From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework

Abstract

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver—a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework—the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome—to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic.