Thyroid in heart, metabolism, brain, kidney; vital importance of T3

Note: Scroll to the bottom of this post for an 'executive summary.'Thyroid disorders have widespread impact and although subclinical hypothyroidism and low triiodothyronine (T3) syndrome are common they are frequently overlooked in practice.Thyroid function is very important for cardiovascular health. The authors of freshly published paper in The American Journal of Medicine remind readers:

"Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists."

The authors apparently rely on TSH as do many others, but in my opinion and as subsequent papers illustrate, this can result in many missed diagnoses...

"As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease."

This includes the...

"...potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases." 

More inspiration to  not overlook the widespread occurrence and clinical importance of low T3 (triiodothyronine, the 'active' thyroid hormone) is offered in a study just published in The Annals of Thoracic Surgery differentiates low triiodothyronine syndrome from gross hypothyroid in the context of coronary artery disease.

"There is strong clinical and experimental evidence that altered thyroid homeostasis negatively affects survival in cardiac patients, but a negative effect of the low triiodothyronine (T3) syndrome on the outcome of coronary artery bypass grafting (CABG) has not been demonstrated. This study was designed to evaluate the prognostic significance of low T3 syndrome in patients undergoing CABG."

The authors evaluated 806 consecutive CABG patients for any effect of baseline free T3 (fT3) concentration and of preoperative low T3 syndrome (fT3 <2.23 pmol/L) on the risk of low cardiac output (CO) and death, finding a significant association:

"There were 19 (2.3%) deaths, and 64 (7.8%) patients experienced major complications. After univariate analysis, fT3, low T3, New York Heart Association class greater than II, low left ventricular ejection fraction (LVEF), and emergency were associated with low CO and hospital death...At multivariate analysis, only fT3, low T3, emergency, and LVEF were associated with low CO, and fT3 and LVEF were the only independent predictors of death."

They summarize these striking results in their conclusion:

"Our study demonstrates that low T3 is a strong predictor of death and low CO in CABG patients. For this reason, the thyroid profile should be evaluated before CABG, and patients with low T3 should be considered at higher risk and treated accordingly." 

In this vein a very interesting paper was published in the journal Acta Cardiologica (Official Journal of the Belgian Society of Cardiology) that identifies low free (bioactive) T3 as a contributor to the development of cardiac dysfunction. The authors outline their intent:

"A low T3 syndrome was described in patients with heart failure (HF), and it appears to be associated with adverse outcome, representing an independent predictor of mortality. However, it is not known if low T3 levels contribute to the pathophysiology of HF. On the other hand, it has been seen that an elevation of brain natriuretic peptides (BNP and NT-proBNP) may represent a warning signal for future cardiovascular disease and may be an early marker of diastolic dysfunction. Therefore we tested the hypothesis that low levels of free-triiodothyronine (FT3) are sufficient to determine an increased concentration of the amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), as the result of an initial and asymptomatic cardiac impairment."

They evaluated thyroid function and measured NT-proBNP in 52 consecutive non-cardiac patients. Dividing them into a low T3 group (19 patients) and a normal T3 group (33 patients) they found...

"The median NT-proBNP concentration of patients with low T3 syndrome was significantly higher than in those with normal FT3 (370 vs. 120 pg/ml). There is a strong and inverse correlation between FT3 and Log NT-proBNP (R = -0.47); this relation persists in a multivariable regression analysis, after adjustment for other potentially confounding variables."

The authors articulate the clinical significance in their conclusion:

"In absence of overt cardiovascular disease, patients with low T3 syndrome present an increased concentration of NT-proBNP. These data suggest that low FT3 levels may be a contributing factor for the development of cardiac dysfunction." 

The same syndrome of subclinical low thyroid manifesting as low T3 applies to stroke as well according to a study published in the European Journal of Clinical Investigation. The authors state:

"Low triiodothyronine (T3) has been associated with increased short-term mortality in intensive care unit patients and long-term mortality in patients with heart disease. The objective of this study was to investigate possible associations of thyroid hormone status with clinical outcome in patients admitted for acute stroke."

Considering T3 values ≤ 78 ng dL (1·2 nmol L as ‘low T3’ and T4 values ≤ 4·66 µg dL (60 nmol L) were as ‘low T4', they examined data for 737 consecutive patients with acute first ever stroke within 24 hours of onset. They measured total T3, thyroxin (T4) and thyroid-stimulating hormone (TSH) levels and evaluated the basic clinical characteristics, stroke risk factors, and brain imaging. Low thyroid (T3) turned out to be a significant predictor:

"Four hundred and seventeen (56%) patients had T3 values ≤ 78 ng dL−1 and 320 had normal T3 values. The 1-year mortality was 27·34% for low T3 and 19·37% for normal T3 cases. A smaller percentage of patients with low T3 values were independent at 1 year compared to those with normal T3 values [54·2% vs. 68·7%, odds ratio (OR) = 0·53]. Cox regression analysis revealed that increased age, haemorrhagic stroke, low Scandinavian Stroke Scale score, increased glucose and low T3 values (hazards ratio 0·69) were significant predictors of 1-year mortality."

Clinicians should bear in mind the authors' conclusion about low T3 thyroid syndrome and stroke:

"A high proportion of patients with acute stroke were found soon after the event with low T3 values. The low-T3 syndrome is an independent predictor of early and late survival in patients with acute stroke, and predicts handicap at 1 year." 

A valuable paper published in the Saudi Medical Journal offers evidence that low T3 is the strongest correlate of suboptimal thyroid function with metabolic syndrome and insulin resistance. The authors determined to...

"...determine the association between thyroid hormones, insulin resistance, and metabolic syndrome in euthyroid women."

They examine forty-five women free of past medical conditions by estimating body fat and measuring fasting blood for total triiodothyronine (T3), total thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), lipids, insulin, and glucose. T3 turned out to be a much more significant indicator than T4:

"The mean age of the participants was 32.6 +/= 9.6 years with a body mass index (BMI) of 29.9 +/= 3.8 kg/m2. Evidence of homeostasis model assessment index for insulin resistance (HOMA-IR) more than 3 was seen in 34 (75%) and metabolic syndrome in 29 (64%) participants. Total T3 showed a positive correlation with triglycerides, low density lipoprotein- cholesterol (LDL-C), total cholesterol, insulin, HOMA-IR and negatively with body fat. Thyroid-stimulating hormone correlated positively with BMI, insulin, HOMA-IR, LDL-C and negatively with HDL-cholesterol (p<0.05). Free triiodothyronine correlated positively with waist circumference and T4 did not correlate with metabolic syndrome parameters."

The authors conclude:

"Our preliminary data show an association between thyroid hormones and some components specific of the metabolic syndrome in euthyroid women. Total triiodothyronine and TSH correlated more with variables of metabolic syndrome than FT3 and T4." 

Low-grade systemic inflammation is a common denominator of aging and almost every chronic disease. It is, of course, a key factor in both type 2 diabetes and thyroid disorders. A study published recently in the Endocrine Journal (Japan Endocrine Society) demonstrates the association of type 2 diabetes with low T3 in the context of low-grade systemic inflammation:

"Previous reports highlight the role of systemic inflammation in the genesis of non-thyroidal illness syndrome and type 2 diabetes mellitus (T2DM). Our objective was to assess whether body mass index and the low-grade systemic inflammation would be associated with changes in thyroid hormone metabolism in patients with type 2 diabetes."

They examined data for 104 subjects, half with type 2 diabetes and half comprised a control group who were paired by age, gender and body mass index. They measured total (T) and free (F) thyroxine (T4) and triiodothyronine (T3), reverse T3 (rT3), the ratios FT3/rT3, FT3/FT4 and FT4/rT3, and obtained additional data on diabetes duration and complications, body mass index, waist circumference, hypertension, HbA1c, and high sensitivity C-reactive protein. T3 stands out here as well:

"Patients with DM presented lower levels of TT4, TT3 and FT3 and higher of FT4, waist circumference and C-reactive protein. Body mass index was inversely correlated with FT4 and TT3. C-reactive protein was positively correlated with rT3 and inversely with FT4/rT3 and FT3/rT3. Body mass index was an independent predictor for FT4 and TT3 levels. Inflammation predicted the FT4/rT3 ratio. C-reactive protein and body mass index were independent predictors for rT3."

Clinical note: this implies that thyroid assessment is incomplete if it doesn't include at least free and total T3 and T4 (along with TSH). The authors conclude with a statement of great significance because it is so common to encounter in clinical practice:

"In conclusion, type 2 diabetes was associated with a low T3 state. Body mass index and the low-grade systemic inflammation are related to the non-thyroidal illness syndrome in these patients, possibly by altering the activity of peripheral deiodinases."I find low-grade systemic inflammation impairment of the activity of deiodinase enzymes to convert T4 into the metabolically active T3 regularly in my patient population. 

More complete assessment of seemingly euthyroid ('normal' thyroid) patients is often dismissed with the  test data limited meagerly to TSH and total T4 levels, a practical flaw that likely fails to uncover many diagnoses. In a study published in the Journal of Clinical Endocrinology & Metabolism, the authors demonstrate that 'low normal' free T4 correlated significantly with metabolic syndrome and cardiovascular risk factors. The authors state:

"Thyroid disease and the metabolic syndrome are both associated with cardiovascular disease...The aim of this study was to explore the hypothesis that thyroid function, in euthyroid subjects, is associated with components of the metabolic syndrome, including serum lipid concentrations and insulin resistance."

They assessed data for 2703 euthyroid adult subjects that included homeostasis model assessment for insulin resistance (HOMA-IR and usual criteria for metabolic syndrome:

"After adjustment for age and sex, free T4 (FT4) was significantly associated with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Both FT4 and TSH were significantly associated with HOMA-IR. Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to 1.66 in the lowest tertile of FT4. FT4 was significantly related to four of five components of the metabolic syndrome (abdominal obesity, triglycerides, high-density lipoprotein cholesterol, and blood pressure), independent of insulin resistance."

Clinical note: so-called euthyroid = 'normal' thyroid or 'subclinical hypothyroid' must not be overlooked in case management of metabolic syndrome and cardiovascular risk. The authors conclude by asserting:

"We have demonstrated an association between FT4 levels within the normal reference range and lipids, in accordance with the earlier observed association between (sub)clinical hypothyroidism and hyperlipidemia. Moreover, low normal FT4 levels were significantly associated with increased insulin resistance. These findings are consistent with an increased cardiovascular risk in subjects with low normal thyroid function." 

More on T3 and metabolic syndrome was presented in a study published in the journal Metabolic Syndrome and Related Disorders (yes, there is a journal by that title) in which the authors examined date for 211 patients with a mean age of about 40 years who had a body mass index (BMI) >30 kg/m(2) without any other hormonal disorder related to obesity. Measurements included fasting blood glucose (FBG), insulin, insulin resistance (HOMA-IR),total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free T3 (FT3), and free T4 (FT4). They used TSH cutoff value of 2.5 mU/L. Sure enough T3 stood out:

"Metabolic syndrome positive patients had significantly higher FBG, triglycerides, FT4, systolic (SBP) and diastolic blood pressure (DBP), and statistically lower HDL-C and FT3/FT4 ratio than metabolic syndrome negative patients. TSH decreased with age and was not related with any metabolic syndrome parameters. The FT3/FT4 ratio negatively correlated with FBG, triglycerides, SBP, and DBP; TT3 positively correlated with HOMA-IR, FBG, and waist circumference."

In other words, as free T3 went down in relation to free T4 fasting blood glucose, triglycerides, and both systolic and diastolic blood pressure went up. And as total T3 went down insulin resistance, fasting blood glucose and waist circumference went up. The authors conclude:

""Metabolic syndrome parameters (except HDL) correlated with TT3, FT4, and the FT3/FT4 ratio. FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome. This relationship can be explained by compensatory effects of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people." 

At the crux of the matter is the manner in which low grade chronic inflammation impairs conversion of the relatively inactive T4 thyroid hormone to the active T3. The authors of a very valuable paper published in The Journal of Clinical Investigation shed light on an important mechanism by describing the role of the pro-inflammatory cytokine IL-6.

"Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T₃) that occurs in chronically ill patients; the degree of reduction in T₃ is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T₄ to active T₃, whereas the type III enzyme (D3) inactivates T₄ and T₃. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS."

They investigated this by measuring the effect of IL-6 the different types deiodinase activities in human cell lines. (Recall that deiodinase enzyme activity is required to convert T4 to T3.) Their results reveal not only the role of pro-inflammatory IL-6, but implicate glutathione (GSH) as a likely key factor:

"Active T₃ generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T₃ production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T₃."

The authors' conclusion contains comments of great clinical significance:

"In conclusion, our findings demonstrated that pathophysiologically relevant concentrations of IL-6 reduce D1 and D2 function and increase that of D3, providing a single mechanistic explanation for the decreased serum T3 and increased rT3 observed in the acute phase of NTIS. The decrease in D1 will both reduce plasma T3 production and impair rT3 deiodination, while the decrease in D2 will supplement this by impairing intracellular T4-to-T3 conversion. On the other hand, the increased D3 protein, which has its function preserved by its more ready access to GSH (or other extracellular reducing agents), will further decrease plasma T3 and increase the production of rT3 from T4. The general increase in the cellular deiodinase proteins is caused by a combination of IL-6–induced ROS (also found with H2O2) and specific activation of JAK/STAT pathways by this cytokine."

In a larger context...

"Although other factors in sick patients may also contribute to NTIS, these observations and unifying hypothesis represent a major step forward in unraveling this longstanding enigma, leading to what we believe to be a previously unrecognized combinatorial pathway that may be viewed largely as a general response to oxidative stress. Our results therefore suggest that rather than a protective or a maladaptive process, the changes in plasma T4, T3, and rT3 are a consequence of cellular stress. Whether antioxidants, such as NAC, could be beneficial as an adjuvant therapy together with other therapeutic measures in critically ill patients remains to be evaluated." 

Further insight into the nature of the low T3 in thyroid dysregulation associated with chronic disease is offered in a study published in the journal Nephrology Dialysis Transplantation on chronic kidney diseae (CKD) and low T3. These authors observe:

"The evaluation of thyroid function in systemic illness remains complex because the changes occur at all levels of the hypothalamic-pituitary-thyroid axis. During illness, a decrease in triiodothyronine (T3) and pulsatile thyroid-stimulating hormone (TSH) release and increases in reverse T3 occur. This constellation of findings is termed the low T3 syndrome, the euthyroid sick syndrome or non-thyroid illness. Low T3 syndrome is the most common manifestation in non-thyroid illness and this phenomenon has been believed to be due to inhibition of 5′-deiodinase, which is a catalyzing enzyme for production of T3 from circulating T4. To date, a variety of alterations in thyroid hormone levels and metabolism have been reported in patients with chronic renal failure and low T3 has been consistently found to be the most common disturbance."

Of widespread importance:

"Several lines of evidence suggested that low T3 was an independent predictor of survival in various illness states. Furthermore, the recent data proposed that biomarkers of inflammation were associated with low T3 levels in haemodialysis and peritoneal dialysis patients and thyroid dysfunction might be implicated in the pathogenetic pathway which link microinflammation to survival in dialysis patients."

They determined to see if low T3 correlated to chronic kidney disease prior to the stage of dialysis:

"However, there are no data about the prevalence of low T3 in persons with chronic kidney disease (CKD) who do not require maintenance dialysis. We hypothesized that the prevalence of low T3 would be increased according to the increase of a CKD stage. This study was performed to explore the prevalence in each stage of CKD and relationship with eGFR."

Their data on 2284 subjects with normal serum TSH and not taking thyroid hormones confirmed their hypothesis, leading to the conclusion:

"This study showed that low T3 syndrome was highly prevalent in CKD and was a remarkable finding in early CKD. Furthermore, serum T3 levels were associated with severity of CKD even in the normal TSH level." 

Along these lines a study showing that low T3 in various conditions including CKD is linked to systemic low grade inflammation reflected in altered cytokines was published in the Iranian Journal of Kidney Diseases. The authors evaluated the interleukins (IL) IL-6 and IL-10 and euthyroid sick syndrome (ESS) in patients with nonthyroidal illnesses (NTI) including chronic kidney disease (CKD), congestive heart failure (CHF), or acute myocardial infarction (MI) while measuring serum levels of IL-6 and IL-10, thyroid stimulating hormone (TSH), total T4, and T3:

"In the 60 patients with NTI, we detected a significantly lower T3 and T4 levels compared to controls, while TSH level was within the reference range. Also, IL-6 level was substantially higher than that in controls and correlated with T3 and T4. Similarly was IL-10 level that correlated with T3, but not with T4. The ILs correlated positively with each other. Only IL-6 was a predictor of low T3. The proportion of patients with subnormal T3, T4, and TSH levels was highest in those with MI along with greatest IL-6 and IL-10 levels compared to patients with CHF and CKD. Patients with CKD showed the least disturbance in IL-6 and IL-10 despite the lower levels of T3, T4, and TSH in a higher proportion of them compared to patients with CHF."

Their discussion of these results contains some key points for clinicians:

"In the current study, we observed a considerably lower serum T3 and total T4 concentrations, signifying thyroid dysfunction, in patients with variable NTIs, while serum TSH showed a mean value that was not significantly different from that in the healthy controls...In this study, we detected a substantially high level of the pro-inflammatory cytokine, IL-6, in patients with NTI, supporting its possible role as an endocrine cytokine with a regulatory effect on many endocrine systems including the thyroid gland."

Here is something readers who test cytokines may have seen too that illustrates a fundamental principal in case management and disease progression: suppression of receptors due to chronically high levels of signaling agents (in this case anti-inflammatory IL-10):

"We also detected a considerably high level of the anti-inflammatory cytokine, IL-10 in the patients with NTI.Therefore, within the cytokine network, activation of pro-inflammatory mediators such as IL-6 is followed by increased production of endogenous inhibitory molecules including the antagonistic cytokine IL-10 in an attempt to suppress release of pro-inflammatory cytokines. This dimorphic response may be related to macrophages resistance to the suppressive effect of IL-10 as a result of down-regulation of the expression of soluble IL-10 receptors. The high IL-10 levels was hoped for to minimize the deleterious effect of the raised IL-6. Taniguchi and colleagues highlighted this potential protective effect of IL-10 in their 25 patients with systemic inflammatory states...In this study, the suppressed thyroid hormones were inversely associated with serum IL-6 elevations."

There was a particularly strong association with heart attacks (MI), consonant with the degree of thyroid dysfunction tracking the severity of non-thyroidal illness:

"We observed a highest level of IL-6 along with lowest measurements of both serum T3 and serum T4 in the patients with MI, while the least changes were noticed in patients with chronic illness exemplified by CHF. This is in accordance with the hypothesis that the magnitude of thyroid hormones’ alteration parallels the severity of the associated NTI." 

Clinical note: It is very important for practitioners to bear in mind that thyroid effect, in addition to thyroid hormone production and conversion, encompasses thyroid hormone transporters and receptors. The felt metabolic and brain effects of thyroid activation depends on all of these. Failing to take them into consideration is a common reason why 'subclinical hypothyroidism', NTIS (nonthyroidal illness syndrome) or ESS (euthyroid sick syndrome) is often overlooked.A paper published in the Journal of Molecular Endocrinology sheds light on the role of MCT8, MCT10, organic anion transporting polypeptides (OATP) transporters:

"Thyroid hormone is a pleiotropic hormone with widespread biological actions. The follicular cells of the thyroid gland produce predominantly thyroxine (T4), but it is mainly 3,3′,5-tri-iodothyronine (T3) that binds to the nuclear thyroid hormone receptor. The biological activity of T3 is therefore largely determined by the intracellular T3 concentration which is dependent on a) the circulating T3 concentration; b) the transport of thyroid hormone across the cell membrane; and c) the presence of iodothyronine deiodinases, which activate or inactivate thyroid hormone. To date, three deiodinases have been characterized as homologous selenoproteins. Both D1 and D2 converts T4 to T3, whereas D3 catalyzes the degradation of T4 to reverse T3 (rT3) and of T3 to 3,3′-T2."

The enzymes that convert T4 to T3 have their active portions inside the cell, and transporters are required to get T4 through the cell membrane into the cytoplasm where the action happens:

"The deiodinases are membrane proteins with their active sites located in the cytoplasm. Therefore, transport across the cell membrane is essential for thyroid hormone action and metabolism. Based on the lipophilic structure of thyroid hormones, it is long thought that thyroid hormone enters the cell through passive diffusion. However, it has become increasingly clear that there are specific thyroid hormone transporters, and that the activity of these transporters in part determines the intracellular thyroid hormone concentration."

Transporters MCT8, MCT10 and OATP have been the most studied:

"To date, several transporters with high affinity for thyroid hormone, but with different tissue distributions and ligand affinities have been identified. This review will focus on the molecular aspects of the monocarboxylate transporter 8 (MCT8) and MCT10, and several members of the organic anion transporting polypeptide (OATP) family...both MCT8 and MCT10 increase the intracellular availability of iodothyronines, as evidenced by the marked increase in their intracellular deiodination by co-transfected deiodinases. However, both MCT8 and MCT10 facilitate not only the cellular uptake but also the efflux of iodothyronines."

In other words, they get necessary thyroid stuff both into and out of the cell. These transporters are subject to genetic variation of course, and some mutations in the MCT8 gene can cause severe psychomotor retardation:

"Mutations in the MCT8 gene cause a syndrome of severe psychomotor retardation and high serum T3 levels in affected male patients, known as the Allan–Herndon–Dudley syndrome. The neurological deficits are probably explained by an impeded uptake of T3 in MCT8-expressing central neurons and, hence, an impaired brain development. This has been reviewed in detail elsewhere. Since mutations in the MCT8 gene have such profound effects, the question arises whether small changes in the MCT8 gene may affect transport activity as well."

...Such as depression, etc. The implication is that much milder disruption of MCT8 transporter function can significantly diminish metabolism in the brain that impairs cognition and mood. The authors conclude their lengthy paper detailing the action of other transports with comments of great clinical significance:

"...it has become clear that thyroid hormone requires active transport across cell membrane to carry out its biological functions...It is surprising that few studies have been published investigating the association of polymorphisms in these transporters with serum thyroid parameters or thyroid hormone-related endpoints, especially since polymorphism studies have yielded new insights into the role of thyroid hormone in several processes in the human body. For instance, a genome-wide linkage scan identified the type 2 deiodinase as a susceptibility locus for osteoarthritis. In addition, genetic variation seems to play a role in psychological well-being..." 

The authors of a paper published in the journal Thyroid Research chime in with an expansion of these observations:

"Thyroid hormones are of crucial importance for the functioning of nearly every organ. Remarkably, disturbances of thyroid hormone synthesis and function are among the most common endocrine disorders affecting approximately one third of the working German population. Over the last ten years our understanding of biosynthesis and functioning of these hormones has increased tremendously. This includes the identification of proteins involved in thyroid hormone biosynthesis like Thox2 and Dehal where mutations in these genes are responsible for certain degrees of hypothyroidism. One of the most important findings was the identification of a specific transporter for triiodothyronine (T3), the monocarboxylate transporter 8 (MCT8) responsible for directed transport of T3 into target cells and for export of thyroid hormones out of thyroid epithelial cells."

They remind of the role of thyroid dysregulation in depression and dementia:

"Disturbed TH action is linked with major health problems especially in critical life phases such as development, disease or ageing. Thus, lack of TH action in the adult brain causes impaired neuro-cognitive function and psychiatric states such as severe depression and dementia. Not only hypothyroidism but also hyperthyroidism affects the CNS and frequently results in agitation, increased irritability and dysregulation of body temperature."

Cardiovascular disease can also have a thyroid component:

"There is ample epidemiological evidence that both, hyper- and hypothyroidism confer an increased risk for cardiovascular morbidity(e.g. arrhythmia, heart failure and stroke) and mortality."

Interestingly in regard to obesity:

"Besides the classic hormones T4 and T3 new data demonstrate that the rare thyroid hormone metabolite 3,5-T2 is effective in the prevention of high fat diet-induced adiposity and prevents hepatic steatosis, however, without exerting the severe side effects on the cardiac system that have been observed with T3-based treatments. The vital importance of thyroid hormones for regulation of thermogenesis and for maintenance of the homeostasis of the mitochondrial energy metabolism has long been established. However, the functional interactions between the activities of uncoupling proteins (UCP) which are triggered by T3 and catecholamines affecting brown adipose tissue (BAT) as well as skeletal muscle of the adult, provide new possibilities for therapeutic intervention in obesity that have only recently become apparent."

They summarize a 'bird's-eye' view of hormone physiology:"Thus in the present concept of thyroid hormone action, the cellular thyroid hormone status is defined by thyroid hormone transporters, thyroid hormone membrane receptors, thyroid hormone molecules and TAM mediated actions.There is no question that aging increases the tendency to subclinical hypothyroid conditions:

"Epidemiology has shown unequivocally that with age the ratio of subclinical to clinically manifest thyroid disorders increases, thus thyroid disorders are a disease of the ageing population. In light of the demographic changes of our societies, improvements of human health care systems should not be limited to better management of only cardiovascular disorders, cancer, and neurodegenerative diseases. We believe that modern and future-oriented health politics and policy making institutions need to take an endocrine organ into account that has been known for decades, but is still not fully “revealed”, the thyroid gland." 

Appreciation of the weighty influence of the MCT8 transporter is enhanced by recognition of its role in the global neurological impairment of intrauterine growth restriction (IUGR) as described in a study published in the Journal of Endocrinology:

"Intrauterine growth restriction (IUGR) describes the failure of a fetus to attain its genetically determined growth potential, with the most common underlying etiology being uteroplacental failure associated with abnormal placental development. IUGR is often characterized by continued head and brain growth at the expense of other less vital organs resulting in an elevated brain:liver weight ratio postnatally. IUGR complicates 5–10% of pregnancies and is associated with increased perinatal mortality. Survivors demonstrate an increased prevalence of cognitive impairment compared with babies born appropriately grown for gestational age."

They measured changes in cortical MCT8 expression with IUGR by immunohistochemistry performed on brain sections obtained from appropriately grown for gestational age (AGA) human fetuses and MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses which was compared with that in the occipital cortex of gestationally matched AGA fetuses:

"When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses... Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development...This study is the first to demonstrate significantly reduced cortical MCT8 expression within the developing CNS of human fetuses stillborn with severe IUGR. Our results suggest that altered TH transporter activity in cerebral neurons could be a contributory factor to the pathophysiology of neurodevelopmental impairment associated with IUGR." 

As described in an earlier post (Depression, aging and brain inflammation: indications for sustainable treatment) there is evidence that the global driving factor of biological aging is inflammation in the hypothalamus, practitioners doing case management of thyroid conditions should know the importance of thyroid hormone feedback in the hypothalamus and pituitary as described in a paper published in Molecular and Cellular Endocrinology:

"A major change in thyroid setpoint regulation occurs in various clinical conditions such as critical illness and psychiatric disorders. As a first step towards identifying determinants of these setpoint changes, we have studied the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus and anterior pituitary."

Their examination of these agents through immunoreactivity and immunostaining revealed important activity of hypothalamic glial cells:

"These findings suggest that the prohormone thyroxine (T4) is taken up in hypothalamic glial cells that convert T4 into the biologically active triiodothyronine (T3) via the enzyme D2, and that T3 is subsequently transported to TRH producing neurons in the PVN. In these neurons, T3 may either bind to TRs or be metabolized into inactive iodothyronines by D3. By inference, local changes in thyroid hormone metabolism resulting from altered hypothalamic deiodinase or MCT8 expression may underlie the decrease in TRH mRNA reported earlier in the PVN of patients with critical illness and depression."

The pituitary, of course, also comes into play:

"In the anterior pituitary, D2 and MCT8 immunoreactivity occurred exclusively in folliculostellate (FS) cells. Both TR and D3 immunoreactivity was observed in gonadotropes and to a lesser extent in thyrotropes and other hormone producing cell types."

The authors summarize their results:

"Based upon these neuroanatomical findings, we propose a novel model for central thyroid hormone feedback in humans, with a pivotal role for hypothalamic glial cells and pituitary FS cells in processing and activation of T4. Production and action of T3 appear to occur in separate cell types of the human hypothalamus and anterior pituitary." 

Hormone receptors are a critical link in the signaling chain for thyroid as for other hormones and neurotransmitters. Receptor function can be impaired by elevated hormone levels, genetic mutation and chronic inflammation. A paper published in Pediatric Endocrinology Reviews serves as a reminder to consider thyroid hormone receptor function in case management:

"The important physiological actions of the thyroid hormones are mediated by binding to nuclear thyroid hormone receptors (TRs), encoded by two genes TRalpha and TRbeta. These receptors act as hormone-dependent transcription factors by binding to DNA motifs located in the regulatory regions of target genes..."

Receptor resistance to thyroid hormones can cause a hypothyroid state in the presence of normal TSH and thyroid hormone levels:

"TRbeta gene mutations cause resistance to thyroid hormones (RTH), characterized by inappropriately high thyroid-stimulating hormone (TSH) levels due to lack of feedback inhibition of thyroid hormones on the hypothalamus and pituitary gland, and to reduced sensitivity of other TRbeta target tissues to thyroid hormones. Very recently, patients heterozygous for TRalpha mutations have been identified. These patients exhibit clinical symptoms of hypothyroidism in TRalpha target tissues such as intestine or heart and near normal circulating TSH and thyroid hormone levels." 

Chronic low-grade inflammation, also termed micro-inflammation, is an almost universal 'fact of life' in chronic disorders and aging. Its link to peripheral thyroid resistance and low T3 is seen in high magnification in Nephrology Dialysis Transplantation in which the authors observe its role in continuous ambulatory peritoneal dialysis (CAPD) patients with end-stage renal disease (ESRD):

"Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied...We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free tri-iodothyronine (fT3) in a cohort of 41 CAPD patients without heart failure and inter-current illnesses." 

They found multiple correlations, including low free T3 as a predictor of mortality:

"CAPD patients had lower fT3 levels than healthy subjects of similar age. Free T3 levels were directly related to those of serum albumin and inversely to IL-6 and CRP. Age, haemoglobin levels and diastolic blood pressure were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3...Plasma fT3 levels were lower in patients who died compared with survivors. In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors." 

The association of micro-inflammation and low free T3 noted by the authors likely applies to numerous other conditions:

"The relationship between fT3, CRP and serum albumin suggests that inflammation–malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients." 

Clinicians should also keep in mind that low T3 can be the only thyroid abnormality contributing to psychiatric depression. A paper published in the Journal of Endocrinological Investigation focuses on the link between low T3 syndrome and depression.

"In euthyroid sick syndrome [non-thyroidal illness (NTI)], a number of investigators have described TSH and serum thyroid hormone abnormalities, low T3, low T3 and T4, increased T4, low TSH, etc. Those cases of NTI where there is only T3 decrease [and normal serum T4, free T4 (FT4), and TSH levels] are specifically referred to as low T3 syndrome. However, the information in regard to low T3 syndrome in psychiatric subjects who are clinically euthyroid and do not have any other systemic illness is scanty. In our facility, since thyroid function is routinely assessed in psychiatric patients at admission, this provided the opportunity to study low T3 syndrome in a large group of psychiatric patients."

The authors found low T3 syndrome in a substantial percentage of depressed patients:

"Out of 250 subjects with major psychiatric depression, 6.4% exhibited low T3 syndrome (mean serum T3 concentration 0.94 nmol/l vs normal mean serum concentration of 1.77 nmol/l). The low T3 levels could not be ascribed to malnutrition or any other illness and the metabolic parameters were all normal...The depression might constitute an illness having the same relation to low T3 as found in the low T3 syndrome previously described in euthyroid sick subjects. The present findings, besides describing low T3 syndrome in psychiatric patients without systemic illnesses, suggest the possibility of subgrouping in clinical psychiatric depression which may have a broader clinical significance." 

A point of premiere clinical importance is that supplemental T3 can be the treatment of choice in depression with hypothyroid as asserted by the authors of an excellent paper published in Minerva Endocrinologica:

"Hypothyroidism has been linked to depression as there is irrefutable evidence that it triggers affective disease and psychic disorders. Depressive patients have a higher frequency of hypothyroidism and patients with hypothyroidism have a higher occurrence of depressive syndrome. Hypothyroidism exhibits considerable alterations in blood flow and glucose metabolism in the brain. Furthermore, patients with major depression may have structural abnormalities of the hippocampus that can affect memory performance. Thyroid peroxidase antibodies have, moreover, been positively associated with trait markers of depression."

Remember that more than 90% of hypothyroid in developed countries is autoimmune thyroiditis (Hashimoto's disease) with the presence of thyroid peroxidase antibodies, a frequent finding on laboratory tests that can be very significant even at 'predictive' (low) levels. Furthermore...

"Depressive symptomatology is variable and is influenced by susceptibility and the degree, though not always, of thyroid failure. In addition, glucose homeostasis and rapid weight loss have been associated to thyroid hormones and increased depressive symptoms. Thyroxine treatment in patients older than 65 years does not improve cognition. In contrast, T3 administration is the therapy of choice in patients with resistance to antidepressive drugs, and especially to SSIR. Genetic variants of thyroid hormone transporters or of deiodinases I and II may predispose to depression and, therefore, a personalized approach should be implemented." 

Also of great interest is the finding that treatment of subclinical hypothyroid/non-thyroidal illness syndrome (NTIS) with T3 can improve the response to chemotherapy in breast cancer as reported in a study published in BMC Cancer:

"Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the response to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence during chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy."

The authors examined thyroid hormone levels and NTIS prevalence at initial diagnosis of breast cancer and during chemotherapy in 685 patients (369 with breast cancer, 316 with breast benign lesions). They also measured the influence of thyroid hormones on chemotherapeutic efficacy by the chemosensitization test and compared chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T3) versus chemotherapeutics only. A distinct benefit from treatment by T3 emerged from their data:

"In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased significantly during chemotherapy. T3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T3, finding pretreatment with lower dose of T3, using higher dose of T3 together with 5-Fu or during chemotherapy with 5-Fu were all available to achieve chemosensitization, but pretreatment with lower dose of T3 until the end of chemotherapy may be a safer and more efficient therapy."

Their conclusions are highly important for breast cancer management:

"Taken together, thyroid hormones decreasing during chemotherapy was found in lots of breast cancer patients. On the other hand, thyroid hormones can enhance the chemotherapeutic efficacy through gathering tumor cells in actively proliferating stage, which may provide a new adjuvant therapy for breast cancer in future, especially for those have hypothyroidism during chemotherapy." 

Thyroid function tests may be often oversimplified to the detriment of the patient. As studies shown above and many more have shown, low T3 can be a complicating factor in a wide range of disorders. Dysregulation of thyroid function has multiple forms and causes. In a paper entitled Pitfalls in the measurement and interpretation of thyroid function tests published in Clinical Endocrinology & Metabolism the authors review conditions in which measuring TSH alone can be be particularly misleading:And they offer a diagram of different patterns of thyroid function tests and their causes: Finally, a paper recently published in Nature Reviews Endocrinology articulates an eloquent case for adding T3 to T4 and the need to recognize the patients who may need it:

"Impaired psychological well-being, depression or anxiety are observed in 5–10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T4 and decreased free T3 serum concentrations, which result in the abnormally low free T4:free T3 ratios observed in 30% of patients on levothyroxine."

Furthermore...

"Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone."

No wonder then that more are resorting to the combination of T4 (levothyroxine) and T3 (liothyronine):

"Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T4:free T3 ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T3 available for binding to T3 receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered." 

'Executive Summary'

This post is merely a 'sampling' of the vast subject of thyroid hormone regulation and case management. Forthcoming posts will examine other aspects. Here are key points contained in this limited presentation:

• Thyroid activity is vitally important for all systems throughout the body. Thyroid dysfunction can play a role in common cardiovascular, metabolic, renal and brain disorders.
• Low T3 syndrome, also known as subclinical hypothyroidism, ‘euthyroid sick syndrome’ and ‘non-thyroidal illness syndrome’ occurs frequently and contributes to morbidity and mortality in numerous ways, adding to the burden of cardiovascular disease, metabolic syndrome (insulin resistance), type 2 diabetes, kidney disease, overweight, depression and dementia.
• Low T3 is often overlooked due to insufficient testing in clinical practice when TSH and T4 are appear normal.
• Chronic low grade inflammation is ubiquitous contributing cause to low T3.
• Disturbances of enzymes that convert T4 to T3, transporters that usher thyroid agents into and out of cells, and peripheral receptor resistance are common and also contribute to Impaired thyroid function.
• T3 can enhance to response to chemotherapy in the treatment of breast cancer.
• Treatment of a hypothyroid component in depression can require T3.