Free Thyroid Hormone Concentrations Research Articles

6784 A Case of Euthyroid Hyperthyroxinemia due to Thyroid Binding Globulin Excess Syndrome

Abstract Disclosure: A.S. Iyer: None. Background: Congenital thyroid binding globulin (TBG) excess is a rare phenomenon associated with elevated serum total T3 and total T4 concentrations but normal serum concentrations of free thyroid hormones, with clinically euthyroid patients. While TBG excess can be caused by pregnancy, estrogen-secreting tumors, and estrogen therapy, congenital TBG excess follows an X-linked pattern, with hemizygous males most affected, and heterozygous females showing a spectrum of disease due to random inactivation of one X chromosome. Clinical Case: A 39-year-old Caucasian female presented as a referral from the Gastroenterology clinic due to concern for thyroid resistance syndrome. Symptoms included chronic constipation (improving with Miralax®), gradual weight gain of 8 pounds in one year, fatigue, and palpitations. She reported that her total thyroid hormone levels have always been elevated, with other thyroid labs remaining within normal limits, along with family history of similar labs noted in her two sons, father, and paternal grandmother. Upon initial encounter, TSH was 1.637 (0.430-3.550 uIU/mL), total T4 15.4 (4.8-11.7 ug/dL), total T3 231 (80-200 ng/dL), free T4 0.97 (0.70-1.25 ng/dL), free T3 3.2 (1.7-3.7 pg/mL), and albumin 4.2 (3.5-5.0 g/dL). The patient was not on oral contraceptive pills and she denied any pregnancies in the last three years. Thyroid ultrasound showed a normal-appearing homogeneous thyroid gland with a small cyst with colloid and no cervical lymphadenopathy. Initial differential diagnosis included TBG excess syndrome versus familial dysalbuminemic hyperthyroxinemia. Permission was obtained from the patient to access one of her son’s medical records from age 8-weeks old when he was also evaluated for abnormal thyroid labs. TSH was 2.144 (0.350-6.500 uIU/mL), total T4 28.2 (5.0-12.0 ug/dL), free T4 1.55 (0.8-1.8 ng/dL), and free T3 4.0 pg/mL (no reference available). Thyroid binding globulin was found to be elevated at 81 (12-26 mcg/mL) in her son and found to be elevated to 78.0 (13.5-30.9 mcg/mL) in this patient, confirming a diagnosis of TBG excess syndrome. Conclusions: TBG excess syndrome should be considered in the differential of patients with high total T3 and total T4 levels with normal levels of free T3, free T4, and TSH, especially in individuals who have a known family history and who have minimal or nonspecific symptoms. Definitive diagnosis will make further testing and treatment unnecessary. However, if these patients develop hypo- or hyperthyroidism, then use of TSH and free levels of T4 and T3 is necessary to direct management and avoid confusion. Reference: Pappa, T., and S. Refetoff. “Thyroid hormone transport proteins: Thyroxine-binding globulin, transthyretin, and albumin.” Reference Module in Neuroscience and Biobehavioral Psychology, 2017, https://doi.org/10.1016/b978-0-12-809324-5.03494-5. Presentation: 6/2/2024

The Association between Vitamin D Status and the Impact of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Women with Subclinical Hypothyroidism.

Metformin inhibits enhanced secretion of anterior pituitary hormones. Its impact on prolactin and gonadotropin concentrations is absent in individuals with hypovitaminosis D. The aim of this prospective cohort study was to investigate whether vitamin D status determines the effect of metformin on hypothalamic-pituitary-thyroid axis activity in levothyroxine-naïve women. The study included three groups of women of reproductive age with subclinical non-autoimmune hypothyroidism, which were matched for age, thyroid-stimulating hormone (TSH) concentration, and insulin sensitivity: untreated women with vitamin D deficiency/insufficiency (group A), women effectively supplemented with exogenous calciferol (group B), and untreated women with normal 25-hydroxyvitamin D concentrations (25OHD) (group C). Owing to concomitant type 2 diabetes or prediabetes, all subjects were treated with metformin. Concentrations of 25OHD, TSH, total and free thyroid hormones, glucose, insulin, glycated hemoglobin (HbA1c), prolactin, and peripheral markers of thyroid hormone action were assayed before metformin treatment and six months later. Based on hormone concentration, structure parameters of thyroid homeostasis were calculated. Except for 25OHD concentrations, there were no between-group differences in baseline values of the measured variables. Metformin reduced glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), and HbA1c in all study group, but these effects were less pronounced in group A than in the remaining groups. The reduction in TSH and Jostel's index was observed only in groups B and C, and its degree correlated with baseline TSH concentrations, baseline 25OHD concentrations, and the degree of improvement in HOMA1-IR. The drug did not affect circulating levels of 25OHD, free and total thyroid hormones, prolactin, other structure parameters of thyroid homeostasis, and markers of thyroid hormone action. The obtained results allow us to conclude that low vitamin D status in young women mitigates the impact of metformin on thyrotroph secretory function.

Large method differences for free thyroid hormone assays in the hyperthyroid range can affect assessment of hyperthyroid status: Comparison of Abbott Alinity to Roche Cobas, Siemens Centaur and equilibrium dialysis LC-MS/MS

BackgroundFree T4 (FT4) determination is one of the most commonly performed biochemical tests in endocrinology. Treatment of thyroid dysfunctions is adjusted based on the severity of symptoms and biochemical test results. For Graves’ hyperthyroidism, clinical guidelines recommend using FT4 as a (rough) guide to dose antithyroid drugs, together with other clinical information. It is well known that different platforms and methods give different FT4 results; however, large non-linear method differences at high FT4 concentrations are less well recognized. Current clinical guidelines do not make it clear that method differences in the hyperthyroid range can affect recommendations. MethodSerum samples from patients with very low (biochemically hypothyroid) to very high (hyperthyroid) concentrations of FT4 and/or free T3 (FT3) were analyzed using Abbott Alinity and compared to concentrations measured using Roche Cobas, Siemens ADVIA Centaur (FT4 only) and an in-house equilibrium dialysis liquid chromatography tandem mass spectrometry (LC-MS/MS) method. ResultsAlinity measured markedly lower FT4 and FT3 concentrations compared to the other methods, particularly at high FT4 concentrations. Regression analysis indicated that Alinity FT4 had a non-linear (curved) relationship to FT4 measured by the other methods. The method differences affected guideline-recommended treatments for hyperthyroidism. ConclusionMeasured free thyroid hormone concentrations are highly method-dependent, especially at high FT4 concentrations. Clinicians treating hyperthyroid patients should be aware that patients appear much less hyperthyroid from FT4-measurements performed using Alinity compared to Cobas or Centaur. Guideline-recommended antithyroid drug dosages based on FT4 (including multiples of the upper reference range) have to be adjusted to the FT4 method used. FT4 results from different methods should be clearly distinguished (e.g. separate lines) in medical records.

Analysis of free, unbound thyroid hormones by liquid chromatography-tandem mass spectrometry: A mini-review of the medical rationale and analytical methods.

Measurement of hormones is important for the diagnosis and management of endocrine diseases. The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are among the most commonly measured hormones in clinical laboratories, and it is the concentration of free (not bound to proteins) thyroid hormones that is clinically most relevant. Free thyroid hormones are commonly measured using automated immunoassays, however, these are known to produce erroneous results due to interferences for some patients. Measurement of free thyroid hormones using equilibrium dialysis or ultrafiltration combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is considered a more accurate and robust method for free thyroid hormone analysis and overcomes many of the limitations of immunoassays. However, LC-MS/MS-based methods are often considered too technically difficult and not amendable to high throughput by clinical chemists and are not offered by many clinical laboratories. This mini-review aims to make it easier for clinical laboratories to implement LC-MS/MS-based measurement of free thyroid hormones. It describes the medical rationale for measuring free thyroid hormones, the benefits of LC-MS/MS-based methods with respect to interferences affecting immunoassay-based methods and physical separation methods. This mini-review highlights important parameters for ultrafiltration and equilibrium dialysis to obtain physiologically relevant free thyroid hormone concentrations and focuses on methods and devices used in clinical chemistry.

Rosuvastatin potentiates the thyrotropin-lowering effect of metformin in men with non-autoimmune subclinical hypothyroidism and prediabetes.

Metformin treatment decreases thyrotropin levels in individuals with hypothyroidism and this effect seems to be mediated by the 5'-adenosine monophosphate-activated protein kinase pathway in the pituitary. The activity of this pathway is also stimulated by statins. The current study was aimed at investigating whether the impact of metformin on hypothalamic-pituitary-thyroid axis activity is affected by statin use. The study included three matched groups of men with non-autoimmune hypothyroidism and prediabetes: patients treated for at least 6 months with high-intensity rosuvastatin therapy (20-40 mg daily) [groups A (n=24) and C (n=19)] and men not receiving statin therapy [group B (n=24)]. Over the entire study period (6 months), groups A and B received metformin (2.55-3g daily). Moreover, groups A and C continued rosuvastatin therapy. The lipid profile, glucose homeostasis markers, and plasma concentrations of thyrotropin, total and free thyroid hormones, prolactin, FSH, LH, ACTH and insulin-like growth factor-1 were determined at baseline and 6 months later. Fifty-nine patients completed the study. There were differences between groups A and C and group B in baseline values of total cholesterol, LDL-cholesterol, gonadotropins and ACTH. Although observed in both groups of metformin-treated patients, the effect on thyrotropin levels was more pronounced in group A than in group B. The impact on fasting glucose and insulin sensitivity was stronger in group B than group A. In turn, only in group A metformin tended to reduce gonadotropin levels. There were no differences between follow-up and baseline values of lipids, total and free thyroid hormones, prolactin, ACTH and insulin-like growth factor-1 in both these groups. In group C, all assessed variables remained at a similar level. The results of the current study suggest that rosuvastatin potentiates the inhibitory effect of metformin on thyrotrope secretory function.

Proportion of serum thyroid hormone concentrations within the reference ranges in athyreotic patients on levothyroxine monotherapy: a retrospective study

BackgroundIn patients receiving thyroid-stimulating hormone (TSH) suppressive therapy with levothyroxine (LT4) after total thyroidectomy for thyroid cancer, thyroid function tests should be performed to adjust the LT4 dose. Specifically, serum TSH concentrations are commonly measured because TSH suppression is necessary according to thyroid cancer risk. The aim of the present study was to elucidate whether free thyroxine (FT4) or free triiodothyronine (FT3) indicates better for adjusting the dose in athyreotic patients on LT4 monotherapy after total thyroidectomy.MethodsWe retrospectively studied the compatibility of free thyroid hormone (FT4 and FT3) concentrations with reference ranges in athyreotic patients on LT4 monotherapy after total thyroidectomy.ResultsWe identified 2210 consecutive patients from their medical records. Of these patients, 250 had both FT4 and FT3 concentrations in addition to TSH. Two hundred seven had serum TSH concentrations below the reference range (0.5–5.0 μIU/mL), while 43 had them within the reference range. In the 207 patients with TSH concentrations below the reference range, 61 patients (29.5%) had FT4 concentrations within the reference range (0.9–1.7 ng/dL) and 146 patients (70.5%) had FT4 concentrations above the reference range. In contrast, 10 patients (4.8%) had FT3 concentrations below the reference range (2.3–4.0 pg/mL) and 8 (3.9%) had FT3 concentrations above the reference range; 189 patients (91.3%) had concentrations within the reference range. Of the 43 patients with TSH concentrations within the reference range, 25 (58.1%) had FT4 concentrations within the reference range and 18 (41.9%) had FT4 concentrations above the reference range. While, 11 patients (25.6%) had FT3 concentrations below the reference range and one (2.3%) had FT3 concentrations above the reference range; hence, 31 patients (72.1%) had FT3 concentrations within the reference range.ConclusionThis study showed that measuring FT3 concentrations rather than FT4 concentrations as the subsequent parameter of thyroid function might be more useful for disease management in terms of the proportion of serum thyroid hormone concentrations within the reference ranges. Furthermore, FT3 measurement could be useful in providing more detailed treatments, including avoiding more aggressive TSH suppressive therapy and identifying the presence of low T3 syndrome in the background.

The Diurnal Variation of Thyroid Hormones in Individuals Attending Tertiary Care Hospital, Kanchipuram District

Free thyroxin hormones FT4 and FT3 are unbounded thyroid hormone are biologically active and involves in regulation of metabolism. Measuring the concentrations of free thyroid hormones is of great diagnostic value. A cross sectional study was carried out during the March 2019 to September 2019 in patients between 18 years to 60 years. A total of 60 samples were collected from 30 patients attending Karpaga Vinayaga Institute of Medical Sciences at morning (6am-8am) and 2nd sampling at night (8pm-9pm). FT4, FT3 and TSH were measured by Enzyme linked immunosorbent assay, using Avantor kit.In our study 36.67% participants were males, 63.3% participants were females. The mean FT3, FT4 and TSH in day are 2.43±0.56, 1.14±0.44 and 2.74±3.16 respectively. The mean night FT3, FT4 and TSH are 2.66±0.55, 1.3±0.61 and 3.21±3.18 respectively. The one sample t test shows difference of FT3, t 4.489 and p value 0.000, FT4, t value 3.092 and p value 0.004 and TSH t value 3.394 and p value 0.002. The time of blood sampling has an important role in the interpretation of TSH levels. However fluctuations in diurnal variations in thyroid hormone levels are less. In our study although statistically significant, all the values are within the normal biological reference interval Further studies in larger cohorts is essential to desire important conclusions.

The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target.

Elevated concentrations of free thyroid hormones are established cardiovascular risk factors, but the association of thyrotropin (TSH) levels to hard endpoints is less clear. This may, at least in part, ensue from the fact that TSH secretion depends not only on the supply with thyroid hormones but on multiple confounders including genetic traits, medication and allostatic load. Especially psychosocial stress is a still underappreciated factor that is able to adjust the set point of thyroid function. In order to improve our understanding of thyroid allostasis, we undertook a systematic meta-analysis of published studies on thyroid function in post-traumatic stress disorder (PTSD). Studies were identified via MEDLINE/PubMed search and available references, and eligible were reports that included TSH or free thyroid hormone measurements in subjects with and without PTSD. Additionally, we re-analyzed data from the NHANES 2007/2008 cohort for a potential correlation of allostatic load and thyroid homeostasis. The available evidence from 13 included studies and 3386 euthyroid subjects supports a strong association of both PTSD and allostatic load to markers of thyroid function. Therefore, psychosocial stress may contribute to cardiovascular risk via an increased set point of thyroid homeostasis, so that TSH concentrations may be increased for reasons other than subclinical hypothyroidism. This provides a strong perspective for a previously understudied psychoendocrine axis, and future studies should address this connection by incorporating indices of allostatic load, peripheral thyroid hormones and calculated parameters of thyroid homeostasis.

Time-dependent changes in FT4 and FT3 levels measured using mass spectrometry after an acute ingestion of excess levothyroxine in a case with hypothyroidism

BackgroundThyrotoxicosis is common disorder among endocrine dysfunctions. It is not rare that the free thyroid hormone level exceeds the measurement range of immunoassay. Such extreme high concentration of free thyroid hormone is generally considered to be impossible to measure correctly because of changes in the balance between free hormones and binding proteins by dilution of serum. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), however, higher concentrations are able to be determined.Case presentationWe present a case of a 21-year-old female with congenital hypothyroidism who had taken a total of 5 mg levothyroxine over three consecutive days following discontinuance of the medication for a month. Immunoassay performed 3 hours after the last ingestion showed that the patient’s free thyroxine (FT4) was over 100 pmol/L and her free triiodothyronine (FT3) was 24.5 pmol/L. With a temporary cessation of levothyroxine, the patient was kept for observation without any other medication. Two days after the last ingestion, FT4 was still over 100 pmol/L and FT3 was increased to 28.8 pmol/L. After an additional 4 days, both FT4 and FT3 levels decreased. Through this period, no thyrotoxic symptom or physical sign had appeared. We also measured FT4 and FT3 levels in her cryopreserved serum by ultrafiltration LC-MS/MS. Her FT4 level measured by ultrafiltration LC-MS/MS on the visiting day and 2 days later were 160.0 and 135.5 pmol/L, respectively, indicating that the toxic dose of levothyroxine was partly changed to T3 during the 2 days. The FT3/FT4 ratios were revealed to be low, accounting for the patient’s benign clinical course despite temporal toxic exposure to levothyroxine. It is implied that prior discontinuation of supplementary levothyroxine increases potential vacant binding sites for thyroid hormone as a buffer to prevent toxic T3 effect.ConclusionIt was helpful to clarify the time dependent changes in free thyroid hormone levels by ultrafiltration LC-MS/MS in discussing the clinical course in this case. Though mass spectrometry has a disadvantage in speed for routine laboratory use, its accurate measurement, particularly of levels exceeding the measurable range of the immunoassay, provides valuable information for more appropriate management of extreme thyrotoxicosis.

Function of Cathepsin K in the Central Nervous System of Male Mice is Independent of Its Role in the Thyroid Gland.

Cathepsin K deficiency in male mice (Ctsk-/-) results in decreased numbers of hippocampal astrocytes and altered neuronal patterning as well as learning and memory deficits. Additionally, cathepsin K carries essential roles in the thyroid gland where it contributes to the liberation of thyroid hormones (TH). Because TH are essential for brain development, in particular for the cerebellum, we investigated whether cathepsin K's function in the thyroid is directly linked to the brain phenotype of Ctsk-/- mice. Serum levels of thyroid stimulating hormone, brain concentrations of free TH, and deiodinase 2 (Dio2) activity in brain parenchyma as well as cerebellar development were comparable in Ctsk-/- and WT animals, suggesting regular thyroid states and TH metabolism. Despite unaltered transcript levels, protein expression of two TH transporters was enhanced in specific brain regions in Ctsk-/- mice, suggesting altered TH supply to these regions. Thyrotropin releasing hormone (Trh) mRNA levels were enhanced threefold in the hippocampus of Ctsk-/- mice. In the striatum of Ctsk-/- mice the mRNA for Dio2 and hairless were approximately 1.3-fold enhanced, while mRNA levels for monocarboxylate transporter 8 and Trh were reduced to 60% and 40%, respectively, pointing to altered striatal physiology. We conclude that the role of cathepsin K in the thyroid gland is not directly associated with its function in the central nervous system (CNS) of mice. Future studies will show whether the brain region-specific alterations in Trh mRNA may eventually result in altered neuroprotection that could explain the neurobehavioral defects of Ctsk-/- mice.

Hypothyroidism after fine needle aspiration biopsy of thyroid nodules: A case report

Introduction. Fine needle aspiration biopsy is a non-surgical invasive diagnostic method for the cytological evaluation of the thyroid gland. Complications of fine needle aspiration biopsy are rare. Case Report. A female patient, 64 years of age, underwent left-sided nodulectomy in 2006, due to a follicular adenoma of the thyroid gland. In September of 2016, ultrasonography of the thyroid gland confirmed a node in the right lobe, approximately 10 mm in the longest diameter. The thyroid-stimulating hormone level was within the reference range (1,8 mIU/L), as well as calcitonin and carcinoembryonic antigen levels, but with elevated anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies, so fine needle aspiration was indicated. The cytological finding indicated a suspected follicular lesion and total thyroidectomy with an ex tempore biopsy was proposed in November of 2016. Prior to the surgery, hormone levels were measured and high thyroid-stimulating hormone levels were recorded (79 mIU/L). Further investigation showed low levels of free thyroid hormone concentrations, and levothyroxine was initiated at a dose of 75 mcg per day and the surgical treatment was delayed. The indicated dose of levothyroxine resulted in satisfactory values of the thyroid gland free hormones, and in February 2017, right-sided lobectomy was performed, whereas the histopathological findings indicated lymphocytic thyroiditis. Levothyroxine replacement therapy showed satisfactory results in the postoperative period. Further outpatient ultrasonographic monitoring showed a residual thyroid tissue, with slightly non-homogeneous echostructure in the left thyroid bed, 12 x 11 x 32 mm in size. Regular follow-up was suggested. Conclusion. Hypothyroidism has not been reported as a fine needle aspiration complication in the available literature.

Evaluation of Thyroid Function during Pregnancy: Have We Taken a Wrong Turn?

Recently, the American Thyroid Association (ATA)2 issued new guidelines for the diagnosis and management of thyroid diseases during pregnancy and the postpartum period (1). The document is an excellent review of current literature relating to the assessment of thyroid status during pregnancy. While universal screening for thyroid disease before or during pregnancy remains controversial, thyroid status can be accurately screened with thyroid-stimulating hormone (TSH), and additional testing such as free thyroxine (FT4) is required only when TSH is abnormal. However, one of the recommendations of the ATA document stood out: Recommendation 3 reads, “Accurate estimation of the FT4 concentrations can also be done by calculating a FT4 index.” The FT4 index is a virtually obsolete estimation of FT4 that has been replaced by newer and more accurate FT4 immunoassays and LC-MS/MS. This recommendation is based on the panel's observation that “Current uncertainty around FT4 estimates in pregnancy has led some to question the wisdom of relying on any FT4 immunoassays during pregnancy.” Here I would like to review the source of this uncertainty and propose an alternative interpretation of the literature. ### SOURCES OF UNCERTAINTY In 1991, Roti et al. compared 10 different radioimmunoassay methods for free triiodothyronine (FT3) and FT4 (2). They observed that whereas FT4 concentrations were often lower in pregnant (third trimester) women than nonpregnant women, the TSH concentrations remained within the reference interval. These findings suggested that many of the assays available at that time for the measurement of serum free thyroid hormone concentrations did not seem adequate to evaluate the real thyroid status of pregnant women. Indeed, since then numerous studies have demonstrated that FT4 measured by …

Metabolomic profile in hyperthyroid patients before and after antithyroid drug treatment: Correlation with thyroid hormone and TSH concentration

Hyperthyroidism (HT) is characterized by an intense metabolic impact which affects the lipid, carbohydrate and amino acids metabolism, with increased resting energy expenditure and thermogenesis. Metabolomics is a new comprehensive technique that allows to capture an instant metabolic picture of an organism, reflecting peculiar molecular and pathophysiological states. The aim of the present prospective study was to identify a distinct metabolomic profile in HT patients using 1H NMR spectroscopy before and after antithyroid drug treatment. This prospective study included 15 patients (10 female, 5 male) who were newly diagnosed hyperthyroidism. A nuclear magnetic resonance (1H NMR) based analysis was performed on plasma samples from the same patients at diagnosis (HypT0) and when they achieved euthyroidism (HypT1). The case groups were compared with a control group of 26 healthy volunteers (C). Multivariate statistical analysis was performed with Partial Least Squares-Discriminant Analysis (PLS-DA). PLS-DA identified a distinct metabolic profile between C and untreated hyperthyroid patients (R2X 0.638, R2Y 0.932, Q2 0.783). Interestingly, a significant difference was also found between C and euthyroid patients after treatment (R2X 0.510, R2Y 0.838, Q2 0.607), while similar cluster emerged comparing HypT0vs HypT1 patients. This study shows that metabolomic profile is deeply influenced by hyperthyroidism and this alteration persists after normalization of thyrotropin (TSH) and free thyroid hormone (FT3, FT4) concentration. This suggests that TSH, FT3 and FT4 assays may not be insufficient to detect long lasting peripheral effects of the thyroid hormones action. Further studies are needed to clarify whether and to what extent the evaluation of metabolomics profile may provide relevant information in the clinical management of hyperthyroidism.

Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming.

The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

Iodine supplementation during pregnancy of hypothyroid women treated with L-thyroxine neither influences neonatal TSH nor prevents decrease in maternal free thyroid hormone concentrations in second and third trimesters.

Pregnant women require about 250 μg of iodine daily. Hypothyroid women treated with L-thyroxine do not utilise iodine, and metabolism of L-thyroxine tablets is an additional source of iodine for their foetuses. The aim of the study was to evaluate the influence of iodine supplementation in hypothyroid pregnant women treated with L-thyroxine on neonate TSH concentration and maternal thyroid parameters. Ninety-two pregnant women with primary hypothyroidism on adequate thyroid hormone replacement were voluntarily divided into two groups: "thyroxine" (n = 38) treated with L-thyroxine only, and "thyroxine + iodine" (n = 54) treated additionally with 150 μg/day of iodine since 10th gestational week. Primary outcomes were the maternal thyroid function tests (TSH, fT4, fT3) and neonatal TSH concentrations at the 3-4th day of life. Urinary iodine concentration was measured at first and third trimester to compare iodine status in both groups. Iodine supplementation significantly increased median urinary ioduria in the third trimester (from 95.15 μg/L to 151.50 μg/L), but did not prevent the decrease of maternal fT4 and fT3 concentrations in the second and third trimester. Median neonate TSH concentration in both groups was within normal range, but was 33% higher in the "thyroxine + iodine" than in the "thyroxine" group (1.91 mU/L vs. 1.34 mU/L). Moreover, 8.77% of newborns in the "thyroxine + iodine" group had TSH > 5 mIU/L. We did not find evidence for a positive influence of iodine supplementation on thyroid function of either hypothyroid pregnant women sufficiently treated with L-thyroxine or their neonates. (Endokrynol Pol 2016; 67 (4): 367-374).

Grey matter abnormalities in untreated hyperthyroidism: A voxel-based morphometry study using the DARTEL approach

ObjectiveHyperthyroidism is frequently associated with pronounced neuropsychiatric symptoms such as impulsiveness, irritability, poor concentration, and memory impairments. Functional neuroimaging has revealed changes in cerebral metabolism in hyperthyroidism, but regional changes in cortical morphology associated with specific neurological deficits have not been studied so far. To investigate the pathophysiology underlying hyperthyroid-associated neural dysfunction, we compared grey matter volume (GMV) between adult hyperthyroid patients and matched healthy controls using voxel-based morphometry (VBM). Materials and methodsHigh resolution 3D T1-weighted images were acquired by 3T MRI from 51 hyperthyroid patients and 51 controls. VBM analysis was performed using SPM8. Correlations between regional GMV and both serum free thyroid hormone (TH) concentrations and disease duration were assessed by multiple regression analysis. ResultsCompared to controls, GM volumes in the bilateral hippocampus, parahippocampal gyrus, calcarine, lingual gyrus, and left temporal pole were lower and bilateral supplementary motor area GMV higher in hyperthyroid patients. Serum free triiodothyronine (FT3) concentration was negatively correlated with the normalized regional volume (NRV) of the left parahippocampal gyrus and serum free thyroxine (FT4) concentration negatively correlated with the NRV of the left hippocampus and right parahippocampal gyrus. Disease duration was negatively correlated with the NRV of the left hippocampus, bilateral parahippocampal gyrus, and left temporal pole. ConclusionHyperthyroid patients exhibited reduced GMV in regions associated with memory, attention, emotion, vision, and motor planning. Negative correlations between GMV and both free TH and disease duration suggest that chronic TH elevation induces abnormalities in the adult cortex.

Evaluation of LOCI® technology-based thyroid blood tests on the Dimension Vista® analyzer

ObjectivesTo assess the performance of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) determinations by luminescent oxygen channeling immunoassay (LOCI®) technology on the Dimension Vista® analyzer (Siemens Healthcare Diagnostics). Design & methodsWe assessed 1) functional sensitivity for TSH (FSe-TSH), and intra- and inter-assay variations for TSH, FT4 and FT3 on Vista®; 2) comparisons of serum and heparin-treated plasma on Vista®; 3) comparisons of a) plasma TSH by Vista® versus electrochemiluminescence (ECLIA) on Roche Modular® analyzer, and b) plasma FT4 and FT3 by Vista® versus Immunotech®-Beckman radioimmunoassay (RIA); and 4) association of albumin and prealbumin levels with free thyroid hormone concentrations on Vista®. Results1) FSe-TSH concentration was below 0.005mIU/L. Maximum intra-assay CVs (2.1%, 1.4%, 5.2%) and inter-assay CVs (16.5%, 5.1%, 5.8%) were good for TSH, FT4 and FT3 respectively. 2) Heparin-treated plasma samples consistently gave slightly higher values than serum for TSH, FT4 and FT3. 3) Passing–Bablok regression gave: TSH: [LOCI]=0.91[ECLIA]−0.08 (concordance correlation coefficient ρc=0.95); FT4: [LOCI]=1.05[RIA]−1.55 (ρc=0.80); and FT3: [LOCI]=1.05[RIA]−0.06 (ρc=0.81). 4) Both serum albumin and prealbumin concentrations were positively associated with FT3 levels and negatively associated with FT4 levels in patients. ConclusionLOCI® is accurate for TSH, FT4 and FT3 analysis. Despite a slight significant bias compared to ECLIA, LOCI® is precise for TSH and fulfills the third-generation criteria. However, the poor concordance between LOCI® and RIA for FT4 and FT3, and the dependence of these hormones on binding proteins require further investigation.

Clinical Implications and Management of Sub Clinical Hyperthyroidism: A Review

Sub clinical hyperthyroidism (SCH) is characterized by normal free thyroid hormone concentrations along with a low or undetectable serum TSH (thyrotropin) level. The increased use of TSH as a screening measure and improved assay sensitivity is contributing to the diagnosis of sub clinical hyperthyroidism more frequently than ever in our clinical practise leading to the increased prevalence of the disease. The significance of SCH remains uncertain for most patients as some will revert to normal thyroid status over time whereas others will either remain static or progress to overt thyroid disease in the future. The detrimental effects of a persistently suppressed TSH has now been extensively studied and its effect on the cardiovascular system, the skeleton, mood disturbance, quality of life is quite significant leading to considerable morbidity and mortality. Majority of the patients are asymptomatic and lack overt features but the relevance of treatment is more focussed in elderly patients where the risk of developing cardiac arrhythmia and loss of bone mineral density is much more than young people in whom a conservative approach is usually preferred. The issue is contentious, the situation is challenging and the benefits of treatment are debatable. The consensus for who, when and how to treat is growing but still hasn’t been universally accepted. We attempt to review the recent literature available for sub clinical hyperthyroidism and suggest an analytical approach to its investigations and management.

Gender-specific regulation of response to thyroid hormone in aging

BackgroundSimilar to other systems, the endocrine system is affected by aging. Thyroid hormone, the action of which is affected by many factors, has been shown to be associated with longevity. The most useful marker for the assessment of thyroid hormone action is TSH level. Although age and gender are believed to modify the pituitary set point or response to free thyroid hormone concentration, the precise age- and gender-dependent responses to thyroid hormone have yet to be reported.MethodsWe analyzed the results of 3564 thyroid function tests obtained from patients who received medication at both out- and inpatient clinics of Shinshu University Hospital. Subjects were from among those with thyroid function test results in the normal or mildly abnormal range. Based on a log-linear relationship between the concentrations of FHs and TSH, we established the putative resistance index to assess the relation between serum FH and TSH levels.ResultsFree thyroid hormone and TSH concentration showed an inverse log-linear relation. In males, there was a negative relationship between the free T3 resistance index and age. In females, although there were no relationships between age and FHs, the indices were positively related to age.ConclusionsThese findings indicated that there is a gender-specific response to thyroid hormone with aging. Although the TSH level is a useful marker for the assessment of peripheral thyroid hormone action, the values should be interpreted carefully, especially with regard to age- and gender-related differences.

Hypocalcemia following Treatment for Hyperthyroidism

A 17-year-old female was referred to the endocrinology clinic after blood test results suggestive of hyperthyroidism. She had mild symptoms of thyrotoxicosis, including menstrual disturbance with intermittent palpitations and tremor. On examination, the patient was normotensive, tachycardic (100 beats/min), and of slim build with poor dentition. She had a small diffuse goiter without retrosternal extension or bruit. There was conjunctival injection but no evidence of lid lag or proptosis. Auscultation of the precordium revealed murmurs in systole and diastole consistent with mixed aortic valve disease. The only child of healthy nonconsanguineous parents, the patient had previously been well. Her medical history included mild learning difficulties, a bicuspid aortic valve, recurrent urinary tract infections, and severe constipation as a child that required a colostomy, which was later reversed. Apart from an osmotic laxative, she received no other regular medication. A recent echocardiogram had demonstrated a bicuspid aortic valve with good flow and minor regurgitation. Biochemically, the patient had an undetectable serum concentration of thyroid-stimulating hormone (TSH)4 (<0.03 mIU/L; reference interval, 0.3–5.6 mIU/L) and an increased concentration of free thyroid hormone (fT4) [43 pmol/L (3.3 ng/dL); reference interval, 7.5–21.1 pmol/L]. Her baseline serum concentrations of total calcium [2.27 mmol/L (9.08 mg/dL)] and phosphate [1.26 mmol/L (3.9 mg/dL)] were both within their reference intervals (2.20–2.60 mmol/L and 0.75–1.36 mmol/L, respectively). The serum albumin concentration was 41 g/L (reference interval, 35–50 g/L), and the magnesium concentration was 0.71 mmol/L (reference interval, 0.74–1.00 mmol/L). The results of her other biochemical tests were unremarkable. An immunologic analysis demonstrated increased thyroid peroxidase antibodies (582 IU/L; reference interval, 0–60 IU/L) and increased TSH receptor antibodies (6.9 U/L; reference interval, 0–1.5 U/L), confirming Graves disease. Thyroid imaging revealed a diffusely enlarged thyroid gland, with no visible parathyroid tissue apparent on ultrasound and MRI evaluations. ### QUESTIONS TO CONSIDER 1. What effect does thyrotoxicosis …