Lipid Biomarkers: Total to HDL Cholesterol Ratio

Optimal Takeaways

Assessing the ratio of total cholesterol to HDL-cholesterol provides information about cholesterol metabolism and processing in the body. An increasing ratio indicates a relative decrease in HDL, the lipoprotein that scavenges and clears excess cholesterol. An elevated ratio is associated with an increased risk of atherosclerosis, carotid plaque, and non-alcoholic fatty liver disease. A lower ratio is considered desirable.

Standard Range: 0.00 - 5.00 Ratio

The ODX Range: 0.00 - 3.00 Ratio

Low total cholesterol:HDL-C ratio suggests a decreased risk of cardiovascular disease.

High total cholesterol:HDL-C ratio is associated with an increased risk of cardiovascular disease, atherosclerosis, arterial stiffness, and major adverse cardiac events (Acevedo 2012, Wen 2019, Kappelle 2011), as well as NAFLD (Ren 2019).

Overview

The ratio of total cholesterol to HDL-cholesterol (TC:HDL), also known as the atherogenic or Castelli Index, is considered a better predictive indicator of CVD than isolated biomarkers such as LDL-C. A ratio of 3:1 is desirable in general, with targets for secondary prevention in women and men below 3 and 3.5, respectively (Pagana 2022, Millan 2009).

In a cross-sectional study of 1,624 adults 25-64, TC:HDL was the most significant predictor of increased intima-media thickness, an indicator of subclinical carotid atherosclerosis. Non-HDL and HDL-C were also significant indicators, while LDL-C was not. Researchers noted that a TC:HDL above 5.1 increased the risk of carotid plaque 1.5-2-fold (Acevedo 2012).

A TC:HDL ratio of 4 or above was also associated with arterial stiffness, another indicator of atherosclerosis. In a large population study of 16,733 healthy individuals, a TC:HDL ratio of 4 or above was associated with arterial stiffness, even if LDL-C was below 70 mg/dL (1.8 mmol/L) (Wen 2019).

The association of elevated TC:HDL with early signs of atherosclerosis also translates into adverse cardiovascular events. A prospective study assessed the value of TC:HDL in predicting MACEs in 6,948 individuals free of CVD at baseline. Results indicate that TC:HDL was significantly higher in those who experienced MACEs, with a mean of 5.78. Those suffering from MACEs also had significantly higher baseline TC, LDL-C, non-HDL-C, triglycerides, and hs-CRP and were more likely to be older and male, smoke, and have diabetes, obesity, and hypertension (Kappelle 2011).

A large prospective study of 73,302 individuals at high risk for CVD but without a diagnosis of CVD found that all-cause mortality and hospitalization for stroke and coronary heart disease were lowest with a TC:HDL of 2.96, higher with a median ratio of 4.42 and highest with a ratio of 5.58 (Orozco-Beltran 2017). A 17-year follow-up of 6,537 women found the lowest incidence of ischemic heart disease in those with a mean TC:HDL of 2.4, while the highest incidence occurred in those with a TC:HDL of 5.6 (Calling 2021).

The prospective Atherosclerosis Risk in Communities (ARIC) study of 14,403 subjects confirmed the value of using the TC:HDL ratio for identifying cardiovascular event risk in those without atherosclerotic cardiovascular disease at baseline. A TC:HDL at or above a cut-off of 4.2 significantly increased risk, especially when LDL-C or non-HDL-C were below median values of 135 mg/dL (3.48 mmol/L) and 158 mg/dL (4.09 mmol/L), respectively (Quispe 2020).

The TC:HDL ratio may also be predictive of NAFLD. The Jinchang cohort study of 31,121 subjects found that the incidence of NAFLD increased significantly as the TC:HDL ratio increased. Researchers conclude that TC:HDL was a better predictor of NAFLD than TC or HDL-C alone and better than the Apo B/ApoA1 ratio. They also point out that the risk factors for low HDL-C—obesity, diabetes, and lack of exercise—are also risk factors for NAFLD (Ren 2019).

References

Acevedo, Mónica et al. [Total/HDL cholesterol ratio and non HDL cholesterol as predictors for increased intima media thickness]. Revista medica de Chile vol. 140,8 (2012): 969-76. doi:10.4067/S0034-98872012000800001

Calling, Susanna et al. “Total cholesterol/HDL-C ratio versus non-HDL-C as predictors for ischemic heart disease: a 17-year follow-up study of women in southern Sweden.” BMC cardiovascular disorders vol. 21,1 163. 5 Apr. 2021, doi:10.1186/s12872-021-01971-1

Kappelle, P J W H et al. “Apolipoprotein B/A-I and total cholesterol/high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein.” Journal of internal medicine vol. 269,2 (2011): 232-42. doi:10.1111/j.1365-2796.2010.02323.x

Millan, Jesus et al. “Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.” Vascular health and risk management vol. 5 (2009): 757-65.

Orozco-Beltran, Domingo et al. “Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.” PloS one vol. 12,10 e0186196. 18 Oct. 2017, doi:10.1371/journal.pone.0186196

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Quispe, Renato et al. “Total cholesterol/HDL-cholesterol ratio discordance with LDL-cholesterol and non-HDL-cholesterol and incidence of atherosclerotic cardiovascular disease in primary prevention: The ARIC study.” European journal of preventive cardiology vol. 27,15 (2020): 1597-1605. doi:10.1177/2047487319862401

Ren, Xiao Yu et al. “Total cholesterol to high-density lipoprotein cholesterol ratio is a significant predictor of nonalcoholic fatty liver: Jinchang cohort study.” Lipids in health and disease vol. 18,1 47. 11 Feb. 2019, doi:10.1186/s12944-019-0984-9

Wen, Jia et al. “Associations of non-high-density lipoprotein cholesterol, triglycerides and the total cholesterol/HDL-c ratio with arterial stiffness independent of low-density lipoprotein cholesterol in a Chinese population.” Hypertension research : official journal of the Japanese Society of Hypertension vol. 42,8 (2019): 1223-1230. doi:10.1038/s41440-019-0251-5