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.

Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Immunotherapy can take 3 years to desensitize to allergens

Sublingual immunotherapyImmunotherapy can induce tolerance for allergens, but what is a realistic time frame? A study recently published in JAMA demonstrates that 3 years of sublingual desensitizing treatment is effective, but 2 years is no different than placebo. This research helps practitioners working in the larger context of immune plasticity, and patients, to consider pragmatic parameters for case management. The authors note:

“Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.”

But since reducing the inconvenience and expense of treatment is always desirable, the they set out to…

“…assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.”

3 years of immunotherapy effective, 2 years comparable to placebo

In a randomized double-blind, placebo-controlled, 3–parallel-group study of adult patients with moderate to allergic rhinitis that was severe enough to interfere with normal daily activities and sleep), thirty-six subjects received 2 years of sublingual immunotherapy (SLIT; daily tablets containing 15 µg of a major allergen and monthly placebo injections), another 36 received subcutaneous immunotherapy (SCIT; monthly injections containing 20 µg of the allergen and daily placebo tablets); and 34 received double placebo. The nasal allergen challenge was performed before and at 1 and 2 years during treatment; and at 3 years, which was1 year after treatment concluded. Their data make clear that, while the effectiveness of 3 years of treatment is well established, 2 years of treatment did essentially nothing.

“Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score [total nasal symptom score] for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).”

In other words, there were no significant differences between the placebo group and the treatment groups, or between the two treatment groups, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.

Medscape Family Medicine quotes an editorial by Linda S. Cox, MD:

“…the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time,” because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification. However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include “the duration of treatment required for optimal long-term efficacy.” The time commitment requirement may be an important factor in patients’ decisions to initiate therapy.” Therefore, it is important to clarify the optimum duration of treatment. The findings of this study suggest that “2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy.”

Clinical note

This study leaves open the question as to whether adjunctive forms of immunomodulation can accelerate sustained benefit or improve outcomes in other ways, but it does offer one reference by which clinicians and patients can appreciate the dynamic and time frame of therapies addressing immune and neuroplasticity.

The authors conclude:

“Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.”

Thyroid disorders in children and adolescents: clinical review

JAMA Pediatrics: Thyroid disordersThyroid disorders are widespread and can occur at any age. An excellent clinical review just published in JAMA Pediatrics offers a comprehensive and detailed yet succinct review of the various types that occur in children and adolescents. The authors state:

“Normal thyroid gland function is critical for early neurocognitive development, as well as for growth and development throughout childhood and adolescence. Thyroid disorders are common, and attention to physical examination findings, combined with selected laboratory and radiologic tools, aids in the early diagnosis and treatment.”

They provide a “provide a practical review of the presentation, evaluation, and treatment of thyroid disorders commonly encountered in a primary care practice” based on 479 articles relevant to…

“…the incidence, pathophysiology, laboratory evaluation, radiological assessment, and treatment of hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer in children and adolescents. Eighty-three publications were selected for inclusion in this article based on their relevance to these topics.”

They cover these topics:

  • Congenital hypothyroidism
  • Acquired hypothyroidism
  • Hyperthyroidism
  • Thyroid nodules

Autoimmune thyroiditis is by far the most common

Pediatric thyroid examReaders here surely know that autoimmunity prevails as the leading cause of hypothyroidism in developed countries. As part of the ‘epidemic’ of loss of immune tolerance it can occur amidst a constellation of other autoimmune phenomena, some noted here:

Autoimmune hypothyroidism (Hashimoto thyroiditis) is the most common cause of acquired hypothyroidism in children, adolescents, and adults. The prevalence of autoimmune hypothyroidism in childhood is an estimated 1% to 2% with a 4:1 female predominance. Approximately 50% of cases have a family history of autoimmune thyroid disease… An additional autoimmune disorder in the same patient is also associated with an increased risk, most commonly diabetes, alopecia, vitiligo, and celiac disease.”

Interestingly, hypothyroidism is not typically associated with weight gain in this population:

“The most common symptoms of hypothyroidism are fatigue, cold intolerance, constipation, and menstrual irregularities. Children may present with pubertal delay or, in cases of severe longstanding hypothyroidism, precocious puberty. A goiter is the most common physical examination finding. Other examination findings include bradycardia, delayed reflexes, and myxedema of the face and extremities. Hypothyroidism causes poor linear growth and/or growth failure and, if undiagnosed, may compromise adult height. However, contrary to common belief, hypothyroidism is rarely the etiology of weight gain. In fact, excess weight gain is associated with mild elevations in thyrotropin (between 5 and 10 mIU/L), with normalization of the thyrotropin level after achieving weight loss.”

Thyroid examination and diagnosis

I recommend that practitioners desiring a review of thyroid examination and diagnosis in the pediatric patient peruse the entire paper for details on the examination and diagnosis of each condition.

Pediatric endocrinologist Andrew J. Bauer, MD, on of the authors, demonstrates an exam on a healthy child and others illustrating the main diagnoses in this helpful video…

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.”

Autoimmune diabetes (type 1): half develops after age 30

EASD abstract on autoimmune diabetesAutoimmune diabetes (type 1), earlier thought to occur almost exclusively in the pediatric population, is dramatically increasing among adults. Data recently presented at the 2016 Annual Meeting of the European Association for the Study of Diabetes (EASD) and reported in Medscape confirms that it now occurs as frequently in adults over 30 as it does in children.

Onset of type 1 diabetes is just as likely to occur in people older than 30 years of age as in those younger, new research shows.”

This is a manifestation of the giant increase in autoimmune and autoinflammatory conditions present but too often overlooked in clinical practice.

Autoimmune diabetes lurks in the general population

MedscapePractitioners active in case management of autoimmune conditions are already aware of this, but to many it may come as a surprise.

“Obtained using genetic data from the UK Biobank, the startling results refute the long-held belief that type 1 diabetes is primarily a “juvenile” condition…Clinically, the findings are particularly relevant for primary care, where people who develop autoimmune-mediated diabetes in adulthood are often misdiagnosed as having type 2 and prescribed metformin instead of insulin.”

Dr Nicholas JM Thomas, of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, United Kingdom, who presented the data, is quoted in Medscape:

“I think it’s an eye-opener and obviously has implications for how we diagnose and manage people and also the education people receive. We very much focus on childhood and adolescence and perhaps people diagnosed later don’t get the same education.”

Autoimmune diabetes can be mixed with type 2 (metabolic)

2016-10-23_17-29-31Experienced clinicians will recognize that HgbA1c going up in a lean adult almost always implies an autoimmune component. Harder to recognize is a person for whom both are occurring: there is insulin resistance with compensatory elevated insulin forcing the storage of calories as fat resulting in overweight or obesity but combined with further carbohydrate intolerance due to an autoinflammatory attack on beta cells, insulin, the GAD enzyme, or other factors that further damage blood glucose regulation. It can develop rapidly or slowly as LADA (latent autoimmune diabetes of adults).  I am seeing this in practice and I’m sure others paying attention are too.

Medscape further quotes Dr. Thomas:

“He advised that clinicians should at least be aware that adults can develop autoimmune diabetes, as either classic type 1 or the slower-onset phenomenon known as “latent autoimmune diabetes of adulthood (LADA).”

“It’s knowing this does happen, and therefore just keeping an open mind when you spot someone who’s not behaving like type 1 or not responding as you would anticipate when you go through the usual treatment guidelines for type 2,” he said, citing the example of British Prime Minister Theresa May, who was diagnosed with type 1 diabetes at age 56 and who “progressed very rapidly.”

He reiterated that type 1 diabetes is evenly distributed within the first 6 decades of life, but after age 30, the increase in type 2 diabetes makes the type 1 cases harder to recognize and treat correctly.

Diagnosis

Antibody measurements, particularly to the islet cells, insulin and glutamic acid decarboxylase 65 are a mainstay even though subject to the vulnerabilities of antibody expression. And there is a new approach:

“Dr Thomas and colleagues used a “robust, novel, genetic approach” using a risk score comprising 30 single nucleotide polymorphisms associated with type 1 diabetes (T1D-GRS).”

Firstly the clinician should be alert to impaired blood glucose control in adult patients who are not overweight or for whom the correct diet (LCHF) and targeted therapies are not yielding the result they should. This is a tipoff that the case has to be managed as autoimmune diabetes or LADA with the underlying causes for loss of immune tolerance investigated and targeted for therapy.

The session comoderator Catharine Owen, MD, associate professor of diabetes at the Oxford Center for Diabetes, Endocrinology, and Metabolism, United Kingdom, is also quoted in Medscape:

“I think it’s absolutely crucial for people to be aware that type 1 diabetes can present at any age. Physicians shouldn’t be complacent when people aren’t responding to oral agents, or they’re not bringing A1c down to target when they should.”

Leaky gut: inflammation, chronic fatigue and depression

Neuroendocrinology Letters--leaky gut and chronic fatigueLeaky gut‘ is abnormal intestinal permeability that occurs when the epithelial tissues that comprise the gut barrier have been damaged. When intact the gut barrier prohibits antigenic contents of the intestines from access to the gut-associated lymphoid tissue (GALT) right on the other side of the intestinal wall. Gut barrier integrity (absence of leaky gut) is crucial to prevent loss of immune tolerance (autoimmunity) since the GALT comprises 60-80% of all immune tissue in the body.

Normalization of leaky gut improves chronic fatigue

LPS (lipopolysaccharide from bacterial cell walls) is so highly antigenic that it’s used as an adjuvant in vaccines. Translocation of LPS across a damaged gut barrier elicits systemic inflammation, accompanied by oxidative and nitrosative stress. A study published in Neuroendocrinology Letters demonstrates how normalization of the antibody responses to LPS not only ameliorates but can predict the clinical outcome in chronic fatigue syndrome (CFS). The authors state:

“There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).”

They investigated this by measuring serum concentrations of IgA and IgM to LPS of several gram-negative enterobacteria CFS patients, both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, while consuming a leaky gut diet during 10-14 months. They also measured corresponding result with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and after 10-14 months on the NAIOSs.

Good clinical response to lowered IgA and IgM

The improvement in CFS scores that they documented was very gratifying:

Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).”

The authors’ comments on their data can hardly be overemphasized for clinicians participating in case management of chronic fatigue and fibromyalgia:

“The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.”

High IgA response to normal gut bacteria fires up inflammation in CFS

Journal of Affective DisordersAn interesting study published in the Journal of Affective Disorders documents how LPS from commensal gut bacteria that translocates into the GALT provokes inflammation that drives CFS. The authors note:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.”

These authors investigated the IgA/IgM responses to the LPS of 6 different enterobacteria by measuring serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). When they correlated with biomarkers for inflammation, CMI and the symptoms of ME/CFS the results were noteworthy:

“Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.”

This is extremely important in clinical practice due to the great functional significance of both systemic inflammation and autonomic nervous system regulation. The authors conclude:

“The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”

Autoimmune attack on serotonin production

Another fascinating paper also published in the Journal of Affective Disorders reveals that bacterial translocation through the gut barrier into immune lymphoid tissue can provoke antibodies that attack 5-HT, the precursor of serotonin, contributing to chronic fatigue and depression. The authors state:

“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.”

The examined 117 patients with ME/CFS for autoimmune activity against 5-HT, measuring plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria. This was correlated with the fibromyalgia and chronic fatigue syndrome rating scale. Their data show a strong association:

“The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.”

This is very significant for clinicians involved in case management of fatigue, depression, chronic pain and autonomic dysregulation. The authors sum it up:

“The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions…These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.”

Leaky gut, LPS and depression

Yet another study in the same journal investigated increased IgA and IgM antibodies aimed at gut commensal bacteria specifically in depression. The authors measured antibodies directed against Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in depressed patients and normal controls, and found a very significant correlation to symptoms of depression and fatigue:

“The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms.”

Clinical note

The treatment of chronic fatigue and depression demands a holistic, multidisciplinary approach. A core feature with a number of potential contributing causes that can vary in each case is up-regulation of immune pathways driving inflammation in the brain and against elements in neurotransmitter production. The authors highlight these considerations in their discussion:

“The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression…The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways.”

Compounds that modulate neuroinflammation induced by LPS

Neurochemistry InternationalA wide range of therapeutic resources are available to the functional practitioner to employ, depending on the individual case, that can ameliorate autoimmune inflammation triggered by reactions to the LPS of bacteria translocated through a leaky gut. By way of one example among many, a paper published in Neurochemistry International shows that anthocyanins (polyphenolic compounds imparting a blue color, found in vegetation such as blueberries) can ameliorate inflammation triggered by reactions to LPS.

“Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.”

This benign intervention produced a gratifying result:

“The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF-kB…Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex.”

Of particular note to the clinician:

“Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders.”

Thyroid autoimmunity and iron deficiency in pregnancy

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

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

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

Thyroid autoimmunity and iron deficiency are common

Their data also demonstrated a significant coupling between the two:

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

MedscapeMedscape Medical News comments on these findings:

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

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

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

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

The authors conclude:

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

Allergy skin prick reactions change with lancet weight

PLOS ONE IgE allergy SPT and lancet weightAllergy reactions of the acute (immediate) hypersensitivity type mediated by IgE immunoglobulins are commonly tested by skin prick testing (SPT) with suspect antigens. Research just published in PLOS One reveals that differences in lancet weight add to the factors that can cause diagnostic inaccuracy. The authors state:

“Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization…Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort.”

SPT lancet setupThey conducted SPT for allergy on subjects by applying solutions of histamine (1 mg/mL and 10 mg/mL) and one control solution (saline) with lancets of four different weights (25 g, 85 g, 135 g and 265 g) and observed wheal size, neurogenic inflammation, bleeding, and pain response.

Apparent allergy reactions with greater lancet weight

They found that differences in lancet weight can be a significantly misleading factor in the diagnosis of IgE allergy.

“The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm.”

Wheal diameters

Clinicians should bear this in mind when analyzing SPT results, especially when they are confounding or otherwise in question. The authors conclude:

“The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure.”

GERD pathology caused by immune reaction, not acid

JAMA study shows GERD pathology cause by inflammatory reaction.GERD (gastroesophageal reflux disease) may be caused by a dysregulated inflammatory reaction to the stimulus of gastric hydrochloric acid in the lower esophagus, not ‘burning’ by the acid itself, according to preliminary research just published in JAMA (Journal of the American Medical Association). The authors note:

“The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid.”

They examined patients whose reflux esophagitis was in remission while on acid-blocking medications (proton pump inhibitors (PPIs) with biopsies from noneroded areas of the distal esophagus along with surface changes after medication was stopped.

GERD pathogenesis inflammatory cytokine-mediated from within

The authors were investigating for the first time in human subjects for all the mechanisms of inflammatory damage.

“Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity).”

The fascinating and clinically important implication of their data is that inflammatory damage in GERD happens primarily from the inside out:

“At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week and 2 weeks); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased, mucosal impedance decreased, and all patients had evidence of esophagitis.”

The key point here is that the pathological changes noted above occurred without without the loss of cells on the surface. Like so many other conditions, from osteoarthritis to acne, which were formerly thought to be due primarily to trauma (mechanical or chemical) or infection, esophageal damage in GERD appears due to the character of the inflammatory response to a stimulus (in this case some gastric acid).

Medscape Medical News quotes the authors:

“”[E]sophageal basal cell and papillary hyperplasia developed in areas without surface erosions. If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

Medscape also quotes the author of a linked editorial:

“Peter Kahrilas, MD, from Northwestern Feinberg School of Medicine, Chicago, Illinois, notes that the “provocative findings from this investigation are in the details”: the earliest pathology occurred deep in the epithelium, not at the mucosal surface, and repair mechanisms started before the death of surface cells previously thought to provoke these changes…[A]lthough the inciting pathophysiology is unquestionably the reflux of gastric and duodenal secretions into the esophagus, this evidence suggests that the effect of that reflux is the initiation of cytokine-triggered inflammation rather than the long held belief of a direct chemical effect of acid, pepsin, and bile on the esophageal epithelium,” he wrote.”

The authors conclude:

“In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte–predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury.”

Clinical Note

GERD, even gastroduodenal ulcer, often occurs in an environment with deficient gastric acid. While medically blocking acid production or neutralizing it with an alkalizing agent (Maalox®, etc.) typically halts symptoms, doing so disables digestion of proteins and the first line of defense against GI pathogens while impairing assimilation of magnesium and vitamin B12—hence the association with PPI medications and increased cardiovascular risk. Incomplete protein digestion byproducts can also promote sensitization of the immune system to those foods and contribute to autoimmune disorders. Better for clinicians to endeavor to normalize cardio-esophageal sphincter function by ensuring well-regulated vagal stimulation of the gut while supporting digestion and removal of irritants as necessary.