Dyslipidemia in liver cirrhosis: Pathophysiology and emerging therapeutic approaches

Table 1 Risk factors, mechanisms, and clinical manifestations of dyslipidemia in cirrhosis

Risk factor	Pathophysiological mechanisms	Clinical manifestations	Ref.
Cardiometabolic comorbidities (diabetes, hypertension, obesity, MASLD)	(1) Insulin resistance promotes hepatic de novo lipogenesis and VLDL secretion; (2) Adipokine imbalance (↑leptin, ↓adiponectin); and (3) PNPLA3 and TM6SF2 variants impair triglyceride mobilization and VLDL secretion, fostering steatosis and atherogenic dyslipidemia	(1) Overlap of MetS and cirrhosis (up to 60% of patients); and (2) Central obesity, hypertriglyceridemia and low HDL-C accelerate fibrosis and CV events (“liver-heart-metabolism” axis)	[4,20,24-26,37-41]
Hepatic dysfunction and impaired lipid handling	(1) Loss of hepatocyte mass reduces apolipoprotein synthesis (ApoA-I and ApoB), VLDL secretion and LDL receptor activity to ↓total cholesterol, LDL-C, HDL-C; and (2) Cholestasis to paradoxical hypertriglyceridemia (impaired LPL activity)	(1) In compensated cirrhosis: Modest lipid reductions and near-normal TG; (2) In decompensated cirrhosis: Lowest TC and HDL-C in Child-Pugh C; and (3) Hypocholesterolemia predicts poor survival and transplant-free mortality	[8,9,11,20-23,28,31-33]
Chronic systemic inflammation and viral/metabolic injury	(1) Oxidative LDL uptake by Kupffer cells to cytokine release (TNF-α, IL-6); (2) Stellate cell activation to fibrosis; (3) HCV alters VLDL assembly and lowers LDL-C; (4) MASLD dyslipidemia promotes lipotoxicity and carcinogenesis; and (5) Lipidomic signatures in HCC	(1) Increased sd-LDL and oxidized LDL despite low absolute LDL-C; (2) Paradoxical ↑CAD incidence in cirrhosis; and (3) Dyslipidemia linked to fibrogenesis, HCC risk and extra-hepatic morbidity	[24,25,27,29,30,34-36,41]

MASLD: Metabolic dysfunction-associated steatotic liver disease; VLDL: Very low-density lipoprotein; PNPLA3: Patatin-like phospholipase domain-containing protein 3; TM6SF2: Transmembrane 6 superfamily member 2; ApoA-I: Apolipoprotein A-I; ApoB: Apolipoprotein B; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; LPL: Lipoprotein lipase; TNF: Tumor necrosis factor; IL: Interleukin; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; MetS: Metabolic syndrome; CV: Cardiovascular; TG: Triglycerides; TC: Total cholesterol; sd-LDL: Small dense low-density lipoprotein; CAD: Coronary artery disease.