TSH elevation associated with pregnancy problems

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

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

Thyroid hormone levels before pregnancy

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

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

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

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

Preconception TSH elevation increases risk of adverse pregnancy outcomes

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

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

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

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

Clinicians should also bear in mind:

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

Regarding case management, the authors conclude:

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

See also Subclinical hypothyroidism in pregnancy.

Subclinical hypothyroidism worsens cardiometabolic profile

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

Clarifying the definition of normal thyroid function

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

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

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

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

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

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

Subclinical hypothyroidism increases cardiometabolic risk

Thus the authors set out to…

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

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

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

TSH, total and LDL cholesterol not so useful

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

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

Mechanisms

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

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

Practitioners should be attentive to the authors’ conclusion:

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

Iodine supplementation reminder

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

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

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

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

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

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

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

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

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

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.”

 

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.”

Circadian rhythms of inflammation

Arthritis Research & TherapyCircadian variation of symptoms caused by inflammation is common to conditions including rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, asthma, depression and many more. The adrenal circadian rhythm is an important factor when serum cortisol is inadequate relative to inflammation. An excellent paper published in Arthritis Research & Therapy examines the dynamics and clinical significance of circadian variation in inflammation associated with glucocorticoid regulation, an important consideration for anti-inflammatory treatment.

Brain’s central circadian oscillator connects with immune system

The suprachiasmatic nucleus of the hypothalamus that generates the circadian rhythm connects profusely to other brain centers and to the immune system through the HPA axis.

“The circadian activity of this particular nucleus is transferred to the immune system via the hypothalamic hypothalamic-pituitary-adrenal (HPA) axis, leading to the typical undulation of clinical symptoms in chronic inflammatory diseases with a maximum in the early morning hours. In this review we will describe circadian rhythms in rheumatoid arthritis (RA) and other rheumatic and chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic and chronic inflammatory diseases, the problem of adrenal suppression by glucocorticoid (GC) therapy, and whether or not chronotherapy with prednisone is more effective and aggravates adrenal suppression.”

This pertains to the classic aggravation of stiffness and pain in the morning as well as the oscillation of other symptoms caused by inflammation, including neuropsychiatric disorders.

Nocturnal inflammation, melatonin and cortisol

As melatonin goes up at night cortisol, which ‘keeps a lid on’ inflammation, goes down and inflammatory biomarkers are seen to increase.

“Classical symptoms of RA, such as morning stiffness and swelling, show a clear temporal relationship with nocturnally elevated levels of proinflammatory cytokines, as a consequence of a cascade of increased nocturnal inflammation. Several of these cytokines, such as tumor necrosis factor (TNF) alpha and interleukin (IL)-6, are highly increased in patients with active RA in the early hours of the day, but are found at very low levels after noon.”

This is characteristic of a healthy cortisol rhythm…

“Also, the cortisol rhythm – which is also present in healthy individuals, and therefore is primary, with low levels at night – may explain nocturnal inflammation. Since cortisol is the strongest endogenous anti-inflammatory substance, its downregulation during the evening and night is linked to an increase of inflammation during the early morning, and its upregulation in the early morning is most probably related to inhibition of inflammation during the day. The early morning inflammatory signs, typical for many inflammatory rheumatic conditions, can thus be explained.”

Polymyalgia rheumatica, ankylosing spondylitis and asthma

These conditions too have cyclic undulations that correspond to the circadian rhythm of immune activity, with implications for treatment.

“Furthermore, in polymyalgia rheumatica (PMR), symptoms of pain and stiffness typically are most prominent during the early morning, similar to RA…Of note, in ankylosing spondylitis – another inflammatory arthritic condition – pain and stiffness also seem to be most prominent during the early morning hours. Finally, it is now also evident that symptoms of diseases such as RA, which is T helper 1 dependent, but also asthma, which is T helper 2 dependent, are influenced by diurnal rhythms and natural regulatory T cells. In particular, secretion of IL-2, interferon gamma and IL-10 by naïve CD4+ T cells follows a diurnal rhythm.”

This ties together the nervous, immune and hormonal systems that interact in a rhythmic fashion:

“All of these processes are closely linked to regulatory interactions between the endocrine, nervous and immune systems, with distinct 24-hour daily rhythms (neuroendocrine immunology).”

HPA axis dysfunction in chronic inflammatory disorders

HPA axis function in inflammationNormally the adrenocortical response should track the circadian oscillator or inflammation. The authors describe a fascinating study in which the cortisol response to infusions of the pro-inflammatory cytokine IL-6 were delineated:

“In a fairly heroic study in 18 healthy young men, either saline or low or high doses of recombinant human IL-6 were infused into one femoral artery for 3 hours. Subjects experienced clinical symptoms such as shivering and discomfort during high-dose IL-6 administration, but were asymptomatic during low-dose IL-6 administration. Plasma cortisol concentrations did not change during infusion of saline but markedly increased during both high and low doses of IL-6. While concentrations of plasma cortisol declined after 2 hours of infusion in low doses of IL-6, they remained elevated in high doses of IL-6 at 3 hours of infusion…The increase of cortisol levels in reaction to IL-6 infusion is provoked by activation of the HPA axis. Remarkably, the relation between IL-6 levels and the adrenocorticotropic hormone (ACTH)/cortisol levels is linear. In a study of 15 healthy young men in which recombinant IL-6 was applied subcutaneously, plasma ACTH concentrations and plasma cortisol levels increased dose dependently, and the ratio of hormone to IL-6 serum levels was constant.”

By contrast however, in chronic inflammation levels of cortisol are insufficient to ‘put out the fire.’

In chronic inflammation, cortisol secretion appears to be inadequate in relation to inflammation. In a retrospective study with 34 patients with RA, 46 patients with reactive arthritis and 112 healthy subjects, the authors measured serum levels of IL-6, TNF and cortisol. The absolute levels of IL-6 were lower in healthy controls than in reactive arthritis and RA patients. However, the ratio of serum cortisol to serum cytokines was much higher in healthy controls than in reactive arthritis and RA patients, due to similar cortisol levels in all groups.”

And in another RA study…

“…comparing the circadian course of ACTH and cortisol levels in patients with RA and in healthy subjects, despite 10 times higher serum levels of cytokines in patients with RA, serum level curves of ACTH and cortisol were identical. The ACTH/cortisol hormone secretion in patients with RA is thus inadequate in relation to inflammation.”

And giant cell arteritis…

“In a study comparing serum values of ACTH, cortisol and CRP in patients with PMR/giant cell arteritis and controls, ACTH and cortisol levels were not different in patients with PMR/giant cell arteritis and controls, whereas the ratios of serum ACTH/serum CRP and serum cortisol/serum CRP were significantly lower in PMR/giant cell arteritis patients than in healthy controls. Thus, in PMR/giant cell arteritis there also appears to be an inadequate cortisol secretion in relation to inflammation in terms of relative adrenal insufficiency.”

The liver-HPA-kidney axis in chronic inflammation

In important observations that call to mind principles of traditional Chinese medicine (TCM), the authors delineate the function of hepato-hypothalamic-pituitary-adrenal-renal axis:

“Recently, evidence has accumulated, been reviewed and presented as a concept that dysfunction of the HPA axis in chronic inflammation is not simply an adaptation to chronic stress, but may be due to increased negative feedback of active cortisol on the HPA axis. The HPA axis has been recognized to be extendable to a hepato-hypothalamic-pituitary-adrenal-renal axis by GC [glucocorticoid] metabolism.”

The liver in chronic inflammation

HPA axis dysfunction in inflammationThe kidney inactivates cortisol to protect its receptor from over-stimulation and subsequent suppression, and the liver turns it back on:

“Active cortisol is converted to inactive cortisone mainly by the kidney, via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. On the other hand, the major organ for converting inactive cortisone to active cortisol is the liver, via 11β-HSD1.”

Pro-inflammatory cytokines over-activate the liver 11β-HSD1 enzyme:

Expression of 11β-HSD1 is markedly enhanced by TNF and proinflammatory cytokines. The liver therefore becomes an important player in systemic inflammation, even if the conversion also occurs in multiple other tissues including the brain, adipocytes, vascular cells, osteoblasts and fibroblasts. Given the role of the 11β-HSD1 in GC metabolism, its effect on the HPA axis and its interaction with inflammatory cytokines, it is hypothesized that in chronic inflammatory diseases, cytokine-induced increased expression of 11β-HSD1 induces a change in the HPA axis. Increased negative feedback of active cortisol on the HPA axis induced during inflammation may thus be the mechanism of dysfunction of the HPA axis in chronic inflammation.”

Tertiary adrenal insufficiency

Synthetic glucocorticoids such as prednisone suppress adrenal function through the same negative feedback mechanism:

“During the physiological regulation of the HPA axis, cortisol release is terminated by negative feedback regulation of cortisol on the hypothalamus and anterior pituitary. Also, synthetic GCs – as applied in GC therapy – can cause negative feedback regulation, leading to adrenal suppression in terms of tertiary adrenal insufficiency.”

Besides the clinical presentation, this can be confirmed by low cortisol and ACTH levels and lack of increase in plasma cortisol with the corticotropin-releasing hormone (CRH) or ACTH stimulation test. The magnitude of the dose matters:

“The frequency of adrenal suppression increases with increasing GC dosages. In arthritis and asthma patients treated with prednisone equivalent doses ranging from 5 to 20 mg, cortisol response in the ACTH test was normal (that is, cortisol rise ≥7 μg/dl) in all of the patients taking a single morning dose of 5 to 7.5 mg prednisone, was blunted (that is, cortisol rise <7 μg/dl) in 33% and 47% of the patients taking 10 to 12.5 mg and 15 mg prednisone, respectively, and was suppressed (no rise) in 44% of the patients taking 20 mg prednisone.”

Duration also takes its toll:

After 12 weeks of 7.5 mg prednisolone, the mean values for the 60-minute response to ACTH were reduced by 35%. Following treatment, 46% of patients taking 7.5 mg prednisolone failed to reach the normal maximum cortisol response to ACTH, even if the HPA axis response generally remained within the normal range.”

Chronotherapy with prednisone

Primary concerns are maximizing effectiveness while minimizing adrenal suppression through negative feedback regulation. Several daily divided doses worsen the tendency to suppression:

“In the 1960s several studies confirmed that splitting the daily dose into several divided doses strongly increases the risk of adrenal suppression. For example, whereas endogenous cortisol secretion was not altered with a single dose of 8 mg triamcinolone given at 8:00 a.m., application of four divided 2 mg doses resulted in marked suppression of cortisol levels.”

Timing of the single dose also matters:

“The time point of application of the single daily dose also plays a role for adrenal suppression. This can be explained easily: circadian GC secretion exhibits two peaks, one large peak in the morning around 8:00 a.m. and a smaller peak in the afternoon around 2:00 p.m. Of note, cortisol levels are high during the first peak in the morning, causing downregulation of ACTH levels via negative feedback regulation. In consequence, cortisol secretion is also downregulated. At a certain point, reduced cortisol levels cause upregulation of ACTH again, leading in turn also to upregulation of cortisol secretion during the second peak in the afternoon. If exogenous GCs were applied in the evening, the so-called quiet period for the adrenal gland, this would cause a negative signal on ACTH and therefore also cortisol secretion in the morning.”

Note: With a healthy cortisol rhythm the afternoon “bump” in cortisol may be barely discernible. A single daily dose is easier to manage but many patients require two to control inflammation.

Several studies evaluating nocturnal doses at 2:00 a.m. yielded better results for morning stiffness than conventional morning doses. But the impracticality of dosing at 2:00 am plus questions about HPA suppression led to the development of a modified-release (MR) prednisone tablet that releases the dose four hours after ingestion (2 a.m. if taken at 10 p.m.).

MR prednisone produced a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone…These results lead to the question of whether chronotherapy with MR prednisone affects adrenal suppression. The influence of long-term, low-dose chronotherapy with MR prednisone on the HPA axis was investigated by CRH tests in a subgroup of 28 patients in the CAPRA-1 study…There were no measurable differences in mean cortisol changes after CRH injection between baseline and the end of the study. Furthermore, there was no indication that changing treatments from immediate-release prednisone to MR prednisone increased the risk of HPA axis insufficiency, or resulted in deterioration of preexisting suppression.There was thus no difference between immediate-release prednisone and MR prednisone in numbers of normal/suppressed/no response reactions. In addition, no adverse events that could be attributed to HPA axis insufficiency were observed during treatment with low-dose MR prednisone for the entire treatment period of 12 months.”

Dosing at 2:00 a.m. (by modified release) may even benefit HPA axis activity:

“A recent study showed an increase of endogenous cortisol after 2 weeks of MR prednisone therapy in patients with active RA who had received no GCs by any route in the preceding 3 months. MR prednisone released at 2:00 a.m. suppressed the pathological early morning rise in plasma IL-6 in RA. The nocturnal rise in plasma cortisol was not suppressed but was enhanced with a peak value increase from 14.1 to 19.3 μg/dl, consistent with a changing relationship between HPA axis and immune system activation. This observation may be an indication that the HPA axis is preserved and is activated even more during MR prednisone treatment compared with pre-MR prednisone treatment.”

Clinical Note

Nutrition JournalMinimizing adrenal suppression while enhancing anti-inflammatory effectiveness by circadian dosing of prednisone also implies that effect of other anti-inflammatory agents can be enhanced by chronotherapeutic timing. Curcumin is one of the most extensively researched natural anti-inflammatory agents. A study published in the Nutrition Journal on the comparative absorption of curcumin formulations demonstrates that a newer preparation markedly extends the plasma concentrations of bioactive components including the key metabolite tetrahydrocurcumin.

“The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.”

A curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) were compared to a standardized curcumin mixture (CS). There was a dramatic result in favor of the CHC preparation.

“Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).”

Plasma concentrations time-curves for curcumin productsTetrahydrocurcumin is particularly valuable…

“Tetrahydrocurcumin plays an important role in the antioxidant mechanism of curcumin and has been shown to be the most potent antioxidant of the curcuminoids measured in this study. In addition, tetrahydrocurcumin has been reported to have health promoting benefits. It has been shown to have greater anti-inflammatory potency than curcumin in carrageenan-induced paw edema.”

The data shows that the CHC preparation yields high levels of curcuminoids that would sustain through the night into the morning if taken at bedtime to cover the critical inflammatory period when cortisol levels are naturally low. Adrenal suppression is, of course, not a concern with curcumin. This is advantageous not just for rheumatological disorders but all conditions involving chronic inflammation.

The authors of the first study conclude:

“From a GC perspective, circadian rhythms of the HPA axis and connected subsystems, including the immune system, appear to be essential for understanding of pathophysiology and treatment in rheumatology. The circadian rhythm of the HPA axis in chronic inflammatory diseases may be defective in terms of not bringing the body into a position to overcome the signs and symptoms of the disease. GC therapy serves as a necessary aid to overcome the disease and perhaps restore the deranged circadian rhythm. In a number of patients (around 50%), GC therapy causes adrenal suppression, probably mainly due to as yet undefined individual factors (apart from dose, substance and duration of therapy). In order not to aggravate adrenal suppression, GC therapy should be applied in accordance with the circadian rhythm, to achieve greatest efficacy along with highest safety. It has been suggested that when the single morning dose is not effective enough to achieve sufficient disease control, especially in patients with strong night symptoms and morning stiffness, split doses in the morning and afternoon, or chronotherapy with MR prednisone, can to some extent avoid aggravation of adrenal suppression.”

Thyroid hormone conversion affects hypothyroid treatment

Endocrine ConnectionsLevothyroxine (l-T4, the synthetic form of thyroxine/T4) is the standard agent used for hormone replacement therapy in the treatment of hypothyroid. The relatively inactive thyoxine must be converted outside the thyroid gland into the active form of thyroid hormone triiodothyronine (T3). A study recently published in the journal Endocrine Connections reminds clinicians that all too often patients are not adequately supported—and testing only TSH and T4 is insufficient for thyroid case management—because the conversion of T4 to the active T3 is impaired. The authors state regarding thyroid hormone replacement:

“This is mainly done by administration of synthetic levothyroxine (l-T4)…However, this does not accurately reflect the natural direct secretion pattern of both thyroid hormones triiodothyronine (T3) and thyroxine (T4) by the thyroid gland.”

Measuring just TSH is not enough

Too many factors can influence TSH levels to solely depend on it as a biomarker for treatment of hypothyroid.

“Although TSH measurement has dominated procedural management of thyroid replacement by its apparent ease and good standardisation, a disturbingly high proportion of patients remains unsatisfied with the treatment they receive. This has prompted some authors including our group to question the validity of relying on the TSH level as the sole measure of dose adequacy in l-T4-treated patients. We have shown that the homeostatic equilibria between TSH and peripheral thyroid hormones are modulated by various influences such as age, body mass and the treatment modality itself. As a controlling element, the effective TSH level derived in a healthy normal population cannot necessarily be inferred to be equally optimal for a given patient on l-T4 medication, because the constitutive equilibria between TSH and thyroid hormones, especially FT3, differ in health and disease.

The authors examined the relationship of the dose of levothyroxine with clinical and biochemical outcomes such as the levels of TSH, free T4 (FT4) and free T3 (FT3), especially the interaction between TSH and the functionally paramount FT3 target. They also analyzed the influences of gender, age, disease category and the efficiency of T3 conversion from T4 with calculated deiodinase activity.

Higher levels of T4 can be associated with even lower T3

Free T4 was not reliable in predicting the level of free T3 in treating hypothyroid with levothyroxine.

“In l-T4 treatment, equilibria typical of the healthy state were found not to be invariant, but profoundly altered…We found that a poor converter status was associated with a higher l-T4 dose and higher serum FT4 levels but still lower absolute FT3 concentrations, compared to the more efficient converters. This paradoxically relates the higher T4 supply to a worsened rather than improved absolute FT3 level. This is not to say that an increasing dose will not raise on average the FT3 but that the dose response varies widely among individuals, and conversion inefficiency in some patients may outweigh the dose effect in terms of achievable absolute FT3 concentrations.”

Higher doses of levothyroxine can hinder conversion to T3

Trying to improve hypothyroid functional status by just increasing l-T4 dosage can backfire:

A high l-T4 dose may not invariably remedy T3 deficiency owing to T4-induced conversion inefficiency but could actually hinder its attainment through the inhibitory actions of the substrate itself and/or reverse T3 (rT3) on deiodinase type 2 activity…escalating only the l-T4 dose fails to normalize serum T3 in the rat, and as a result, irrespective of local variations by type of deiodinase, all organs examined such as the brain, liver and skeletal muscle were hypothyroid at the tissue level in the presence of a normal serum TSH…The lack of TSH stimulation and absence or functional deficiency of the thyroid gland may also impair T4–T3 conversion…Another important consideration is that, just as FT4 and FT3 dissociate under l-T4 therapy, so do TSH and FT3.”

Even when TSH is suppressed by l-T4 treatment the FT3 can remain at hypothyroid levels:

“While a high proportion of patients was able to achieve a target of a suppressed TSH below the lower reference limits or a TSH value <1 mU/l in autoimmune thyroiditis, their FT3 levels at the same time frequently remained below the median FT3 level found in normal subjects. The situation differs from conditions in which l-T4 absorption may be impaired and, as a consequence, elevated TSH levels persist. Thus, not even an l-T4 dose in which TSH is fully suppressed and FT4 by far exceeds its upper reference limit can guarantee above average FT3 levels in these patients, indicating an FT3–TSH disjoint.”

Unwanted clinical consequences can result even though lowered remains within the reference range:

“As a consequence, although dose escalation may help some patients who maintained a sufficiently efficient thyroid hormone conversion to raise their FT3 for euthyroidism and well-being, the strategy may not be invariably successful in all patients. In two studies, ∼15% of athyreotic patients could not even raise their FT3 above the lower reference limit on l-T4. Another controlled follow-up study after hemithyroidectomy for benign euthyroid goitre suggests that this deficiency may have unwanted clinical consequences. In this study, weight gain after 2 years in association with a lowered thyroid function within the laboratory reference range was interpreted as a clinical manifestation of a permanently decreased metabolic rate.”

Clinicians must not ignore the importance of FT3

Measuring only TSH or TSH and T4 is inadequate for evaluation of hypothyroid:

Dosing strategies solely based on a TSH definition of euthyroidism neglect the important role of FT3, which has recently emerged as an equally significant parameter in defining thyroid physiology. Central and peripheral regulatory mechanisms do not constitute divided levels of control, as has previously been assumed. Rather they are integrated via feed-forward control of deiodinase activity by TSH and operate jointly to maintain T3 homeostasis as an overarching goal.”

Thus T4 monotherapy itself can make things worse:

“While acknowledging the role of genetically determined differences in deiodinase activity affecting conversion rates, the poor converter status described here appears to emerge mainly as a consequence of the T4 monotherapy itself, induced by the mechanisms discussed above. Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in l-T4 treatment.”

Treatment may require T3 replacement

As usual, therapy must be individualized:

“Overall, patients differ widely in the degree of the conversion impairment they suffer. This, in turn, may influence their dose requirements of l-T4 and, at a comparable weight-adjusted l-T4 dose, their levels of TSH suppression and circulating FT3 concentrations.”

Regarding combinations of T3 and T4:

“We speculate that l-T4-induced conversion inefficiency could prevent some vulnerable subjects from reaching true tissue normality on T4 monotherapy alone. Those were not analysed separately in the numerous earlier T3/T4 trials and could be possible candidates for a combined T3/T4 treatment option, as recognized by some authors and the guidelines of the European Thyroid Association.”

Clinicians who participate in case management of hypothyroid should bear in mind the authors’ conclusions:

“The findings of the present study have several clinical implications. First, they recognize thyroid hormone conversion efficiency, as defined by the calculated global deiodinase activity or more simply the T3–T4 ratio, is an important determinant of l-T4 dose requirements and the biochemical response to treatment. Second, in view of a T4-related FT3–TSH disjoint, FT3 measurement should be adopted as an additional treatment target. Third, in cases where an FT3–FT4 dissociation becomes increasingly apparent following dose escalation of l-T4, an alternate treatment modality, possibly T3/T4 combination therapy, should be considered, but further randomized controlled trials are required to assess the benefit versus risk in this particular group.”

Adrenal suppression by inhaled steroids is common

European Journal of EndocrinologyInhaled steroids (glucocorticoids/corticosteroids) are commonly prescribed for asthma but their systemic effect is often overlooked. A clinical study just published in the European Journal of Endocrinology offers evidence that inhaled steroids such as fluticasone (Flovent®), budesonide (Pulmicort®), and beclomethasone (Qvar®) frequently cause serious adrenal suppression. They also show that simply measuring morning cortisol can help indicate whether adrenal insufficiency is occurring. The authors state:

“Up to 3% of US & UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy.”

A better way to measure adrenal suppression due to inhaled steroids

The definitive test for adrenal failure or insufficiency due to autoimmunity (Addison’s disease), oral or inhaled steroids is stimulate the adrenals with ACTH (adrenocorticotropic hormone, known as Synacthen.cosyntropin, and tetracosactide), then measure after 30 and 60 minutes the amount of cortisol produced. This is inconvenient and costly as a screening test for patients using inhaled steroids.

“The 250_g short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.”

So the authors investigated to determine whether measuring morning cortisol could be validated as a quicker and easier assessment.

“We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.”

Inhaled steroids suppress adrenal function in a dose dependent manner

In their data 20% of patients on inhaled steroids had adrenal suppression as shown by Synacthen stimulation:

“2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008-2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs, without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion.”

Moreover, this did in fact correspond to the morning cortisol measurements:

“Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348nmol/L provided 100% specificity for passing the SST; a cortisol value <34nmol/L had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.”

Clinical implications

Too often patients are left in the dark about the systemic effects of inhaled steroids. This helpful study reminds practitioners that there can be global adverse effects stemming from adrenal suppression with possible long-term consequences for case management of a wide variety of disorders; and that this can be screened by simply measuring morning cortisol. The authors conclude:

Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine, which patients should undergo dynamic assessment of adrenal function.”

Low-normal thyroid function and cardiometabolic disorders

European Journal of Clinical InvestigationLow-normal thyroid function commonly shows up in lab results in my general practice, mostly due to the diffuse autoimmune phenomena so widespread now, but it seems to be often overlooked. A study just published in the European Journal of Clinical Investigation offers more evidence that low-normal thyroid function should be respected as a risk factor, in this case for cardiovascular and metabolic disorders. The authors state:

“Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid [‘normal’] reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD).”

The authors surveyed a range of reviews and meta-analyses derived from clinical and basic research papers, obtained published up to November 2014 and found:

Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far.”

See earlier posts for studies reporting additional adverse effects from low-normal thyroid and low-normal free T3. Practitioners should be alert to anti-thyroid antibodies indicating a pre-Hashimoto’s state and test for iodine insufficiency (by 24 hour urine collection) when indicated. The authors conclude:

“Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain.”