Dyslipidemia in liver cirrhosis: Pathophysiology and emerging therapeutic approaches

Abstract

Dyslipidemia in liver cirrhosis represents a dynamic consequence of progressive hepatocellular failure rather than a conventional metabolic disorder, arising from coordinated disruptions in lipoprotein synthesis, remodeling, and clearance. Cirrhotic liver remodeling is associated with reduced apolipoprotein production, impaired very low-density lipoprotein export, downregulation of low-density lipoprotein receptor-mediated uptake, and cholestasis-driven accumulation of atypical lipoproteins, including lipoprotein X and lipoprotein Z, which distort standard lipid metrics and contribute to oxidative and inflammatory signaling. These molecular perturbations are further shaped by disease etiology, insulin resistance, and cytokine-mediated inhibition of lipid-processing pathways, generating stage-specific lipid phenotypes that correlate with prognosis and systemic complications. Given the altered hepatic handling of lipid-modifying drugs and the limited applicability of statins in advanced disease, this review synthesizes current mechanistic and translational evidence on non-statin lipid-lowering therapies in cirrhosis. Available data indicate that ezetimibe and fibrates modulate intestinal cholesterol flux and peroxisome proliferator-activated receptor-α signaling, respectively, but their effects on cirrhotic lipid networks remain incompletely defined. In contrast, proprotein convertase subtilisin/kexin type 9 inhibitors and RNA-based therapies such as inclisiran reduce circulating atherogenic lipoproteins through receptor-dependent pathways with minimal hepatic biotransformation, although clinical and molecular data are largely restricted to compensated cirrhosis. Emerging agents targeting upstream cholesterol synthesis and intrahepatic thyroid hormone receptor-β signaling further highlight the potential to influence hepatic lipid oxidation and fibrogenic signaling, yet evidence in cirrhosis is sparse. Collectively, the data underscore dyslipidemia as an integrated molecular feature of cirrhosis and identify non-statin therapies as tools to interrogate, rather than simply correct, disrupted hepatic lipid biology, emphasizing the need for stage- and mechanism-specific investigation.

Keywords: Liver cirrhosis; Dyslipidemia; Hepatic lipid metabolism; Lipoprotein dysfunction; Cholestasis; Cardiometabolic risk

Core Tip: Dyslipidemia in liver cirrhosis reflects fundamental alterations in hepatic lipid biology, including impaired apolipoprotein synthesis, defective lipoprotein export, receptor downregulation, and cholestasis-driven accumulation of atypical particles such as lipoprotein X and lipoprotein Z. These molecular disturbances generate stage-specific lipid phenotypes that challenge conventional cardiovascular risk assessment and drug targeting. Non-statin lipid-lowering agents provide mechanistically informative tools to probe these disrupted pathways; however, their effects in cirrhosis remain largely defined by pharmacologic rationale rather than direct clinical evidence. Understanding how disease stage and etiology reshape hepatic lipid handling is essential for rational application and future development of lipid-modifying strategies in cirrhotic populations.