Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease

Context and significanceThe multimorbidity pattern of metabolic dysfunction-associated steatotic liver disease (MASLD) remains underexplored. Here, researchers performed a comprehensive exploration of the health impacts associated with MAFLD. Our findings reveal MASLD's significant impact not only on liver health but also as a significant contributor to elevated risk of all-cause mortality and 96 comorbidities across digestive, circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic systems. Sequential patterns of MASLD-related extrahepatic comorbidities were identified, particularly in circulatory, metabolic, and inflammatory diseases. This study highlights MASLD's extensive health consequences and underscores the importance of targeted strategies to disrupt the pathways linking MASLD to various downstream diseases in affected individuals.Highlights•Metabolic dysfunction-associated steatotic liver disease causes multisystem impairments•Sequential comorbidities are found in circulatory, metabolic, and inflammatory diseases•Genetic data support links to liver, metabolic, and cardio-cerebrovascular diseasesSummaryBackgroundThe global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined.MethodsA phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia.FindingsThe observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases.ConclusionsThis study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD.FundingX.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).Graphical abstract