Extrahepatic manifestations of metabolic dysfunction-associated steatotic liver disease: An updated clinical overview

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide and is closely linked to obesity, insulin resistance, type 2 diabetes, and dyslipidemia. It ranges from simple steatosis to steatohepatitis (metabolic dysfunction-associated steatohepatitis), which can progress to fibrosis, cirrhosis, or liver cancer. Beyond liver-related issues, MASLD is a systemic disease strongly associated with extrahepatic complications such as cardiovascular disease (CVD), chronic kidney disease (CKD), cancers, endocrine disorders, musculoskeletal problems, and sleep apnea. CVD and cancer are the leading causes of death in MASLD patients, with liver-related mortality ranking third. Fibrosis severity is the key predictor of overall and cause-specific mortality. MASLD significantly increases the risk and progression of type 2 diabetes, CVD, and CKD. It is also linked to increased risks of extrahepatic cancers, particularly colorectal, pancreatic, and breast cancers. Endocrine conditions such as hypothyroidism and polycystic ovary syndrome and musculoskeletal disorders, including sarcopenia and osteoporosis, frequently co-occur with MASLD. Obstructive sleep apnea independently contributes to the severity of liver disease and shares overlapping metabolic pathways. Surgical and transplant outcomes are worse in patients with MASLD due to impaired liver regeneration and increased postoperative risks. The recent approval of resmetirom offers a new therapeutic option, whereas lifestyle changes remain the cornerstone of management. Given the multisystemic impact of MASLD, a patient-centered approach is essential for effective treatment and improved long-term results. In this article, we provide an overview of key extrahepatic conditions commonly associated with MASLD and their clinical significance.