Misleading FT4 and FT3 Due to Immunoassay Interference From Autoantibodies.

BACKGROUND: Immunoassays used to measure total and free thyroxine (T4 and FT4) and total and free triiodothyronine (T3 and FT3) can provide inaccurate results due to interference from endogenous autoantibodies. CASE REPORT: A 74-year-old female treated for hypothyroidism with levothyroxine replacement had elevated thyroid stimulating hormone (TSH), FT4, and FT3. Due to concern for hyperthyroidism, levothyroxine was discontinued and further workup was initiated. A pituitary MRI revealed a microadenoma but the alpha-subunit was normal. She was given octreotide for suspected TSH secreting pituitary adenoma without improvement in her TSH, FT4, or FT3 levels. She was referred to our clinic, where inaccurate lab values for FT4 and FT3 were suspected. RESULTS: Testing via equilibrium dialysis liquid chromatography tandem mass spectrometry (LC-MS/MS) method revealed lower levels of FT4 and FT3. Subsequent testing included heterophile blocking tube treatment, polyethylene glycol (PEG) precipitation, and anti-T3/T4 autoantibody levels. The tests revealed thyroid hormone autoantibodies (THAAs) as the cause of immunoassay interference. CONCLUSIONS: When thyroid hormones are elevated and TSH is not suppressed, confirmatory testing with another method such as equilibrium dialysis LC-MS/MS, which is not susceptible to interference from autoantibodies, should be considered.

Cross-Reactivity between Chemical Antibodies Formed to Serum Proteins and Thyroid Axis Target Sites.

In some instances, when chemicals bind to proteins, they have the potential to induce a conformational change in the macromolecule that may misfold in such a way that makes it similar to the various target sites or act as a neoantigen without conformational change. Cross-reactivity then can occur if epitopes of the protein share surface topology to similar binding sites. Alteration of peptides that share topological equivalence with alternating side chains can lead to the formation of binding surfaces that may mimic the antigenic structure of a variant peptide or protein. We investigated how antibodies made against thyroid target sites may bind to various chemical-albumin compounds where binding of the chemical has induced human serum albumin (HSA) misfolding. We found that specific monoclonal or polyclonal antibodies developed against thyroid-stimulating hormone (TSH) receptor, 5'-deiodinase, thyroid peroxidase, thyroglobulin, thyroxine-binding globulin (TBG), thyroxine (T4), and triiodothyronine (T3) bound to various chemical HSA compounds. Our study identified a new mechanism through which chemicals bound to circulating serum proteins lead to structural protein misfolding that creates neoantigens, resulting in the development of antibodies that bind to key target proteins of the thyroid axis through protein misfolding. For demonstration of specificity of thyroid antibody binding to various haptenic chemicals bound to HSA, both serial dilution and inhibition studies were performed and proportioned to the dilution. A significant decline in these reactions was observed. This laboratory analysis of immune reactivity between thyroid target sites and chemicals bound to HSA antibodies identifies a new mechanism by which chemicals can disrupt thyroid function.

Evaluation of the structure, autoimmunity, and functions of the thyroid gland in familial Mediterranean fever patients.

Objective Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder that is frequently seen in the eastern Mediterranean region. The thyroid gland can be affected in FMF patients through autoimmunity or amyloidosis. Here, we aimed to evaluate the structure and functions of the thyroid gland in addition to possible autoimmunity in FMF patients. Subjects and methods The study was conducted by the Endocrinology and Metabolism and Internal Medicine Departments. Thirty FMF patients and 30 age and gender-matched healthy controls were enrolled in the study. Free thyroxin (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (anti-TPO) autoantibodies were investigated. Detailed thyroid grayscale and Doppler Ultrasonography examinations and shear-wave elastosonography (SWE) were performed in the patient and control groups. Results Anti-TPO was detected in 24% (n = 7) of the patients. On the grayscale US, mean thyroid volumes were similar between the FMF and the control groups (p > 0.05). By Doppler US, thyroid vascularity observed was detected in 10.3% (n = 3) of the patients. SWE revealed that the mean velocity value of right vs. left lobe in the patient group was 1.77 ± 0.45 m/s and 1.95 ± 0.51 m/s, respectively. Compared to the control group, the mean velocity values were significantly higher in the right (p = 0.004) and left (p = 0.01) lobes of the patient group. The mean stiffness value in the patient group was also significantly higher in the right and left lobes [10.13 ± 5.65 kPa (p = 0.005) and 12.24 ± 6.17 kPa (p = 0.02), respectively]. Conclusion Recognizing the complications of FMF early in the course of the disease is as important as the early diagnosis of the disorder. Based on this, thyroid functions and changes in its structure should be evaluated carefully for early diagnosis of a possible coexisting thyroid disorder. Arch Endocrinol Metab. 2020;64(1):66-70.

Evaluation of the structure, autoimmunity, and functions of the thyroid gland in familial Mediterranean fever patients

ABSTRACT Objective Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder that is frequently seen in the eastern Mediterranean region. The thyroid gland can be affected in FMF patients through autoimmunity or amyloidosis. Here, we aimed to evaluate the structure and functions of the thyroid gland in addition to possible autoimmunity in FMF patients. Subjects and methods The study was conducted by the Endocrinology and Metabolism and Internal Medicine Departments. Thirty FMF patients and 30 age and gender-matched healthy controls were enrolled in the study. Free thyroxin (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (anti-TPO) autoantibodies were investigated. Detailed thyroid grayscale and Doppler Ultrasonography examinations and shear-wave elastosonography (SWE) were performed in the patient and control groups. Results Anti-TPO was detected in 24% (n = 7) of the patients. On the grayscale US, mean thyroid volumes were similar between the FMF and the control groups (p > 0.05). By Doppler US, thyroid vascularity observed was detected in 10.3% (n = 3) of the patients. SWE revealed that the mean velocity value of right vs. left lobe in the patient group was 1.77 ± 0.45 m/s and 1.95 ± 0.51 m/s, respectively. Compared to the control group, the mean velocity values were significantly higher in the right (p = 0.004) and left (p = 0.01) lobes of the patient group. The mean stiffness value in the patient group was also significantly higher in the right and left lobes [10.13 ± 5.65 kPa (p = 0.005) and 12.24 ± 6.17 kPa (p = 0.02), respectively]. Conclusion Recognizing the complications of FMF early in the course of the disease is as important as the early diagnosis of the disorder. Based on this, thyroid functions and changes in its structure should be evaluated carefully for early diagnosis of a possible coexisting thyroid disorder. Arch Endocrinol Metab. 2020;64(1):66-70

Rapid cycling bipolar disorder is associated with antithyroid antibodies, instead of thyroid dysfunction.

BACKGROUND: Conclusions regarding the association between antithyroid antibodies or thyroid dysfunction and rapid cycling bipolar disorder (RCBD) have been conflicting. Previous studies suggest that the impact of antithyroid antibodies on mental wellbeing seems to be independent of thyroid function. Here, we investigated their independent association with RCBD in a large, well-defined population of bipolar disorder (BD). METHODS: Fast serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid Stimulating Hormone (TSH), TPO-abs and Tg-abs were simultaneously measured in 352 patients with BD. Clinical features of BD were collected through semi-structural interview conducted by trained interviewers with background of psychiatric education. RESULTS: Neither hypothyroidism nor hyperthyroidism was significantly associated with RCBD. Both TPO-abs and Tg-abs were significantly related to RCBD, even after controlling for gender, age, marriage status, education, antidepressants treatment, comorbidity of thyroid diseases, and thyroid function (serum levels of FT3, FT4 and TSH). Although TPO-abs and Tg-abs were highly correlated with each other, binary logistic regression with forward LR selected TPO-abs, instead of Tg-abs, to be associated with RCBD. TPO-abs was significantly, independently of Tg-abs, associated with hyperthyroidism, while Tg-abs was marginally significantly related to hypothyroidism at the presence of TPO-abs. CONCLUSION: TPO-abs might be treated as a biomarker of RCBD. Further exploring the underlying mechanism might help understand the nature of RCBD and find out new treatment target for it.

Association of IL6 gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), are archetypes of organ-specific autoimmune diseases, but the prognosis of patients with AITD varies. Autoimmune diseases, including AITDs, are believed to develop in response to both genetic and environmental factors. Interleukin (IL)-6 plays a major role in B cell differentiation and T cell proliferation, and methylation of the IL6 gene is associated with IL-6 production. To clarify the role of IL6 gene methylation in the pathogenesis and prognosis of AITDs, we measured the methylation levels of -666, -664, -610, -491 and -426 CpG sites in the IL6 gene. We measured the methylation levels of 5 CpG sites in 29 patients with HD, 31 patients with GD and 16 healthy volunteers using pyrosequencing. The methylation level at each of the -664, -491 and -426 CpG sites was negatively correlated with the age at the time of sampling. Multiple regression analysis indicated that patients with HD, including severe or mild HD, showed higher methylation levels at the -426 CpG site than control subjects. Patients with intractable GD showed lower methylation levels at the -664 and -666 CpG sites than patients with GD in remission. In conclusion, IL6 gene methylation levels were related to the susceptibility to HD and the intractability of GD.

The relationship between inflammatory factors, oxidative stress and DIO-1 concentration in patients with chronic renal failure accompanied with or without euthyroid sick syndrome.

Objective To investigate the relationship between inflammatory factors, oxidative stress and type 1 deiodinase (DIO-1) concentration in patients with chronic renal failure (CRF) with or without euthyroid sick syndrome (ESS). Methods This study recruited patients with CRF and divided them into two groups: group 1 had low free triiodothyronine (FT3) levels; and group 2 had normal FT3 levels. Group 3 consisted of healthy volunteers. Serum levels of interleukin (IL)-6, IL-1ß, tumour necrosis factor (TNF)-α, 8-isoprostane and DIO-1 were measured using enzyme-linked immunosorbent assays. Multiple regression analysis was used to analyse correlations between parameters. Results Sixty patients were enrolled into each group and the groups were comparable in terms of vital signs, white blood cell count, free thyroxine and thyroid stimulating hormone concentrations. The serum DIO-1 concentration was significantly higher in group 2 than in groups 1 and 3. Multivariate regression analysis revealed that the DIO-1 concentration was inversely correlated with the TNF-α concentration. Conclusions Patients with CRF without ESS showed higher concentrations of DIO-1 than patients with ESS. The DIO-1 concentration was inversely correlated with the TNF-α concentration, which might indicate that the inflammatory response was milder in the patients with CRF without ESS than in those with ESS.

Thyroid Function and Autoimmune Indications in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: Previous studies have shown that functional abnormalities of the thyroid are associated with the pathogenesis of several neurological diseases. However, their relationship in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis remains to be defined. METHODS: Forty-three patients with anti-NMDAR encephalitis were examined for thyroid function and autoimmune indications, in comparison with 225 healthy controls (CTL). Patients were further classified into 2 subgroups based on their free tri-iodothyronine (fT3) levels. Moreover, fT3 levels were also investigated after at least three months of follow-up. The clinical characteristics of the patients and CTL were described in detail. RESULTS: Serum levels of fT3 and thyroid-stimulating hormone (TSH) were found to be relatively lower in patients with anti-NMDAR encephalitis than in CTL (both p < 0.001). Low T3 syndrome also occurred more frequently in anti- NMDAR encephalitis (25.6 vs. 0.4%, p < 0.001). However, no statistical differences were detected between patients and CTL in terms of the positive rate of thyroid antibodies and other types of thyroid dysfunction. Patients with low T3 levels tended to have a longer hospital stay (p = 0.006), a higher rate of abnormal brain magnetic resonance imaging (MRI) findings (p = 0.033), a higher frequency of consciousness declination (p = 0.029), and a higher modified Rankin scale (mRS) score during hospitalization. Low fT3 levels were also associated with abnormal MRI findings, a decline in consciousness, and the mRS score on admission. In addition, fT3 seemed to gradually return to normal levels upon improvement of the mRS score (r = -0.649, p = 0.002). CONCLUSIONS: Low T3 syndrome often copresents in anti-NMDAR encephalitis and indicates a longer hospitalization, abnormal MRI findings, consciousness declination, and a higher clinical severity. However, fT3 levels do not seem to influence the prognosis of anti-NMDAR encephalitis.

Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function.

Innate immune cells, including macrophages, have recently been identified as target cells for thyroid hormone. We hypothesized that optimal intracellular concentrations of the active thyroid hormone triiodothyronine (T3) are essential for proinflammatory macrophage function. T3 is generated intracellularly by type 2 deiodinase (D2) and acts via the nuclear thyroid hormone receptor (TR). In zebrafish embryos, D2 knockdown increased mortality during pneumococcal meningitis. Primary murine D2 knockout macrophages exhibited impaired phagocytosis and partially reduced cytokine response to stimulation with bacterial endotoxin. These effects are presumably due to reduced intracellular T3 availability. Knockdown of the main TR in macrophages, TRα, impaired polarization into proinflammatory macrophages and amplified polarization into immunomodulatory macrophages. Intracellular T3 availability and action appear to play a crucial role in macrophage function. Our data suggest that low intracellular T3 action has an anti-inflammatory effect, possibly due to an effect on macrophage polarization mediated via the TRα. This study provides important insights into the link between the endocrine and innate immune system.

Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.

OBJECTIVES: Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. METHODS: Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-<4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models. RESULTS: Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01). CONCLUSIONS: Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.

Reversible and unilateral corticospinal tract disease secondary to autoimmune free-T3-thyrotoxicosis.

68-year-old female patient with no significant medical history presents with a 3-month history of progressive neurological symptoms, which began with left eye ptosis, blurred vision and non-painful jaw discomfort, followed by left spastic weakness and hyper-reflexia with positive Babinski and Hoffman signs. An elevated T3 level, a positive peroxidase and an antigraves antibody level led to an ultrasound, which confirmed a sub acute-chronic autoimmune thyroiditis. A nerve conduction studies/electromyogram showed normal motor and sensory velocity conduction with a small amplitude compound motor action potential, indicative of likely axonal damage. Following treatment with carbimazole, the neurological symptoms greatly improved. The authors concluded that the left pyramidal syndrome was secondary to autoimmune free T3-thyrotoxicosis.

Correlation of thyroid antibodies with TSH, T3 and T4 hormones in patients diagnosed with autoimmune thyroid disorders.

The serum concentrations of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies are directly correlate in the induction and diagnosis of autoimmune thyroid disorders (AITDs). Therefore, the evaluation of serum anti-TPO and anti-TG antibodies in relation to thyroid function test parameters including thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4). This evaluation would be helpful in early diagnosis of abnormal thyroid function and associated autoimmune thyroid diseases. In this cross-sectional study, the serum anti-TPO, anti-TG, T3, T4 and TSH levels of 311 suspected patients of autoimmune thyroid disorders and 40 control subjects were evaluated. The data were presented as mean, ± standard deviations of the mean. Pearson correlation and chi-square tests were used to assess the correlation coefficients and significance in the contingency tables. The thyroid function test parameters in normal and AITDs suspected patients were significantly different in correlation to elevated serum levels of anti-TPO antibody. A significant association was detected between female gender and elevated levels of anti-TPO (P value = 0.047). A higher percentage of women showed elevated levels of anti-TG, but it was not statistically significant (P value= 0.107). The findings of the study reveal a strong correlation between thyroid function test and thyroid antibodies levels, elaborating the clinical importance of thyroid antibodies in clinical examination and follow-up of patients with autoimmune thyroid disorders.

Thyroid hormone disorders and sepsis.

Sepsis is a systemic inflammatory response syndrome with high mortality, which results from severe infection and can lead to secondary organ dysfunction. It is one of the most common cause of death in intensive care unit. Clinical reports have shown that sepsis was often accompanied by thyroid dysfunction, which is called "low triiodothyronine (T3)" syndrome and characterized by decreased blood total T3 and free T3, and by normal or decreased thyroxine (T4) and thyroid stimulating hormone (TSH). This syndrome may greatly affect the prognosis of patients with sepsis. The main purpose of this review is to illustrate the role of thyroid hormone disorder in the development and prognosis of sepsis.

Comprehensive growth performance, immune function, plasma biochemistry, gene expressions and cell death morphology responses to a daily corticosterone injection course in broiler chickens.

The massive meat production of broiler chickens make them continuously exposed to potential stressors that stimulate releasing of stress-related hormones like corticosterone (CORT) which is responsible for specific pathways in biological mechanisms and physiological activities. Therefore, this research was conducted to evaluate a wide range of responses related to broiler performance, immune function, plasma biochemistry, related gene expressions and cell death morphology during and after a 7-day course of CORT injection. A total number of 200 one-day-old commercial Cobb broiler chicks were used in this study. From 21 to 28 d of age, broilers were randomly assigned to one of 2 groups with 5 replicates of 20 birds each; the first group received a daily intramuscular injection of 5 mg/kg BW corticosterone dissolved in 0.5 ml ethanol:saline solution (CORT group), while the second group received a daily intramuscular injection of 0.5 ml ethanol:saline only (CONT group). Growth performance, including body weight (BW), daily weight gain (DG), feed intake (FI) and feed conversion ratio (FC), were calculated at 0, 3 and 7 d after the start of the CORT injections. At the same times, blood samples were collected in each group for hematological (TWBC's and H/L ratio), T- and B-lymphocytes proliferation and plasma biochemical assays (total protein, TP; free triiodothyronine hormone, fT3; aspartate amino transaminase, AST; and alanine amino transaminase, ALT). The liver, thymus, bursa of Fabricius and spleen were dissected and weighed, and the mRNA expression of insulin-like growth factor 1 gene (IGF-1) in liver and cell-death-program gene (caspase-9) in bursa were analyzed for each group and time; while the apoptotic/necrotic cells were morphologically detected in the spleen. From 28 to 35 d of age, broilers were kept for recovery period without CORT injection and the same sampling and parameters were repeated at the end (at 14 d after initiation of the CORT injection). In general, all parameters of broiler performance were negatively affected by the CORT injection. In addition, CORT treatment decreased the plasma concentration of fT3 and the mRNA expression of hepatic IGF-1. A significant increase in liver weight accompanied by an increase in plasma TP, AST and ALT was observed with CORT treatment, indicating an incidence of liver malfunction by CORT. Moreover, the relative weights of thymus, bursa and spleen decreased by the CORT treatment with low counts of TWBC's and low stimulation of T & B cells while the H/L ratio increased; indicating immunosuppressive effect for CORT treatment. Furthermore, high expression of caspase-9 gene occurred in the bursa of CORT-treated chickens, however, it was associated with a high necrotic vs. low apoptotic cell death pathway in the spleen. Seven days after termination of the CORT treatment in broilers, most of these aspects remained negatively affected by CORT and did not recover to its normal status. The current study provides a comprehensive view of different physiological modulations in broiler chickens by CORT treatment and may set the potential means to mount a successful defense against stress in broilers and other animals as well.

[Immunoanalytical profile of free tri-iodothyronine]. / Profil immunoanalytique de la tri-iodothyronine libre.

Tri-iodothyronine (T3) is the active form of thyroid hormone at the nuclear cell level. About 80% of tri-iodothyronine is produced by peripheral deiodination of thyroxine. The determination of the free form of this hormone is useful for the diagnosis and the follow-up of hyperthyroidism. In routine clinical laboratories, immunoassays remain the most used technics. After recalling the main points related to the physiological data, the authors point out the possible errors during the analytical steps of the assay.

Anti-ruthenium antibodies mimic macro-TSH in electrochemiluminescent immunoassay.

BACKGROUND: Macro-hormones are circulating conjugates of hormones with immunoglobulins, which often artefactually elevate biochemical test results. Particularly when causing only moderate elevation no suspicion will be raised. By far the most frequently encountered macro-hormone is macro-prolactin. Here we report a female patient with rheumatoid arthritis who had persistently and grossly elevated thyroid stimulating hormone (TSH) but normal free thyroxine in electrochemiluminescent assays. Although clinically euthyroid, she was put on thyroxine therapy which caused hyperthyroid symptoms. METHODS: An analytic interference by macro-TSH was assumed by dilution experiments, polyethylene-glycol-precipitation, the addition of a heterophilic antibody blocking reagent and size exclusion chromatography. RESULTS: Further workup, however, revealed the presence of anti-ruthenium antibodies. CONCLUSIONS: To our knowledge this is the first report of anti-ruthenium antibodies selectively interfering with a TSH assay and causing erratic gross elevation of TSH mimicking macro-TSH.

Thyroid peroxidase antibody positivity and triiodothyronine levels are associated with pediatric Graves' ophthalmopathy.

BACKGROUND: Graves' ophthalmopathy (GO) occurs commonly in children with Graves' disease (GD). However, there are limited studies on the clinical manifestations and thyroid autoantibodies in pediatric GO. The aim of this study was to investigate the prevalence and risk factors of GO in childhood GD. METHODS: Clinical and biochemical data from children and adolescents with GD were retrospectively reviewed. Eighty patients under 19 years of age were included in the present study. We compared the clinical and biochemical differences between patients with and without GO. RESULTS: Thirty-nine percent of the patients had GO, and 81% of the GO patients were females. Of these, two patients showed unilateral GO. Triiodothyronine (T3) levels were higher in GO patients than in those without GO. Anti-thyroglobulin antibody and thyroid stimulating hormone receptor antibody titers were not significantly different between the two groups. Anti-thyroid peroxidase antibody (TPO Ab) positivity was 68% in the patients with GO and only 47% in the patients without GO. In multivariate regression analysis, high T3 levels and TPO Ab positivity were related to the presence of GO. CONCLUSION: In children and adolescents with GD, TPO Ab positivity and high T3 levels could act as predictive factors for the presence of GO.

A patient-specific model of the negative-feedback control of the hypothalamus-pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis.

The purpose of modelling the negative-feedback control mechanism of the hypothalamus-pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis is to describe the clinical course of euthyroidism, subclinical hypothyroidism and overt hypothyroidism for patients. Thyroid hormone thyroxine (T4) and triiodothyronine (T3) levels are controlled by negative-feedback control through thyroid-stimulating hormone (TSH). T4, like other hormones, can be bound or unbound; the unbound T4 (FT4) is used as a marker for hypothyroidism. Autoimmune thyroiditis is a disease in which the thyroid-infiltrating lymphocytes attack autoantigens in follicle cells, destroying them over a long time. To describe the operation of the feedback control, we developed a mathematical model involving four clinical variables: TSH, FT4, anti-thyroid peroxidase antibodies and the thyroid gland's functional size. The first three variables are regularly measured while the last variable is determined through relationships between the other three variables. The problem of two different time scales for circulating hormones and thyroid damage is addressed using singular perturbation theory. Analysis of the mathematical model establishes stability and conditions under which the diseased state can maintain the slow movement toward diseased state equilibrium. Although we have used four variables in modelling the feedback control through the HPT axis, the predicted clinical course given any set of parameters is shown to depend on the steady-state levels of TSH and FT4. This observation makes possible the development of the clinical charts based only on the levels of TSH, time and potential steady-state values. To validate the model predictions, a dataset obtained from a Sicilian adult population has been employed.

The thyroid hormone triiodothyronine controls macrophage maturation and functions: protective role during inflammation.

The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor ß1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems.

A high frequency of circulating th22 and th17 cells in patients with new onset graves' disease.

T-helper (Th) 22 and Th17 cells are involved in the pathogenesis of autoimmune diseases. However, their roles in the pathogenesis of Graves'disease (GD) are unclear. This study is aimed at examining the frequency of peripheral blood Th22, Th17, and Th1 cells and the levels of plasma IL-22, IL-17, and IFN-γ in patients with GD. A total of 27 patients with new onset GD and 27 gender- and age-matched healthy controls (HC) were examined for the frequency of peripheral blood Th22, Th17, and IFN-γ cells by flow cytometry. The concentrations of plasma IL-22, IL-17, and IFN-γ were examined by enzyme-linked immunosorbent assay. The levels of serum TSHR antibodies (A-TSHR), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were examined by radioimmunoassay and chemiluminescent assay, respectively. The levels of serum TSAb were examined by enzyme-linked immunosorbent assay. In comparison with those in the HC, significantly elevated percentages of Th22 and Th17 cells, but not Th1 cells, and increased levels of plasma IL-22 and IL-17, but not IFN-γ, were detected in GD patients (P<0.0001, for both). The percentages of both Th22 and Th17 cells and the levels of plasma IL-22 and IL-17 were correlated positively with the levels of serum TSAb in GD patients (r = 0.7944, P<0.0001; r = 0.8110, P<0.0001; r = 0.7101, p<0.0001; r = 0.7407, p<0.0001, respectively). Th22 and Th17 cells may contribute to the pathogenesis of GD.