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.”

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

Alzheimer’s disease and blood-brain barrier leakage

RadiologyAlzheimer’s disease is not a unitary condition but variable in causation at the individual level like all complex chronic disorders. Neuroinflammation, metabolic damage, vascular compromise, accumulation of noxious debris (amyloid β and tau), impairments in brain CSF and lymphatic drainage and other causes can all variously contribute to Alzheimer’s and other dementias. Now original research recently published in the journal Radiology demonstrates that leakiness of the blood-brain barrier (BBB) can permit an environment hostile to neuronal health that contributes to cognitive decline, Alzheimer’s and other dementias. The authors state:

“Evidence is increasing that impairment of the cerebral microvasculature is a contributing factor in the pathophysiology of Alzheimer disease (AD). However, the exact pathway remains unclear. Results of histologic evaluation and albumin sampling studies show that an increased permeability of the blood-brain barrier (BBB) is likely a key mechanism.”

An intact blood-brain barrier is essential for brain health

The BBB is a collection of cells and other structures in the cerebrovascular wall that when healthy permits only privileged access into the brain from the extra-cerebral blood compartment.

“It regulates the delivery of important nutrients to the brain through active and passive transport mechanisms and prevents neurotoxins from entering the brain. It also has a clearance function, meaning that it removes surplus substances from the brain. A well-functioning BBB is essential to keeping the brain tissue in a healthy condition. Results of previous studies suggest that deterioration of the BBB can cause an ill-conditioned environment for neuronal cells and other pathologic changes such as small-vessel abnormality, protein deposits, inflammation, and neuronal cell death. These changes eventually may lead to cognitive decline and dementia.”

Early Alzheimer’s shows abnormal BBB permeability

Blood-brain barrier degradation has earlier been demonstrated in advanced Alzheimer’s disease. Here the authors examined whether or not BBB leakage contributes to the early stages of disease.

“To investigate whether BBB leakage contributes to the early pathophysiology of AD, we hypothesized that patients with early forms of AD already show increased BBB permeability in comparison with age-matched control subjects. For this pilot study, we used a dedicated dynamic contrast-enhanced MR imaging acquisition protocol with dual-time resolution that separates the filling of the blood vessels from the leakage. We also investigated differences in local blood plasma volume fraction, and the relationship between BBB permeability and global cognition.”

The analyzed data for patients diagnosed with mild cognitive impairment (MCI) due to AD or patients or patients with early AD (a continuum of cognitive decline who had been referred by general practitioners because of memory concerns, in comparison with healthy controls. Individuals with dementia of vascular origin were excluded, as were those with major cardiovascular and neuropsychiatric disorders, Parkinson’s, MS, trauma, major structural abnormalities of the brain, and alcohol or drug abuse. They indeed demonstrated a marked distinction between their study subjects and controls:

“The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total GM (grey matter) and cortex but not in the WM, normal-appearing WM, deep GM, or WM hyperintensities…When adjustments were made for all covariates, the patients exhibited a significantly higher leakage volume in the WM and GM and also in the normal-appearing WM, deep GM, cortex, but not in WM hyperintensities…The median blood plasma volume was significantly lower in the patients than in the control subjects in all tissue classes.”

BBB leakage rate shown in early Alzheimer's

BBB leakage rate shown on the right, with some periventricular hot spots

BBB leakage in early Alzheimer’s is widespread

The leakage is not due to vascular abnormalities, and leakage volume was even more striking than rate:

The results of this study showed increased BBB leakage in patients with early AD. The leakage was globally distributed throughout the cerebrum and was associated with declined global cognitive performance. By using dynamic contrast-enhanced MR imaging with dual-time resolution, we found an increased BBB leakage rate in the GM of patients with early AD. By also showing very subtle BBB impairment in the WM, leakage volume proved to be even more sensitive to the differences in BBB leakage than was the leakage rate. Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class such as WM hyperintensities, normal-appearing WM, or cortex. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.”

Breakdown in tight junctions like the intestinal barrier

The intestinal barrier, critical for healthy immune system regulation, loses integrity with a breakdown of the tight cellular junctions. So too with the blood-brain barrier.

“The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis.”

Toxic accumulations in the brain and cognitive impairment

The authors have demonstrated that BBB leakage tracks cognitive impairment in early Alzheimer’s:

“We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.”

BBB and amyloid β

Clearance of amyloid β is also impaired:

“…amyloid β is actively transported across the BBB, whereas gadolinium leaks passively through the tight junctions. Previous work with positron emission tomographic data has shown that clearance of amyloid β is also impaired in patients with AD. An impaired clearance of amyloid β would mean that the BBB is impaired in different ways, contributing to the pathologic cascade leading to AD.”

Most importantly…

“Therefore, BBB leakage may help to provide a biomarker for early diagnosis, or at least a marker indicating vulnerability for the development of dementia. Successful prediction of dementia eventually might lead to optimized treatment, delay, or even prevention of the disease.”

Clinical note

Early diagnosis is key here, and for those of us without dynamic gadolinium contrast-enhanced MR imaging at hand I highly recommend the Blood Brain Barrier Permeability™ screen from Cyrex Labs (Array 20) which offers the clinician the ability to detect early changes in BBB permeability. Clinicians experienced in rehabilitation of the gut barrier will be familiar with resources to evaluate and remediate inflammation and other insults to the blood-brain barrier.

The authors conclude:

“…in this pilot study, MR imaging was used to show global, diffusely distributed BBB leakage in patients with early AD, which suggests that a compromised BBB is part of the early pathology of AD and might be part of a cascade of pathologic events that eventually lead to cognitive decline.”

  • “Patients with early Alzheimer disease have significantly more tissue characterized by blood-brain barrier leakage than do healthy control subjects, both in the normal-appearing white matter and in the gray matter.
  • Blood-brain barrier leakage in the gray matter correlates with lower scores on the Mini-Mental State Examination.”

DHEA predicts coronary heart disease risk

Journal of the American College of CardiologyDHEA (dehydroepiandosterone) an adrenal steroid hormone also produced in the brain, is associated with many inflammatory and other disorders. A study recently published in the Journal of the American College of Cardiology shows that low DHEA can predict coronary heart disease in older men. This is especially important because there is still a high incidence of sudden cardiac death in individuals who do not have the traditional risk factors. The authors state:

“The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory.”

To test predictive value for major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events, they measured  baseline levels in a large cohort of men aged 69-81 and correlated this with a 5-year follow-up for complete cardiovascular clinical outcomes.

DHEA predicts coronary heart disease but not stroke

The predictive accuracy persisted even when traditional cardiovascular risk factors were adjusted for :

“During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality.”

Changing the assessment of cardiovascular risk

The authors of an editorial in the same issue of JACC assert:

Everything we once thought we knew about the therapeutic use of estrogen for the prevention of cardiovascular disease (CVD) in women is wrong. Everything we once knew about the role of sex in CVD is still right; men are affected a decade earlier than women. We are still enamored with the idea that sex steroids, particularly androgens, have, if not a causal role in CVD development, at least an association. We simply cannot get the notion out of our heads that androgens (or relative lack of estrogen) drive endothelial dysfunction and atherogenesis, and potentially, even plaque fracture. In this light, new studies that assess the risk associated with low levels of a particularly abundant sex steroid (dehydroepiandrosterone [DHEA] and its sulfated congener [DHEA-S], which can serve as the precursor substrate for either testosterone or estradiol) are of particular interest.”

They note an important difference between the two forms:

“Furthermore, this study measured both DHEA and DHEA-S, and showed a more pronounced negative relationship between mortality and DHEA than that with DHEA-S. This suggests that DHEA could be a more important predictor of outcomes, despite low plasma DHEA concentrations relative to DHEA-S. This has significant implications, because most previous negative studies examined only DHEA-S levels.”

A new arrow in the quiver

Cardiovascular disease is complex and multi-causal…

“Despite advances in primary and secondary prevention of CHD events, there is still a high incidence of death due to CHD, including sudden cardiac death in individuals who do not have traditional coronary disease risk factors…An ideal solution might be the use of weighted patterns of biomarkers, which would take into consideration typical biochemical interactions and provide a personalized biochemical fingerprint to more exactly define an individual’s risk of future events. DHEA may represent a new arrow in the quiver of biomarkers…The findings reported here should, at the least, spur further interest in understanding DHEA as a biomarker of CVD risk.”

Clinical Note

It is, of course, never desirable to recommend or take any hormone, OTC or not, without measuring free-fraction hormone levels comprehensively at baseline and after appropriate intervals. Clinicians, however, can add DHEA levels to CHD risk assessment in older men.

The authors conclude:

Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

Increasing calcium intake does not prevent fractures

BMJCalcium is still, contrary to the best available evidence, often recommended to reduce fracture risk. Research just published in BMJ (British Medical Journal) adds more evidence that increasing calcium intake by diet or supplementation does not prevent fractures. The authors conducted a systematic review of randomized controlled trials and observational studies…

“To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.”

Besides evaluating recommendations to increase dietary calcium intake to prevent fractures, they compared the anti-fracture effect of increasing calcium through dietary sources with the efficacy of calcium supplements by compiling data from randomized controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome in subjects over 50.

No significant fracture reduction from dietary or supplemental calcium

When the data were thoroughly examined the evidence for efficacy of calcium intake vanished.

“There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. “

As for supplements…

“In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.”

Osteoporosis is not a calcium deficiency disorder

Clinicians involved in case management of osteoporosis and osteopenia know (or should know) that these disorders are due to failure to maintain the protein matrix of the bone, the component that provides resilient strength and to which the minerals attach, not a deficiency of the minerals themselves, including calcium. (Calcium deficiency, or osteomalacia, is also known as ‘rickets.’) The authors comment further on their findings regarding diet:

“The recommended dietary calcium intake for older adults is 1200 mg/day.Most studies, however, did not report Creduced risk of fracture in individuals with this level of calcium intake compared with lower intakes. Thus, observational research does not support a hypothesis of dietary “calcium deficiency” in which there are reductions in fracture risk from increasing dietary calcium intake across the range of intakes (<300->1200 mg/day) in studies in this review.”

And…

“There was no effect of calcium supplements on any fracture outcome in the largest trials at lowest risk of bias. …These results suggest that widespread untargeted use of calcium supplements in older individuals is unlikely to result in meaningful reductions in incidence of fracture.”

As the authors note:

“…it should not be assumed that short term changes in bone density will be sustained or translate into fracture prevention.”

Calcium and cardiovascular risk

Calcium supplementation has been associated with increased cardiovascular risk (see Calcium supplements increase risk of heart attack), probably by opposing the anti-inflammatory effects of magnesium. The authors comment on this and other risks:

“In our randomised controlled trial and subsequent meta-analyses, the cardiovascular risks of calcium were similar to or exceeded the benefits of calcium on fracture prevention. In addition, 10-20% of people experience gastrointestinal side effects such as constipation, which cause a considerable number to stop taking the supplements. Thus, because of the small benefits of use and unfavourable risk:benefit profile, calcium supplements should not be recommended for fracture prevention either at an individual or population level.”

Regarding the one study with elderly frail women…

“…it is possible that many participants had unrecognised osteomalacia, the treatment of which might have led to the benefits observed…Our analyses highlight that the results from this study of a frail population with marked vitamin D deficiency are so different to those from other large randomised controlled trials and so influential in any pooled analysis that they should probably not be combined in pooled analyses with studies that enrolled different patient groups. Furthermore, recommendation of use of calcium and vitamin D supplements generally for older adults to prevent fracture based on results heavily influenced by this study of frail women in residential care is inappropriate.”

Do not recommend calcium to patients for osteoporosis fracture risk

Medscape Medical News reports in regard to this research:

This is not the first recent review to find a lack of evidence for calcium supplements. The US Preventive Services Task Force reached similar conclusions in 2013.”The question is not so much why the guidelines were formed, but why is it, since there have been all these trials accumulated since 2000, they haven’t changed,” Dr Bolland [lead author] said.”

The authors conclude:

“On the basis of the trial data summarised here, we do not think further randomised controlled trials of calcium supplements with or without vitamin D with fracture as the endpoint in the general population are needed…our analyses indicate that dietary calcium intake is not associated with risk of fracture, and there is no evidence currently that increasing dietary calcium intake prevents fractures….There was no risk reduction in fracture at any site in pooled analyses of the randomised controlled trials of calcium supplements at lowest risk of bias, and there was evidence of publication bias in small-moderate sized trials. Collectively, these results suggest that clinicians, advocacy organisations, and health policymakers should not recommend increasing calcium intake for fracture prevention, either with calcium supplements or through dietary sources.”

No significant improvement through bone mineral density either

Additional research in the same issue of BMJ examined data for the effects of calcium intake on BMD (bone mineral density) and found no meaningful benefit.

“Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥1000 versus <1000 mg/day and ≤500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥800 mg/day.”

Based on this the authors of the BMD study conclude:

“In summary, increasing calcium intake from dietary sources increases BMD by a similar amount to increases in BMD from calcium supplements. In each case, the increases are small (1-2%) and non-progressive, with little further effect on BMD after a year. Subgroup analyses do not suggest greater benefits of increasing calcium intake on BMD in any subpopulation based on clinically relevant baseline characteristics. The small effects on BMD are unlikely to translate into clinically meaningful reductions in fractures. Therefore, for most individuals concerned about their bone density, increasing calcium intake is unlikely to be beneficial.”

Perverse influence of industry

In an accompanying editorial, the author comments on the use of guidelines that are contrary to the scientific evidence:

“By use of guidelines such as those by NOF and the International Osteoporosis Foundation (IOF), marketing now extends to all older people with dietary intakes below the recommended 1200 mg calcium and 800-1000 IU vitamin D daily. By this definition virtually the whole population aged over 50 is at risk.Most will not benefit from increasing their intakes and will be exposed instead to a higher risk of adverse events such as constipation, cardiovascular events, kidney stones, or admission for acute gastrointestinal symptoms.The weight of evidence against such mass medication of older people is now compelling, and it is surely time to reconsider these controversial recommendations…The profitability of the global supplements industry probably plays its part, encouraged by key opinion leaders from the academic and research communities. Manufacturers have deep pockets, and there is a tendency for research efforts to follow the money (with accompanying academic prestige), rather than a path defined only by the needs of patients and the public. The research agenda and recommendations can also be influenced by the conflicts of interest that arise when leading academics have shares or management positions in companies making and marketing supplements.”

NEJM Journal WatchA New England Journal of Medicine Journal Watch interview with lead author Dr. Mark Bolland can be heard here.

Interview on investigation into the flawed U.S. dietary guidelines

From BMJ.com:

Saliva cortisol associated with brain volume, cognitive function

NeurologyCortisol is closely linked to brain health through both its effects on the brain and its circadian regulation by the hippocampus, also the brain center for short-term memory. A study recently published in the journal Neurology shows that measurements of salivary cortisol can be an indicator for cognitive impairment and loss of brain volume.

“We investigated the associations of morning and evening salivary cortisol levels with regional brain volumes and cognitive functioning in community-dwelling older persons without dementia. “

The authors collected data for 4,244 subjects without dementia between 71 and 81 years of age who had a brain MRI  and assessment of cognitive function. To measure cortisol saliva was collected at home 45 minutes after awakening and again at night. These were used to observe the relationship among cortisol levels, brain volumes, and cognitive functioning.

Higher evening cortisol linked with cognitive impairment and loss of brain volume

Clinicians should recall that healthy adrenal regulation by the hippocampus displays a cortisol rhythm characterized by the highest level in the morning with a downward slope ending in the lowest level at night.

Higher evening cortisol was associated with smaller total brain volume (highest vs lowest tertile −16.0 mL; 95% confidence interval −19.7 to −12.2 mL, adjusted for age, sex, education, intracranial volume, smoking, steroid use, white matter lesions, and brain infarcts on MRI). The smaller volumes were observed in all brain regions, but were significantly smaller in gray matter than in white matter regions. Poorer cognitive functioning across all domains was also associated with higher evening cortisol. Higher levels of morning cortisol were associated with slightly greater normal white matter volume and better processing speed and executive functioning, but not with gray matter volume or with memory performance.”

Note also the positive indication of higher morning cortisol in reference to the cortisol circadian rhythm.

Clinical Note

The salivary cortisol circadian rhythm is easily measured in practice and a sensitive indicator for fundamental functions that must be well managed including inflammation,  glucose regulation, stress and brain function.

The authors conclude:

“In older persons, evening and morning cortisol levels may be differentially associated with tissue volume in gray and white matter structures and cognitive function. Understanding these differential associations may aid in developing strategies to reduce the effects of hypothalamic-pituitary-adrenal axis dysfunction on late-life cognitive impairment.”

Stunning discovery links brain and immune system

NatureLong established scientific dogma asserts that there is no direct connection by vessels between the brain and immune system, yet the link between systemic inflammation, brain inflammation and neurodegeneration is vividly evident in clinical practice (see Systemic inflammation drives brain neurodegeneration and numerous related posts). Now investigators report in the prestigious journal Nature the stunning discovery of a central nervous system lymphatic system connecting the brain and immune system in a paper entitled Structural and functional features of central nervous system lymphatic vessels.

“One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.”

Changes the landscape of neuroimmunology

Brain inflammation, a key factor in neuropsychiatric and neurodegenerative disorders, is linked directly to systems-wide immune function.

The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

Neuroinflammation’s mechanism re-defined

Neuroscience NewsAutism and bipolar disorder, Alzheimer’s and MS, and every other neuroinflammatory brain based disorder must be considered in this light. A commentary entitled Researchers Find Missing Link Between the Brain and Immune System in Neuroscience News states:

“That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis.”

Quoting lead author Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG):

“Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels…It changes entirely the way we perceive the neuro-immune interaction…We believe that for every neurological disease that has an immune component to it, these vessels may play a major role.

Metabolic purpose of sleep

ScienceThe discovery of lymphatic vessels providing brain drainage reminds of the remarkable research entitled Sleep Drives Metabolic Clearance from the Adult Brain, published in the competing journal Science, that brilliantly demonstrates the metabolic purpose of sleep. The authors state:

“The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.”

In other words, they demonstrated that brain cells shrink during sleep to increase the interstitial space by a whopping 60%, and further showed that this results in marked increase drainage of toxic metabolites through the ‘glymphatic‘ system. This paper was published before the stunning discovery of the brain’s own lymphatic system.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ), α-synuclein, and tau, are present in the interstitial space surrounding cells of the brain. In peripheral tissue, lymph vessels return excess interstitial proteins to the general circulation for degradation in the liver. Yet despite its high metabolic rate and the fragility of neurons to toxic waste products, the brain lacks a conventional lymphatic system. Instead, cerebrospinal fluid (CSF) recirculates through the brain, interchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. The convective exchange of CSF and ISF is organized around the cerebral vasculature, with CSF influx around arteries, whereas ISF exits along veins. These pathways were named the glymphatic system on the basis of their dependence on astrocytic aquaporin-4 (AQP4) water channels and the adoption of functions homologous to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%, suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity. The interstitial concentration of Aβ is higher in awake than in sleeping rodents and humans, possibly indicating that wakefulness is associated with increased Aβ production. We tested the alternative hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance.”

The convective movement of brain interstitial fluid that they describe is only enhanced by lymphatic vessels that drain the brain. Sleep is the time when the brain ‘takes out the trash’.

Tremendous clinical significance

Cranial therapy that restores the amplitude and symmetry of the rhythmic expansion and contraction the skull associated with the circulation of cerebrospinal spinal fluid (CSF) and lymphatic exchange in the brain can be appreciated in this context along with the immunological implications. Further commenting in Neuroscience News:

“The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.”

Maps of the lymphatic system

Insulin resistance indicated by neutrophil-lymphocyte ratio

BMC Endocrine DisordersInsulin resistance (IR) is central to type 2 diabetes and a contributing cause to cardiovascular and neurodegenerative disorders, chronic kidney disease (CKD), a number of cancers and more. A study recently published in BMC Endocrine Disorders the ratio between neutrophils and lymphocytes (neutrophil-lymphocyte ratio, NLR) is a valuable and inexpensive predictive marker for insulin resistance. The authors note:

“Insulin resistance (IR) is a reduction in reaction or sensitivity to insulin and is considered to be the common cause of impaired glucose tolerance, diabetes, obesity, dyslipidemia, and hypertensive diseases….several studies have confirmed the relationship between systemic inflammation and insulin resistance, in which an altered immune system plays a decisive role in the pathogenesis of DM. The immune response to various physiological challenges is characterized by increased neutrophil and decreased lymphocyte counts, and NLR is often recognized as an inflammatory marker to assess the severity of the disease.”

Furthermore…

“Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR.”

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

So they investigated the neutrophil-lymphocyte ratio in 413 patients with T2DM, 310 of whom had a HOMA-IR value (fasting plasma glucose (mmol/L) multiplied by fasting serum insulin (mIU/L) divided by 22.5) of > 2.0, indicating insulin resistance. They were compared to a control group of 130 healthy subjects and found a strong association:

“The NLR values of the diabetic patients were significantly higher than those of the healthy control, and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0. Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR. Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95%) for every one unit increase in NLR.”

 Diabetes, cancer and cardiovascular diseases

In relation to their confirmation of NLR as a predictor for insulin resistance the authors observe…

“Many epidemiological studies have determined that DM is associated with chronic inflammation, which may contribute to the acceleration of diabetic microangiopathy and the development of macroangiopathy; IR is a characterized of T2DM, whereas the exact molecular action leading to IR is not yet understood, several studies have associated IR with inflammation, experimental studies have demonstrated a link between chronic inflammation and insulin resistance through mechanisms involving obesity and atherosclerosis. NLR has been recently defined as a novel potential inflammation marker in cancer and cardiovascular diseases. NLR can easily be calculated using the neutrophil-lymphocyte ratio in peripheral blood count. Calculating NLR is simpler and cheaper than measuring other inflammatory cytokines, such as IL-6, IL-1β, and TNF-α.”

Diabetes and chronic inflammation

These findings highlight the relationship between chronic inflammation, insulin resistance and type 2 diabetes.

“he pathological activation of innate immunity leads to inflammation of the islet cells, resulting in a decrease in pancreatic beta-cell mass and impaired insulin secretion. Patients with T2DM are in a state of low-degree chronic inflammation that induces hypersecretion of inflammatory factors, such as CRP, IL-6, TNF-α, and MCP-1, which results in a constantly elevated neutrophilic granulocyte count. One mechanism by which increased levels of neutrophils could mediate IR may be through augmented inflammation. The increase in NLR appears to underlie the elevated levels of pro-inflammation, as evident from the persistent neutrophil activation and enhanced release of neutrophil proteases with T2DM.”

 NLR tracks HgbA1c and triglycerides

Glycation of hemoglobin (HgbA1c) and triglycerides (TG) both go up as insulin resistance progresses along with the neutrophil-lymphocyte ratio.

“A logistic regression analysis of the following risk factors was conducted: NLR, TG and HbA1c. In our study, in conjunction with the rising of the level of HbAlc, the degree of IR increased significantly. HbA1c showed an association with early-phase insulin secretion assessed by insulinogenic index. Heianza et al. reported that elevated HbA1c levels of above 41 mmol/mol (>5.9%) were associated with a substantial reduction in insulin secretion and insulin sensitivity as well as an association with β-cell dysfunction in Japanese individuals without a history of treatment of diabetes. Increased accumulation of TG has been observed in human muscle tissue of obese and type 2 diabetic subjects, and associated with IR, which is in agreement with the present study. IR reduces the inhibition effect of lipolysis in adipose tissue, resulting in the increase of the free fatty acid (FFA) level in plasma.”

NLR is a superior biomarker

Although susceptible to modification by dehydration, elevated PSA or catecholamine release induced by exercise, the NLR is more sensitive than the neutrophil count alone or CRP levels.

“NLR represents a combination of two markers where neutrophils represent the active nonspecific inflammatory mediator initiating the first line of defense, whereas lymphocytes represent the regulatory or protective component of inflammation. NLR is superior to other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leukocyte counts) because of its better stability compared with the other parameters that can be altered by various physiological, pathological, and physical factors. Thus, as a simple clinical indicator of IR, NLR is more sensitive compared with the neutrophilic granulocyte count and CRP levels, which are widely used as markers of IR.”

Clinical bottom line

Practitioners should not fail to make use of this significant, inexpensive biomarker that is under our noses every day. The authors sum it up:

“…in the present study, NLR serves an important function in predicting the risk of IR. IR in diabetic patients is related to chronic inflammation, and NLR may be helpful in assessing the prognoses of these patients…We recommend that the NLR values of diabetic patients be calculated as NLR is a cheap, predictive, and prognostic marker for IR. High NLR values were independently related to IR.”