Non-cardiovascular morbidity and mortality associated with MASLD: current evidence

Abstract

Metabolic associated steatotic liver disease (MASLD) is the hepatic manifestation of cardiorenometabolic syndrome and affects approximately 30% of the world's adult population. Although cardiovascular disease remains the leading cause of death, recent evidence demonstrates that MASLD also independently increases non-cardiovascular morbidity and mortality, particularly from advanced liver disease, malignancies, and chronic kidney disease (CKD), reinforcing the concept of a systemic disease with significant extrahepatic repercussions.

Hepatic fibrosis is the main determinant of clinical outcomes and the most robust predictor of mortality. Progression to metabolic steatohepatitis (MASH), advanced fibrosis, and cirrhosis increases the risk of portal hypertension, liver failure, and hepatocellular carcinoma (HCC). However, a considerable percentage of HCC cases related to MASLD develop in the absence of cirrhosis, limiting traditional surveillance strategies and highlighting the need for risk stratification models based on biomarkers and non-invasive tests.

The oncological burden associated with MASLD has become increasingly relevant. Recent population studies and meta-analyses show a significant increase in the risk of colorectal, pancreatic, breast, endometrial, and renal cancers, even after adjusting for obesity and type 2 diabetes. The mechanisms involved include insulin resistance, chronic low-grade inflammation, lipotoxicity, oxidative stress, and immunometabolic alterations that promote carcinogenesis. A recent meta-analysis demonstrated that MASLD is associated with a 24% increase in cancer-related mortality (HR 1.24; 95% CI 1.19–1.29), highlighting that the prognostic impact of the disease extends beyond liver involvement.

CKD is another major complication. Systemic inflammation, activation of profibrotic pathways, endothelial dysfunction, and insulin resistance contribute to the progressive decline of renal function, regardless of the presence of hypertension or diabetes. The coexistence of chronic kidney disease (CKD) and MASLD approximately doubles the risk of overall mortality and is associated with greater healthcare resource utilization.

Finally, emerging evidence links MASLD to sarcopenia, frailty, osteoporosis, obstructive sleep apnea, cognitive impairment, and poorer quality of life, reinforcing its multisystemic nature. Consequently, clinical management must extend beyond cardiovascular prevention to include the early identification of advanced fibrosis, assessment of oncological and renal risk, and intensive treatment of metabolic dysfunction through a multidisciplinary approach. This paradigm shift is essential to reducing the overall burden of morbidity and mortality associated with MASLD.