Stefan Norbert, Yki-Järvinen Hannele, Neuschwander-Tetri Brent A
Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Lancet Diabetes Endocrinol. 2025 Feb;13(2):134-148. doi: 10.1016/S2213-8587(24)00318-8. Epub 2024 Dec 13.
The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future.
代谢功能障碍相关脂肪性肝病（MASLD）的全球流行在世界范围内日益加剧。患有MASLD的人可能会发展为肝硬化和肝细胞癌，并且患2型糖尿病、心血管疾病、慢性肾脏病和肝外癌症的风险增加。大多数患有MASLD的人死于心脏相关原因。这一结果归因于MASLD与心脏代谢疾病的共同发病机制，包括不健康的饮食习惯、功能失调的脂肪组织、胰岛素抵抗和亚临床炎症。此外，脂肪变性和炎症的肝脏通过增加葡萄糖生成和促凝血因子释放、血脂异常以及肝细胞因子和微小RNA的释放失调来影响血管系统和心脏。然而，MASLD病理生理学的影响因素存在很大异质性，这可能会影响其进展速度、与心脏代谢疾病的关系以及对治疗的反应。对患有MASLD的人最有效的非药物治疗方法包括减肥。矛盾的是，一些改善MASLD患者肝脏健康的有效药物治疗方法与体重无变化甚至体重增加有关，并且在心脏代谢危险因素的变化方面也观察到了类似的反应异质性。在本综述中，我们讨论了MASLD在发病机制、结局和基于代谢的治疗反应方面的异质性。尽管目前尚无足够证据支持将精准医学应用于MASLD的风险预测、预防和治疗，但我们探讨了关于这种异质性的知识是否可能有助于在未来实现这一目标。
