Thyroid and Adrenal Influences on the Cardiovascular System
Erik Lundquist, MD, ABFM, AboIM, IFMCP
Annalouise O’Connor, BS, PhD
The endocrine system is a complex and sophisticated dance of hormones and their influence on end organ targets within the human body. This dance begins often in the brain and is influenced by a sophisticated biofeedback mechanism. The endocrine system is made up of multiple different glands that produce these hormones throughout the body. Outside and environmental influences have a significant impact on the release of stimulating hormones, the receptors they bind to, and the effectiveness of the stimulation on their target. The key to the dance of the endocrine system is to try to bring balance to the system.
For purposes of this chapter we will be focusing on the hypothalamus-pituitary-adrenal-thyroid (HPAT) axis and the influence this system has on the cardiovascular system. The purpose of the cardiovascular system is to supply oxygen and nutrients throughout the body. The cardiovascular system is affected by the endocrine system. The endocrine system in turn is dependent on the cardiovascular system for the delivery of its hormones to appropriate target tissues. This symbiotic and synergistic relationship ties these two systems together intimately. One cannot survive without the other.
This chapter will be divided into two sections, one on the thyroid and one on the adrenals.
The following are the objectives of this chapter:
Understand the function and metabolism of hormones and neurotransmitters as they relate to the thyroid and adrenal systems.
Explain how thyroid and adrenal hormones impact the cardiovascular system.
Identify the laboratory tests available and how to use these to understand the production, transport, receptor sensitivity, and metabolism of the hormones and neurotransmitters involved with the adrenal and thyroid systems.
Examine the impact that stress has on the cardiovascular system as mediated through different adrenal and thyroid hormonal influences.
Review the evidence behind targeted nutritional and lifestyle treatments to optimize thyroid and adrenal function, particularly in how they relate to the cardiovascular system.
Signs and Symptoms of Thyroid Dysfunction
The thyroid system has a multifaceted impact on the heart and vascular system, and changes in thyroid hormone status has knock-on effects to many aspects of this system including lipid metabolism, heart rate and contractility, endothelial function, vascular resistance, and blood pressure control.1 Additionally, a change in thyroid status, specifically hypothyroidism, is linked to an increased risk of metabolic syndrome and type 2 diabetes, which pose additional cardiovascular risk.2 Indeed, thyroid dysfunction, both overt and subclinical, and hyper- and hypothyroidism increase the risk of heart failure, cardiovascular events, and death.1
The prevalence of thyroid disorders is fairly substantial in the United States. The spectrum of thyroid disorders include hypothyroidism, hyperthyroidism, and autoimmune thyroiditis, which can be manifested as hypothyroidism, as with Hashimoto disease, or hyperthyroidism, as with Graves disease. Because so many individuals with thyroid dysfunction are undertreated or undiagnosed it is important for their cardiac minded clinician to understand the prevalence, symptoms, and disorders associated with thyroid dysfunction.
According to the Colorado thyroid disease prevention study that measured individuals with a thyroid stimulating hormone (TSH) above 4.5, there are approximately 30 to 35 million individuals in the United States with thyroid disorders. Of those, approximately half are undiagnosed. Of those who are diagnosed, approximately 10 to 14 million have Hashimoto disease (a form of autoimmune thyroiditis resulting in hypothyroidism) and a much smaller portion
have Graves disease, which is another form of autoimmune thyroiditis resulting in hyperthyroidism. A large portion of these individuals are women, with some studies estimating as high as 80%.3
have Graves disease, which is another form of autoimmune thyroiditis resulting in hyperthyroidism. A large portion of these individuals are women, with some studies estimating as high as 80%.3
Thyroid hormones also help to regulate core body temperature, maintain proper brain metabolism, manage body energy expenditure and heat generation, and influence body composition and weight and digestive tract function.
Symptoms associated with hypothyroidism include the following:
Cold intolerance and cold hands and feet
Menstrual irregularities and infertility
Fatigue
Weight gain
Constipation
Hair loss
Dry skin
Frequency of urination
Mental fog, dizziness, and depression
Bradycardia
Arthralgias and myalgias (seen mostly with patients with Hashimoto disease)
Hypothyroid symptoms can include the following:
Heat intolerance
Diarrhea/loose stools
Rapid weight loss
Goiter and thyromegaly
Anxiety and insomnia
Tachycardia, palpitations, and arrhythmias
Tremors and muscle fasciculations
Hair changes, such as hair loss
Thyroid Physiology and Metabolism
Thyrotropin releasing hormone (TRH) is released by the hypothalamus in response to external cues and biofeedback by thyroxine levels in the blood.4 TRH then binds to receptors on the anterior pituitary, which stimulates the release of thyrotropin, or TSH.4 TSH then binds to receptors on the thyroid gland, stimulating production of enzymes needed in thyroid hormone synthesis (such as protease, peptidase, and peroxidase), as well as the production and release of thyroglobulin into the colloid of the thyroid gland. At this point, binding of iodine to tyrosine residues on thyroglobulin is required for the production of thyroxine (T4) and triiodothyronine (T3). TSH binding stimulates iodide transport into the cell via sodium iodide (I-) symporters that sit on the surface of the thyroid follicular cells. Iodide is then oxidized to form iodine (I2) by thyroid peroxidase. Iodine is then taken up into the colloid of the thyroid gland where it binds to tyrosine residues on thyroglobulin for the production of T4 or T3.5
T4 and T3 are then released into the blood where 99% is quickly bound by thyroid binding globulin. Approximately 80% to 90% of all thyroid hormone production is in the form of T4. T4 is considered a “storage” thyroid hormone and must be reduced to the more active T3 before it can be utilized by the cells and tissues of the body. Enzymes that reduce thyroid hormones by removing an iodine molecule are known as the deiodinases. There are three primary types of selenium-dependent iodothyronine deiodinases (known as D1, D2, D3) that are responsible for thyroid hormone metabolism.5 To properly treat thyroid disorders as well as to order and interpret thyroid function testing, it is critical to understand how thyroid hormones are metabolized and what physiologic and external factors can have influences on their metabolism. For this reason, an in-depth discussion has been included in this chapter.
Both D1 and D3 are intercellular enzymes, located on the plasma membrane of cells that affect the conversion of circulating T4 and T3. D1 influences an increase in cellular metabolism because it reduces T4 to the potently active form of thyroid hormone, T3. D3 influences a decrease in cellular metabolism by reducing T4 to the mostly inhibitory form of reverse triiodothyronine (rT3). Both fT3 and rT3 can bind to the same receptors within the nucleus of the cell to either promote gene expression and therefore increase cellular metabolism, in the case of fT3, or inhibit gene expression and decrease cellular metabolism, as in the case of rT3. I find it helpful to think of fT3 as the gas and rT3 as the brakes.
D1 also reduces rT3 to diiodothyronine (T2), reducing the potential for a decrease in metabolism from circulation. In humans, it appears that D1 has a much greater affinity for rT3 than for T4; thus its primary purpose is to reduce circulating levels of rT3. D1 is found mostly in the liver, kidneys, and thyroid. D1 is induced by T3, vitamin A (in the form of retinoic acid), cyclic AMP, and TSH. D1 is downregulated by selenium deficiency, fasting, some cancers, and chronic inflammation, particularly interleukin-6 and interleukin-1 beta. It can be inhibited by some pharmaceutical drugs, notably amiodarone, propranolol, propylthiouracil, dexamethasone, and ipodate.
D3 converts circulating fT3 to the significantly less potent metabolite T2; it also converts T4 to reverse T3 decreasing a potential for an increase in metabolism stimulated by circulating fT3. The body’s production of D3 diminishes after birth and is found mostly in the brain and pituitary. During gestation it is produced by the placenta where its primary role is believed to be associated with protecting the fetus from hyperthyroid states. However, certain disease processes can upregulate D3, causing altered cellular metabolism and release of growth factors such as TGF-beta. Other factors that may influence D3 production include starvation, some cancers, and hyperthyroidism.6,7
Deiodinase type 2, D2, is found intracellularly within the endoplasmic reticulum primarily in the central nervous system, pituitary, thyroid, bone, brown adipose tissue, and skeletal muscle. Owing to its location inside the cytosolic compartment, the activity of D2 is a primary determinant of intracellular T3 availability and thyroid receptor occupancy within the nucleus. Although T3 generated from the activity of D1 is known to equilibrate rapidly with the plasma, D2-generated T3 remains within the cell and takes several hours to equilibrate with plasma. It is upregulated by
the sympathetic nervous system, high-fat diet, as well as cyclic AMP. Its primary physiological role is hypothalamic-pituitary feedback as well as thermogenesis in brown adipose tissue. It also helps to increase plasma levels of T3.
the sympathetic nervous system, high-fat diet, as well as cyclic AMP. Its primary physiological role is hypothalamic-pituitary feedback as well as thermogenesis in brown adipose tissue. It also helps to increase plasma levels of T3.
Lastly, certain types of bacteria help in the recirculation of T3 from the inactive conjugated forms, T3 sulfate and T3 glucuronide. This can account for up to 20% of circulating T3 in healthy individuals. Gut dysbiosis, small intestinal bacterial overgrowth, and leaky gut can significantly reduce this contribution leading to an increase in excreted T3 in the conjugated form.8
Thyroid Function Testing
To evaluate thyroid hormone status, plasma testing is available for total T4, free T4, total T3, free T3, reverse T3, and T3 uptake. To evaluate antibodies that can influence thyroid function, the following tests are available through most commercial laboratory tests: thyroid peroxidase antibody (TPO Ab), thyroglobulin (TG Ab) antibody, TSH receptor antibody (TR Ab), thyroid stimulating immunoglobulin (TSI), and thyroid-binding globulin inhibitory immunoglobulin (TBII).
The following are considered to be positive indicators of Hashimoto disease: TPO Ab, TG Ab.
The following are considered to be positive indicators of Graves disease: TR Ab, TBII.
Also, owing to the critical nature of the following minerals and vitamins in thyroid function it is recommended to test their serum and/or urine levels. These include red blood cell (RBC) selenium, RBC zinc, RBC magnesium, iodine, ferritin, vitamin D, and vitamin A. A discussion of the value of each of these will be detailed later in the chapter.
Other laboratory tests to consider would include adrenal function testing (to be discussed later in the chapter) and sex hormone function testing, because of their influence on the thyroid system as well as the cardiovascular system.
Specialty laboratory testing would include nutritional evaluation (examples include NutrEval by Genova Diagnostics, Micronutrient Test by Spectracell), iodine loading tests (Hakala Labs), heavy-metal testing (Genova, Doctor’s Data, Thorne, Great Plains Labs, ZRT Labs), and gastrointestinal function testing (Genova, Salveo, Vibrant, GI Map). Infections that may be contributing to autoimmune disorders may include Yersinia enterocolitica, Helicobacter pylori, Borrelia burgdorferi (Lyme disease), and Epstein-Barr virus.
Laboratory Interpretation
One of the big challenges and controversies with thyroid function testing has been the interpretation of TSH as the primary measurement of thyroid function. Historically we have been taught that, if the TSH was elevated, greater than the upper limits of normal, then this was a problem likely associated with hypothyroidism. The next test was to check a total T4 to see if it was low, normal, or elevated. If it was elevated, typically >4.5 mIU/L, then it was assumed that the individual had primary hyperthyroidism with the pituitary gland releasing too much TSH, overstimulating the thyroid gland to produce too much T4. This was most likely secondary to a pituitary adenoma. But if the T4 level was normal, this was described as subclinical hypothyroidism. If the T4 level was below normal, typically < 0.9 ng/dL, then the individual had hypothyroidism and should be treated with synthetic bioidentical T4 medication.
Dr Dennis St. John O’Reilly analyzed the evidence and the history surrounding the concept of using TSH concentration as a measurement of T4 replacement. It became clear through his analysis that early in the 1970s TSH was being used on theoretical grounds but without proper assessment, as an indicator of clinical thyroid status. He stated, “the overlap between the statistically derived normal and abnormal ranges is accepted in diagnostic test, giving rise to faults positive and false negative results. These concepts have not been applied to measurements of thyroid stimulating hormone. Rather than accepting that the test can be fallible, we transfer the problem to the patient.” Meaning, that if a patient is experiencing hypothyroid symptoms yet has a normal TSH level, then the problem must be something else (ie, in the patient’s head) and not that his thyroid function is abnormal.9
There is currently little to no scientific data on the relative importance of biochemical thyroid function testing and its association with clinical symptoms and signs when addressing and assessing thyroid dysfunction. The secretion of TSH is influenced by multiple factors other than direct negative feedback inhibition by either T4 or T3. Although we have some understanding of euthyroid sick syndrome or nonthyroid illness with critical care patients and its effects on intracellular thyroid metabolism, changes in TSH, T4, T3, and reverse T3 concentrations during other systemic illnesses are poorly understood.
The National Health and Nutrition Examination Survey III (NHANES) evaluated levels of TSH, T4, and thyroid antibodies in the US population from 1988 to 1994. The results of the study identified that 80% of the 17,000 people evaluated had a serum TSH below 2.5 mIU/L. Hashimoto disease, evidenced by positive TPO antibodies, had a prevalence that was lowest (<3%) when the TSH was between 0.1 and 1.5 mIU/L in women and 0.1 to 2.0 mIU/L in men. In individuals who had a TSH >20 mIU/L, positive TPO antibodies were seen in over 50% of the individuals. The reference limits of TSH may be skewed by individuals with occult autoimmune thyroid dysfunction but who test negative for TPO antibodies. Thyroglobulin antibodies were not checked in the study.10,11
The utility of evaluating serum T3 levels has also been grossly under recommended. In fact, practice guidelines from the American Association of Clinical Endocrinologists in collaboration with the American Thyroid Association published the following in their most recent guidelines. “Serum T3 measurement, whether total or free, has limited utility in hypothyroidism because levels are often normal due to hyper stimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of type 2 iodothyronine deiodinase. Moreover, levels of T3 are low in the absence of thyroid disease in patients with severe illness because of reduced peripheral conversion of T4 to T3 and increase in activation of thyroid hormone.”12
The T3/rT3 Ratio
Looking at the T3/rT3 ratio helps to identify cellular hormone bioavailability and status and how this may impact overall physical function. A study of elderly men highlighted how rT3 is related to overall physical function. The results demonstrated that serum rT3 levels increased significantly with age and with the presence of comorbidities. A low T3/rT3 ratio was associated with a lower physical performance score, independent of their chronic disease. Low levels of free T4 were related to a better 4-year survival, suggesting possible adaptive mechanisms to prevent excessive catabolism of skeletal muscle and other tissue. The authors concluded “the T3/rT3 ratio is the most useful marker for tissue hypothyroidism and as a marker of diminished cellular functioning.” This shows the value of these tests and does not support the most recent position of the American Association of Clinical Endocrinologists of no recommendations for routine testing of reverse T3.13
Another study of T3/rT3 was conducted in subjects with and without type 2 diabetes (n = 140) to see if there was an increase in cardiovascular events associated with nonthyroid illness. Type 2 diabetes is commonly associated with nonthyroid illness, a condition with normal TSH and T4 levels but often with intracellularly low T3 levels and elevated reverse T3 levels. When the two groups were compared, those with type 2 diabetes with a history of cardiovascular events were noted to have low levels of total T3, free T3, and T3/rT3 ratios despite having higher free T4 and similar TSH levels when compared with the control group. The inflammatory biomarker serum amyloid A levels correlated positively with reverse T3 levels and inversely with T3/rT3 levels. This study demonstrates that T3/rT3 levels can be used as an independent marker for cardiovascular event risk.14
Table 25.1 SUMMARY OF LABORATORY TESTS AVAILABLE FOR ASSESSMENT OF THYROID STATUS AND RELEVANT REFERENCE RANGES | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||
WHY CHECK FOR THYROID ANTIBODIES?
Autoimmune thyroiditis is one of the most common autoimmune diseases in the United States with some estimates as high as 7% to 8% of the population, roughly 24 million individuals, and is the most common cause of hypothyroidism.15 A retrospective cohort analysis of 1100 patients with newly diagnosed Hashimoto disease and 4609 non-Hashimoto controls in the Taiwan National Health Insurance Research Database reported that the risk of developing coronary heart disease (CHD) was significantly greater in women under 49 years with Hashimoto disease compared with controls. This increased risk was not observed in men. After adjusting for comorbidities, Hashimoto disease was an independent risk factor for CHD; however, the risk was enhanced when diagnosis was combined with hypertension or hyperlipidemia. Untreated Hashimoto disease or T4 treatment for less than 1 year carried the highest CHD risk16 (Table 25.1).
CAVEATS OF LABORATORY TESTING
Serum levels of mineral are kept relatively constant. RBC mineral status can shed more light on the functional requirements of certain minerals.
When testing for iodine, urine is a best functional test and then serum; however, if serum levels are low, you can assume that total body levels are low. Also, serum is much more convenient than collecting a first morning void or a 24-hour urine sample for your patients.
When performing urine iodine testing it is important to keep in mind that the kidneys excrete approximately 90% of ingested iodine. If a 24-hour urine collection is not practical, a random urinary iodine to creatinine ratio can be used instead. A medium of 50 to 100 µg of iodine per liter is considered mild iodine deficiency, 20 to 49 µg of iodine per liter is moderate deficiency, and less than 20 µg of iodine per liter signifies severe deficiency.17
Thyroid Influences on the Cardiovascular System
Thyroid hormones have pleiotropic effects on the cardiovascular system. Both hypothyroidism and hyperthyroidism are associated with increased cardiovascular risk markers as summarized in the following. Key aspects of risk will be examined in more detail later in this chapter.
Hypothyroid18:
Impaired cardiac contractility and diastolic function
Systolic and diastolic congestive heart failure
Increased systemic vascular resistance
Diastolic hypertension
Decreased endothelial-derived relaxation factor
Dyslipidemia
Coronary heart disease and myocardial infarction
Increased C-reactive protein
Increased homocysteine
Hyperthyroid18:
Palpitations
Coronary heart disease and angina
Exercise intolerance
Atrial fibrillation, atrial flutter, and premature atrial contractions (PACs)
Ventricular arrhythmias, premature ventricular contractions (PVCs), ventricular tachycardia, and fibrillation
Exertional dyspnea
Cardiac hypertrophy
Systolic hypertension
Peripheral edema
Hyperdynamic precordium
Congestive heart failure
Impact of Hypothyroidism on Lipid and Lipoprotein Metabolism
Thyroid hormones regulate lipid and lipoprotein metabolism and act as part of a system to regulate the balance between lipid synthesis and lipid clearance and degradation, helping to fine-tune the availability of lipids to meet the body’s needs. Hypothyroidism has been linked with plasma cholesterol since the 1930s and was considered a marker for levothyroxine treatment response before assays for TSH and FT4 were readily available.19 Hypothyroidism shifts the system to one favoring lipid synthesis over degradation and clearance, and this is reflected in a more atherogenic lipid profile.20 Cross talk between these atherogenic lipid changes and other adverse consequences of hypothyroidism, including obesity21 and reduced antioxidant capacity,22 contribute to an environment of increased cardiovascular risk.1 The adverse changes in lipoprotein and lipid metabolism are summarized in Table 25.2. The general pattern observed is that lipid status worsens in parallel to rising TSH concentrations. Although lipid abnormalities are present with subclinical hypothyroidism, these become increasingly evident with progression to overt hypothyroidism.20
THYROID FUNCTION AND LOW-DENSITY LIPOPROTEIN METABOLISM
The lipid profile of hypothyroid patients is characterized by an increase in plasma total- and low-density lipoprotein (LDL)-cholesterol (LDL-C).20 Some studies also report an increase in small dense LDL (sdLDL)23 and higher levels of lipid peroxidation24 and higher circulating oxidized LDL (oxLDL).23,25 Published data on LDL particle number (LDL-P) in hypothyroidism are lacking. Thyroid hormone is known to stimulate the expression of the LDL receptor (LDL-R) in the liver via increasing SREBP-2 and/or by direct effects on LDL-R promoter sites.26,27 Studies in model systems show that reduced signaling in hypothyroid states decreases the number of LDL-R in the liver28 resulting in reduced clearance of LDL from circulation.19 Additionally, levels of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) are increased with hypothyroidism, but normalization of levels is observed by correction of thyroid status in humans.29 In addition to regulating the LDL-R and clearance
of LDL-C, thyroid hormone also reduces the production of apolipoprotein B (apoB), and loss of thyroid hormone signaling in hypothyroid states is associated with an increase in apoB production, which is reversed in humans with normalization of thyroid status.29,30 The potential for impaired LDL clearance as a result of reduced expression of the LDL-R and upregulation of PCSK9, as well as the increased synthesis of apoB, is considered to underpin the increased LDL-C in circulation associated with hypothyroidism.
of LDL-C, thyroid hormone also reduces the production of apolipoprotein B (apoB), and loss of thyroid hormone signaling in hypothyroid states is associated with an increase in apoB production, which is reversed in humans with normalization of thyroid status.29,30 The potential for impaired LDL clearance as a result of reduced expression of the LDL-R and upregulation of PCSK9, as well as the increased synthesis of apoB, is considered to underpin the increased LDL-C in circulation associated with hypothyroidism.
Table 25.2 ADVERSE LIPID CHANGES REPORTED IN PATIENTS WITH HYPOTHYROIDISM | ||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||
THYROID FUNCTION AND HIGH-DENSITY LIPOPROTEIN AND REVERSE CHOLESTEROL TRANSPORT
Hypothyroidism is not generally associated with a change in high-density lipoprotein cholesterol (HDL-C),19 although differences in HDL composition are reported, notably an increase in HDL2 subparticles (the more protective form of HDL particles) and apo-A1.31,32 This increase in HDL2 count can be reduced with treatment leading to euthyroidism. These changes in HDL particle number are thought to be related to induction of hepatic lipase (HL) enzyme by thyroid hormone. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels seen in hyperthyroidsm.33 The reduction in HDL2 during treatment correlates with an increase in the activity of HL during normalization of thyroid status in humans.32 This relationship between reduced HL and increased HDL2 particles has been demonstrated in studies in other populations also.33 Despite this apparent increase in protective HDL, other studies in animal models have shown that hypothyroidism can lead to an increase in oxidized LDL with a reduction in reverse cholesterol transport (RCT). Thyroid hormone is involved in the regulation of SR-B1, and treatment of hypothyroidism with thyroid hormone analogues in these models leads to upregulation of SR-B1 expression.34 SR-B1 is an enzyme involved in the efflux of cholesterol from macrophages to HDL, a critical step in RCT.34 The activity of paraoxonase-1 (PON-1), an enzyme associated with HDL in plasma involved in protecting against LDL oxidation and supporting HDL functionality, was shown to be reduced in both subclinical and overt hypothyroid patients compared with controls.35,36 A study in patients who underwent thyroidectomy due to thyroid carcinoma demonstrated that cholesterol efflux capacity was reduced in the overt hypothyroid state and remained low with radioactive iodine therapy.37 Further studies to understand the impact of hypothyroidism and reverse cholesterol transport and HDL function are needed; however, the evidence suggests that HDL functionality may be impaired in these patients.
THYROID HORMONE AND CHOLESTEROL ELIMINATION
A final step in reverse cholesterol transport can be considered the removal of cholesterol from the body through bile. Overall, thyroid hormone stimulates the conversion of cholesterol to bile acids in the liver, and therefore, the excretion of cholesterol from the liver, by increasing the expression of cholesterol 7 alpha hydroxylase (CYP7A1), the rate limiting enzyme in cholesterol breakdown and bile acid synthesis, and other transporters (ABCG5 and ABCG8) that promote the movement of cholesterol into bile.19 Lack of thyroid hormone may reduce the breakdown and turnover of cholesterol in the liver and increase the cholesterol content of the liver.20 Additionally, TSH itself has been reported to regulate hepatic lipid metabolism in model systems and may suppress bile acid synthesis,38,39 although more in vivo evidence is needed. Although studies have cast doubt over the role of bile acid synthesis19changes driving the lipid abnormalities seen in human hypothyroidism,40,41 reduced bile flow as evidenced by bile duct stone procedures and blockages in this patient cohort have been reported.42,43
THYROID FUNCTION AND TRIGLYCERIDES
Hypothyroidism is associated with an increase in plasma triglycerides in some studies, and postprandial hypertriglyceridemia, which is considered more atherogenic than fasting levels,44,45 has been demonstrated to be increased, with one study showing that patients with TSH >5 mIU/L had a sevenfold increased risk of postprandial hypertriglyceridemia.46 Apolipoprotein B48, a marker of intestinally derived triglycerides, was also increased in overt hypothyroidism compared with controls during the postprandial period.47 These changes in triglyceride metabolism can compound issues with HDL and LDL metabolism discussed earlier. For example, hypertriglyceridemia can lead to reduced anti-inflammatory capacity of HDL48 and reduced capacity for HDL to deliver cholesterol esters to hepatic cells.49
Some but not all studies have suggested that thyroid hormone stimulates lipoprotein lipase (LPL).19 Reduced LPL could reduce the clearance of triglyceride-rich lipoproteins from circulation,50 which may explain the increased postprandial triglyceridemia identified in hypothyroid states. Thyroid hormone also controls the release of VLDL-TG from the liver, and reduced thyroid hormone signaling in hypothyroidism increases hepatic VLDL-TG secretion, which can negatively impact plasma triglyceride concentration.19 HL is sensitive to thyroid hormone status, and hypothyroidism is associated with a reduction in HL activity, which can be recovered by thyroid hormone replacement therapy.34 A decline in HL activity can impair the chemical composition of isolated LDL particles owing to triglyceride enrichment.20 In hypothyroidism, hypertriglyceridemia appears to develop as a result of impaired removal of endogenous triglyceride and increased hepatic production of triglyceride.20
Hypothyroidism is associated with, in addition to changes in synthesis and clearance, an accumulation of triglyceride within the liver, leading to an increased risk of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in this population.51 Mechanistically, thyroid hormone enhances the activity of HLs, lipophagy, and mitochondrial biogenesis and oxidation of fatty acids, the primary processes utilized by the liver to reduce steatosis.34 Therefore, a reduction in thyroid hormone signaling can impair the process by which triglyceride and fatty acids are metabolized and cleared from within the liver. Additionally, TSH itself may stimulate lipogenesis,38 and in addition to T3 and T4, 3,5-diiodothyronine (T2) influences hepatic lipid metabolism through non-THR-mediated signaling.34
THYROID FUNCTION AND LP(a)
SUMMARY
Overall, the available data show that dyslipidemia is prevalent in hypothyroidism and that restoration of thyroid hormone levels improves lipid abnormalities.19
Physicians should check for hypothyroidism in patients with raised LDL. Hypothyroidism has been reported in 4.2% to 5.2% of patients with hyperlipidemia,54,55,56 suggesting that thyroid failure may go undetected, and testing patients with hyperlipidemia for hypothyroidism is warranted to guide clinical intervention.12,57,58,59 This may be in contrast to current clinical practices, as recent evidence suggests that, in newly diagnosed hyperlipidemia, only 50% of patients are typically screened for hypothyroidism.55
Studies have demonstrated that subclinical hypothyroidism is linked to a small increased risk of cardiovascular disease (CVD)60,61 and coronary heart disease events and mortality,62,63 particularly in younger patients (<50 years old),63 those with TSH >10 mIU/L,62 and those with increased cardiovascular risk.60
Although there are currently no randomized controlled trials to suggest that treatment with thyroid hormones will lead to reduced CV risk or dyslipidemia in individuals with subclinical hypothyroidism, given the data suggesting that correcting the thyroid hormone abnormality can lower biomarkers that carry an elevated CV risk, treatment may be warranted to prevent potential long-term risks.
Hypothyroidism and Heart Failure
Thyroid hormone plays a key role in the regulation of cardiac function and peripheral circulation, with thyroid hormone signaling impacting cardiovascular hemodynamics, cardiac filling, myocardial contractility, and systemic vascular resistance. Loss of thyroid hormone signaling and hypothyroidism is a risk factor for the development of heart failure. Prospective cohort studies in the United States and Europe demonstrate that the risk of heart failure events is increased in individuals with subclinical hypothyroidism, even after adjustment for other cardiovascular risk factors.64 In patients with heart failure, the presence of hypothyroidism (including subclinical hypothyroidism) is associated with an increased risk of all-cause mortality and cardiac mortality and/or hospitalization compared with euthyroid patients with heart failure.65 TSH has been associated with progression of heart failure in patients with condition, and patients with modestly increased TSH above 5.5mIU/L were at greater risk of heart failure progression (defined as mortality after hospitalization or transplant).66
As stated earlier, thyroid hormone has a wide-ranging impact on the heart and vasculature. In the heart, thyroid hormone drives a gene expression program that regulates aspects of contraction and relaxation. Thyroid hormone increases the expression of the gene encoding cardiac myosin heavy chain-alpha (MHCα) and reduces the expression of the gene encoding the beta isoform MHCβ, leading to an enhanced velocity of contraction.67 The upregulation of β-1 adrenergic receptor gene expression is also involved in enhancing contraction velocity, as well as in increasing the heart rate.67 Thyroid hormone signaling leads to upregulation of SERCA2, a calcium pump involved in muscle relaxation, and leads to downregulation of the SERCA2 inhibitor phospholamban (PLN), leading to an overall increase in the velocity of the diastolic relaxation.67 Additionally, thyroid hormone suppresses cardiac fibrosis through a combination of downregulating collagen gene expression and upregulating metalloproteinases and upregulates the expression of Na/K-transporting ATPases.67
Thyroid hormone signaling contributes to reduced systemic vascular resistance and upregulating the expression of a number of molecules and pathways involved in vasodilation in the endothelial and vascular smooth muscle cells of the vasculature. Thyroid hormone actives nitric oxide synthase in vascular smooth muscle cells,68 and endothelial nitric oxide is also thought to play a role in thyroid hormone-induced vasodilation.69 In animal models, T3 increased adrenomedullin, a vasodilatory peptide,70,71 and has also been shown to increase other vasodilatory molecules.72,73
The cardiac changes observed in hypothyroid states are summarized in Table 25.3. In subclinical hypothyroidism, the abnormalities in cardiac function observed are the same but less severe than those showed in the overt form.
A decrease in signaling of many of the known thyroid hormone direct and indirect targets have been demonstrated in animal models of hypothyroidism. Several studies have demonstrated these mechanisms in humans also. For example, the expression of the gene encoding MHCα was shown to be reduced and expression of the gene encoding MHCβ
was increased in human cardiac tissue from a patient with hypothyroidism and heart failure, and these gene expression changes as well as cardiac function were reversed with restoration of euthyroid.74 Endothelium-derived NO has also been shown to be impaired in patients with hypothyroidism75 and improves with thyroid hormone replacement.76,77
was increased in human cardiac tissue from a patient with hypothyroidism and heart failure, and these gene expression changes as well as cardiac function were reversed with restoration of euthyroid.74 Endothelium-derived NO has also been shown to be impaired in patients with hypothyroidism75 and improves with thyroid hormone replacement.76,77
Table 25.3 SUMMARY OF CARDIAC CHANGES IN HYPOTHYROID STATES67 | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
HYPOTHYROIDISM, CARDIAC REMODELING AND REACTIVATION OF A FETAL GENE EXPRESSION PROGRAM
One interesting finding related to hypothyroidism-related heart failure is the reactivation of a fetal gene expression pattern and how this contributes to reduced cardiac function.78
Cardiac remodeling can occur in response to stressors such as ischemia, mechanical loading, and metabolic alterations. Initially this response helps to maintain cardiac function and creates a low-energy state, which is thought to protect the damaged myocardium. However, over time a sustained remodeling response is viewed as maladaptive, leading to a decline in cardiac function.78 One of the characteristics of this stress-induced remodeling is a dedifferentiation of cardiac cells driven by a reactivation of a “fetal gene expression program.” Indeed, this initially adaptive and protective dedifferentiation in response to stress is thought to be a prerequisite for regeneration after stress.79 However, a redifferentiation “deficit” may result in heart failure, and particularly thyroid deficit-related heart failure.78 Pathways controlling dedifferentiation and redifferentiation in response to stress appear to be at least in part driven by thyroid hormone. The thyroid hormone system is an ancestral hormone system and plays a role in tissue remodeling after injury in many tissues and species, including in cardiac dedifferentiation/redifferentiation following stress.78 This was shown clearly in experiments that inhibited thyroid hormone signaling in cardiomyocytes, leading to dedifferentiation and a switch to a fetal pattern of gene expression, including myosin isoform expression (increase in MHC-β).80,81,82 However, importantly these cells retain the ability to redifferentiate with T3 treatment.81
LOW-T3 SYNDROME AND HEART FAILURE
Altered thyroid hormone bioavailability has been documented in cardiac patients with thyroid disorders. This is most commonly seen as reduced T3 and an increase in rT3 (inactive metabolite) with normal or low TSH. This low-T3 syndrome (also known as euthyroid sick syndrome or non-thyroid illness syndrome) is considered a coordinated systemic reactions to illness and has been reported in 20% to 30% of patients with heart failure.83,84,85 Low-T3 syndrome negatively impacts prognosis for patients following myocardial infarction and coronary bypass surgery and during the progression of heart failure.86,87 Altered peripheral thyroid hormone bioavailability is associated with a high incidence of cardiac events and a greater risk of heart transplantation.83,84,88,89 The precise mechanisms of low-T3 syndrome are not known; however, alterations in enzyme activity involved in T4 to T3 conversion and T3 to rT3 conversion,78 in addition to change in TSH or TRH section, or in thyroid hormone binding or transport into tissues have all been implicated.67
LOCAL CARDIAC HYPOTHYROIDISM IN HEART FAILURE
Hypothyroidism can also occur locally in the heart during heart failure, independent of serum levels of thyroid hormones, and LV function appears to be more closely related to thyroid cardiac levels than serum thyroid hormone levels in heart failure.67 Several mechanisms have been suggested to explain the change in local thyroid hormone concentrations, and upregulation of D3 in heart failure, reduction in uptake of thyroid hormone into tissue, change in TH receptor expression within cardiomyocytes have all been implicated in local reduction in thyroid hormone and signaling in heart failure.67
SUMMARY
AHA/ACC Guidelines for the Diagnosis and Management of Heart Failure in Adults recommend that thyroid function tests be evaluated in all newly presenting patients with heart failure, and whether determining the cause of heart failure, that current and history of thyroid disorder be evaluated. Thyroid disorders should be treated. Reevaluation of thyroid function should be triggered by any new atrial fibrillation or exacerbation of ventricular arrhythmias.90
Clinical studies suggest TH supplementation may improve cardiac function in heart failure.67
Hyperthyroid and Hypertension
The impact of thyroid hormone on vascular resistance discussed earlier in addition to the positive inotropic effect and increased heart rate can lead to enhanced cardiac output commonly seen in patients with hyperthyroidism.1 Additionally, the impact of thyroid hormones on the renin-angiotensin-aldosterone system is also related to cardiac output. Thyroid hormones reduce vascular resistance, which stimulates renin release and sodium reabsorption, leading to increased venous return to the heart and an increase in blood volume of 5.5%,1,91 and ultimately an increase in cardiac output, which can be up to 300% higher in patients with overt hyperthyroidism.92
These hemodynamic changes can increase systolic blood pressure,92 and studies indicate that patients with hyperthyroidism have significantly higher systolic blood pressure compared with euthyroid controls.93,94,95 Systolic blood pressure, as well as cardiac output, is reduced with antithyroid treatment.95 Blunted nocturnal decline in blood pressure has also been reported in some small studies to occur in hyperthyroid states.96,97,98 In contrast to the blood pressure changes that occur in overt hyperthyroidism, studies have generally indicated that subclinical hyperthyroidism does not increase the risk of hypertension.99
Pulmonary hypertension has been reported in 35% to 65% of hyperthyroid individuals100,101,102,103 and can be corrected following total thyroidectomy.104 Pulmonary hypertension that occurs in thyroid disorders is considered to have unclear and/or multifactorial mechanisms.105 Despite the pathogenic mechanisms being unknown, several hypotheses have been outlined. First, the increase in cardiac output and elevated circulatory volume lead to an increased and rapid venous return to the right ventricle causing pressure overload and consequent increase
in pulmonary arterial pressure. This hemodynamic stress can cause endothelium shear stress within the pulmonary system, creating endothelial dysfunction and downstream vasoconstriction in pulmonary beds.106 Direct action of thyroid hormones on pulmonary vascular system has been demonstrated,107,108 and pulmonary vascular remodeling in hyperthyroid states promoting pulmonary hypertension has been suggested.106 Second, an autoimmunity-induced pulmonary hypertension has been proposed. Levels of TSH receptor antibodies in Graves disease (which accounts for up to 80% of hyperthyroid cases109) have been shown to be positively associated with pulmonary arterial pressure,102 and vascular endothelial changes secondary to the autoimmune inflammatory environment have been proposed to play a role in the development of pulmonary hypertension.110 More clinical studies are needed in individuals diagnosed with hypertension or pulmonary hypertension to further understand the specific causes.
in pulmonary arterial pressure. This hemodynamic stress can cause endothelium shear stress within the pulmonary system, creating endothelial dysfunction and downstream vasoconstriction in pulmonary beds.106 Direct action of thyroid hormones on pulmonary vascular system has been demonstrated,107,108 and pulmonary vascular remodeling in hyperthyroid states promoting pulmonary hypertension has been suggested.106 Second, an autoimmunity-induced pulmonary hypertension has been proposed. Levels of TSH receptor antibodies in Graves disease (which accounts for up to 80% of hyperthyroid cases109) have been shown to be positively associated with pulmonary arterial pressure,102 and vascular endothelial changes secondary to the autoimmune inflammatory environment have been proposed to play a role in the development of pulmonary hypertension.110 More clinical studies are needed in individuals diagnosed with hypertension or pulmonary hypertension to further understand the specific causes.
The hemodynamic changes that occur with thyroid hormone excess if left untreated can negatively influence cardiac morphology and function. Long-term hyperthyroidism can lead to left ventricle hypertrophy, arterial stiffness, and reduced diastolic function and left ventricle performance.111 Exercise intolerance, a sign that the heart cannot further accommodate the increased cardiac demand required in physical activity, can be considered one of the primary signs of heart failure in hyperthyroidism.111 These changes in cardiac performance can couple with the loss of sinus rhythm (discussed later) to increase the risk and progression of heart failure in these patients. Hyperthyroidism (overt and subclinical) is associated with an increased risk of heart failure, but the degree of heart failure is influenced by other factors including age, duration and cause of hyperthyroidism, and the presence of other cardiovascular risk markers.111
Hyperthyroid and Sinus Tachycardia and Atrial Fibrillation
The inotropic and chronotropic effects of thyroid hormones on the heart, in addition to the negative impact of thyroid hormone excess on vascular function overtime, can lead to rhythm disturbances.
Sinus tachycardia is the most common rhythm disturbance seen in hyperthyroid patients112,113 but can be overshadowed clinically by an increased risk of atrial fibrillation.
Hyperthyroidism increases the risk of atrial fibrillation,114 and the overall prevalence of atrial fibrillation in hyperthyroidism has been reported at 13.8% (compared with 2.3% of a control euthyroid population).113 The risk of developing atrial fibrillation in hyperthyroidism is increased in men, older people, and those with coexistent CVD diagnosis.115 Several studies show a positive correlation between plasma T4 and atrial fibrillation risk,1 and patients treated with levothyroxine causing exogenous subclinical hyperthyroidism have an increased risk of dysrhythmic events.1 Treatment to normalize thyroid hormone levels reverses atrial fibrillation.1 Atrial fibrillation in hyperthyroid patients increases the risk of developing cerebrovascular and pulmonary embolism.111
Treatment for Thyroid Disorders
Thyroid Replacement Therapy
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
