The Hepato-Cardio-Renal Axis in Cirrhosis: Hemodynamic and Mechanistic Insights, Diagnostic Biomarkers, and Expanding Therapeutic Horizons

Liver cirrhosis is increasingly recognized as a multisystemic disorder, profoundly impacting cardiac and renal function, giving rise to tightly coupled cirrhotic cardiomyopathy (CCM) and hepatorenal syndrome (HRS), and creating a vicious cycle of the hepato-cardio-renal axis. In this narrative review, we propose viewing CCM and HRS as triad dysfunction, driven by shared hemodynamic and molecular mechanisms linking portal hypertension, splanchnic vasodilation, hyperdynamic circulation, and systemic inflammation. We further synthesize the progression of intrahepatic resistance and splanchnic vasodilation to the hyperdynamic circuit, leading to triggers for CCM and HRS. Diagnostic biomarkers such as natriuretic peptides, troponins, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), along with emerging imaging techniques like artificial intelligence-cirrhosis-electrocardiogram (ACE), echocardiography, and point-of-care ultrasound (poCUS) are reviewed. We also discuss therapeutic horizons, while vasoconstrictors with albumin and diuretics remain crucial pharmacological care. Beyond drugs, transjugular intrahepatic portosystemic shunt (TIPS), liver transplantation, and lifestyle and nutritional modifications play a vital role. Persistent challenges arise due to constant reliance on the organ-centric approach, lack of true predictors of response, and risk of unmasking latent cardiac and renal vulnerability. Finally, future direction demands a paradigm shift to an integrated axis-aware, genetic, molecular, and cellular approach and the use of artificial intelligence to enable individualized risk stratification and improve long-term outcomes in cirrhotic patients with cardiorenal involvement.