TSH elevation associated with pregnancy problems

Preconception TSH and pregnancy outcomesTSH (thyroid stimulating hormone) when elevated even within the ‘normal’ range at preconception, can result in adverse pregnancy outcomes. Further evidence for this was presented in a studyrecently published in Clinical Endocrinology, that examines whether subclinical hypothyroidism (SCH) has negative effects on pregnancy.

“Subclinical hypothyroidism (SCH), defined as elevated TSH and normal free T4 (fT4) levels, with an incidence of 2–13·7%, is the most common thyroid disorder during pregnancy. SCH has also been associated with adverse foeto-maternal outcomes…”

Thyroid hormone levels before pregnancy

Adverse effects of SCH during the first trimester and after have been documented in earlier studies, but there has been much less data for preconception thyroid hormone levels.

“To the best of our knowledge, this study was the first large-scale study to investigate the association between maternal TSH levels within the 6 months before conception and the risk of adverse pregnancy outcomes in a population at low risk. The second aim was to determine whether the first-trimester specific reference range or nonpregnant reference range for TSH should be applied during preconception evaluation.”

This was a large study, with 248,501 pairs of volunteer couples recruited from a free National Pre-pregnancy Checkups Project from 2010 to 2012 in China, out of which 184,611 women who later became pregnant were examined by measuring maternal thyroid stimulating hormone within 6 months before conception.

“Participants were grouped according to TSH: 0·48–2·49 mIU/l (n = 133 232, 72%), 2·50–4·28 mIU/l (n = 44 239, 24%) and 4·29–10·0 mIU/l (n = 7140, 4%). Multivariable logistic regression models were used to study the association between TSH and pregnancy outcomes.”

Preconception TSH elevation increases risk of adverse pregnancy outcomes

Even when within what is often still considered the normal non-pregnant range, thyroid stimulating hormone elevation predicted pregnancy problems.

“The overall incidence of adverse pregnancy outcomes was 28·6%. Compared with TSH 0·48–2·50 mIU/l, TSH 2·50–4·29 mIU/l was associated with spontaneous abortion [aOR: 1·10,], preterm birth (aOR: 1·09) and operative vaginal delivery (aOR: 1·15, 95% CI: 1·09–1·21), while TSH 4·29–10 mIU/l was correlated with spontaneous abortion (aOR: 1·15), stillbirth (aOR: 1·58), preterm birth (aOR: 1·20), caesarean section (aOR: 1·15) and large for gestational age (LGA) infants (aOR: 1·12).”

The authors discuss the implication of these odds ratios that are small yet significant.

“The present study involving 194 154 subjects demonstrated that preconception high TSH was associated with a small but significant increased risk of overall adverse pregnancy outcomes, including spontaneous abortion, preterm birth and LGA infants, regardless of whether we used first-trimester-specific upper limit (2·50 mIU/l) or nonpregnant reference upper limit (4·29 mIU/l). Our data support that women planning a pregnancy within 6 months should be regarded as ‘pregnant status’ and that closer observation may be required once TSH levels exceed 2·50 mIU/l, rather than the nonpregnant reference upper limit.”

Clinicians should also bear in mind:

Borderline TSH elevation has been shown to portend deleterious impacts on various pregnancy outcomes. In the present study, we found that the higher the preconception TSH, the higher the incidence of adverse pregnancy outcomes. This was concordant with other studies, although they measured TSH during pregnancy, rather than before conception. Thyroid hormones themselves directly affect foetal development and utero-placental maturation; hence, maternal hypothyroidism can influence pregnancy outcomes, especially in early gestation.”

Regarding case management, the authors conclude:

“…preconception high TSH levels were associated with a small but significant increased risk of overall adverse events, including preterm birth, CS delivery and LGA infants, even within normal nonpregnant range. TSH <2·5 mIU/l is more suitable for the assessment of women planning a pregnancy in China, but one should not make a hasty decision to initiate treatment at this point without repeating TSH measurement and checking TPO antibody status. Prospective randomized controlled trials examining the role of levothyroxine supplement in mildly hypothyroid prepregnant women are warranted in the future.”

See also Subclinical hypothyroidism in pregnancy.

Subclinical hypothyroidism worsens cardiometabolic profile

Subclinical hypothyroidism and cardiometabolic biomarkersSubclinical hypothyroidism (SCH), poor thyroid effect throughout the body in the presence of ‘normal’ thyroid serum tests, is a widespread yet under-appreciated clinical challenge. A recent study published in the Journal of the Endocrine Society documents adverse cardiometabolic biomarkers in the presence of subclinical hypothyroidism. Additionally, practitioners must bear in mind that more than adequate iodine intake can worsen the condition.

Clarifying the definition of normal thyroid function

The authors note that uncertainty around the definition of normal thyroid function can go beyond contention involving different opinions on laboratory reference ranges by examining the effect of suboptimal thyroid function on the entire organism.

“As thyroid function has multisystemic effects, its derangement could affect a broad range of cardiometabolic pathways potentially related to clinical manifestations. However, the definition of normal thyroid function has been intensely debated, with some experts advocating for lowering the upper limit of normal for thyroid stimulating hormone (TSH) and others for maintaining the current standard. In this regard, thyroid-related risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD) may impact the definition of TSH normality.”

They note some of the mechanisms by which SCH can adversely affect cardiovascular and metabolic function:

“The potential relationship of thyroid hypofunction with T2D and CVD may be mediated by abnormalities in lipids, lipoprotein subclasses, endothelial function, coagulation, inflammatory pathways, and insulin resistance.”

This hardly exhausts the list of adverse physiological effects since every part of the body, including the brain, requires the stimulus of thyroid hormone to produce energy and function. The public health implications are enormous.

“Detailed assessment of thyroid function effects on these mediators/markers may have high population health implications, especially along the milder hypofunction spectrum within euthyroidism and SCH. Understanding the role of thyroid function in cardiometabolic pathways may guide the clinically relevant definition of thyroid function and unveil potential targets for controlling related morbidity.”

Subclinical hypothyroidism increases cardiometabolic risk

Thus the authors set out to…

“…examine thyroid function across the spectrum of euthyroid to HT in relationship to cardiometabolic pathways represented by lipids, lipoproteins, inflammation, coagulation, glycemic, and insulin resistance biomarkers.”

They examined data for 28,024 apparently healthy middle-aged and older women, and indeed found that cardiometabolic health worsens on a gradient from normal thyroid (euthyroid) function, through subclinical hypothyroidism, to full-blown hypothyroid:

Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance: larger very-low-density lipoprotein size (nm); higher low-density lipoprotein (LDL) particle concentration (nmol/L), and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid to SCH and HT. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.”

TSH, total and LDL cholesterol not so useful

They note that it was other biomarkers that revealed the actual progressive risk:

“In this population of apparently healthy middle-aged and older women, individuals with SCH and HT had differences in the lipid and lipoprotein subclass profile that indicated worsening insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol. Of the other biomarkers, only hs-CRP and HbA1c were associated with SCH and HT. For TSH quintiles mostly within the normal range, lipid and lipoprotein results for TSH quintiles were generally similar but null for other biomarkers. Hence, progressive thyroid hypofunction was associated with insulin-resistant and proatherogenic lipids and lipoproteins profile in a graded manner, with potential clinical consequences.”

Mechanisms

Besides thyroid as a driver of metabolic activity, insulin resistance appears to play a key role. They point out that insulin resistance appears to affect lipoprotein metabolism before glucose metabolism, an observation important for clinicians to bear in mind.

Thyroid hormones act as modulators of cholesterol synthesis and degradation through key enzymes. One of the main mechanisms is the stimulus of thyroid hormones over sterol regulatory element–binding protein 2, which in turn induces LDL receptor gene expression. However, it was shown that the association of HT and higher LDL cholesterol levels is present only in insulin-resistant subjects. Indeed, the lack of LDL cholesterol differences could be explained by our insulin-sensitive study population (low HbA1c levels). HT has also been associated with lower catabolism of lipid-rich lipoproteins by lipoprotein lipase, hepatic lipase, and decreased activity of cholesterol ester transfer proteinthat mediates exchanges of cholesteryl esters of HDL particles with triglyceride-rich LDL and VLDL particles. These mechanisms might explain the relationship of thyroid hypofunction with atherogenic and insulin-resistant lipid and lipoprotein abnormalities. Finally, the milder differences noted in HbA1c compared with LPIR across thyroid categories may be explained by the earlier effects of insulin resistance on lipoprotein metabolism than on glucose metabolism.”

Practitioners should be attentive to the authors’ conclusion:

“In this large population of apparently healthy women, individuals with SCH had differences in their biomarker profile that indicated worsening lipoprotein insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol levels. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.

Iodine supplementation reminder

More than adequate iodine increases autoimmune thyroiditisClinicians who may be tempted to reflexively offer iodine supplementation for thyroid disorders including subclinical hypothyroidism should remember the body of evidence showing this can fire up autoimmune thyroiditis. One example by way of a reminder is a study published in the European Journal of Endocrinology showing that more thanequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis. The authors describe their intent:

“With the introduction of iodized salt worldwide, more and more people are exposed to more than adequate iodine intake levels with median urinary iodine excretion (MUI 200–300 μg/l) or excessive iodine intake levels (MUI >300 μg/l). The objective of this study was to explore the associations between more than adequate iodine intake levels and the development of thyroid diseases (e.g. thyroid dysfunction, thyroid autoimmunity, and thyroid structure) in two Chinese populations.”

They examined thyroid hormones, thyroid autoantibodies in serum, iodine levels in urine were measured. and B-mode ultrasonography of the thyroid for 3813 individuals, in two areas with differing levels of iodine exposure. The levels of iodine intake were: Rongxing, MUI 261 μg/l; and Chengshan, MUI 145 μg/l. (MUI =median urinary iodine excretion.) They found a blatant difference in thyroid biomarkers:

“The prevalence of subclinical hypothyroidism was significantly higher for subjects who live in Rongxing than those who live in Chengshan. The prevalence of positive anti-thyroid peroxidase antibody (TPOAb) and positive anti-thyroglobulin antibody (TgAb) was significantly higher for subjects in Rongxing than those in Chengshan. The increase in thyroid antibodies was most pronounced in the high concentrations of TPOAb (TPOAb: ≥500 IU/ml) and low concentrations of TgAb (TgAb: 40–99 IU/ml) in Rongxing.”

Their results suggest there is a discrete window for thyroid intake:

“Compared with the adequate iodine intake level recommended by WHO/UNICEF/ICCIDD MUI (100–200 μg/l), our data indicated that MUI 200–300 μg/l might be related to potentially increased risk of developing subclinical hypothyroidism or autoimmune thyroiditis. This result differs from the WHO’s suggestion that MUI >300 μg/l may increase the risk of developing autoimmune thyroid diseases.”

Practitioners should be cautious with dosing of supplemental iodine in keeping with the authors’ conclusion:

“In conclusion, compared with the population with MUI 145 μg/l in Chengshan, the population with MUI 261 μg/l in Rongxing had a higher risk to develop autoimmune thyroiditis and subclinical hypothyroidism. Thus, more than adequate iodine intake might not be recommended for the general population in terms of keeping a normal function of thyroid.”

Readers may wish to also see the earlier post Hypothyroidism can be provoked by small amounts of supplemental iodine.

Thyroid autoimmunity and iron deficiency in pregnancy

European Journal of Endocrinology on thyroid autoimmunity in pregnancyThyroid autoimmunity and iron deficiency are both common in pregnancy, posing a risk for numerous adverse fetal and maternal outcomes, including miscarriage. A clinical study just published in the European Journal of Endocrinology the important connection between thyroid autoimmunity and low iron, both of which can be recognized at an early stage. The authors state:

“Thyroid disorders and iron deficiency (ID) are associated with obstetrical and fetal complications. Iron is essential for the normal functioning of thyroid peroxidase (TPO-abs) and ID is frequent during pregnancy. The aim of this study was to compare the prevalence of thyroid autoimmunity (TAI) and dysfunction during the first trimester of pregnancy in women with and without ID.”

They measured ferritin to determine iron status, TPO-abs (thyroid peroxidase antibodies) for thyroid autoimmunity, and thyroid-stimulating hormone (TSH) and free T4 (FT4) thyroid function. Note that their definitions for iron deficiency (ID) and thyroid autoimmunity (TAI) were extremely ‘generous’ with ID defined as ferritin <15µg/L and TAI as TPO-abs >60kIU/L. Practitioners in this country should also note their definition of subclinical hypothyroidism (SCH) as TSH was >2.5mIU/L.

Thyroid autoimmunity and iron deficiency are common

Their data also demonstrated a significant coupling between the two:

ID was present in 35% of women. Age and BMI were comparable between both groups. In the ID group, the prevalence of TAI and SCH was significantly higher, compared with that in the non-ID group (10% vs 6% and 20% vs 16% respectively). Ferritin was inversely correlated with serum TSH and positive with FT4 levels. In the logistic regression model, ID remained associated with TAI after correction for confounding factors. The association with SCH was absent after correction for the confounders in the logistic regression model, but remained present in the linear regression model.”

MedscapeMedscape Medical News comments on these findings:

“While previous studies have indicated that iron deficiency during pregnancy can affect from 24% to 44% of women, this is the first to show the secondary effect of an increased prevalence of thyroid autoimmunity.”

Thyroid autoimmunity poses serious maternal and fetal risks. Also stated in Medscape:

“Senior author Kris G Poppe, MD, PhD, head of the Endocrine Clinic, University Hospital CHU St-Pierre, Brussels, Belgium, told Medscape Medical News that this finding is important because thyroid autoimmunity in pregnant women increases the risk of miscarriage, preterm delivery, and low birth weight compared with unaffected women.”

For important points on the multiple adverse affects of thyroid autoimmunity on pregnancy and the neonate see the earlier post Subclinical hypothyroidism in pregnancy. Standard of care for pregnancy planning and management should always include testing ferritin, thyroid antibodies and function.

The authors conclude:

ID was frequent during the first trimester of pregnancy and was associated with a higher prevalence of TAI, higher serum TSH, and lower FT4levels.”

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

The American Journal of MedicineNote: 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.”

 

The Annals Of Thoracic SurgeryMore 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.”

 

Acta CardiologicaIn 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.”

 

European Journal of Clinical InvestigationThe 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.”

 

Saudi Medical JournalA 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.”

 

Endocrine JournalLow-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.

 

Journal of Clinical Endocrinology & MetabolismMore 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.”

 

Metabolic Syndrome and Related DisordersMore 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.”

 

Journal of Clinical InvestigationAt 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.”

 

Nephrology Dialysis TransplantationFurther 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.”

 

Iranian Journal of Kidney DiseasesAlong 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.

Journal of Molecular EndocrinologyA 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.”

Thyroid hormone transporters MCT8 and MCT10Transporters 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…”

 

Thyroid ResearchThe 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.”

Old and new concepts of thyroid hormone actionThey 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.”

 

Journal of EndocrinologyAppreciation 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.”

 

Molecular and Cellular EndocrinologyAs 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.”

 

Pediatric Endocrinology ReviewsHormone 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.”

 

Nephrology Dialysis TransplantationChronic 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.”

 

Journal of Endocrinological InvestigationClinicians 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.”

 

Minerva EndocrinologicaA 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.”

 

BMC CancerAlso 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.”

 

Clinical Endocrinology & MetabolismThyroid 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:

When measuring TSH alone may misleadAnd they offer a diagram of different patterns of thyroid function tests and their causes:

Microsoft PowerPoint - ybeem_930_Koulouri et al - FIGURES - FINA

 

Nature Reviews EndocrinologyFinally, 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.

Cognitive impairment associated with low but still ‘normal’ TSH

Journal of Clinical Endocrinology & MetabolismCognitive impairment can occur at any age with suboptimal thyroid function—neurons require thyroid stimulus as much as any other cells. A study just published JCEM (The Journal of Clinical Endocrinology & Metabolism) offers evidence that TSH (thyroid stimulating hormone) levels when low but still ‘normal’ are associated with cognitive impairment and dementia. The authors state:

“The association between subclinical hyperthyroidism and the risk of dementia has been validated in several studies. However, the effect of thyroid function within reference range on the risk of cognitive dysfunction including mild cognitive impairment (MCI) and dementia is still unclear…Our aim was to investigate the association between thyroid function and the risk of MCI and dementia in euthyroid elderly subjects.”

313 participants who were euthyroid (normal thyroid) and not demented at the beginning of their study were followed for 5 years and evaluated for baseline thyroid function and cognitive impairment or dementia during the study period. They found a significant association between low-normal TSH levels and cognitive impairment:

“At baseline evaluation, 237 subjects were cognitively normal, and 76 subjects were MCI. Diagnoses of cognitive function in 259 subjects remained unchanged or improved during the study period (non-progression group), whereas 54 subjects showed progression of cognitive impairment to MCI or dementia (progression group). In the progression group, baseline serum TSH levels were lower than those in non-progression group. Baseline serum free-T4 levels were not significantly different between these two groups. The association between lower baseline serum TSH levels and the development of MCI or dementia was maintained after adjustment for conventional baseline risk factors.”

Clinical note: Practitioners should bear in mind the various possible factors besides subclinical hyperthyroidism that can suppress TSH to low ‘normal’ levels that on their own contribute to cognitive impairment including chronic inflammation.

The authors conclude:

Lower serum TSH level within reference range was independently associated with the risk of cognitive impairment including MCI and dementia in elderly subjects.”

Hypothyroidism can be provoked by small amounts of supplemental iodine

Summary: Care must be taken when considering iodine supplementation because it can provoke latent thyroid autoimmunity resulting in hypothyroidism.

A noteworthy study just published in The American Journal of Clinical Nutrition adds more evidence that iodine supplementation, even in small amounts, can produce hypothyroidism. The authors state:

“The beneficial health effects associated with Universal Salt Iodization are well known. Yet, little is known about the possible adverse health effects in people with high iodine intake and the safe daily intake upper limit in the Chinese population…The objective of this study was to explore the safe upper level of total daily iodine intake among adults in China.”

They examined 256 adults with apparently normal thyroid function in a 4 week double-blind, placebo-controlled, randomized controlled trial. The subjects were randomly assigned to 12 different levels of iodine supplementation ranging from 0 to 2000 micrograms per day (2000 μg = 2 milligrams). Iodine from both supplements and diet was taken into consideration. They were then evaluated for thyroid function, thyroid size, and urinary iodine. The outcome was striking for what would seem to be a modest amount:

“The mean iodine intake from the diets and salt intake of the participants were 105 ± 25 and 258 ± 101 μg/d, respectively. In comparison with the placebo group, all iodide-supplemented groups responded with significant increases in median urinary iodine concentrations and in thyroid-stimulating hormone concentration. Thyroid volume decreased after 4 wk in the high-iodine intervention groups (1500–2000 μg). Subclinical hypothyroidism appeared in the groups that received 400 μg I (5%) and 500–2000 μg I (15–47%).”

This is striking in that even 400 micrograms, only 0.4 milligrams, provoked subclinical hypothyroidism in a significant percentage of patients. This is why I published an earlier post regarding the need for care in the use of iodine for radiation protection, to say nothing of the inappropriate supplementation of large amounts of iodine without due care. In this study the highest intervention group which was still only 2 mg per day had noticeable thyroid shrinkage. The authors conclude:

“This study showed that subclinical hypothyroidism appeared in the participants who took the 400-μg I supplement, which provided a total iodine intake of ∼800 μg/d. Thus, we caution against a total daily iodine intake that exceeds 800 μg/d [0.8 milligrams] in China and recommend further research to determine a safe daily upper limit.”

Borderline TSH can strongly predict future hypothyroidism

Summary: Borderline levels of TSH (thyroid stimulating hormone) still within the reference ranges typically printed in laboratory reports can indicate low thyroid function (and predict hyperthyroid on the other end of the scale). A thorough assessment of the more than two dozen patterns of thyroid dysfunction is necessary for an accurate diagnosis.

Clinicians and patients may often be misled by TSH levels that appear normal, but experienced practitioners know that they can mask the presence thyroid disorders. Because hypothyroidism affects function globally, a study just published in the Journal of Clinical Endocrinology & Metabolism that practitioners in all specialties should be vigilant. The authors state:

Serum TSH in the upper part of the reference range may sometimes be a response to autoimmune thyroiditis in early stage and may therefore predict future hypothyroidism. Conversely, relatively low serum TSH could predict future hyperthyroidism…The objective of the study was to assess TSH within the reference range and subsequent risk of hypothyroidism and hyperthyroidism.”

The authors examined 10,083 women and 5,023 men without previous thyroid disease who had a baseline TSH of 0.20–4.5 mU/liter for the predictive probabilities of developing hypothyroidism or hyperthyroidism according to categories of baseline TSH during follow-up 11 years later. Their data drew a strong result:

“During 11 yr of follow-up, 3.5% of women and 1.3% of men developed hypothyroidism, and 1.1% of women and 0.6% of men developed hyperthyroidism. In both sexes, the baseline TSH was positively associated with the risk of subsequent hypothyroidism. The risk increased gradually from TSH of 0.50–1.4 mU/liter [women, 1.1%; men, 0.3%] to a TSH of 4.0–4.5 mU/liter (women, 31.5%; men, 14.7%). The risk of hyperthyroidism was higher in women with a baseline TSH of 0.20–0.49 mU/liter (3.9%) than in women with a TSH of 0.50–0.99 mU/liter (1.4%) or higher (∼1.0%).”

Too many patients with thyroid dysfunction fall between the cracks of routine care. This evidence strongly supports the importance of a complete assessment of thyroid function when these disorders, especially autoimmune thyroid disease, are suspected. The authors conclude:

TSH within the reference range is positively and strongly associated with the risk of future hypothyroidism. TSH at the lower limit of the reference range may be associated with an increased risk of hyperthyroidism.”

Thyroid dysfunction in peri- and post-menopause

This paper published in the medical journal Menopause International touches on the huge topic of thyroid dysfunction before, during and after menopause. As the author states, “Thyroid dysfunction is common, especially among women over the age of 50. In caring for peri- and post-menopausal women, it is important to recognize the changing clinical manifestations of thyroid disease with age.” Subclinical hypo and hyperthyroidism (thyroid dysfunction in the presence of normal TSH levels), an extremely important topic that you will see more about here, is noted in particular. The author notes, “…caution is required in diagnosing and treating thyroid dysfunction in women who are taking oral estrogens or selective estrogen receptor modulators.” The functional approach that fully examines and treats the two dozen underlying patterns of thyroid dysfunction with appropriate tests and therapies is far more extensive than indicated here. See Dr. Kharrazian’s book for an overview for the layperson. Recommended book on thyroid conditions