TC/HDL Ratio

The TC/HDL ratio is a valuable marker in assessing cardiovascular health. This ratio reflects the balance between total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol.

The TC/HDL ratio is a calculation that divides total cholesterol (TC) by high-density lipoprotein (HDL) cholesterol. It is used as a marker of cardiovascular risk, with higher ratios indicating a higher risk of heart disease.

HDL cholesterol is known as "good" cholesterol because it helps remove excess cholesterol from the bloodstream and returns it to the liver.   High levels of total cholesterol in the setting of low levels of HDL cholesterol, especially higher low-density lipoprotein (LDL) cholesterol, can contribute to plaque buildup in the arteries and lead to heart disease.

Understanding the implications of the TC/HDL ratio and how to manage it can be crucial for maintaining heart health. This article explores the definition, function, dietary sources, recommended intake, lab testing, interpretation of results, related biomarkers, and natural ways to support and optimize TC/HDL ratio.

Definition and Function of TC/HDL Ratio

What is the Total Cholesterol/HDL (TC/HDL) Ratio?

To understand the significance of the TC/HDL ratio, it is important to understand the different fractions of cholesterol present in the bloodstream.  

Cholesterol is shuttled through the body in lipoprotein particles, and some types confer a higher risk of cardiovascular disease than others.  

There are five main types of lipoprotein particles: their individual cardiac risk, or atherogenicity, depends on their size, the direction in which they’re traveling (to or away from the liver), and the lipoproteins attached to them.  [8.]

Chylomicrons: chylomicrons contain lipids absorbed from the digestive system and are too large to have a direct effect on cardiovascular health

High-density lipoprotein (HDL): HDL particles contain the ApoA1 lipoprotein and tends to carry cholesterol back to the liver; therefore, HDl is considered “good” cholesterol.  [12.]

Non-HDL particles: these include very low-density lipoproteins [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and lipoprotein(a), or Lp(a).  These particles all contain Apo-B lipoproteins, are traveling from the liver to peripheral tissues, and are small enough to cause atherosclerosis; for all of these reasons, they are considered to increase cardiovascular risk.  [2.]

In the basic lipid panel, the Total Cholesterol biomarker is used to describe the sum of HDL + Non-HDL particles.  Often, this is similar to HDL + LDL particles (the markers typically present on a standard lipid panel), but not always.  [8.]

The TC/HDL Ratio

The total cholesterol/HDL cholesterol (TC/HDL) ratio is an important indicator of vascular risk, with higher ratios indicating a higher risk of heart disease. 

An increase in total cholesterol, especially LDL cholesterol, is a marker for atherosclerosis, while low HDL cholesterol is associated with multiple risk factors, including metabolic syndrome. The TC/HDL ratio is a strong predictor of coronary heart disease and is considered more sensitive than total cholesterol alone, because it better describes the presence of atherogenic non-HDL particles in comparison to non-atherogenic HDL particles.

When triglyceride levels are high, the TC/HDL ratio is preferred over calculating LDL cholesterol.  [15.]

Individuals with high TC/HDL ratios have an increased cardiovascular risk due to imbalances in atherogenic and protective lipoproteins.  [15.]

Function of Cholesterol: What Does Cholesterol Do in the Body?  

Cholesterol is crucial for various functions in the body. It forms an integral part of cell membranes, providing structural stability and flexibility. Cholesterol is also a precursor for steroid hormones like cortisol and testosterone, and it plays a role in the synthesis of bile acids, aiding in fat digestion. 

Additionally, cholesterol is essential for vitamin D synthesis, nerve impulse transmission, cell membrane stability, and the formation of lipid rafts involved in cell signaling. 

The synthesis of cholesterol and coenzyme Q10 share a pathway, impacting medication management for high cholesterol, as CoQ10 is vital for cellular energy production.

How Does Cholesterol Participate in Cardiovascular Disease?  What Does the TC/HDL Ratio Tell Me About My Risk?

The TC/HDL ratio is a ratio between non-HDL and HDL particles, vs. HDL particles alone.  A higher TC/HDL ratio means a higher amount of non-HDL particles are present in the bloodstream, which increases cardiovascular risk.

Non-HDL particles are also called atherogenic particles because they have the potential to cause and/or drive the atherogenic process.  While LDL particles are considered the main culprits, all non-HDL particles should be considered.  [8.]

Non-HDL Particles in Atherogenesis

The following is a brief outline of the pathogenesis of atherosclerosis, highlighting the role of LDL particles: 

LDL cholesterol plays a central role in atherogenesis, the process underlying atherosclerosis. LDL enters the arterial intima through transcytosis across the endothelium, where it is retained through interactions with arterial wall proteoglycans, particularly in areas exposed to disturbed blood flow. 

Additionally, LDL particles exhibit heterogeneity, with small dense LDL displaying heightened atherogenic potential due to prolonged circulation time and increased affinity for arterial wall components. 

Once in the intima, LDL is susceptible to oxidation, leading to the formation of oxidized LDL (oxLDL) and triggering a sterile inflammatory response. This response recruits monocytes that differentiate into macrophages, promoting the formation of cholesterol-laden foam cells. 

The immune response to oxLDL involves T cells and B cells, with CD4+ Th1 cells promoting atherogenesis and B cells producing antibodies targeting oxLDL. Efficient efferocytosis, the clearance of dying cells, is crucial for resolving inflammation but is often defective in atherosclerosis, leading to the accumulation of apoptotic cells and sustained inflammation. 

Plaque stability is influenced by the composition of plaque tissue, with lipid-rich plaques prone to rupture and triggering thrombosis. 

Lowering LDL levels is essential for reducing key mechanisms of plaque instability, highlighting the importance of LDL-lowering therapies in managing atherosclerosis.

HDL Particles in Maintaining Cardiovascular Health 

The primary function of HDL is to transport cholesterol from peripheral tissues to the liver, contributing to lipid distribution. HDL is recognized for its anti-atherogenic and anti-inflammatory properties, as it retrieves cholesterol from atherosclerotic plaques' foam cells and returns it to the liver, reducing plaque size and inflammation. 

HDL synthesis occurs mainly in the liver and intestines, involving the production of apolipoprotein A-I (Apo-AI) and the transfer of cholesterol and phospholipids to HDL via various transporters. 

HDL's role in cholesterol metabolism is crucial for maintaining cardiovascular health, as it helps prevent the development and progression of atherosclerosis.

What Causes High Cholesterol?

Lifestyle

An unhealthy lifestyle is the most common cause of high cholesterol.  This includes a diet high in saturated fats, a sedentary lifestyle, and smoking, which all raise LDL cholesterol levels.  Additionally, excessive stress and/or alcohol may raise LDL cholesterol.  

Genetic Causes

Various genetic disorders can lead to high cholesterol levels, increasing the risk of cardiovascular disease. Familial hypercholesterolemia (FH) is a well-known condition caused by mutations in genes like LDLR, APOB, or PCSK9, resulting in high LDL cholesterol levels from birth.  [4.]

Another rare disorder, familial defective apoB-100 (FDB), stems from mutations in the APOB gene, impairing LDL particle binding to receptors.  [30.]

Autosomal recessive hypercholesterolemia (ARH) arises from mutations in the LDLRAP1 gene, affecting LDL particle internalization. Sitosterolemia is caused by mutations in ABCG5 or ABCG8 genes, leading to elevated LDL cholesterol and plant sterols. 

Polygenic hypercholesterolemia involves multiple genetic variants impacting lipid metabolism, while familial combined hyperlipidemia (FCHL) and familial dysbetalipoproteinemia result from complex genetic interactions, raising LDL cholesterol and triglyceride levels.

Other Medical Conditions

Hypothyroidism: Hypothyroidism, or underactive thyroid, can lead to elevated LDL cholesterol levels as thyroid hormones play a crucial role in lipid metabolism. Reduced thyroid hormone levels can slow down the clearance of LDL cholesterol from the bloodstream.  [28.]

Nephrotic Syndrome: Nephrotic syndrome, a kidney disorder characterized by proteinuria, can cause high LDL cholesterol levels due to increased hepatic production of lipoproteins and decreased clearance of LDL from the circulation.  [31.]

Obesity: Obesity is often associated with high LDL cholesterol levels. Excess adipose tissue leads to dysregulation of lipid metabolism, resulting in increased LDL cholesterol production and decreased clearance.  [4.]

Polycystic Ovary Syndrome (PCOS): PCOS, a hormonal disorder common in women of reproductive age, can be associated with high LDL cholesterol levels.  It’s thought to be due to insulin resistance and hormonal imbalances, although the etiology is not confirmed.  [13.]

Cholestasis: liver disorders, especially cholestasis, disrupt cholesterol metabolism and can lead to various forms of hypercholesterolemia, including the appearance of Lp-X. Mistaking Lp-X for LDL cholesterol can disrupt accurate cardiovascular risk assessment and result in unnecessary lipid-lowering therapy. 

Lp-X, also known as lipoprotein-X, is an abnormal lipoprotein particle found in the bloodstream. It is typically composed of phospholipids, free cholesterol, and apolipoprotein B, but lacks normal lipid constituents like triglycerides and cholesterol esters. Lp-X is often seen in conditions of liver dysfunction, particularly cholestasis, and its presence can interfere with accurate measurement of LDL cholesterol levels, potentially leading to misinterpretation of cardiovascular risk.

Regular lipid panel assessments, including apo B-100 measurement, are essential for liver transplant (LT) recipients, both during evaluation and post-transplantation. Apo B-100 measurement aids in distinguishing between atherogenic and non-atherogenic hypercholesterolemia, providing valuable insights into cardiovascular risk and the effectiveness of therapy, particularly in the context of coexisting cholestasis and Lp-X with true atherogenic hypercholesterolemia after lipid therapy.  [19.]

Anorexia Nervosa: Individuals with anorexia nervosa may develop high LDL cholesterol levels due to malnutrition and starvation. Decreased caloric intake can lead to increased hepatic production of cholesterol and altered lipid metabolism.  [32.]

Medications

Protease inhibitors: Certain antiretroviral medications used to treat HIV/AIDS, such as lopinavir and ritonavir, can lead to elevated cholesterol levels.  [25.]

Thiazide diuretics: While effective for managing high blood pressure and fluid retention, thiazide diuretics can sometimes raise cholesterol levels, especially LDL cholesterol.  [29.]

Atypical antipsychotics: atypical antipsychotics, used to treat psychiatric disorders like schizophrenia and bipolar disorder, can sometimes lead to elevated cholesterol levels.  However, different medications may have different metabolic effects.  [21.]

Isotretinoin: This medication, commonly prescribed for severe acne, has been associated with elevated cholesterol and triglyceride levels in some individuals.  [5.]

Immunosuppressants: Drugs used to suppress the immune system following organ transplantation, such as cyclosporine and tacrolimus, may contribute to elevated cholesterol levels.  [14.]

Oral contraceptives: certain birth control pills can increase cholesterol levels, especially LDL cholesterol.  [18.] 

Antidepressants: Some antidepressant medications, such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), might contribute to alterations in cholesterol metabolism, though the effects can vary among individuals.  [27.]

Lab Testing for Total Cholesterol Levels

General Testing Information and Sample Type

Typically, cholesterol assessment starts with a lipid panel, which includes the following biomarkers: total cholesterol, LDL and HDL cholesterols, and triglycerides, as well as the TC/HDL ratio.

People are increasingly aware of the benefits of advanced testing for cholesterol levels in order to support wellness, reduce their risk of cardiovascular disease, and inform personalized medical decisions.  To address the desire for more information about cholesterol health, lab companies are increasingly offering more comprehensive assessments.  

A few examples include:

The Cardiometabolic Profile by Doctor’s Data

The CadioPro Advanced Profile by Access Medical Labs

The Cardiometabolic Comprehensive Profile by BostonHeart Diagnostics

‍The LPP Plus by Spectracell Laboratories

These tests, including the standard lipid profile, are all blood tests that require a venipuncture.  Fasting is typically recommended for these tests.  In some cases, a mobile phlebotomist can come to you to have the blood draw performed from the home or office, and the sample can then be taken to the lab by the phlebotomist. 

Interpreting Test Results

Reference Range for TC/HDL Ratio

Reference ranges may vary among laboratories and clinicians.  The reference range for TC/HDL ratio is below 5, but a lower ratio is correlated with decreased risk.  One study of over 6000 women showed the lowest risk for an acute myocardial infarction was in women with a TC/HDL ratio of less  than or equal to 3.5, and the risk almost doubled in women with a TC/HDL ratio of greater than 5.  [3.]

Clinical Significance of High TC/HDL Ratio

A higher total cholesterol (TC) to high-density lipoprotein (HDL) ratio is clinically significant as it indicates an imbalance in cholesterol levels that may increase the risk of cardiovascular disease (CVD). 

Elevated TC levels, especially when paired with low HDL levels, suggest a higher concentration of atherogenic lipoproteins like LDL cholesterol, which can contribute to the development of atherosclerosis. 

A higher TC/HDL ratio is associated with increased risk of coronary heart disease (CHD) including acute myocardial infarction and is considered a stronger predictor of cardiovascular risk than either parameter alone. [3., 15.] 

Monitoring and managing the TC/HDL ratio can be an important part of cardiovascular risk assessment and preventive care.

Clinical Significance of Low TC/HDL Ratio

There is no widely-accepted level of TC/HDL ratio that is considered too low.  However, one large study of over 30,000 people over 8 years demonstrated an increased risk of all-cause mortality in individuals with a TC/HDL ratio >5.07 and <2.86.  However, for cardiovascular-related mortality, the cutoff was significant with a TC/HDL ratio above 4.22.  [35.]

This study indicates that low cholesterol levels may have a negative impact on health independent of cardiovascular health 

Related Biomarkers: What Should Be Tested Besides Total Cholesterol?

The standard lipid panel is a good place to begin to evaluate an individual’s risk of developing heart disease.  There are a variety of other biomarkers available that can provide increased information above and beyond a standard lipid panel.  Some of these include: 

VLDL Particles: very-low-density lipoprotein (VLDL) particles are a precursor to LDL particles and play a crucial role in lipid metabolism. Elevated VLDL levels are associated with increased risk of atherosclerosis and cardiovascular disease.  [7.]

Total LDL Particles (LDL-P): measuring the number of LDL particles gives different information than LDL-C, which is the amount of cholesterol that’s carried by LDL particles.  

Knowing the number of LDL particles present in the bloodstream provides a more comprehensive assessment of cardiovascular risk than LDL-C alone because the size of LDL particles also confers cardiovascular risk, with smaller LDL particles being more atherogenic.  

Therefore, in two people with the same LDL-C number, the person with a higher LDL-P (and therefore more small LDL particles present in his or her bloodstream) has a higher risk for a cardiovascular event than the person with the lower LDL-P.  [17.]

Remnant Lipoprotein: remnant lipoproteins, remnants of VLDL and chylomicrons after triglyceride hydrolysis, are atherogenic particles associated with increased risk of cardiovascular events, even in individuals with normal LDL cholesterol levels. [20., 33.]

Dense LDL III and Dense LDL IV: small dense LDL (sdLDL) subfractions, particularly LDL III and LDL IV, are more atherogenic than larger, buoyant LDL particles. Measuring these subfractions provides additional information for assessing cardiovascular risk beyond traditional lipid panels.  [22.]

Buoyant HDL 2b: buoyant HDL 2b particles are considered particularly cardioprotective due to their role in reverse cholesterol transport. Higher levels of buoyant HDL 2b are associated with reduced risk of cardiovascular events.  [10.]

Lipoprotein(a): Elevated lipoprotein(a) levels are an independent risk factor for cardiovascular disease, particularly in individuals with a family history of premature heart disease.  It is important to note that Lp(a) levels are genetically determined and change little, if at all, in response to diet and lifestyle.  [26.]

Apolipoprotein B (ApoB): Apolipoprotein B is a structural component of atherogenic cholesterol particles including VLDL, IDL, LDL and Lp(a)  particles and is considered a more accurate predictor of cardiovascular risk compared to LDL cholesterol levels alone, particularly in the setting of insulin resistance and diabetes.  [2.]

Apolipoprotein A1 (apoA1): apoA1 is attached to the surface of HDL particles, and is associated with a cardioprotective effect.  Elevated apoA1 levels are associated with improved HDL functionality and reduced cardiovascular risk, while low levels are independently linked to increased risk of cardiovascular events. 

Monitoring apoA1 levels allows for better risk prediction and assessment of therapeutic efficacy in managing cardiovascular disease risk. [12.]

hs-CRP (High-Sensitivity C-Reactive Protein): elevated hs-CRP levels are indicative of systemic inflammation and are associated with increased risk of cardiovascular events, including myocardial infarction and stroke.  [9.]

Homocysteine: elevated homocysteine levels are associated with increased risk of cardiovascular disease, including atherosclerosis, stroke, and venous thromboembolism.  [24.] 

How to Support Healthy Cholesterol Levels

Lifestyle Modifications

• Maintain a healthy weight through regular physical activity and a balanced diet. 
• Reduce sedentary behavior and incorporate more movement throughout the day to support a healthy metabolism.
• Manage stress levels through relaxation techniques such as meditation or yoga. High stress has been correlated with metabolic dysfunction.  [21.]
• Ensure adequate sleep duration and quality to support metabolic health.  [17.]

Dietary Changes  [6.]

• Consume a diet rich in whole foods, including fruits, vegetables, whole grains, lean proteins, and healthy fats.  
• Limit intake of highly processed foods, sugary beverages, and foods high in saturated and trans fats.
• Increase fiber intake from sources like legumes, nuts, seeds, and whole grains to promote satiety and regulate blood sugar levels.
• Monitor portion sizes and practice mindful eating to prevent overeating and promote weight management.
• Follow a plant-based diet, and reduce intake of high-fat animal products. 

Exercise Recommendations  [16., 34.]

• Engage in a combination of aerobic exercise, strength training, and flexibility exercises to improve metabolic function.
• Aim for regular physical activity throughout the week, incorporating both cardiovascular exercise and resistance training sessions.
• Gradually increase exercise intensity and duration over time to challenge the body and promote fitness gains.
• Incorporate activities you enjoy to increase adherence to exercise routines and maintain long-term consistency.
• Consult with a healthcare provider or fitness professional to develop a personalized exercise plan based on individual fitness levels and health goals.

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