Impact of Cardiometabolic Risk Factors on Hepatic Fibrosis and Clinical Outcomes in MASLD: A Population-based Multi-Cohort Study

Evaluating five cardiometabolic risk factors (CMRFs) is crucial for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the impact of CMRFs on hepatic fibrosis and long-term clinical outcomes in patients with MASLD. Two cross-sectional cohorts (Korean magnetic resonance elastography [n = 6,684] and US vibration-controlled transient elastography [n = 6,230]) were included to assess the impact of five CMRFs and their combinations on hepatic fibrosis. Two longitudinal cohorts (UK Biobank [n = 408,544; mean follow-up, 14.3 years] and Korea National Health Insurance data [n = 355,640; mean follow-up, 11.7 years]) were included to evaluate long-term outcomes, including liver-related events, hepatocellular carcinoma events, and overall, cardiovascular, and liver-related death. The risk of MASLD associated with CMRFs was assessed using logistic or Cox regression analysis, referencing participants without steatotic liver disease. Across all four cohorts, patients with type 2 diabetes mellitus had the highest risk of hepatic fibrosis and long-term clinical outcomes. Among the five CMRFs, impaired fasting glucose (CMRF2) was the most significant risk factor for both hepatic fibrosis and long-term clinical outcomes. High blood pressure (CMRF3) was the second most significant risk factor for hepatic fibrosis, following CMRF2. Low high-density lipoprotein cholesterol level (CMRF5) exhibited comparable significance for long-term clinical outcomes. These clinical outcomes worsened with increasing severity of glucose abnormalities (normal and impaired fasting glucose levels and type 2 diabetes mellitus). Patients with MASLD and CMRF2 exhibited a two-to-four times higher risk of hepatic fibrosis and liver-related events compared with those without impaired fasting glucose levels, similar to MASLD accompanied by any four CMRFs. The impact of the five CMRFs on hepatic fibrosis and long-term clinical outcomes varied across different clinical outcomes and population characteristics. However, impaired fasting glucose (CMRF2) consistently demonstrated the highest risk. Understanding the impact of the five cardiometabolic risk factors (CMRFs) used in the diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) on hepatic fibrosis and long-term clinical outcomes can improve the quality of care in the general population by facilitating the identification of at-risk individuals with MASLD. In our results, although the impact of each of the five CMRFs on hepatic fibrosis and long-term clinical outcomes varied depending on the type of clinical outcomes and the characteristics of the population, impaired fasting glucose (CMRF2) consistently showed the highest risk. Patients with MASLD and CMRF2 exhibited a two-to-four times higher risk of hepatic fibrosis and liver-related events compared with those without impaired fasting glucose levels, similar to MASLD accompanied by any four CMRFs. The utilization of impaired fasting glucose (CMRF2) can raise awareness among primary care providers regarding high-risk groups at the time of MASLD diagnosis.