Opportunistic case-finding of liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) by leveraging integrated care pathways of type 2 diabetes

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

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.

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.

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

Yet more evidence that MAFLD is more than a name change

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.

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.

Background & Aims:Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) represent progressive stages of liver disease, with distinct metabolic and cellular alterations. This study investigates the progression from MASLD to MASH through metabolomics, lipidomics, and assessment of hormones.Methods:Male C57BL/6NTac mice were fed a high-fat diet for 16 weeks to induce MASLD and for 29 weeks to develop MASH. Aged-matched controls on a normal diet were used for comparison. Histology confirmed the progression of MASLD to MASH. We performed metabolomic and lipidomic profiling of liver, colon, and stool samples to identify metabolic and lipid alterations. Plasma enteroendocrine hormones and cytokines were quantified. Immunofluorescence was performed to assess enteroendocrine cells changes in the colon and the association of serotonin (5-HT) with fibronectin in the liver.Results:Metabolomic and lipidomic analysis revealed significant alterations at different stages of the disease. Specifically, cholic acid was increased across the liver, colon, and stool in both MASLD and MASH mice compared to controls. Compared to the control group, MASLD mice exhibited an increase in enteroendocrine hormones, GLP-1, GIP, and PYY, whereas no changes were observed in MASH mice. Comparing MASLD to MASH livers, we found hepatic 5-HT levels were increased in MASH mice compared to MASLD mice. The MASH liver also exhibited a colocalization between fibronectin and 5-HT, suggesting a potential role of 5-HT in liver fibrosis.Conclusions:Our study provides novel insights into the progressive metabolic and hormonal changes from MASLD to MASH. The increase in cholic acid and differential enteroendocrine hormone responses highlight the complex interactions between the gut and liver in metabolic liver diseases. These findings suggest that enteroendocrine hormones may play a role in the progression of MASLD to MASH as well as liver fibrosis, offering potential therapeutic avenues for targeting the gut-liver axis in metabolic liver diseases.

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/Aims:Metabolic dysfunction-associated fatty liver disease is a crucial global health concern. Studies have shown that metabolic dysfunction-associated fatty liver disease patients are at higher risk of severe coronavirus disease 2019. However, there are no precise measures of the correlation between the degree of metabolic dysfunction-associated fatty liver disease fibrosis and coronavirus disease 2019 severity. This study evaluated the association between metabolic dysfunction-associated fatty liver disease with varying degrees of fibrosis and coronavirus disease 2019 prognosis.Materials and Methods:All hospitalized coronavirus disease 2019 patients who had liver steatosis as determined by computed tomography scan were included. Metabolic dysfunction-associated fatty liver disease was diagnosed in accordance with international consensus criteria. Liver fibrosis was assessed using the nonalcoholic fatty liver disease fibrosis score, FIB-4 and FIB-8 indexes. Coronavirus disease 2019 severity was defined using World Health Organization criteria. Logistic regression was used to determine the associations between varying degrees of fibrosis and the severity of coronavirus disease 2019.Results:A total of 996 confirmed hospitalized coronavirus disease 2019 cases with complete data were reviewed; of these, 296 (29.7%) cases of metabolic dysfunction-associated fatty liver disease were diagnosed. Metabolic dysfunction-associated fatty liver disease patients with any fibrotic state had more severe coronavirus disease 2019 than nonmetabolic dysfunction-associated fatty liver disease patients (adjusted odds ratio 1.912, 95% CI 1.363-2.684; P < .05). Multiple logistic regression analysis showed that metabolic dysfunction-associated fatty liver disease patients with significant fibrosis according to the FIB-8 score were more likely to have severe coronavirus disease 2019 (adjusted odds ratio 5.458, 95% CI 1.481-20.110; P < .05).Conclusion:The presence of metabolic dysfunction-associated fatty liver disease in hospitalized coronavirus disease 2019 patients strongly correlated with the severity of coronavirus disease 2019. The hepatic FIB-8 index appears to provide the best prognostic value among the fibrosis scores in metabolic dysfunction-associated fatty liver disease patients with coronavirus disease 2019.

Menopause and metabolic dysfunction-associated steatotic liver disease

BACKGROUND The relationship between different subgroups of type 2 diabetes (T2D) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis has not been thoroughly studied. This study aims to determine the association between T2D subgroups and the risk of developing advanced liver fibrosis using the Fibrosis-4 (FIB-4) index, a non-invasive marker for assessing liver fibrosis risk. MATERIAL AND METHODS A total of 1205 patients with T2D were categorized into 4 distinct subgroups: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The FIB-4 index was calculated for each patient to estimate the degree of liver fibrosis, with the following cutoff points: <1.3 indicating no or mild fibrosis, 1.3-2.67 suggesting moderate fibrosis, and >2.67 indicating advanced fibrosis (F3-F4). Logistic regression was used to compare the odds of advanced fibrosis across these subgroups. RESULTS The SIRD subgroup exhibited significantly higher odds of advanced liver fibrosis (F3-F4), compared with the other subgroups, as indicated by elevated FIB-4 scores (P<0.05). In contrast, the SIDD and MOD subgroups had lower odds of advanced fibrosis, while the MARD subgroup showed an intermediate association. CONCLUSIONS The findings suggest that the FIB-4 index, as a noninvasive assessment tool, effectively stratifies liver fibrosis risk among different T2D subgroups. This stratification can inform more personalized management strategies for patients with MASLD, underscoring the importance of accounting for the heterogeneity within T2D in clinical assessments of liver fibrosis risk.

“Dual aetiology fatty liver disease”: A recently proposed term associated with potential pitfalls

Letter regarding “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”