Non-HDL to HDL cholesterol ratio as a biomarker associated with decompensation in chronic liver disease

Abstract

Aim: Chronic liver disease (CLD) is characterized by progressive impairment of hepatic function and frequent lipid metabolism abnormalities, with reductions in high-density lipoprotein cholesterol (HDL-C) and other lipoprotein fractions shown to parallel worsening liver dysfunction and predict adverse clinical outcomes such as decompensation and mortality. Established prognostic scores like Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) capture aspects of disease severity, but composite lipid indices such as the non-HDL/HDL-C ratio (NHHR), which balance atherogenic and protective lipoproteins, have emerged as potentially informative biomarkers in metabolic and liver disorders. This study evaluated the association of NHHR with clinical decompensation in CLD. Methods: This cross-sectional study included 220 adults with CLD of mixed etiologies. Baseline demographics, liver disease severity scores, and fasting lipid profiles were obtained. NHHR was calculated, and patients were categorized into tertiles. Spearman correlation coefficients were calculated to examine relationships between NHHR and clinical severity markers. Multivariable logistic regression was used to evaluate the association between NHHR and clinical decompensation. Model performance was compared using receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: Among 220 patients with CLD (mean age 54.5 ± 11.9 years, 63% male), 96 (43.6%) had decompensated disease. Higher NHHR tertiles were associated with increasing MELD-3.0 scores (P = 0.028) and lower serum albumin (P < 0.001). NHHR correlated positively with MELD-3.0, bilirubin, and international normalized ratio (INR) and inversely with albumin and platelet count. Decompensation prevalence rose across NHHR tertiles (31.1% to 53.4%, P < 0.001). NHHR was independently associated with decompensation (adjusted OR 1.55, 95% CI 1.21–1.98, P < 0.001) and improved model discrimination (AUC 0.79 vs. 0.73).

References

[1] Tham EKJ, Tan DJH, Danpanichkul P, Ng CH, Syn N, Koh B, et al. The Global Burden of Cirrhosis and Other Chronic Liver Diseases in 2021. Liver Int. 2025; 45: e70001.

[2] Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023; 79: 516-37.

[3] Privitera G, Spadaro L, Marchisello S, Fede G, Purrello F. Abnormalities of Lipoprotein Levels in Liver Cirrhosis: Clinical Relevance. Dig Dis Sci. 2018; 63: 16-26.

[4] Cui B, Yang W, Guo G, Fan X, Wang X, Hui Y, et al. The Clinical Significance of Lipids/Lipoproteins Impairment in the Context of Cirrhosis: An Updated Review. Gene Expr. 2022; 21: 2-8.

[5] Ghadir MR, Riahin AA, Havaspour A, Nooranipour M, Habibinejad AA. The relationship between lipid profile and severity of liver damage in cirrhotic patients. Hepat Mon. 2010; 10: 285-8.

[6] Zhang Y, Hu X, Chang J, Chen J, Han X, Zhang T, et al. The liver steatosis severity and lipid characteristics in primary biliary cholangitis. BMC Gastroenterol. 2021; 21: 395.

[7] Chrostek L, Supronowicz L, Panasiuk A, Cylwik B, Gruszewska E, Flisiak R. The effect of the severity of liver cirrhosis on the level of lipids and lipoproteins. Clin Exp Med. 2014; 14: 417-21.

[8] Janičko M, Veselíny E, Leško D, Jarčuška P. Serum cholesterol is a significant and independent mortality predictor in liver cirrhosis patients. Ann Hepatol. 2013; 12: 581-7.

[9] He X, Liu X, Peng S, Han Z, Shen J, Cai M. Association of Low High-Density Lipoprotein Cholesterol Levels with Poor Outcomes in Hepatitis B-Associated Decompensated Cirrhosis Patients. Biomed Res Int. 2021; 2021: 9927330.

[10] Trieb M, Horvath A, Birner-Gruenberger R, Spindelboeck W, Stadlbauer V, Taschler U, et al. Liver disease alters high-density lipoprotein composition, metabolism and function. Biochim Biophys Acta. 2016; 1861: 630-8.

[11] Cui B, Guo G, Hui Y, Wang X, Liu W, Sun C. The prognostic value of high-density lipoprotein cholesterol in patients with decompensated cirrhosis: a propensity score matching analysis. J Clin Lipidol. 2022; 16: 325-34.

[12] Gao B, Xiao J, Zhang M, Zhang F, Zhang W, Yang J, et al. High-density lipoprotein cholesterol for the prediction of mortality in cirrhosis with portal vein thrombosis: a retrospective study. Lipids Health Dis. 2019; 18: 79.

[13] Shi K, Zhang Y, Li Y, Wang X, Feng Y, Wang X. High-density lipoprotein cholesterol as a prognostic marker for 90-day transplant-free mortality in hepatitis B virus-related acute-on-chronic liver failure. Front Cell Infect Microbiol. 2025; 14: 1458818.

[14] Mo R, Zhang Z, Zhou Y, Wang Y, Yin P, Zhang C, et al. A new prognostic model based on serum apolipoprotein AI in patients with HBV-ACLF and acutely decompensated liver cirrhosis. Lipids Health Dis. 2025; 24: 35.

[15] Unger LW, Forstner B, Schneglberger S, Muckenhuber M, Eigenbauer E, Scheiner B, et al. Patterns and prevalence of dyslipidemia in patients with different etiologies of chronic liver disease. Wien Klin Wochenschr. 2019; 131: 395-403.

[16] Rao BH, Nair P, Koshy AK, Krishnapriya S, Greeshma CR, Venu RP. Role of High-Density Lipoprotein Cholesterol (HDL-C) as a Clinical Predictor of Decompensation in Patients with Chronic Liver Disease (CLD). Int J Hepatol. 2021; 2021: 1795851.

[17] Trieb M, Rainer F, Stadlbauer V, Douschan P, Horvath A, Binder L, et al. HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure. J Hepatol. 2020; 73: 113-20.

[18] Wang B, Li L, Tang Y, Lin T, Wu J, Wang G, et al. Changes in non-high-density lipoprotein to high-density lipoprotein ratio (NHHR) and cardiovascular disease: insights from CHARLS. Lipids Health Dis. 2025; 24: 112.

[19] Tan MY, Weng L, Yang ZH, Zhu SX, Wu S, Su JH. The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio with type 2 diabetes mellitus: recent findings from NHANES 2007-2018. Lipids Health Dis. 2024; 23: 151.

[20] Kim SW, Jee JH, Kim HJ, Jin SM, Suh S, Bae JC, et al. Non-HDL-cholesterol/HDL-cholesterol is a better predictor of metabolic syndrome and insulin resistance than apolipoprotein B/apolipoprotein A1. Int J Cardiol. 2013; 168: 2678-83.

[21] Yang Y, Li S, An Z, Li S. The correlation between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) with non-alcoholic fatty liver disease: an analysis of the population-based NHANES (2017-2018). Front Med (Lausanne). 2024; 11: 1477820.

[22] Yang X, Yan H, Guo R, Chen Y. Association between the NHHR and hepatic steatosis and liver fibrosis: a population-based study. Sci Rep. 2025; 15: 8462.

[23] Zhang Y, Luo PY, Tang YN, Wang J, Gao S, Fan YC, et al. Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD): data from the NHANES III (1988-1994). Nutr Metab (Lond). 2025; 22: 46.

[24] Huang X, Li J, Zhang L, Zhang C, Li C. The association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and non-alcoholic fatty liver disease in US adults: a cross-sectional study. Sci Rep. 2024; 14: 24847.

[25] Ruf A, Dirchwolf M, Freeman RB. From Child-Pugh to MELD score and beyond: Taking a walk down memory lane. Ann Hepatol. 2022; 27: 100535.

[26] European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69: 406-60.

[27] Habib A, Mihas AA, Abou-Assi SG, Williams LM, Gavis E, Pandak WM, et al. High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics. Clin Gastroenterol Hepatol. 2005; 3: 286-91.

[28] Llovet JM, Planas R, Morillas R, Quer JC, Cabré E, Boix J, et al. Short-term prognosis of cirrhotics with spontaneous bacterial peritonitis: multivariate study. Am J Gastroenterol. 1993; 88: 388-92.

[29] An T, Song Y, Yang Y, Guo M, Liu H, Liu K, et al. Non-HDL-cholesterol to HDL-cholesterol ratio is an independent risk factor for liver function tests abnormalities in geriatric population. Lipids Health Dis. 2018; 17: 296.

[30] Xuan Y, Zhu M, Xu L, Huangfu S, Li T, Liu C, et al. Elevated non-HDL-C to HDL-C ratio as a marker for NAFLD and liver fibrosis risk: a cross-sectional analysis. Front Endocrinol (Lausanne). 2024; 15: 1457589.

[31] Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012; 32: 2813-20.