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.

Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”

 

Levothyroxine therapy and normal TSH yet hypothyroid symptoms

JCEM levothyroxine fails to normalize thyroid T3Levothyroxine (LT4, synthetic thyroxine) is the standard therapy given by most physicians for hypothyroid. Yet clinicians experienced in functional case management of thyroid disorders know that patients may often continue to feel poorly due to inadequate T3 (triiodothyronine, the ‘active’ thyroid hormone converted from T4 outside the gland). A study just published in The Journal of Clinical Endocrinology and Metabolism offers undeniable evidence that many patients taking only levothyroxine are receiving inadequate treatment. Because TSH responds to T4 and not T3 levels, poor function persists even with normal TSH and . The authors state:

“The ideal therapeutic goal in hypothyroidism would be to restore clinical and biochemical euthyroidism via physiologic thyroid hormone replacement. This concept may seem straightforward, but there are subtleties that have only recently been recognized by the medical community. For the last four decades, the standard approach for thyroid hormone replacement in hypothyroidism has been administration of levothyroxine (LT4) at doses that normalize the serum TSH.”

Levothyroxine dogma persists despite prior evidence

An abundance of data contrary to the dogma has already been emerging for years (see these earlier posts: Thyroid hormone conversion affects hypothyroid treatment; Low ‘normal’ free T3 thyroid hormone predicts death in older patients even without overt hypothyroidThyroid in heart, metabolism, brain, kidney; vital importance of T3). Finally the dogma of standard therapy that has endured in fossilized resistance is being overcome.

“The hypothesis that LT4 ‘monotherapy’ will maintain an adequate serum pool of T4 and that the iodothyronine deiodinases will then provide physiologic regulation of T3 availability has been held with much conviction. The dogma in clinical thyroidology that LT4 monotherapy at doses that normalize serum TSH is sufficient to restore euthyroidism has come into question as evidence suggests a significant proportion of patients treated with LT4 continue to experience residual symptoms of hypothyroidism, including psychological and metabolic effects.”

Tremendous importance for public health

The authors underline the huge significance for public health:

“Hypothyroidism is a prevalent condition and levothyroxine is commonly prescribed; in 2015 levothyroxine was the single most commonly prescribed medication in the US. Thus understanding whether all parameters of hypothyroidism are universally restored by LT4 monotherapy has great clinical significance.”

They set about to determine whether LT4 at doses that normalize serum TSH is associated with normal markers of thyroid status and functional thyroid health by examining data for 9,981 participants with normal serum TSH were identified; 469 were LT4-treated from the giant US National Health and Nutrition Examination Survey. They used this to 9,981 participants with normal serum TSH were identified; 469 were LT4-treated.

Levothyroxine fails to adequately improve T3

Their data show clearly that in many cases levothyroxine monotherapy fails to ensure an adequate T3:T4 ratio and thyroid functional health:

Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to ∽15–20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants: had higher BMI despite report of consuming less calories/day/kg; were more likely to be taking beta-blockers, statins, and anti-depressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum HDL and lower serum LDL, triglycerides, and CRP. Age was associated with serum free T3:free T4 ratio in all participants; caloric intake was associated in LT4-treated individuals.”

The lower serum TSH in LT4-treated patients was associated with a different metabolic profile but not higher T3.  Commenting on the significance for quality of life they state:

“The major strength of the present studies is the availability of biochemical data as well as markers of quality of life (QOL) in a large population sample to assess for clinical relevance. There were major differences in 7 (out of a total of 21) objective (BMI, total cholesterol, HDL, LDL; beta-blocker, statin and antidepressant use), and 5 (out of a total of 31) subjective (nutrient intake, reported physical activity) clinical parameters between LT4 -treated participants and matched controls. While we recognize that these parameters are not specific markers of hypothyroidism and we cannot determine whether they were different between the groups prior to LT4 treatment, this does not mitigate the fact that these data present a strong challenge the dogma that having a normal serum TSH equates with euthyroidism in LT4 -treatment.

Clinical Note

It should go without saying that almost all hypothyroidism in developed countries is due to autoimmune thyroiditis (Hashimoto’s disease). Besides muddying the waters in terms of quantifying the functional effects, practitioners must bear in mind that the systemic burden of inflammation associated with autoimmunity has diverse negative effects, in addition to impairing type 2 deiodinase (D2) conversion of T4 to T3.

Commenting in Medscape Medical News, senior author Antonio C Bianco, MD, professor of medicine at Rush University Medical Center in Chicago, Illinois stated:

“Patients have told us this for years — they complain of having a hard time losing weight and feeling sluggish and depressed. Now, for the first time, we have documentation that supports the patients’ complaints, demonstrating that…[this] was not only in their minds, as some have suggested.”

The authors conclude:

“…NHANES participants with normal serum TSH levels on LT4 monotherapy exhibit lower serum T3:T4 ratios than healthy euthyroid controls. LT4 -treated individuals have higher BMIs despite reporting lower calorie intake corrected by body weight, report lower physical activity levels, and are more often taking statins, beta- blockers, and antidepressantsthe concept that establishing a normal serum TSH renders individuals on LT4 monotherapy clinically euthyroid should be revisited and QOL measures should be more highly prioritized in hypothyroidism research and professional guidelines.”

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.

Metabolic health status and aging determined by inflammation, not weight

JCEM Vol 98 Number 9Metabolic health is not reliably determined by weight or BMI (body mass index). Lean individuals can suffer from cardiovascular and other diseases involving metabolism, and  evidence has been mounting that supports the notion of a subtype of obesity that is metabolically healthy. A study recently published in JCEM (The Journal of Clinical Endocrinology & Metabolism) shows that inflammation can determine metabolic health in both obese and non-obese populations. The authors state:

Inflammation is a potential mechanism linking obesity and cardiometabolic risk… The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers.”

To do so they measured serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts in 2047 men and women who they classified as obese (BMI more than 30 kg/m2) and nonobese (BMI less than kg/m2). They established metabolic health status with five definitions that included markers such as blood pressure, triglycerides, LDL, HDL, total cholesterol, fasting glucose, and insulin resistance (HOMA). Several of the inflammatory markers were more strongly associated with metabolic health:

“According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2–3.5), IL-6 (ORs, 1.7–2.9), plasminogen activator inhibitor-1 (ORs, 1.7–2.9), and white blood cells (ORs, 2.1–2.5) and higher adiponectin concentrations (ORs, 2.6–4.0).”

In other words, lower C3, CRP, TNF-α, IL-6, PAI-1, and white blood cells, along with higher adiponectin were associated with metabolic health in both groups. Lower C3, IL-6, PAI-1 and higher adiponectin were most strongly indicative of metabolic health among the obese. The authors’ conclusion highlights what clinicians should bear in mind:

Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed. “

 

CMAJ Vol 185 Num 13Furthermore, inflammation is turning out to be a key determinant of the quality of aging. The authors of a paper recently published in CMAJ (Canadian Medical Association Journal) state:

Chronic inflammation has been implicated in the pathogenesis of age-related conditions, such as type 2 diabetes, cardiovascular disease, cognitive impairment and brain atrophy… For example, obesity increases inflammation, and chronic inflammation, in turn, contributes to the development of type 2 diabetes by inducing insulin resistance, and to coronary artery disease by promoting atherogenesis. Thus, raised levels of inflammation appear to be implicated in various pathological processes leading to diseases in older age… We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.”

They examined interleukin-6 (IL-6) levels for 3044 middle-aged adults at baseline and 5 years earlier and correlated it with cause-specific mortality, chronic disease and functioning from hospital and register data and clinical examinations. The authors focused on IL-6 because:

“Of the various markers of systemic inflammation, interleukin-6 is particularly relevant to aging outcomes. There is increasing evidence that interleukin-6 is the pro-inflammatory cytokine that “drives” downstream inflammatory markers, such as C-reactive protein and fibrinogen. Interleukin-6, in contrast to C-reactive protein and fibrinogen, is also likely to play a causal role in aging owing to its direct effects on the brain and skeletal muscles. In addition, results of Mendelian randomization studies of interleukin-6 and studies of antagonists are consistent with a causal role for interleukin-6 in relation to coronary artery disease, again in contrast to C-reactive protein and fibrinogen.”

They created four aging phenotypes at the 10-year follow-up defined as:

  • Successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning)
  • Incident fatal or nonfatal cardiovascular disease
  • Death from noncardiovascular causes
  • Normal aging (all other participants)

Chronic inflammation as determined by higher IL-6 levels was clearly associated with the poorer aging phenotypes:

“Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53) and increased the risk of future cardiovascular events (OR 1.64) and noncardiovascular death (OR 2.43).”

IL-6 is not the only useful metric for chronic inflammation in aging, but the authors interpret their data as offering good evidence for its use:

Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice.

And, not surprisingly, two measurements of IL-6 were better than one:

“Our results on the associations between inflammation, cardiovascular events and death from noncardiovascular causes are concordant with those reported in the literature. However, our results also show that measuring chronic inflammation twice may be a better predictor of future cardiovascular disease and noncardiovascular death than measuring inflammation only once.”

In conclusion:

“We found that chronic inflammation characterized by a high interleukin-6 level (> 2.0 ng/L) measured twice over the 5-year exposure period nearly halved the odds of successful aging after 10 years of follow-up compared with maintaining a low level of interleukin-6 (< 1.0 ng/L twice over the exposure period). Our study showed that high interleukin-6 levels at baseline were inversely associated with most of the individual components that characterize successful aging…”

 

Experimental GerontologyIn this context it’s important to consider the role of autoimmunity in inflammation that produces poor aging outcomes. A paper just published in Experimental Gerontology shows how an increase in the Th17/Treg ratio, a pro-inflammatory shift that is a hallmark of autoimmune phenomena, is also associated with increased inflammation of aging called ‘inflammaging‘.

Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammagingT helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro-inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described.”

The authors investigated the proportion of pro-inflammatory TH17 cells (CD4 + IL23R +) and anti-inflammatory Tregs (regulatory T cells that modulate the immune response and depend on vitamin D) along with their respective cytokines IL-17 and IL-10 in human healthy donors:

“The data revealed a continual increase of basal CD4 + IL23R + cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced.”

Clinical note: This is of great practical significance since almost all the manifold disorders associated with aging, from diminished cognitive function to osteoporosis, have an inflammatory component. The authors conclude:

“…changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age.”

High protein beats high carbohydrate diet for biomarkers of metabolic syndrome

Diabetes CareRegulating insulin is the key factor metabolic syndrome, diabetes and weight loss. In accordance with that, a randomized controlled trial just published in the journal Diabetes Care offers more evidence that a higher protein (with carbohydrate) diet improves multiple biomarkers better than a high carbohydrate diet. The authors determined to…

“……study the effects of high-protein versus high-carbohydrate diets on various metabolic end points (glucoregulation, oxidative stress [dichlorofluorescein], lipid peroxidation [malondialdehyde], proinflammatory cytokines [tumor necrosis factor-α and interleukin-6], adipokines, and resting energy expenditure [REE]) with high protein–low carbohydrate (HP) and high carbohydrate–low protein (HC) diets at baseline and after 6 months of dietary intervention.”

In other words, how does high protein compare with high carbohydrate in the regulation of blood sugar, inflammation, and the metabolic rate of energy production? To answer this they randomized obese, pre-menopausal women ages 20–50 years without diabetes or pre-diabetes to be on either a high carbohydrate (55% carbohydrates, 30% fat, and 15% protein) or high protein (40% carbohydrates, 30% fat, and 30% protein) diet for 6 months. They measured the above-mentioned biomarkers at the beginning and the end of the 6 months. The high protein diet won out dramatically for every one of the metabolic end points:

“After 6 months of the HP versus HC diet (12 in each group), the following changes were significantly different by Wilcoxon rank sum test for the following parameters: dichlorofluorescein (−0.8 vs. −0.3 µmol/L), malondialdehyde (−0.4 vs. −0.2 μmol/L), C-reactive protein (−2.1 vs. −0.8 mg/L), E-selectin (−8.6 vs. −3.7 ng/mL), adiponectin (1,284 vs. 504 ng/mL), tumor necrosis factor-α (−1.8 vs. −0.9 pg/mL), IL-6 (−1.3 vs. −0.4 pg/mL), free fatty acid (−0.12 vs. 0.16 mmol/L), REE (259 vs. 26 kcal), insulin sensitivity (4 vs. 0.9), and β-cell function (7.4 vs. 2.1).”

That’s a resting energy expenditure (number of calories burned at rest) of 259 kcal for the high protein diet versus 26 kcal for the high carbohydrate regimen. Other marked differences included insulin sensitivity (as would be expected), inflammation, pancreatic function and oxidative stress. The authors conclude:

“To our knowledge, this is the first report on the significant advantages of a 6-month hypocaloric HP diet versus hypocaloric HC diet on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in normal, obese females without diabetes.”

Sugar calories are worse for diabetes and obesity than others

PLOS ONEAttentive clinicians who have been exhorting their patients for years to avoid excessively stimulating insulin production with sugar are heartily welcoming the superb research just published in PLoS One (Public Library of Science) that drives a stake through the heart of the mistaken notions that calories from sugar have the same effect as others, and that obesity causes diabetes. The authors observe:

“Global diabetes prevalence has more than doubled over the last three decades, with prevalence rates far exceeding modeled projections, even after allowing for improved surveillance…Most of the worldwide rise is thought to be type 2 diabetes linked to the “metabolic syndrome” – the cluster of metabolic perturbations that includes dyslipidemia, hypertension, and insulin resistance. Obesity associated with economic development — particularly from lack of exercise and increased consumption of calories — is thought to be the strongest risk factor for metabolic syndrome and type 2 diabetes…”

But as the data from a number of studies shows…

“…several countries with high diabetes prevalence rates have low obesity rates, and vice versa. High diabetes yet low obesity prevalence are observed in countries with different ethnic compositions…Trends in diabetes and obesity are also dyssynchronous within some nations…”

Moreover…

“This population-level puzzle is accompanied by individual-level data. About 20% of obese individuals appear to have normal insulin regulation and normal metabolic indices (no indication of diabetes) and normal longevity, while up to 40% of normal weight people in some populations manifest aspects of the “metabolic syndrome”.

It’s been known for some time that sugars do a lot more damage than just contribute to obesity:

One controversial hypothesis is that excessive sugar intake may be a primary and independent driver of rising diabetes rates. Sugars added to processed food, in particular the monosaccharide fructose, can contribute to obesity, but also appear to have properties that increase diabetes risk independently from obesity. For example, liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, which drives hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates the insulin signaling pathway, leading to hepatic insulin resistance. Sugary foods have been significantly associated with the development of insulin resistance in laboratory-based studies. Reactive oxygen species are produced by the Maillard reaction, damaging pancreatic beta cells, and leading to a subcellular stress response (the “unfolded protein response” in the endoplasmic reticulum) that drives insulin inadequacy. In concert, insulin resistance and reduced insulin secretion lead to overt diabetes.”

To determine whether added sugars or obesity are the primary driver of the world-wide diabetes pandemic, the authors…

“…conducted a statistical assessment of panel data (repeated multi-variate data from multiple countries over a time period) to empirically evaluate whether changes in sugar availability, irrespective of changes in other foodstuffs, can in part account for the divergence in diabetes prevalence rates worldwide.”

To do so they used repeated cross-sectional data on diabetes and nutritional components of food from 175 countries over ten years, correlating with the prevalence overweight and obesity and the incidence of diabetes. Their exhaustive and detailed data accumulation and rigorous, multifaceted statistical analyses are the very model of superlative research. Their data provides the evidence to fuel important changes in public health policy:

“…we found that every 150 kcal/person/day increase in sugar availability (about one can of soda/day) was associated with increased diabetes prevalence by 1.1% (p <0.001) after testing for potential selection biases and controlling for other food types (including fibers, meats, fruits, oils, cereals), total calories, overweight and obesity, period-effects, and several socioeconomic variables such as aging, urbanization and income. No other food types yielded significant individual associations with diabetes prevalence after controlling for obesity and other confounders. The impact of sugar on diabetes was independent of sedentary behavior and alcohol use, and the effect was modified but not confounded by obesity or overweight. Duration and degree of sugar exposure correlated significantly with diabetes prevalence in a dose-dependent manner, while declines in sugar exposure correlated with significant subsequent declines in diabetes rates independently of other socioeconomic, dietary and obesity prevalence changes. Differences in sugar availability statistically explain variations in diabetes prevalence rates at a population level that are not explained by physical activity, overweight or obesity.”

There are, of course, mutiple factors that can contribute to diabetes and metabolic syndrome. The rising tide of autoimmunity (as readers here are likely aware) and inflammation supported by other causes including adipokines generated in visceral fat are notable. But the importance of this study is to reverse the mistaken notion that obesity is the primary cause of insulin resistance diabetes; it is, for the most part, the other way around, with the excessive rise in insulin compensatory for receptor resistance that forces the storage of calories as fat.

“The worldwide secular trend of increased diabetes prevalence likely has multiple etiologies, which may act through multiple mechanisms. Our results show that sugar availability is a significant statistical determinant of diabetes prevalence rates worldwide. By statistically studying variation in diabetes rates, food availability data and associated socioeconomic and demographic variables across countries and time, we identified that sugar availability appears to be uniquely correlated to diabetes prevalence independent of overweight and obesity prevalence rates, unlike other food types and total consumption, and independent of other changes in economic and social change such as urbanization, aging, changes to household income, sedentary lifestyles and tobacco or alcohol use. We found that obesity appeared to exacerbate, but not confound, the impact of sugar availability on diabetes prevalence, strengthening the argument for targeted public health approaches to excessive sugar consumption. We also noted that longer exposure to high sugar was associated with accentuated diabetes prevalence, while reduced sugar exposure was associated with decline in diabetes prevalence, and that the sugar-diabetes relationship appeared to meet criteria for temporal causality without being the result of selection biases or the effect of secular trends that may be artifacts of economic development or changes in surveillance…In summary, population-level variations in diabetes prevalence that are unexplained by other common variables appear to be statistically explained by sugar.”

Considering the massive dimensions of the diabetes pandemic and its grievous depredations, reducing sugar consumption is one of the leading public health issues of our time.

Weight loss and insulin resistance improved by branched-chain amino acids

Diabetologia Vol 55 Issue 2Weight loss and improvement in insulin resistance naturally go hand in hand, and a study just published in the journal Diabetologia confirms that consumption of branched-chain amino acids (BCAAs) helps both. Isoleucine, leucine and valine are already known to promote muscle growth and repair, influence brain signaling for appetite and metabolic rate, help with burn recovery, and be remedial for autism when it includes genetic mutations in BCAA pathways. The investigators’ intent was to discern biomarkers for weight loss and insulin resistance:

Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss.”

They cast a wide net to assay 60 metabolites, including non-essential fatty acids (NEFA), β-hydroxybutyrate, ketones, insulin and glucose at the beginning of their study and after 6 months for 500 subjects who had lost at least 4 kg of weight during Phase I of the Weight Loss Maintenance (WLM) trial. They also calculated the standard metric for insulin resistance, the homeostatic model assessment of insulin resistance (HOMA-IR) and added the change in HOMA-IR with weight loss (∆HOMA-IR).” BCAAs stood out from the pack of metabolites in association with weight loss and improvement in insulin resistance:

“Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was −0.80 ± 1.73. Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR and independently associated with ∆HOMA-IR. ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR. These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR.”

Fpr clinicians, this evidence supports the use of BCAAs in case management of weight loss and recovery of insulin sensitivity. The authors conclude:

A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.”

Baby’s genes change by what Mom eats

Genes can be changed by environment influences, and fascinating research just published in The Journal of the Federation of American Societies for Experimental Biology shows how what mothers eat can alter the genes of their offspring. The authors state:

“Previous studies indicated that the intake of α-linolenic acid (ALA) can alter the concentration of both ω-6 and ω-3 fatty acids in both mother and offspring, with consequences on postnatal brain development. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in the Fads2 DNA methylation in both maternal and offspring livers, at the end of lactation period.”

Epigenetic changes in DNA methylation of genes refers to an alteration in how the genes express that has been caused by an external stimulus, in this case maternal consumption of alpha-linoleic acid.  In other words, their study investigated how maternal consumption of alpha-linoleic acid changed the genes in the babies’ livers.

“Both Fads2 promoter and intron 1 DNA methylation were increased in the groups receiving postnatal flaxseed oil containing 50% ALA (mothers or pups), while bivariate analysis indicated a significant association of the Fads2 epigenetic status in the liver between each mother and its offspring. In addition, Fads2 expression was negatively correlated with promoter methylation at the individual level in maternal livers. This study also indicated that the interplay between ALA availability during gestation and lactation can differentially alter the expression of desaturases and elongases involved in ω-6 and ω-3 metabolic pathways.”

Desaturases and elongases are enzymes involved in the modification of essential fatty acids to either pro-inflammatory or anti-inflammatory forms. Changes in the genes that code for them is significant for the genetic expression of tendencies for inflammation. The vast panoply of inflammation related disorders could be influenced by this, which include cardiovascular disease, cancers, diabetes, obesity and autoimmune conditions. The editor-in-chief of the this journal, Gerald Weissmann, MD, noted wryly:

“New York City may be laughed at by some for banning large, sugary sodas and for encouraging a healthy diet. As we begin to understand the effects of diet on epigenetics, New York may go from being considered a funny ‘nanny-state’ to becoming appreciated as a public health visionary.”

What we eat modifies our genetic expression…

A low carbohydrate diet can increase cardiovascular disease

Research just published in BMJ (the British Journal of Medicine) presents substantial evidence that a low carbohydrate high protein diet can increase the risk of cardiovascular disease. The authors’ intent was to…

“…study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health.”

They followed a cohort of 43,396 Swedish women, ages of 30-49 years at the beginning of the study, for an average of 15.7 years, then correlated data on incident cardiovascular diseases with decreasing carbohydrate intake, increasing protein intake, and a combination of these to give a low carbohydrate-high protein score. This was adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables. The results show that there are better ways to reap the cardiovascular benefits of a low glycemic diet than a low carbohydrate high protein regimen:

A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate-high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall. No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease, ischaemic stroke, haemorrhagic stroke , subarachnoid haemorrhage, and peripheral arterial disease.”

Key clinical point: there is abundant evidence that regulating blood glucose and insulin with a wholesome low glycemic diet (such as with the ‘modified Mediterranean’ or ‘paleo-Mediterranean’ diets) confers important benefits. Sacrificing healthy low glycemic carbohydrates replete with anti-inflammatory flavonoids for an across-the-board low carbohydrate regimen with increased protein can, as we see here, promote rather than diminish chronic inflammation. The authors conclude:

Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease.”