and in vivo and was associated with oxidative stress levels and inflammation. Moreover, bioinformatics analyses revealed that miRNA-182-5p and Foxo3 are targets of mmu_circ_0009303 and miRNA-182-5p, respectively. In the in vitro MASLD model, mmu_circ_0009303 promoted fat deposition in NCTC1469 cells, which was induced by free fatty acid (FFA) through the regulation of miRNA-182-5p/Foxo3. The expression of miRNA-182-5p and Forkhead box O3 (Foxo3) was associated with mmu_circ_0009303 expression in the liver of mice with MASLD, which was induced by a high-fat diet. Furthermore, mmu_circ_0009303 may be involved in regulating the expression of lipid metabolism-related regulatory proteins, such as CPT1A, SLC27A4, ACBD3, SREBP1, FAS, PPARα, and PPARγ. Taken together, mmu_circ_0009303 promotes oxidative stress, inflammation, and excessive fat accumulation in NCTC1469 cells induced by FFA through the regulation of miRNA-182-5p/Foxo3 and lipid metabolism-related regulatory proteins. These findings provide a potential target for the treatment of MASLD.

Diabetes Mellitus (DM) is a global health concern that affects millions of people globally. The present review aims to narrate the clinical guidelines and therapeutic interventions for Type 2 Diabetes Mellitus (T2DM) patients. Furthermore, the present work summarizes the ongoing phase 1/2/3 and clinical trials against T2DM.

A meticulous and comprehensive literature review was performed using various databases, such as PubMed, MEDLINE, Clinical trials database (https://clinicaltrials.gov/), and Google Scholar, to include various clinical trials and therapeutic interventions against T2DM.

Based on our findings, we concluded that most T2DM-associated clinical trials are interventional. Anti-diabetic therapeutics, including insulin, metformin, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), and Sodium- Glucose cotransporter-2 (SGLT-2) inhibitors are frontline therapeutics being clinically investigated. Currently, the therapeutics in phase IV clinical trials are mostly SGLT-2 inhibitors, implicating their critical contribution to the clinical management of T2DM.

Despite the success of T2DM treatments, a surge in innovative treatment options to reduce diabetic consequences and improve glycemic control is currently ongoing. More emphasis needs to be on exploring novel targeted drug candidates that can offer more sustained glycemic control.

Non-alcohol fatty liver disease (NAFLD) is a metabolic disorder that represents the hepatic manifestation of systemic process, and is a strong risk factor for diabetes Meletus, whereas the presence of DM increases the severity of NAFLD/NASH and its progression. Data on the impact of diabetes on NASH phenotype is sparse from northern India. We studied and compared the clinical profile of NALFD in the presence and absence of DM and the effect of diabetes on NASH.

We did a cross-sectional analysis of data from NAFLD patients (n = 90) who were divided into diabetic and non-diabetic cohorts and their respective demographic, biochemical, imaging and histological features were recorded and compared.

Out of 90 patients, 53.3% were females with a mean age of 44 ± 12 years. The mean BMI and WHR of the study cohort were 28.9 ± 3.4 and 1.01 ± 0.15, respectively. The current study showed that 35.8% were diabetics. The mean age and WHR were 52 ± 11 years vs 40 ± 10 years and 1.1 ± 0.17 vs 0.99 ± 0.09, respectively, in diabetic and non-diabetic NAFLD patients. Non-invasive fibrosis scores, including BARD (2.8 vs 1.73), FIB-4 (3.4 vs 2.2) and NFS (0.97 vs -1.13), were significantly higher in diabetic NAFLD compared to non-diabetic NAFLD (P < 0.03). The histological grade of steatosis and fibrosis as depicted by the mean NAS score (5.7 ± 1.2 vs 4.63 ± 0.8) was higher in diabetic NAFLD vs non-diabetic NAFLD; however, only the fibrosis stage was statistically significant between the groups (P < 0.001).

Despite the small no of cases, we should conclude that there is a bidirectional relationship between NAFLD and DM where the progression of one increases the rate of progression of other. Diabetic patients have higher risk of NASH and hence increased risk of liver related mortality and should be screened early for NAFLD/NASH.

There is still no reliable therapeutic targets and effective pharmacotherapy for metabolic dysfunction-associated steatotic liver disease (MASLD). RASD1 is short for Ras-related dexamethasone-induced 1, a pivotal factor in various metabolism processes of Human. However, the role of RASD1 remains poorly illustrated in MASLD. Therefore, we designed a study to elucidate how RASD1 could impact on MASLD as well as the mechanisms involved.

The expression level of RASD1 was validated in MASLD. Lipid metabolism and its underlying mechanism were investigated in hepatocytes and mice with either overexpression or knockdown of RASD1.

Hepatic RASD1 expression was upregulated in MASLD. Lipid deposition was significantly reduced in RASD1-knockdown hepatocytes and mice, accompanied by a marked downregulation of key genes in the signaling pathway of de novo lipogenesis. Conversely, RASD1 overexpression in hepatocytes had the opposite effect. Mechanistically, RASD1 regulated lipid metabolism in MASLD through the PI3K/AKT/mTOR signaling pathway.

We discovered a novel role of RASD1 in MASLD by regulating lipogenesis via the PI3K/AKT/mTOR pathway, thereby identifying a potential treatment target for MASLD.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, coinciding with aging population. However, limited studies have evaluated its incidence and progression to advanced fibrosis in the elderly population. Therefore, our study aimed to investigate the incidence of MASLD and advanced fibrosis in this age group.

We included 878 686 individuals aged ≥60 years from the Korea National Health Insurance Service-Senior cohort. After excluding participants with preexisting MASLD, 329 388 individuals were finally analyzed. Participants were categorized into four groups based on the presence of overweight/obesity and additional risk factors (aRF) included in the cardiometabolic diagnostic criteria of MASLD.

The overall incidence of MASLD was 1.94 per 100 person-years, and the incidence of advanced fibrosis in MASLD patients was 1.78 per 100 person-years. MASLD development was significantly higher in overweight/obese patients (2.65 per 100 person-years) compared to lean patients (1.09 per 100 person-years), and this trend persisted after stratification by the presence of aRF. Similarly, the incidence of advanced fibrosis among MASLD patients was higher in overweight/obese individuals (2.06 per 100 person-years) compared to lean counterparts (0.87 per 100 person-years), irrespective of aRF.

The lower incidence of MASLD in the elderly population compared to the general population underscores the importance of identifying age-specific risk factors. Overweight/obesity emerged as a robust predictor of MASLD development and advanced fibrosis. Additionally, the presence of additional cardiometabolic risk factors further increased the risk of incident MASLD and advanced fibrosis among the elderly.

Polyphenols, known for their potent antioxidant and anti-inflammatory properties, have emerged as promising, natural, and safe complementary treatment options for metabolic-associated steatotic liver disease (MASLD). Among these, curcumin, resveratrol, and silymarin are the most extensively studied; however, their differential effects on MASLD outcomes remain inconclusive. This systematic review and meta-analysis of RCTs aimed to evaluate the efficacy of curcumin, resveratrol, and silymarin in patients with MASLD. A comprehensive search of seven databases was conducted up to September 2024. Odds ratios (OR), mean differences (MD), and standardized MD (SMD) with 95% confidence intervals (CI) were used to assess treatment effects. Primary outcomes included improvement in hepatic steatosis and ALT activity, while secondary outcomes included changes in AST activity, blood lipids, glucose, BMI, blood pressure, and TNF-α. Twenty-seven studies involving 1691 participants were included. Curcumin significantly improved hepatic steatosis compared to placebo (OR: 4.39, 95% CI: 1.45 to 13.27, p = 0.009), followed by resveratrol (OR: 3.18, 95% CI: 1.20 to 8.42, p = 0.02). Silymarin exhibited the strongest effect in reducing ALT levels (MD: -6.44 U/L, 95% CI: -10.03 to -2.85, p = 0.0004), with curcumin (MD: -5.88 U/L, 95% CI: -9.05 to -2.72, p = 0.0003) also showing significant reductions. A marked reduction in AST was observed with silymarin (MD: -6.99 U/L, 95% CI: -8.56 to -5.42, p < 0.00001), followed by curcumin (MD: -3.36 U/L, 95% CI: -5.35 to -1.36, p = 0.001). Furthermore, curcumin intake significantly improved metabolic indicators (TG, FBG, HOMA-IR, and BMI). Resveratrol reduced FBG and DBP. Curcumin had the strongest effect on hepatic steatosis and improved both transaminase levels and metabolic markers. Silymarin demonstrated the greatest reduction in transaminase levels, while resveratrol showed modest benefits in steatosis and metabolic improvements. The three polyphenols appear as promising therapeutics for the treatment of MASLD.

Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Recent studies have suggested an association between H. pylori and metabolic dysfunction associated steatotic liver disease (MASLD). We aim to evaluate the association of H. pylori virulence genes with non-invasive markers of liver injury and fibrosis in MASLD subjects.

A total of 362 dyspeptic patients who underwent gastroscopy were selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), gastric biopsies, and H. pylori virulence genes (cagA, vacA) were evaluated.

A cohort comprised of 61 % women and 39 % men with a median age of 52 (40-60) years. MASLD was observed in 42 %, and H. pylori-positive in 45 %. No differences were observed regarding H. pylori status at co-morbid metabolic conditions. In MASLD cohort, H. pylori-positive was associated with higher AST, ALT, FIB-4 and LSM. Indeed, carriers of cagA/vacA-s1/m1-positive allelic combination were associated with higher AST, ALT, FIB-4 and LSM but not cagA/vacA-s1/m1-negative. The OR for high-risk of significant/advanced- fibrosis by VCTE (≥8 kPa) with H. pylori-positive was 2.56 (95 % CI, 1.2-5.75) and for cagA/vacA-s1/-m1-positive allelic carriers was 4.01 (95 % CI, 1.38-11.56), but non-significant association in cagA/vacA-s1/-m1-negative. After adjusting for age, gender, diabetes, BMI and hypertension the OR for VCTE ≥8 kPa with H. pylori-positive was 2.43 (95 % CI, 1.88-12.44), and cagA/vacA-s1/m1-positive allelic carriers was 4.06 (95 % CI, 1.22-14.49).

In our cohort of functional dyspepsia (FD) patients with MASLD, H. pylori was associated with non-invasive markers of liver injury and fibrosis. Carriers of cagA/vacA-s1/m1-positive allelic combination showed an independent risk of significant/advanced fibrosis by VCTE.

The endogenous FGF21 level is a potential target for diagnosing NAFLD. This study aimed to assess the clinical utility of FGF21 in diagnosing NAFLD and provide new ideas for predicting and preventing NAFLD. A total of 193 patients diagnosed with NAFLD based on diagnostic criteria and 64 healthy individuals were included in the NAFLD and non-NAFLD groups, respectively. Data on the participant names, sex, age, height, weight, blood pressure, serum FGF21 levels, liver function enzyme (AST, ALT, ALP, and GGT) levels, lipid profile (TC, TG, HDL-C, and LDL-C) indicators, and blood glucose levels were collected. The data were statistically analyzed to assess the correlations between serum FGF21 levels and related biochemical markers in NAFLD patients. The areas under the receiver operating characteristic curves (AUCs) of serum FGF21, lipids (TG + TC + HDL + LDL), and FGF21 combined with lipids for the diagnosis of NAFLD were compared. Compared with the non-NAFLD group, the NAFLD group presented significantly higher levels of FGF21. Serum FGF21 levels in the NAFLD group were positively correlated with the TG, TC, and LDL-C levels (P < 0.05). The area under the receiver operating characteristic curve (AUC) of serum FGF21 for the diagnosis of NAFLD was 0.832 (95% CI: 0.77-0.886, P < 0.001). The AUC of FGF21 combined with lipids (TG + TC + HDL + LDL) for the diagnosis of NAFLD was 0.910 (95% CI: 0.874-0.946, P < 0.001). There is a close association between elevated FGF21 levels and the development of NAFLD. The progression of NAFLD is complex and varied, and its pathogenesis is unclear. Early detection, prevention, and intervention may help slow NAFLD development or even reverse the disease. In this study, we found that the FGF21 level could be used as an auxiliary biological indicator for predicting NAFLD, and the role of FGF21 in the progression of NAFLD deserves to be investigated in the future.

The most prevalent chronic liver disease in both developed and developing nations is Metabolic dysfunction-associated Steatotic Liver Disease (MASLD). The condition increases the risk of comorbidities and liver-related morbidity and mortality. The public's awareness and medical personnel's understanding are essential in creating countermeasures to stop the disease's spread; a positive attitude is essential for early screening. This study aimed to explore the knowledge and attitudes of Jordanians living in Amman toward MASLD to determine the public's awareness and medical personnel's understanding of the disease.

A cross-sectional study was conducted using an online self-administered questionnaire that included 5 items for knowledge and 8 for attitude. Demographic questions were also included to further examine how demographic factors affected knowledge and attitude.

Among 906 responders, (63.4%) were females, and (36.6%) were males. The majority age group was 18-30 (56.2%). Only 49.5% had previous knowledge of MASLD, (44.6%) believed they were at risk of developing it. There is a statistical significance between age, gender, educational level, and having a good knowledge of MASLD and a positive attitude towards it (p<0.05).

Generally, Jordan's population has a fair knowledge of MASLD and a positive attitude towards it. Warranting more research into the reasons behind it, and more awareness campaigns.

Non-alcoholic fatty liver disease (NAFLD) and obesity have become one of the most common chronic diseases, and the global prevalence is increasing year by year. Both are accompanied by hypersensitive C-reactive protein (hs-CRP). At present, there are many predictors of NAFLD. Exploring the relationship between hs-CRP and nonalcoholic fatty liver disease in non-obese people will be helpful for risk prediction and clinical screening in high-risk populations.

To explore the relationship between levels of serum hs-CRP and the presence of NAFLD in non-obese people.

A total of 6558 participants who underwent physical examination from March 2017 to November 2017. Multivariate logistic regression was utilized to analyze the risk factors associated with NAFLD.

This study including 4240 males and 2318 females ranging from 20 to 94 years. In 1396 patients with NAFLD, the prevalence rate was 21.3%, among which 1056 (24.9%) males and 340 (14.7%) females had NAFLD. The prevalence of NAFLD was much higher in males compared to females (χ2 = 93.748, P < 0.001). In the nonalcoholic fatty liver group, various factors including hs-CRP, age, WC, BMI, systolic blood pressure and blood pressure diastolic blood pressure were significantly higher than those in the control group. Logistic regression analysis confirmed that hs-CRP was an independent risk factor for NAFLD, even after adjusting for relevant variables.

The prevalence of NAFLD increases with the level of hs-CRP in both men and women who are non-obese. Hs-CRP levels are an important risk factor for nonalcoholic fatty liver disease in non-obese individuals.

Background  Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) frequently coexist due to overlapping risk factors such as metabolic syndrome and obesity. T2DM exacerbates the progression of NAFLD, increasing the risk of cirrhosis and hepatocellular carcinoma. Thus, early detection of liver fibrosis is crucial to prevent severe liver disease. A 2D shear wave elastography (2D SWE) has emerged as a reliable non-invasive method for assessing liver stiffness, potentially reducing the need for liver biopsies and facilitating prompt treatment interventions. Methods This cross-sectional study, conducted over 18 months, included 100 T2DM and NAFLD patients from the Medicine and Diabetes Outpatient Department at SRM Medical College Hospital and Research Centre, Chengalpattu, India. Participants underwent gray-scale ultrasound to classify fatty liver (Grades I, II, and III) and 2D SWE to evaluate liver stiffness. Additional data on fasting and postprandial blood glucose, glycosylated hemoglobin (HbA1c), lipid profiles, liver function tests, and body mass index (BMI) were collected. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 21 (Released 2012; IBM Corp., Armonk, New York, United States). Results The mean age of participants was 47.9 years, with 61% being male. Fatty liver Grades I, II, and III were present in 47%, 41%, and 12% of patients, respectively. SWE results showed that 30% had stiffness values <5 kPa, 53% had values between 5.1-9 kPa, 16% had values between 9.1-13 kPa, and 1% had values >13 kPa. Liver size increased significantly with fatty liver grade (p=0.029). HbA1c levels and blood glucose levels were significantly correlated with fatty liver grades (p<0.0001). Triglyceride levels were higher with increasing fatty liver grades (p<0.0001). A significant correlation was found between gamma-glutamyl transferase (GGT) levels and SWE values (p=0.04). In the lipid profile, significant correlations were noted between SWE values and triglycerides (p=0.005), cholesterol (p=0.026), and very-low-density lipoprotein (VLDL) (p=0.131). Higher levels of HbA1c, fasting blood sugar, and postprandial blood sugar were also significantly correlated with SWE values (p<0.0001). Increasing grades of hepatic steatosis significantly correlated with SWE values (p<0.0001). BMI positively correlated with SWE values (r=0.321, p=0.001). Conclusion This study highlights the prevalence of advanced liver stiffness in patients with T2DM and NAFLD, which correlates significantly with higher grades of fatty liver, elevated HbA1c, blood sugar levels, and abnormal lipid profiles. SWE is a valuable tool for assessing liver stiffness and guiding the management of NAFLD in patients with T2DM.

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, with a prevalence of 38%. In these patients, cardiovascular disease (CVD) is the number one cause of mortality rather than liver disease. Liver abnormalities per se due to MASLD contribute to risk factors such as dyslipidemia and obesity and increase CVD incidents. In this review we discuss hepatic pathophysiological changes the liver of MASLD leading to cardiovascular risks, including liver sinusoidal endothelial cells, insulin resistance, and oxidative stress with a focus on glutathione metabolism and function. In an era where there is an increasingly robust recognition of what causes CVD, such as the factors included by the American Heart Association in the recently developed PREVENT equation, the inclusion of liver disease may open doors to how we approach treatment for MASLD patients who are at risk of CVD.

Apical periodontitis (AP) is the chronic inflammation of the periradicular tissues in response to root canal infection. Whilst AP has been linked with systemic inflammation and noncommunicable diseases, its potential association with nonalcoholic fatty liver disease (NAFLD) is unknown. We aimed to evaluate the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as surrogate markers of hepatic injury, and the systemic inflammatory burden in otherwise healthy individuals with and without AP diagnosis.

Cross-sectional study. Individuals with AP (n = 30) and healthy controls (n = 29) were recruited. The number, mean diameter (mm) and periapical index of the apical lesions of endodontic origin (ALEO) were assessed. ALT and AST levels (pg/mL) were measured through enzyme-linked immunosorbent assays. The serum levels of TNF-α, IL-4, IL-9, IL-10, IL-17A and IL-22 were evaluated by Multiplex assay. Inferential analysis was performed using t-test or Mann-Whitney tests according to data distribution and linear regression models. Data were analysed with StataV16 (p < .05).

ALT and AST levels were significantly higher in individuals with AP compared to controls (p < .05). Serum inflammatory biomarkers showed no significant differences between the study groups. Bivariate and multivariate analyses confirmed that AP diagnosis was independently associated with ALT and AST elevations (p < .05). Additionally, the number of ALEO positively influenced AST levels (p = .002). IL-22 on the other hand, was associated with reduced ALT levels (p = .043).

AP is associated with higher serum hepatic transaminases ALT and AST, potentially contributing to NAFLD physiopathology in young adults.

Nonalcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease that can lead to significant morbidity and mortality primarily due to hepatic complications including fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure, as well as cardiovascular disease. As the development of NASH/MASH is closely linked to cardiometabolic risk factors such as obesity and type 2 diabetes mellitus, its prevalence is increasing along with the prevalence of those conditions. Identifying at-risk patients or those early in the disease process is essential to optimizing care and may prevent future complications. Current treatment options include disease-modifying interventions, off-label use of US Food and Drug Administration (FDA)-approved medications for comorbid conditions, and resmetirom, the recently first-ever FDA-approved medication specifically for use in NASH/MASH. There is also considerable continued activity in related drug development research with several other potential emerging treatments. With the increasing prevalence of NASH/MASH and emerging treatments, it is important for managed care organizations (MCOs) to be prepared to assist in patient care and implement equitable treatment management. Understanding patient perspectives and their experience with NASH/MASH provides insights for MCOs such as the need for education of both health care providers and patients to encourage early diagnosis and for enhancing access to individualized care including resources and support. Additionally, MCOs can consider potential management strategies for new and emerging treatments.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in patients with diabetes; limited data suggested that statins may reduce the risk of NAFLD progression. This study aimed to examine the association between statins and the development or progression of NAFLD in veterans with diabetes. In a new-user negative control design, we conducted a retrospective propensity score (PS)-matched cohort study of patients with diabetes between 2003 and 2015. After excluding patients with other causes of liver disease, we formed PS using 85 characteristics. The primary outcome was a composite NAFLD progression outcome. Primary analysis examined odds of outcome in PS-matched cohort. Post-hoc analysis included a PS-matched cohort of statin users with intensive lowering of low-density lipoprotein-cholesterol (LDL-C) vs low-intensity lowering. We matched 34,102 pairs from 300,739 statin users and 38,038 non-users. The composite outcome occurred in 8.8% of statin users and 8.6% of non-users (odds ratio (OR) 1.02, 95% confidence interval (95% CI) 0.97-1.08). In the post-hoc analysis, intensive lowering of LDL-C compared to low-intensity showed increased NAFLD progression (OR 1.21, 95% CI 1.13-1.30). This study showed that statin use in patients with diabetes was not associated with decreased or increased risk of NAFLD progression. Intensive LDL-C lowering, compared to low-intensity LDL-C lowering, was associated with an increased risk of NAFLD progression.

Elevations in fructose consumption have been reported to contribute significantly to an increased incidence of obesity and metabolic diseases in industrial countries. Mechanistically, a high fructose intake leads to the dysregulation of glucose, triglyceride, and cholesterol metabolism in the liver, and causes elevations in inflammation and drives the progression of nonalcoholic fatty liver disease (NAFLD). A high fructose consumption is considered to be toxic to the body, and there are ongoing measures to develop pharmaceutical therapies targeting fructose metabolism. Although a large amount of work has summarized the effects fructose exposure within the intestine, liver, and kidney, there remains a gap in our knowledge regarding how fructose both indirectly and directly influences immune cell recruitment, activation, and function in metabolic tissues, which are essential to tissue and systemic inflammation. The most recent literature demonstrates that direct fructose exposure regulates oxidative metabolism in macrophages, leading to inflammation. The present review highlights (1) the mechanisms by which fructose metabolism impacts crosstalk between tissues, nonparenchymal cells, microbes, and immune cells; (2) the direct impact of fructose on immune cell metabolism and function; and (3) therapeutic targets of fructose metabolism to treat NAFLD. In addition, the review highlights how fructose disrupts liver tissue homeostasis and identifies new therapeutic targets for treating NAFLD and obesity.

By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is mainly classified into metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and the latter putatively progresses to cirrhosis and hepatocellular carcinoma. Owing to increased incidence and obscure etiology of MASH, its management still remains a tremendous challenge. Recently, hepatocyte PCD has been attracted much attention as a potent driver of the pathological progression from MASL to MASH, and some pharmacological agents have been proved to exert their salutary effects on MASH partly via the regulation of the activity of hepatocyte PCD. The current review recapitulates the pathogenesis of different modalities of PCD, clarifies the mechanisms underlying how metabolic disorders in MASLD induce hepatocyte PCD and how hepatocyte PCD contributes to inflammatory and fibrotic progression of MASH, discusses several signaling pathways in hepatocytes governing the execution of PCD, and summarizes some potential pharmacological agents for MASH treatment which exert their therapeutic effects partly via the regulation of hepatocyte PCD. These findings indicate that hepatocyte PCD putatively represents a new therapeutic point of intervention for MASH.

Natural bioactive compounds with antioxidant, antimicrobial, anticancer, and other biological activities are vital for maintaining the body's physiological functions and enhancing immunity. These compounds have great potential as nutritional therapeutic agents, but they can be limited due to their poor flavor, color, unstable nature, and poor water solubility, and degradation by gastrointestinal enzymes. Liposomes, as ideal carriers, can encapsulate both water-soluble and fat-soluble nutrients, enhance the bioavailability of functional substances, promote the biological activity of functional substances, and control the release of nutrients. Despite their potential, liposomes still face obstacles in nutrient delivery. Therefore, the design of liposomes for special needs, optimization of the liposome preparation process, enhancement of liposome encapsulation efficiency, and industrial production are key issues that must be addressed in order to develop food-grade liposomes. Moreover, the research on surface-targeted modification and surface functionalization of liposomes is valuable for expanding the scope of application of liposomes and achieving the release of functional substances from liposomes at the appropriate time and site. The establishment of in vivo and in vitro digestion models of nutrient-loaded liposomes, in-depth study of gastrointestinal digestive behavior after liposome ingestion, targeted nutrient release, and deciphering the nutritional intervention of human diseases and positive health promotion are promising fields with broad development prospects.

One challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease.

To derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes.

We used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic fibrosis (> 8 kPa). Possible predictors included data from the EHR for age, gender, diabetes, hypertension, FIB-4, body mass index (BMI), LDL, HDL, and triglycerides.

Of 344 patients (56.4% women), 34 had any hepatic fibrosis, and 15 significant hepatic fibrosis. Three variables (BMI, FIB-4, diabetes) were identified from both approaches. When we used variable cut-offs defined by Youden's index, the final model predicting any hepatic fibrosis had an AUC of 0.75 (95% CI 0.67-0.84), NPV of 91.5% and PPV of 40.0%. The final model with variable categories based on standard clinical thresholds (i.e., BMI ≥ 30 kg/m2; FIB-4 ≥ 1.45) had lower discriminatory ability (AUC 0.65), but higher PPV (50.0%) and similar NPV (91.3%). We observed similar findings for predicting significant hepatic fibrosis.

Our results demonstrate that standard thresholds for clinical risk factors/biomarkers may need to be modified for greater discriminatory ability among populations with high prevalence of obesity and diabetes.

Liver cirrhosis due to nonalcoholic steatohepatitis (NASH) is a life-threatening condition with increasing incidence world-wide. Although its symptoms are unspecific, it can lead to decompensation events such as ascites, hepatic encephalopathy, variceal hemorrhage, and hepatocellular carcinoma (HCC). In addition, an increased risk for cardiovascular events has been demonstrated in patients with NASH. Pharmacological treatments for NASH cirrhosis are not yet available, one of the reasons being the lack in surrogate endpoints available in clinical trials of NASH cirrhosis. The feasibility of non-invasive prognostic biomarkers makes them interesting candidates as possible surrogate endpoints if their change following treatment would result in better outcomes for patients in future clinical trials of NASH cirrhosis. In this systematic literature review, a summary of the available literature on the prognostic performance of non-invasive biomarkers in terms of cardiovascular events, liver-related events, and mortality is outlined. Due to the scarcity of data specific for NASH cirrhosis, this review includes studies on NAFLD whose evaluation focuses on cirrhosis. Our search strategy identified the following non-invasive biomarkers with prognostic value in studies of NASH patients: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), enhanced liver fibrosis (ELF™), BARD (BMI, AST/ALT (alanine aminotransferase) ratio, diabetes), Hepamet Fibrosis Score (HFS), liver enzymes (AST + ALT), alpha-fetoprotein, platelet count, neutrophil to lymphocyte ratio (NLR), Lysyl oxidase-like (LOXL) 2, miR-122, liver stiffness, MEFIB (liver stiffness measured with magnetic resonance elastography (MRE) + FIB-4), and PNPLA3 GG genotype. The aim of the present systematic literature review is to provide the reader with a summary of the non-invasive biomarkers with prognostic value in NASH cirrhosis and give an evaluation of their utility as treatment monitoring biomarkers in future clinical trials.

Silibinin has considerable therapeutic potential for the treatment of diabetes through anti-inflammatory, antioxidant, and immunomodulatory properties. However, the therapeutic application of silibinin is quite limited due to its poor bioavailability. In the present study, an attempt was made to improve the antidiabetic efficacy of silibinin by its encapsulation in liposomal vesicles. The liposomes with a high encapsulation efficiency of silibinin (96%) and a zeta potential of -26.2 ± 0.6 mV were developed and studied using nicotinamide/streptozotocin-induced diabetic rats. Administration of silibinin-loaded liposomes to diabetic rats lowered glucose levels, increased insulin levels, and improved pancreatic islet architecture. The anti-inflammatory effect of silibinin-loaded liposomes was demonstrated by a decrease in serum C-reactive protein (CRP) levels and a reduced deposition of collagen fibers in the islets of diabetic rats. Furthermore, silibinin-loaded liposomes were more efficient in lowering glucose, alanine transaminase, triglyceride, and creatinine levels in diabetic rats than pure silibinin. In addition, silibinin-loaded liposomes had a significantly better effect on beta-cell mass and Glut2 glucose receptor distribution in diabetic islets than pure silibinin. The present results clearly show that liposome encapsulation of silibinin enhances its antidiabetic efficacy, which may contribute to the therapeutic benefit of silibinin in the treatment of diabetes and its complications.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.

An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.

Several studies show that gut microbiotas in patients with nonalcoholic fatty liver disease (NAFLD) differ from those in a healthy population, suggesting that this alteration plays a role in NAFLD pathogenesis. We investigated whether prebiotic administration affects liver fat content and/or liver-related and metabolic parameters. Patients with NAFLD and metabolic syndrome (age: 50 ± 11; 79% men) were randomized to receive either 16 g/day of prebiotic (ITFs-inulin-type fructans) (n = 8) or placebo (maltodextrin) (n = 11) for 12 weeks. Patients were instructed to maintain a stable weight throughout the study. Liver fat content (measured by H1MRS), fecal microbiota, and metabolic, inflammatory, and liver parameters were determined before and after intervention. Fecal samples from patients who received the prebiotic had an increased content of Bifidobacterium (p = 0.025), which was not observed with the placebo. However, the baseline and end-of-study liver fat contents did not change significantly in the prebiotic and placebo groups, neither did the liver function tests' metabolic and inflammatory mediators, including fibroblast growth factor-19 and lipopolysaccharide-binding protein. Body weight remained stable in both groups. These findings suggest that prebiotic treatment without weight reduction is insufficient to improve NAFLD.

Iron metabolism and insulin resistance (IR) are closely related to non-alcoholic fatty liver disease (NAFLD). However, the interplay between them on the occurrence and progression of NAFLD is not fully understood. We aimed to disentangle the crosstalk between iron metabolism and IR and explore its impact on NAFLD.

We analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017-2018 to evaluate the association between serum iron metabolism indicators (ferritin, serum iron, unsaturated iron-binding capacity [UIBC], total iron-binding capacity [TIBC], transferrin saturation, and transferrin receptor) and NAFLD/non-alcoholic steatohepatitis (NASH). Mediation analysis was conducted to explore the role of IR played in these relationship.

A total of 4812 participants were included, among whom 43.7% were diagnosed with NAFLD and 13.2% were further diagnosed with NASH. After adjusting the covariates, the risk of NAFLD increases with increasing serum ferritin (adjusted odds ratio [aOR] 1.71, 95% confidence interval [CI] 1.37-2.14), UIBC (aOR 1.45, 95% CI 1.17-1.79), and TIBC (aOR 1.36, 95% CI 1.11-1.68). Higher levels of serum ferritin (aOR 3.70, 95% CI 2.25-6.19) and TIBC (aOR 1.69, 95% CI 1.13-2.56) were also positively associated with NASH. Participants with IR were more likely to have NAFLD/NASH. Moreover, IR-mediated efficacy accounted for 85.85% and 64.51% between ferritin and NAFLD and NASH, respectively.

Higher levels of serum ferritin and TIBC are closely associated with the occurrence of NAFLD and NASH. IR may be considered a possible link between NAFLD or NASH and increased serum ferritin levels.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a dynamic chronic liver disease closely related to metabolic abnormalities such as diabetes and obesity. MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). However, the mechanisms underlying the progression of MASLD and further progression to liver fibrosis and liver cancer are unknown.

In this study, we performed transcriptome analysis in livers from mice with MASLD and found suppression of a potential anti-oncogene, RAS association domain protein 4 (RASSF4). RASSF4 expression levels were measured in liver or tumor tissues of patients with MASH or HCC, respectively. We established RASSF4 overexpression and knockout mouse models. The effects of RASSF4 were evaluated by quantitative polymerase chain reaction, Western blotting, histopathological analysis, wound healing assays, Transwell assays, EdU incorporation assays, colony formation assays, sorafenib sensitivity assays, and tumorigenesis assays.

RASSF4 was significantly down-regulated in MASH and HCC samples. Using liver-specific RASSF4 knockout mice, we demonstrated that loss of hepatic RASSF4 exacerbated hepatic steatosis and fibrosis. In contrast, RASSF4 overexpression prevented steatosis in MASLD mice. In addition, RASSF4 in hepatocytes suppressed the activation of hepatic stellate cells (HSCs) by reducing transforming growth factor beta secretion. Moreover, we found that RASSF4 is an independent prognostic factor for HCC. Mechanistically, we found that RASSF4 in the liver interacts with MST1 to inhibit YAP nuclear translocation through the Hippo pathway.

These findings establish RASSF4 as a therapeutic target for MASLD and HCC.

The nature of the relationship between red meat consumption and nonalcoholic fatty liver disease (NAFLD) remains unclear. Through this meta-analysis, we aimed to determine the association and dose-response relationship between red meat consumption (both processed and unprocessed) and the risk of NAFLD.

We systematically searched CENTRAL, PubMed, Embase, Web of Science and Scopus from inception to February 2022 for observational studies in which the exposure of interest was red meat consumption; the outcome of interest was the risk of NAFLD; and where odds ratios (ORs) or risk ratios were provided or could be calculated. We used random-effects meta-analyses to pool the effect sizes and performed analyses to estimate the linearity of the dose-response relationships between red meat intake and NAFLD risk.

We included 10 studies in this review. The meta-analysis showed a significant association between the intake of red meat (OR = 1.27; 95% confidence interval (CI) = 1.07-1.50, P = 0.000, I2 = 81%), processed red meat (OR = 1.20; 95% CI = 1.04-1.3, P = 0.162, I2 = 34.9%) or unprocessed red meat (OR = 1.28; 95% CI = 1.05-1.55, P = 0.001, I2 = 76.2%) and the risk of NAFLD. We also found a significant linear dose-response association between processed red meat intake and NAFLD, with each 25-g increment of processed red meat intake per day was associated with an 11.1% higher risk of NAFLD (OR = 1.11; 95% CI = 1.01-1.22, P = 0.029), and a nonlinear association between unprocessed meat intake and NAFLD (P = 0.003 for nonlinearity).

Our findings indicate a potential positive association between red meat consumption (both processed and unprocessed) and NAFLD risk, especially in relation to increased intake of processed red meat compared to unprocessed red meat. However, caution is advised in interpreting these results; further research could establish a clearer understanding of the relationship between red meat consumption and NAFLD risk.

PROSPERO: CRD42022332839.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Primary care providers play a critical role in the screening, diagnosis, and management of MASLD and/or metabolic dysfunction-associated steatohepatitis (MASH), though they can face challenges in this setting, particularly where healthcare resources are limited and barriers to care exist. To address these challenges, several guidelines have been developed to provide evidence-based recommendations for the clinical assessment and management of patients with MASLD/MASH.

To provide a unified, simple-to-understand, practical guide for MASLD screening, diagnosis, and management based on current guideline recommendations, for use by primary care providers in daily practice.

Evidence-based recommendations from several international guidelines were summarized, focusing on the similarities and differences between them.

Recommendations are broadly aligned across the guidelines, but several key differences are evident. Practical guidance is provided on screening, identifying target populations for risk stratification, initial evaluation of individuals with suspected MASLD, surveillance, risk stratification and referral, as well as approaches to the management of MASLD and associated comorbidities, with specific considerations for the primary care setting.

Primary care providers are ideally placed to identify at-risk individuals, implement evidence-based interventions to prevent the development of fibrosis and cirrhosis, and effectively manage comorbidities. Equipping primary care providers with the necessary knowledge and tools to effectively manage MASLD/MASH may help to improve patient outcomes and reduce the burden of liver disease.