New Biomarkers Redefine Risk Assessment in Multi-Organ Metabolic Syndrome
A 2025 review maps the pathophysiology of CRHM syndrome and spotlights emerging biomarkers that could transform early detection and treatment.
Summary
Cardiovascular-Renal-Hepato-Metabolic (CRHM) syndrome is a newly conceptualized framework linking heart disease, chronic kidney disease, liver disease, and metabolic disorders through shared mechanisms of chronic inflammation, insulin resistance, oxidative stress, and endothelial dysfunction. Traditional markers like CRP and IL-6 are insufficient for long-term risk prediction. This 2025 review highlights emerging biomarkers—including suPAR, galectin-3, GDF-15, and microRNAs—that offer superior mechanistic insights and could enable earlier diagnosis, better risk stratification, and more targeted therapies such as SGLT2 inhibitors and GLP-1 receptor agonists across this interconnected disease spectrum.
Detailed Summary
CRHM syndrome represents a significant conceptual advance in understanding how cardiovascular disease, chronic kidney disease (CKD), metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, type 2 diabetes, dyslipidemia, and hypertension interact as a unified pathophysiological system. First formally proposed in early 2025, the framework extends the American Heart Association's 2023 Cardiovascular-Kidney-Metabolic (CKM) model by explicitly incorporating the liver's central role in driving systemic metabolic dysfunction.
The pathophysiology is driven by four interlocking mechanisms. Chronic inflammation, fueled by pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), initiates tissue damage and fibrosis across organs. Insulin resistance worsens hyperglycemia and lipid dysregulation, further stressing the cardiovascular, renal, and hepatic systems. Oxidative stress amplifies cellular injury through reactive oxygen species and mitochondrial dysfunction. Finally, endothelial dysfunction impairs vascular integrity, increases arterial stiffness, and promotes ischemia, completing a self-perpetuating cycle of multi-organ failure.
Traditional biomarkers such as CRP, IL-6, and TNF-α lack the specificity needed to predict long-term disease progression within this complex syndrome. The review identifies four categories of emerging biomarkers with stronger mechanistic relevance. Soluble urokinase plasminogen activator receptor (suPAR) is highlighted as a stable marker of systemic chronic inflammation, correlating with CKD progression, atherosclerosis, and coronary artery calcification, with genetic studies linking it to proinflammatory monocyte activation. Galectin-3 regulates fibrosis and inflammation across cardiac, hepatic, and renal tissue, with elevated levels predicting mortality in heart failure and liver fibrosis. Growth Differentiation Factor-15 (GDF-15) reflects mitochondrial dysfunction and cardiovascular aging, making it relevant to both metabolic stress and cardiac deterioration. MicroRNAs, particularly miR-126 and miR-423-5p, show promise as minimally invasive biomarkers for vascular integrity and heart failure progression, respectively.
Therapeutically, elevated levels of these biomarkers can help guide selection of SGLT2 inhibitors for cardiorenal protection and GLP-1 receptor agonists or dual GIP/GLP-1 agonists for metabolic and hepatic complications. The review argues for a precision medicine approach, where biomarker profiles inform individualized, multi-organ treatment strategies rather than siloed specialty care.
Key caveats include the absence of large-scale prospective clinical validation for most of these biomarkers, the lack of standardized assays for routine clinical use, and the challenge of translating mechanistic insights from predominantly Western research populations into globally diverse clinical settings.
Key Findings
- suPAR correlates with CKD, atherosclerosis, and coronary artery calcification, outperforming traditional inflammatory markers.
- Galectin-3 predicts mortality in heart failure and liver fibrosis by driving fibrosis and inflammation across multiple organs.
- GDF-15 reflects mitochondrial dysfunction and cardiovascular aging, linking metabolic stress to cardiac deterioration.
- miR-126 and miR-423-5p serve as promising circulating biomarkers for vascular integrity and heart failure progression.
- SGLT2 inhibitors and GLP-1 receptor agonists are therapeutically guided by elevated CRHM biomarker profiles.
Methodology
This is a narrative review synthesizing published literature on the pathophysiology and biomarkers of CRHM syndrome, drawing on 173 references. The authors synthesize evidence from clinical studies, genetic analyses, and mechanistic research to build a conceptual framework. No original experimental data were generated.
Study Limitations
Most emerging biomarkers discussed lack large-scale prospective clinical validation or standardized assay protocols for routine use. The review does not include original data, limiting causal inference. The evidence base draws heavily from populations in high-income countries, which may limit generalizability to global settings where CRHM burden is rising rapidly.
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