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Wenjing Xiao,1 Xinghe Sun,2 Hui Lv,3 Xiaohui Liu,2 Jihong Zhu1 1Emergency Department of Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department of Cardiology, Peking University International Hospital, Beijing, People’s Republic of China; 3Healthcare Management Center, Peking University International Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jihong Zhu, Emergency Department of Peking University People’s hospital, No. 11 Xizhimen South Street, Beijing, 100044, People’s Republic of China, Tel +8613801398755, Email ZhuJiHong64@sina.com Xiaohui Liu, Department of Cardiology, Peking University International Hospital, Life Park Road No. 1 Life Science Park of Zhong Guancun, Beijing, 102206, People’s Republic of China, Tel +8613651327758, Email liuxiaohui@pkuih.edu.cnBackground: The association between Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) and the development of new carotid plaque in young adults requires further evidence from prospective studies.Methods:  In this study, young adults underwent abdominal and a carotid ultrasounds measurement were included. The carotid plaque progression was assessed in 2 years after baseline. MASLD is defined according to the liver ultrasound findings and self-reported alcohol consumption. Stepped adjusting multivariable logistic regression were employed to analyze the association between MASLD and the outcome. Subgroup analysis was conducted among sex and different amount of metabolic risk factors.Results: A total of 36.54% (2411/6598) of all participants had MASLD at baseline. Among them, 626 (9.49%) participants were found new onset of carotid plaque in two years. Subjects who had progression of plaque had higher proportion of MASLD (53.99% vs 34.71%, SMD=0.396). Statistically significant positive associations were observed in unadjusted logistic regression models in overall or each sex, respectively. After fully adjustment, the association was only significant among female (OR:2.19, 95% CI: 1.28– 3.72) and those had no metabolic risk factor (OR:1.67,95% CI:1.01– 2.76). No significant associations were identified in all male subgroups, whereas the associations were still existing among female subgroups.Conclusion: MASLD was found to be a risk factor of progression of carotid plaque among females and those who had not suffered from metabolic risk factor. Prevention should be focused on young adults who have MASLD at physical examination to reduce their risk of future atherosclerosis.Keywords: MASLD, atherosclerosis, risk factor

Abstract Metabolic dysfunction–associated steatotic liver disease (MASLD) is reversible at early stages, making early identification critical. We previously demonstrated that patient-derived induced pluripotent stem cells (iPSCs) carrying MASLD-associated genetic risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. We quantified oleate-induced lipid accumulation in iPSCs from three cohorts: (1) CIRM (22 cases, 20 controls), (2) POST (18 cases, 16 controls), and (3) UCSF (4 cases, 8 controls). Data from the CIRM cohort was used to define an iPSC-based MASLD risk score, which was subsequently validated in the POST and UCSF cohorts. Lipid accumulation was consistently higher in MASLD iPSCs across cohorts. The risk score achieved 44% sensitivity/75% specificity in POST and 75%/100% in UCSF. These findings suggest that oleate-induced lipid accumulation in iPSCs may be a predictor of MASLD risk. Larger studies incorporating additional cellular phenotypes, clinical, and genetic data could enhance predictive accuracy for MASLD surveillance and prevention. Graphical abstract Graphical Abstract

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7–14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to more than 55%. Although MASLD does not always develop into progressive liver disease, it has become the top indication for liver transplant in the United States for women and those with hepatocellular carcinoma (HCC). Nonetheless, the most common cause of mortality among patients with MASLD remains cardiovascular disease. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with an increased risk of developing de novo T2D, chronic kidney disease, sarcopenia, and extrahepatic cancers. Furthermore, MASLD is associated with decreased health-related quality of life, decreased work productivity, fatigue, increased healthcare resource utilization, and a substantial economic burden. Similar to other metabolic diseases, lifestyle interventions such as a heathy diet and increased physical activity remain the cornerstone of managing these patients. Although several obesity and T2D drugs are available to treat co-morbid disease, resmetirom is the only MASH-targeted medication for patients with stage 2–3 fibrosis that has approved by the Food and Drug Administration for use in the United States. This review discusses MASLD epidemiology and its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD incidence could continue to increase.

Background Conflicting evidence regarding the prognosis of lean metabolic dysfunction-associated steatotic liver disease (MASLD) has raised substantial questions. Aim This study aimed to elucidate the prognosis of lean MASLD by conducting a comprehensive analysis of a vast Asian cohort. Methods This study used a nationwide, population-based database and analyzed 2.9 million patients. The primary endpoints were liver-related events (LREs) and cardiovascular events (CVEs) in patients with lean MASLD, non-lean MASLD, and normal liver control groups. Results The median observation period was 4.2 years. The 5-year incidence values of LREs in the lean MASLD, non-lean MASLD, and normal liver control groups were 0.065%, 0.039%, and 0.006%, respectively. The LRE risk of lean MASLD was significantly higher than that of normal liver control (adjusted hazard ratio [aHR]: 5.94, 95% confidence interval [CI]: 3.95–8.92) but comparable to that of non-lean MASLD (aHR: 1.35, 95% CI: 0.87–2.08). By contrast, for CVEs, the non-lean MASLD group exhibited a higher 5-year cumulative incidence rate (0.779%) than the lean MASLD (0.600%) and normal liver control (0.254%) groups. The lean MASLD group had a reduced risk of CVEs compared with the non-lean MASLD group (aHR, 0.73; 95% CI: 0.64–0.84), and comparable risk of CVEs to the normal liver control group (aHR, 0.99; 95% CI: 0.88–1.12). Conclusion Lean MASLD exhibits a similar LRE risk and a lower CVE risk to non-lean MASLD. Therefore, follow-up and treatment strategies should be tailored to the specific MASLD condition.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL–EASD–EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as the fibrosis-4 index [FIB-4]) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification—including weight loss, dietary changes, physical exercise and discouraging alcohol consumption—as well as optimal management of comorbidities—including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated—is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.