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.

Table 2 Efficacy and safety of emerging non-statin lipid-lowering agents in compensated and advanced cirrhosis

Therapy	Main mechanism of action	Use in compensated cirrhosis	Main risk in cirrhosis (advanced/decompensated)
Ezetimibe	Inhibits intestinal cholesterol absorption (NPC1 L1 transporter)	Possible, with caution	Increased drug exposure in Child-Pugh B/C, higher risk of hepatotoxicity
Fibrates	Activate PPAR-α to ↓triglycerides, ↑HDL	Possible, under monitoring	Elevation of liver enzymes, cholestasis, rhabdomyolysis (especially if combined with statins)
PCSK9 inhibitors (alirocumab, evolocumab)	Monoclonal antibodies inhibiting PCSK9 to ↑LDL receptor recycling, ↓LDL-C	Data limited; theoretically safer since not hepatically metabolized	Limited clinical data in cirrhosis, safety in advanced liver disease not established
Bempedoic acid	Inhibits ATP-citrate lyase (upstream of HMG-CoA reductase)	Potential option, but limited data in cirrhosis	No robust studies in advanced liver disease; potential risk of hepatotoxicity
Inclisiran	Small interfering RNA targeting hepatic PCSK9 synthesis, leading to sustained LDL receptor upregulation and LDL-C reduction	Potential option; limited but favorable pharmacologic profile given minimal hepatic metabolism	Very limited clinical data in cirrhosis; safety in Child-Pugh B/C not established

PCSK9: Proprotein convertase subtilisin/kexin type 9; NPC1 L1: Niemann-Pick C1-like 1 transporter; PPAR: Peroxisome Proliferator-activated receptor; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol; ATP: Adenosine triphosphate; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A.