Fibroblast Growth Factor 21 Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously called non-alcoholic fatty liver disease (NAFLD), has become a leading cause of chronic liver disease in people living with HIV (PLWH), especially in the era of effective antiretroviral therapy (ART). As the life expectancy of PLWH continues to increase, non-AIDS-related comorbidities such as metabolic syndrome, insulin resistance, and cardiovascular disease have become more prevalent, contributing to a rising incidence of MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Studies have shown that the prevalence of MASLD in PLWH ranges from 30% to 50%, with biopsy-based estimates of non-alcoholic steatohepatitis (NASH) approaching 49% and advanced fibrosis up to 23%. This burden is influenced not only by traditional metabolic risk factors but also by HIV-specific mechanisms, including chronic immune activation, lipodystrophy, microbial translocation, and mitochondrial dysfunction associated with ART exposure. Despite its high prevalence and clinical significance, MASLD remains underdiagnosed in PLWH. This scoping review aimed to systematically map the existing literature on MASLD in people living with HIV, including epidemiology, risk factors, diagnostic approaches, fibrosis assessment, and management strategies. Understanding the unique interplay between HIV infection and metabolic liver disease is essential for the early diagnosis and prevention of progression to cirrhosis and hepatocellular carcinoma in this growing patient population.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent manifestation of obesity and other metabolic diseases. Autotaxin (ATX), an enzyme involved in the generation of lysophosphatidic acid (LPA), has recently emerged as a potential biomarker of metabolic inflammation and liver disease progression. Vegetable-based dietary interventions have been shown to reduce liver steatosis, but evidence of the impact of this dietary approach on ATX levels remains limited. Objectives: To evaluate the short-term effects of a bioactive vegetable-enriched diet from the Brassicaceae and Asteraceae families on serum ATX levels and liver-related parameters in individuals with obesity and MASLD, with a specific focus on sex differences. Methods: In this two-month pilot study, 44 obese adults (BMI > 30 kg/m2) underwent clinical and instrumental assessments at baseline (T0) and after the dietary intervention (T1). Results: After the intervention, serum ATX levels significantly decreased (from 206.3 ± 52.8 to 191.7 ± 45.7 ng/mL, p < 0.001), and there were improvements in metabolic parameters (BMI, waist circumference, blood pressure, fat mass, insulin, HOMA-IR, triglycerides, total and LDL cholesterol) and liver indices (CAP, ALT, AST, γGT). The multivariate GEE model confirmed a significant reduction in ATX, independent of age, sex, FFM, LPA, LSM, Hemoglobin A1c, and PAI-1 (β = -9.87, p < 0.001). When stratified by sex, women exhibited a more pronounced reduction in ATX levels (β = -12.24; p = 0.005) compared to men (β = -9.43; p = 0.014). Conclusions: A short-term, vegetable-enriched dietary intervention can significantly reduce serum ATX levels and improve metabolic and liver-related parameters in individuals with MASLD. Sex-specific analysis reveals a greater ATX-lowering effect in women, suggesting potential sex-based differences in ATX metabolism or dietary responsiveness. These findings suggest that ATX may serve as a modifiable biomarker responsive to nutritional intervention and a potential therapeutic target in metabolic liver disease.

Pediatric Liver Transplantation for Inherited Metabolic Liver Disease: A Single-Center Experience

Clinical Features and Outcomes of Lean Metabolic Dysfunction-Associated Steatotic Liver Disease With Increased Alcohol Intake.

Metabolic dysfunction-associated steatotic liver disease is associated with a growing global health burden with increasing prevalence in both adult and pediatric populations. Emerging evidence suggests that the origins of steatotic liver disease may trace back to early life, with the gut microbiota serving as a critical mediator in this developmental programming. This review synthesizes current knowledge on maternal-infant gut microbiota transmission and its role in shaping long-term liver health through the gut-liver axis. We examined key maternal factors, including delivery mode, feeding of breast milk, diet, metabolic status, and antibiotic exposure, that profoundly influence infant microbiota assembly. The critical window of microbiota establishment during the first 1000 days shapes intestinal barrier function, immune development, and metabolic pathways that persist into adulthood. Mechanistically, early dysbiosis contributes to metabolic dysfunction-associated steatotic liver disease pathogenesis through multiple interconnected pathways, including compromised intestinal barrier integrity facilitating endotoxemia, altered short-chain fatty acid production affecting energy metabolism and inflammation, disturbed bile acid signaling disrupting metabolic homeostasis, and epigenetic modifications potentially shaping long-term susceptibility. We critically evaluated emerging microbiota-targeted interventional strategies during pregnancy and infancy, including probiotics, human milk oligosaccharide supplementation, and synbiotic approaches, highlighting their potential for disease prevention. This review uniquely integrates concepts of developmental origins with detailed gut-liver axis mechanisms, emphasizing the maternal-infant microbial continuum as an underexplored but promising target for preventing metabolic liver disease. While significant research challenges remain, particularly in establishing causality and developing personalized interventions, modulation of the early gut microbiome offers an innovative preventive strategy against the rising tide of metabolic dysfunction-associated steatotic liver disease, potentially disrupting the intergenerational cycle of metabolic disease.

Yet more evidence that MAFLD is more than a name change

Metabolic liver disease is the underlying diagnosis in only a small proportion of patients who undergo liver transplantation (LT), but for these patients, LT is lifesaving. Patients with metabolic liver disease often do not present with typical findings of end-stage liver disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liverbased metabolic disease is classified into 3 types: (1) disease that causes structural liver damage with liver failure or cirrhosis, (2) metabolic disease without structural liver damage that affects other organs (especially the central nervous system), and (3) metabolic disease with systemic deficiencies that are partially represented in the liver. There may be overlap in presentation, with some disease forms presenting either with or without structural liver disease. General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable metabolic course that may cause severe central nervous system complications in several of these disease states. Also, although many of these diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.

Aim: Liver transplantation (LT) is performed for several indications in the pediatric population, including malignancy and acute hepatic failure among others. LT has become an important treatment alternative for metabolic diseases. In most pediatric transplant centers, metabolic liver disease is the second most common indication for liver transplantation after biliary atresia. Our studies aim is to compare the post-transplant outcomes of the patients with metabolic and other liver diseases in our transplant program. Materials and Methods: One hundred eighty-nine patients who underwent liver transplantation between 1997 and 2015 due to metabolic diseases and acute or chronic liver failure were included in the study. Results: We enrolled 189 patients in our study. 54% (n = 102) male and 46% (n = 87) female patients were included in the study. Metabolic disease group include 56 patients. Progressive familial intrahepatic cholestasis (PFIC) is the most common disease among metabolic diseases resulting in LT Wilson disease takes second place. Post-transplant immunosuppression was similar for both groups. Although there was no difference in both groups, regarding onset of the post-transplant complications for graft type, recipient age. Biliary and portal vein complications were most particularly defined in the group with nonmetabolic diseases. There was no significant difference in survival between the two groups. Conclusion: Liver transplantation is an important treatment option for acute hepatic failure and end-stage liver diseases. In addition, liver transplantation is an alternative treatment option for some metabolic diseases.

Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.

Background and Aims: Metabolic liver disease is associated with obesity, insulin resistance, cardiovascular disease, and metabolic disorders. A Mediterranean diet (MD), known for its anti-inflammatory and antioxidant properties, is effective in managing various chronic diseases, including liver diseases. This study aimed to explore the influence of adherence to the MD on the risk of chronic metabolic diseases, including steatotic liver disease (SLD), metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-related liver diseases (ALDs). Methods: This retrospective cohort study analyzed 5395 individuals from a single center between 2020 and 2022, grouped by adherence to the MD using the Korean Mediterranean Diet Adherence Score (K-MEDAS). MASLD score, ALD, and cardiovascular risk factors were also assessed. Statistical analyses were performed using 1:1 exact matching and multiple regression to compare the less adherent (K-MEDAS 0–7) and highly adherent (K-MEDAS 8–13) groups. Results: Adjusting for confounding variables, high adherence to the MD was significantly associated with lower rates of SLD (odds ratio [OR] 0.818, 95% confidence interval [CI] 0.700–0.957, p = 0.012), MASLD (OR 0.839, 95% CI 0.714–0.986, p = 0.033), and ALD (OR 0.677, 95% CI 0.671–0.683, p &lt; 0.001). Post-propensity score matching analysis revealed that the highly adherent group exhibited significantly lower triglyceride levels, triglyceride and glucose index, atherogenic Index of Plasma, and Framingham risk scores than the less adherent group. Conclusions: Good adherence to the MD considerably reduces the risk of SLD, MASLD, and ALD, underscoring its protective effects and potential to prevent metabolic liver diseases and their complications.

Metabolic dysfunction-associated steatotic liver disease is a metabolic disease with an increasing incidence. Its pathogenesis involves the interaction of multiple factors. There is currently no specific treatment, so early prevention and treatment are crucial. Mesenchymal stem cells are a type of cell with the ability to self-renew and differentiate in multiple directions. They have a wide range of sources, including umbilical cords, bone marrow, and fat, and have various biological functions such as anti-inflammation, immune regulation, anti-oxidation, and inhibition of fibrosis. They have shown significant potential in the treatment of non-alcoholic fatty liver disease. In recent years, mesenchymal stem cells derived exosomes have been shown to be rich in bioactive substances, and to be involved in intercellular communication, regulating metabolism, reducing inflammatory responses, improving lipid metabolism, inhibiting fibrosis, and other processes that contribute to the treatment of metabolic dysfunction-associated steatotic liver disease. Mesenchymal stem cells and mesenchymal stem cell-derived exosomes play an important role in the pathogenesis and treatment of metabolic dysfunction-associated steatotic liver disease and provide new potential and direction for the treatment of Metabolic dysfunction-associated steatotic liver disease. This article reviews the role and effects of mesenchymal stem cells and mesenchymal stem cell-derived exosomes from different sources in Metabolic dysfunction-associated steatotic liver disease and discusses their prospects as potential therapeutic strategies.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

BACKGROUND Cardiovascular and liver metabolic diseases are interconnected conditions, associated with obesity. However, both can occur in lean individuals, and the distinct clinical profiles and outcomes in this population remain poorly defined. AIM To compare liver and cardiovascular outcomes between lean and non-lean individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS We conducted a systematic review and meta-analysis of studies published in the past 20 years comparing seven outcomes between lean and non-lean with dysfunction-associated steatotic liver disease individuals. A random-effects model was applied to calculate pooled odds ratios (pORs) with 95% confidence intervals (CIs) for the outcomes. RESULTS A total of 31 studies comprising 10735550 participants were included. Non-lean individuals with MASLD had higher odds of liver fibrosis (pOR = 2.0, 95%CI: 1.0, 3.9, P = 0.04) and hepatic steatosis (pOR = 2.1, 95%CI: 1.5, 2.9, P &lt; 0.001) compared to lean individuals with MASLD. Lean individuals with MASLD had lower odds of cirrhosis (pOR = 0.7, 95%CI: 0.5, 0.9, P = 0.007) and hypertension (pOR = 0.7, 95%CI: 0.6, 0.9, P = 0.002) compared to non-lean individuals with MASLD. There was no significant statistical difference in mortality between lean and non-lean MASLD groups (pOR = 1.4, 95%CI: 1.0, 2.0, P = 0.06). Also, no statistically significant differences were found for metabolic dysfunction-associated steatohepatitis (pOR = 1.2, 95%CI: 0.7, 2.0, P = 0.5) and cardiovascular diseases (pOR = 0.9, 95%CI: 0.7, 1.0, P = 0.1). CONCLUSION In our study, lean individuals with MASLD have the similar odds of metabolic dysfunction-associated steatohepatitis, cardiovascular diseases and mortality compared to non-lean MASLD patients. Therefore, there is a need to expand MASLD screening and risk stratification strategies beyond obesity-based metrics alone.

The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease and those with metabolic dysfunction and alcohol-associated liver disease remain unclear. To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases. This observational cohort study included 1866 patients with metabolic dysfunction-associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol-associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non-invasive liver fibrosis scores were assessed using the Cox regression analysis. Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol-associated liver disease than with metabolic dysfunction-associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction-associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor. Although both metabolic steatotic liver disease and metabolic alcohol-associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction-associated steatotic liver disease.