EBM Tools for Practice: The Thyroid-Lipid Axis: Implications for Atherosclerosis and Beyond

Dyslipidemia frequently presents in individuals with thyroid dysfunction, attributed to the influence of thyroid hormones on various key metabolic pathways, thereby contributing to an elevated cardiovascular (CV) risk.¹ In this discussion, we delve into the intricate connection between thyroid dysfunction and lipid metabolism, providing recommendations for effective surveillance and management. 

Overview of Thyroid Dysfunction

Thyroid dysfunction, specifically hypothyroidism and hyperthyroidism, are among the most common endocrine disorders seen in clinical practice. Thyroid dysfunction can present either as subclinical or overt disease. The prevalence of hypothyroidism has gradually increased over recent years, a retrospective study estimated a prevalence of 11.7% in the United States (US) population in 2019. The prevalence of hyperthyroidism is 1.3% (0.5% overt and 0.7% subclinical) in the US population. Prevalence of both hypothyroidism and hyperthyroidism was found to be greater in females, Whites, and Hispanics compared to African Americans, with prevalence increasing with older age.² 

Hyperthyroidism
Subclinical hyperthyroidism is defined biochemically as low serum thyroid stimulating hormone (TSH) (< 0.5 mIU/L) accompanied by normal free thyroid hormone concentrations, including thyroxine (T4) and triiodothyronine (T3) in an asymptomatic patient. The term overt hyperthyroidism refers to elevated levels of T4 and T3 and suppressed TSH concentration (< 0.1 mIU/L) along with clinical symptoms such as weight loss, palpitations, anxiety, heat intolerance, fatigue, or insomnia. Common causes of hyperthyroidism include Graves’ disease, excessive thyroid hormone therapy, autonomously functioning thyroid adenoma, toxic multinodular goiter, and thyroiditis (subacute, post-partum, and medication-induced, such as with amiodarone and checkpoint inhibitors).

Hypothyroidism
Subclinical hypothyroidism is defined as normal serum free T4 in the presence of an elevated TSH concentration in an asymptomatic patient. Mild TSH elevation (4.0-7.0 mU/l) in the elderly (> 80 years old) is considered a normal physiological adaptation to aging.³ The term overt hypothyroidism refers to patients with elevated TSH along with low serum free T4 and clinical symptoms, including weight gain, fatigue, cold sensitivity, depression, muscle weakness, and constipation. The causes of hypothyroidism include chronic autoimmune (Hashimoto’s) thyroiditis, prior ablative or antithyroid drug therapy for hyperthyroidism, prior thyroidectomy, external radiation therapy, long-term sequelae of acute thyroiditis, inadequate T4 replacement therapy, and drugs impairing thyroid function (such as lithium, amiodarone, and immunomodulators).

Euthyroid Sick Syndrome
Euthyroid sick syndrome is a complex physiologic response to critical illness or nutritional deprivation resulting in abnormal thyroid function tests. Also termed non-thyroidal illness syndrome (NTIS), this occurs independent of primary thyroid pathology, and reflects an adaptive response to acute stress. Generally, these patients are observed to have low total and free T3 as well as low or normal TSH levels. The degree of abnormality in these assays has been directly correlated with morbidity and mortality. Current studies underway are investigating the etiology of these changes in the hypothalamus-pituitary-thyroid axis and the utility of treatment with thyroid hormone. Notably, abnormal thyroid function in these patients appears to be reversible with treatment of the underlying illness.⁴ Studies in patients with chronic illness including end stage renal disease and systemic lupus erythematosus demonstrate a positive correlation between low total and free T3 levels in NTIS and elevated triglycerides, low-density lipoprotein cholesterol (LDL), and apolipoprotein B (ApoB).^5,6 The mechanism behind this is likely similar to that seen in hypothyroidism, proposed below. Additionally, lipid parameters in this syndrome are likely impacted by concomitant changes in nutritional status and hypoalbuminemia often seen in critically ill patients. The relationship between NTIS and dyslipidemia remains to be studied further. 

Cardiovascular Risk in Patients with Thyroid Dysfunction

Thyroid dysfunction, when not properly managed, has been linked to heightened CV disease risk.1 These effects manifest through various mechanisms, such as dyslipidemia, hypertension, systolic and diastolic myocardial dysfunction, along with endothelial dysfunction.⁷
 
Both overt and subclinical hypothyroidism are associated with diastolic hypertension, elevated high-sensitivity C-reactive protein (hsCRP), hyperhomocysteinemia, and coagulation abnormalities.¹ Hypothyroidism also causes impaired intracellular glucose breakdown, hindered GLUT4 translocation, reduced glycogen synthesis, and altered glucose oxidation.8 Studies report increased intima-media thickness of the common carotid artery in patients with hypothyroidism, linking them to an elevated risk of ischemic stroke.⁹ The Whickham Survey showed an association of incident coronary heart disease (CHD) with subclinical hypothyroidism over 20 years, mitigated by levothyroxine (LT4) treatment.¹⁰ Some meta-analyses further support the significant association of subclinical hypothyroidism with CHD and CV mortality risks.^11,12 Notably, subclinical hypothyroidism correlates with higher CV events in patients with TSH > 10 mIU/L and in postmenopausal women.^13,14
 
Studies have established a clear association between hyperthyroidism and systolic hypertension, increased pulse pressure, hyperhomocysteinemia and an elevated risk of thrombosis.¹ Moreover, some studies indicate a potential link between hyperthyroidism and insulin resistance, evidenced by a higher homeostasis model assessment of insulin resistance (HOMA-IR) and a lower Matsuda index (which is a measure of insulin sensitivity), further compounding the CV risk.⁸ Additionally, individuals with hyperthyroidism, particularly older patients, are prone to experience angina pectoris due to tachycardia, increased contractility, and myocardial oxygen demand.¹⁵ Hyperthyroidism is associated with a higher risk of ischemic stroke among young adults during a 5-year follow-up study, likely linked to atrial fibrillation (AF) and hypercoagulability.16 Subclinical hyperthyroidism is also correlated with elevated risks of CHD mortality and incident AF, with the highest risks observed when TSH < 0.10 mIU/L.^12,17

These findings underscore the necessity for vigilant monitoring and management of cardiovascular health in individuals diagnosed with thyroid dysfunction, as it significantly impacts their overall cardiovascular risk profile.

Dyslipidemias Associated with Thyroid Dysfunction

Thyroid hormone plays an important role in the synthesis, metabolism, and transport of lipids. Therefore, thyroid dysfunction can significantly impact the lipid profile. There are many proposed mechanisms through which TSH and free thyroid hormones can directly influence lipid metabolism. 

TSH upregulates 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and proprotein convertase subtilisin/kexin type 9 (PCSK9), and inhibits the synthesis of bile acid, thereby increasing LDL-C. Thyroid hormone increases hepatic LDL receptors by upregulating LDL receptor gene expression and decreasing LDL oxidation, thereby decreasing LDL-C.¹⁸ TSH has been demonstrated to have an inverse relationship with cholesterol ester transfer protein (CETP) and hepatic lipase activity. Thus, higher TSH levels may lead to lower high-density lipoprotein (HDL-C) levels, and vice versa. However, it is important to note that the direction of change in HDL subclasses is variable with respect to TSH and requires further study.¹⁹ Thus the impact of thyroid hormone on HDL metabolism has not yet been fully determined. 

In relation to (ApoB) and lipoprotein (a) (Lp(a)) metabolism, higher TSH levels are correlated with decreased catabolism of the lipoproteins, leading to potential increase in secretion of ApoB-containing particles, and a concomitant rise of both ApoB and Lp(a) levels.²⁰ Furthermore, TSH has been shown to increase lipogenesis directly and by increasing the expression of transcription factors. Decreased lipoprotein lipase (LPL) activity in hypothyroid individuals has demonstrated higher serum triglyceride (TG) levels. Accordingly, management of overt hypothyroidism has been observed to decrease the levels of TG as well as multiple lipoproteins.²¹ The effect of thyroid dysfunction on various lipid parameters is summarized in Table 1.

Clinical Management Recommendations

In individuals diagnosed with dyslipidemia, the recommendation is to determine if thyroid dysfunction is a potential underlying etiology for the lipid disorder. This should occur, during the risk stratification and decision-making processes culminating in the initiation of lipid lowering medications. If overt hypothyroidism is confirmed, depending on the overall risk profile of the patient, postponing dyslipidemia treatment until the patient achieves euthyroid status may be a consideration. For those with subclinical hypothyroidism and concurrent dyslipidemia, treatment with LT4 is recommended as a means to address LDL-C and TG levels.²² Liothyronine (LT3) replacement has not been shown to significantly impact the lipid profile and should be avoided, especially in patients with known CV disease, due to a heightened risk of cardiac arrhythmias, heart failure, and stroke associated with LT3 supplementation.^{23, 24} More studies assessing the utility of LT3 in specific populations are needed. Similarly, in patients with hyperthyroidism, it is advisable to reassess the lipid panel once the patient attains euthyroid status. 

Statins, most commonly prescribed to individuals with dyslipidemia, are associated with an increased risk of adverse effects in those with suboptimally controlled hypothyroidism. The most commonly seen adverse effect of statins is myopathy, which can be exacerbated by untreated hypothyroidism.²⁵ In addition, hypothyroidism can be associated with transaminitis due to altered lipid metabolism, myopathy, and hepatic steatosis.²⁶ Statins carry a risk of inducing a spectrum of hepatic effects, from clinically insignificant transaminitis to the rare severe liver injury. This demonstrates the need to closely monitor liver enzymes in hypothyroid patients requiring administration of statins.²⁷ Please refer to the 2020 Endocrine Society Clinical Practice Guidelines regarding lipid management in patients with endocrine disorders for comprehensive guidance.²⁸

Conclusion and Future Directions

A heightened awareness regarding screening for thyroid irregularities in patients with dyslipidemia, including those with subclinical conditions, before commencing lipid-lowering treatment, is necessary. Additionally, there is utility in future investigations to help tailor preventative measures and interventions targeting CV conditions in subsets of patients with thyroid disorders and lipid abnormalities. Understanding the lipid profile and its effects on CV risk, further studies geared towards establishing the mechanism of thyroid hormone effect on Lp(a), would also be valuable. 

Despite earlier exploration of various thyromimetics for lipid lowering, most interventions of this type were discarded due to adverse effects. A 1960s clinical trial on dextrothyroxine (DT4) demonstrated potent lipid lowering effects without CV harm, but it was prematurely halted after 36 months due to a higher fatality rate in the DT4 group.²⁹ While there is renewed interest in novel selective thyromimetic agents for lipid lowering, additional studies are essential to assess the long-term safety and tolerability of these selective thyroid hormone analogs in individuals with dyslipidemia.

Continued research and exploration in these directions can contribute to a more nuanced understanding of the relationship between thyroid dysfunction and dyslipidemia, guiding future treatment strategies and improving patient outcomes.

Dr. Doshi has no financial relationships to disclose. Dr. Aldabyani has no financial relationships to disclose. Dr. Rajpal has no financial relationships to disclose. 

References  

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