Thyroid Hormones and Non‐HDL Ratio Impact on Health

Introduction

Thyroid hormones—primarily thyroxine (T4) and triiodothyronine (T3)—play critical roles in numerous physiological processes such as metabolism, thermogenesis, and growth. The majority of T3 in the bloodstream is generated from peripheral conversion of T4 via deiodinase enzymes. Only a small fraction of these hormones circulate in their free, unbound state (FT4 and FT3), and it is these active hormones that exert metabolic and regulatory effects on the target tissues.

Lipid metabolism is a highly regulated process involving the synthesis, transport, and clearance of cholesterol and triglycerides. Among the various lipid fractions, non‐HDL‐C—which includes low‐density lipoprotein (LDL‐C), very low‐density lipoprotein (VLDL‐C), intermediate-density lipoprotein (IDL‐C), and other apolipoprotein B–containing particles—has been recognized as an important predictor of atherosclerotic cardiovascular disease (ASCVD). Recent studies have pointed out that the non‐HDL‐C to HDL‐C ratio (NHHR) may provide a more comprehensive risk profile for cardiovascular events.

This article reviews the latest findings on the association between thyroid hormone levels and NHHR, discusses underlying mechanisms, and evaluates epidemiological and Mendelian randomization evidence supporting a causal connection between thyroid function and lipid metabolism.

Thyroid Hormones and Lipid Metabolism

Thyroid hormones regulate basal metabolic rate and have wide‐ranging influences on lipid homeostasis. The metabolic effects of FT4 and FT3 are mediated by their ability to modulate the expression of genes involved in cholesterol synthesis and degradation, lipoprotein receptor expression, and the activity of enzymes such as 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG-CoA) reductase. High thyroid hormone levels typically upregulate bile acid synthesis and stimulate the hepatic uptake of cholesterol, leading to reduced serum cholesterol levels. Conversely, hypothyroidism is frequently associated with hypercholesterolemia and atherogenic dyslipidemia.

Recent studies suggest that changes in thyroid hormone levels may be directly linked with alterations in traditional lipid profiles and composite parameters such as the NHHR. In particular, lower levels of FT4 have been negatively associated with non‐HDL cholesterol levels in certain populations. In addition, the balance between free and total thyroid hormone concentrations appears to affect the conversion rate from the precursor T4 to the active T3, which in turn may influence lipoprotein metabolism. The physiological suppression of TSH—commonly seen in hyperthyroid states—also correlates with reduced cholesterol levels and improved clearance of atherogenic lipoproteins.

Understanding these associations is critical because both altered thyroid hormone levels and dyslipidemia are independent risk factors for cardiovascular disease. The interplay between them could serve as a valuable biomarker for assessing the risk of ASCVD, guiding therapeutic decisions, and monitoring the effects of treatment.

Non‐HDL Cholesterol as a Comprehensive Lipid Marker

Non‐HDL cholesterol is calculated by subtracting HDL‐C from total cholesterol (TC), thus incorporating all potentially atherogenic lipoproteins in circulation. Unlike LDL‐C alone, non‐HDL‐C encompasses VLDL, IDL, and other remnants that are implicated in plaque formation and vascular inflammation.

The non‐HDL‐C to HDL‐C ratio (NHHR) is gaining traction as a superior metric due to its ability to account for both detrimental and protective cholesterol fractions. Elevated NHHR is often seen in metabolic syndrome and has been independently associated with an increased risk of coronary heart disease, ischemic stroke, and other cardiovascular events. Furthermore, NHHR has been suggested to have a stronger predictive value for cardiovascular outcomes than isolated measurements of LDL‐C or total cholesterol.

The modulation of NHHR by thyroid hormones is of particular interest, as it suggests that disturbances in thyroid function may alter the lipid profile in ways that directly impact cardiovascular risk. For instance, in states of hypothyroidism, diminished thyroid hormonal activity leads to reduced LDL receptor expression and impaired clearance of atherogenic particles, in turn elevating non‐HDL cholesterol levels.

Below is a summary table highlighting the conceptual associations between thyroid hormones and various lipid parameters:

Table 1. Summary of Key Associations between Thyroid Hormones and Lipid Parameters

Note: The associations in Table 1 are based on current evidence that suggests a balance between thyroid hormone status and lipid metabolism, with the NHHR serving as an integrative marker for evaluating atherogenic risk.

Interplay Between Thyroid Function and NHHR

The mechanisms linking thyroid hormones and the NHHR are multifaceted. One potential pathway is through thyroid hormone regulation of hepatic lipid metabolism. Thyroid hormones modulate gene expression involved in cholesterol synthesis, uptake, and degradation in the liver. For instance, thyroid hormones upregulate hepatic LDL receptors which enhance clearance of atherogenic LDL particles, thereby reducing circulating non‐HDL cholesterol. In hypothyroidism, this receptor-mediated clearance is diminished, leading to the build-up of LDL and other atherogenic particles in the bloodstream.

In addition to direct receptor-mediated effects, thyroid hormones influence bile acid synthesis. Bile acids are derived from cholesterol and are integral to its excretion. Increased thyroid hormone levels are associated with higher bile acid production, which in turn helps lower serum cholesterol. Thus, subtle shifts in thyroid hormone concentrations can indirectly modulate the NHHR through effects on cholesterol turnover.

Another important consideration is systemic inflammation. Chronic low-grade inflammation is a common feature of both metabolic disturbances and thyroid dysfunction. Elevated non‐HDL cholesterol levels have been linked to inflammatory processes, and thyroid hormones, via their regulatory influence on inflammatory mediators, may alter this relationship. For example, increased inflammation in hypothyroid patients may further promote the conversion of T4 to T3, thereby changing the FT4/FT3 ratio—a parameter that has been found to correlate with changes in lipid metabolism.

Collectively, these pathways underscore that thyroid hormones not only regulate metabolic rate and energy expenditure but also fundamentally alter plasma lipoprotein composition. Consequently, the NHHR can serve as a window into how thyroid dysfunction might predispose individuals to cardiovascular disease.

Epidemiological and Mendelian Randomization Evidence

Recent epidemiological studies have established a significant relationship between thyroid function and composite lipid parameters. Analyses of large databases, such as the National Health and Nutrition Examination Survey (NHANES), have demonstrated that an elevated NHHR is negatively associated with FT4 levels and the ratios of FT4/FT3 and TT4/TT3 [1]. After adjusting for various confounders, an increase in the NHHR corresponds to a reduction in free thyroid hormone levels. This suggests that standard dysregulation of thyroid function, even within the range of euthyroidism, can adversely impact lipid profiles in a way that elevates cardiovascular risk.

Mendelian randomization (MR) studies add a layer of causal inference by using genetic variants associated with lipid levels and thyroid function as instrumental variables. In one landmark MR study, researchers used data from the Global Lipids Genetics Consortium to examine whether genetic predispositions affecting lipid levels could causally relate to thyroid hormone alterations. The findings indicated that changes in the NHHR, particularly driven by alterations in HDL‐C and non‐HDL‐C, are causally connected with variations in serum FT4 and the ratios of thyroid hormones [1].

This genetic evidence reinforces epidemiological observations and suggests that the interplay between thyroid hormones and NHHR is not merely correlative but likely causal. Although traditional lipid markers such as LDL‐C and total cholesterol were not independently associated with thyroid dysfunction, the ratio of non‐HDL‐C to HDL‐C does appear to provide significant insights into thyroid-related metabolic disturbances.

Below is a conceptual illustration of how thyroid hormone levels and NHHR interact based on recent findings:

Table 2. Conceptual Overview of the Causal Relationship between Thyroid Hormones and NHHR

Table 2 summarizes the main mechanistic pathways bridging thyroid function and the NHHR, which are key to assessing cardiovascular risk in clinical settings.

Clinical Implications

The growing evidence linking thyroid hormones to the NHHR has several important clinical implications. First, routine evaluation of NHHR in patients with thyroid dysfunction may enhance cardiovascular risk assessment. For example, patients with subclinical hypothyroidism—often characterized by mildly elevated TSH and lower FT4 levels—might benefit from early intervention to address dyslipidemia, even if traditional lipid panels appear only marginally abnormal.

Second, the NHHR may help identify individuals within the “euthyroid” range who nonetheless exhibit subtle metabolic disturbances. Such patients, though biochemically normal on standard thyroid panels, could be at increased risk for subsequent development of cardiovascular disease if their non‐HDL cholesterol levels remain high relative to HDL cholesterol. In this context, NHHR could be used as a marker to initiate lifestyle modifications or even pharmacologic therapies at an earlier stage, thereby preventing atherosclerotic progression.

Furthermore, understanding the causal pathways through MR studies offers the promise of personalized medicine. If certain gene variants predispose individuals to both altered thyroid hormone metabolism and unfavorable lipid profiles, then genetic screening could eventually become part of a more comprehensive risk assessment for cardiovascular disease. This integration of endocrine and cardiovascular diagnostics may lead to more individualized treatment plans that optimize both thyroid function and lipid levels.

From a treatment perspective, addressing thyroid dysfunction may have beneficial effects on lipid profiles. For example, restoring euthyroidism through levothyroxine treatment in hypothyroid patients has been shown to improve cholesterol clearance and reduce non‐HDL cholesterol levels. In contrast, overtreatment resulting in iatrogenic hyperthyroidism might lower cholesterol levels excessively, which also carries its own risks. Lastly, awareness of the NHHR’s predictive value may also encourage clinicians to adopt more comprehensive lipid-lowering strategies, rather than focusing solely on LDL-C targets.

Ultimately, these insights underscore the necessity for clinicians to consider thyroid status in the context of lipid metabolism. Integrating thyroid hormone assays with detailed lipoprotein analyses, such as the NHHR, provides a more robust framework for tailoring cardiovascular risk-reducing strategies. Given the complexity of human metabolism, future clinical guidelines may increasingly recommend combined screening approaches in populations at risk for both thyroid disease and cardiovascular events.

Summary

The interplay between thyroid hormones and the non‐HDL cholesterol to HDL cholesterol ratio represents an important intersection of endocrine and cardiovascular physiology. Thyroid hormones, through their regulatory effects on liver metabolism, LDL receptor expression, and bile acid synthesis, have profound effects on lipoprotein metabolism. Epidemiological studies have demonstrated that decreased FT4 levels and altered thyroid hormone ratios are associated with an increased NHHR—a marker that encapsulates the atherogenic potential of circulating lipids.

Complementary Mendelian randomization studies have further supported the causal relationship between thyroid hormone levels and lipid metabolism, particularly implicating the NHHR as a more robust indicator of metabolic and cardiovascular risk than traditional lipid measures alone. Clinically, this relationship highlights the potential for using the NHHR as a screening tool in patients with thyroid dysfunction, as well as in individuals who appear euthyroid yet remain at risk for cardiovascular disease due to unfavorable lipid profiles.

Ongoing research in this area will likely refine our understanding and may lead to integrated diagnostic and therapeutic strategies that target both thyroid function and lipid metabolism, ultimately reducing the incidence of atherosclerotic diseases and improving overall health outcomes.

Frequently Asked Questions (FAQ)

What exactly is the non‐HDL cholesterol to HDL cholesterol ratio (NHHR)?
A1: The NHHR is a calculation derived by subtracting HDL cholesterol from total cholesterol and then forming a ratio with HDL cholesterol. It represents the balance between atherogenic lipoproteins (non‐HDL cholesterol) and protective HDL cholesterol, providing a comprehensive picture of cardiovascular risk.

How do thyroid hormones affect lipid metabolism?
A2: Thyroid hormones regulate gene expression in the liver, stimulate the production of bile acids, and increase LDL receptor expression. These actions collectively help clear cholesterol from the blood. Low levels of thyroid hormones, as seen in hypothyroidism, are associated with reduced clearance and higher cholesterol levels, particularly non‐HDL cholesterol.

Why is the NHHR considered a better predictor of cardiovascular risk than LDL cholesterol alone?
A3: Unlike LDL cholesterol, NHHR includes all atherogenic lipoproteins—not just LDL, but also VLDL, IDL, and others. This comprehensive measure captures a broader spectrum of risk factors and has been shown to correlate more strongly with cardiovascular outcomes in various studies.

Can thyroid dysfunction lead to changes in the NHHR even if traditional thyroid tests appear normal?
A4: Yes. Some individuals who are considered euthyroid by standard assays might still experience subtle alterations in thyroid function that impact lipid metabolism. The ratio of free thyroid hormones (such as the FT4/FT3 ratio) could be altered, leading to a shift in NHHR even when TSH levels are within normal limits.

What are the clinical implications of the relationship between thyroid hormones and NHHR?
A5: Recognizing the link can guide both thyroid management and cardiovascular risk reduction. Clinicians may use NHHR as an additional screening tool in patients with thyroid dysfunction or at risk for cardiovascular disease. Optimizing thyroid hormone levels could improve lipid profiles and vice versa, emphasizing a more integrated approach to prevention and management.

Are there any genetic factors that influence the relationship between thyroid hormones and NHHR?
A6: Recent Mendelian randomization studies have identified genetic variants that are associated with both lipid metabolism and thyroid function, suggesting a causal link. This paves the way for personalized medicine approaches where genetic screening may help predict individual risks and tailor treatment strategies accordingly.

References

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