Bilateral Keratoconus Induced by Secondary Hypothyroidism After Radioactive Iodine Therapy.

PURPOSE: To present a case of new-onset, bilateral, rapidly progressive keratoconus induced by secondary hypothyroidism after radioactive iodine therapy during the sixth decade of life that was successfully treated with corneal cross-linking. METHODS: Case report and literature review. RESULTS: A 53-year-old woman with no ocular complaints but with a history of Graves' disease and thyrotoxicosis was treated with radioactive iodine therapy and oral levothyroxine for secondary acquired hypothyroidism 3 years prior. Initially, uncorrected distance visual acuity (UDVA) was 20/40 and corrected distance visual acuity (CDVA) was 20/25 in both eyes. Over the following 3 years, the patient developed worsening UDVA and CDVA, with increasing manifest astigmatism of greater than 7.00 diopters (D) in the right eye and 4.75 D in the left eye, with corneal thinning and focal steepening and was diagnosed as having bilateral progressive keratoconus. The patient underwent sequential corneal cross-linking with resultant postoperative CDVA of 20/20 and reduced maximum keratometry and manifest astigmatism in both eyes. The patient's thyroid levels were within normal limits throughout the clinical course. CONCLUSIONS: This case provides evidence of the relationship between keratoconus development and thyroid gland dysfunction. The pathophysiology of this relationship has yet to be completely elucidated, but elevated levels of thyroxine in the aqueous humor and tear film and thyroxine receptors in the cornea likely play a role. Screening topographies for patients with thyroid gland dysfunction may be of value for these higher risk patients. [J Refract Surg. 2018;34(5):351-353.].

Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients.

Autism spectrum disorder (ASD) is a neuro developmental disorder, reported to be on a rise in the past two decades. Thyroid hormone-T3 plays an important role in early embryonic and central nervous system development. T3 mediates its function by binding to thyroid hormone receptors, TRα and TRß. Alterations in T3 levels and thyroid receptor mutations have been earlier implicated in neuropsychiatric disorders and have been linked to environmental toxins. Limited reports from earlier studies have shown the effectiveness of T3 treatment with promising results in children with ASD and that the thyroid hormone levels in these children was also normal. This necessitates the need to explore the genetic variations in the components of the thyroid hormone pathway in ASD children. To achieve this objective, we performed genetic analysis of ligand binding domain of THRA and THRB receptor genes in 30 ASD subjects and in age matched controls from India. Our study for the first time reports novel single nucleotide polymorphisms in the THRA and THRB receptor genes of ASD individuals. Autism Res 2017, 10: 1919-1928. ©2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Thyroid hormone (T3) and thyroid receptors (TRα and TRß) are the major components of the thyroid hormone pathway. The link between thyroid pathway and neuronal development is proven in clinical medicine. Since the thyroid hormone levels in Autistic children are normal, variations in their receptors needs to be explored. To achieve this objective, changes in THRA and THRB receptor genes was studied in 30 ASD and normal children from India. The impact of some of these mutations on receptor function was also studied.

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood.

OBJECTIVE: Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. DESIGN: Observational, retrospective study. PATIENTS: Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. MEASUREMENTS: The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). RESULTS: Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. CONCLUSIONS: Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.

Circulating thyroid stimulating hormone receptor messenger RNA and differentiated thyroid cancer: A diagnostic meta-analysis.

Thyroid stimulating hormone receptor messenger RNA (TSHR-mRNA) is over-expressed in thyroid cancer patients, which indicates that TSHR-mRNA is a potential biomarker of thyroid cancer. However, system evaluation for TSHR-mRNA as a diagnostic biomarker of thyroid cancer is deficient. The performance of TSHR-mRNA for thyroid cancer diagnosis was evaluated in this study. Three common international databases as well as a Chinese database were applied for literature researching. Quality assessment of the included literatures was conducted by the QUADAS-2 tool. Totally, 1027 patients from nine studies eligible for the meta-analysis were included in this study. Global sensitivity and specificity for the positivity of TSHR-mRNA in the thyroid cancer diagnosis is 72% and 82%. The value of AUC for this test performance was 0.84. Our meta-analysis suggests that TSHR-mRNA might be a potential biomarker to complete present diagnostic methods for early and precision diagnosis of thyroid cancer. Notably, this findings need validation thorough large-scale clinical studies.

Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a TRß Mutation.

Resistance to thyroid hormone (RTH) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone. We herein describe a 60-year old man who presented with the clinical features of cardiomyopathy, diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone. A genetic analysis of thyroid hormone receptor (TR) revealed a missense mutation (A268D) in the TRß gene. Clinical manifestations of RTH may be variable due to different tissue distributions of TR subtypes and different actions of mutant receptors. The current case demonstrates that patients with a TRß mutation may have impaired his glucose metabolism and a reduced cardiac function, although patients appear clinically euthyroid.

Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson's and Alzheimer's Disease Patients.

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression.

Early life nutritional intervention causes adult-onset insulin resistance and obesity in rats. Thyroid hormone receptor (TR), in turn, transcriptionally enhances skeletal muscle Glut4 expression. We tested the hypothesis that reduced circulating thyroid-stimulating hormone and T4 concentrations encountered in postnatal (PN4-PN24) high-carbohydrate (HC) milk formula-fed versus the mother-fed controls (MF) would epigenetically interfere with TR induction of adult (100 days) male rat skeletal muscle Glut4 expression, thereby providing a molecular mechanism mediating insulin resistance. We observed increased DNA methylation of the CpG island with enhanced recruitment of Dnmt3a, Dnmt3b and MeCP2 in the glut4 promoter region along with reduced acetylation of histone (H)2A.Z and H4 particularly at the H4.lysine (K)16 residue, which was predominantly mediated by histone deacetylase 4 (HDAC4). This was followed by enhanced recruitment of heterochromatin protein 1ß to the glut4 promoter with increased Suv39H1 methylase concentrations. These changes reduced TR binding of the T3 response element of the glut4 gene (TREs; -473 to -450 bp) detected qualitatively in vivo (electromobility shift assay) and quantified ex vivo (chromatin immunoprecipitation). In addition, the recruitment of steroid receptor coactivator and CREB-binding protein to the glut4 promoter-protein complex was reduced. Co-immunoprecipitation experiments confirmed the interaction between TR and CBP to be reduced and HDAC4 to be enhanced in HC versus MF groups. These molecular changes were associated with diminished skeletal muscle Glut4 mRNA and protein concentrations. We conclude that early postnatal exposure to HC diet epigenetically reduced TR induction of adult male skeletal muscle Glut4 expression, uncovering novel molecular mechanisms contributing to adult insulin resistance and obesity.

Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells.

BACKGROUND: Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain. OBJECTIVE: The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans. METHODS: Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed. RESULTS: RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly. CONCLUSION: These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

Foliculogênese esteroidogênese ovarianas em ratas adultas hipertireóideas / Ovarian folliculogenesis and steroidogenesis in hyperthyreiods adult rats

A foliculogênese e a esteroidogênese ovarianas foram estudadas em ratas adultas hipertireóideas. O hipertireoidismo foi induzido em 27 ratas Wistar com cinco meses de idade pela administração diária de 50ng de L-tiroxina. Outras 27 ratas foram mantidas em estado eutireóideo e serviram como controle. Aos 30, 60 e 90 dias após o início do tratamento, nove ratas de cada grupo foram sacrificadas, os ovários inspecionados, pesados e processados para avaliação histomorfométrica e o plasma sanguíneo colhido para dosagem de T4-livre, estradiol e progesterona. As concentrações plasmáticas de T4-livre foram significativamente maiores nas ratas hipertireóideas aos 30, 60 e 90 dias, e o peso médio dos ovários foi significativamente maior somente aos 90 dias. Já o número de folículos secundários e terciários e de corpos lúteos foi significativamente maior aos 60 ou aos 90 dias, mas a taxa percentual de atresia folicular só foi diferente aos 90 dias. O número de folículos primários e pré-ovulatórios, assim como as concentrações plasmáticas , de estradiol e progesterona, não diferiram entre grupos e entre períodos. Concluiu-se que o hipertireoidismo estimula a foliculogênese ovariana em ratas sexualmente maduras e diminui a atresia folicular.

Roles of an endogenous serum lectin in the immune protection of blue gourami, Trichogaster trichopterus (Pallus) against Aeromonas hydrophila.

The serum of blue gourami, Trichogaster trichopterus (Pallus), contains a calcium-dependent, N-acetyl-galactosamine-binding lectin (BGL) which efficiently activates and enhances the non-specific immune response of fish towards a virulent strain of Aeromonas hydrophila. In the in vitro studies, a lectin concentration range of 0.05-1.0 ng ml(-1) was found to significantly promote phagocytic uptake of the bacteria by macrophages. This effect was further augmented when purified lectin was combined with laminarin (beta-1,3-D-glucan). Supernatants obtained from these lectin-stimulated macrophage cultures also exhibited significant bacteria-killing activities. In addition, complement from naive fish serum, in the presence of purified BGL, was able to kill A. hydrophila. Finally, challenge experiments demonstrated that BGL could confer effective immune protection to naive blue gourami against an Aeromonas infection.

Estudo de adesäo ao tratamento do hipotiroidismo / Study of adhesion at the hypothyroidism treatment

Para avaliarmos o impacto da adesäo no controle do hipotiroidismo em nosso meio, estudamos 100 portadores de hipotiroidismo mal controlados (Mo de TSH: 12U/L) acompanhados no HC-UNICAMP e no HUCFF-UFRJ, 80 mulheres e 20 homens de nível sócil-econômico e cultural similar. Após serem examinados e orientados quanto à importância de seu uso adequado, os pacientes recebiam hormônio tiroidiano em uma das 4 apresentaçöes comercialmente disponíveis em nosso meio, de forma aleatória e em dose similar à anteriormente prescrita, por um período médio de 3 meses. Os 25 pacientes de cada grupo possuíam características clínicas e sócio-econômico-culturais semelhantes com renda per capita mensal em torno de U$100,00 (X2:NS). Mensalmente os doentes eram examinados por um mesmo médico. Realizávamos um controle do número de comprimidos restantes e embalagens vazias, dosagens de TSH e de T4 livre. Nossos resultados mostram que 82 por cento dos pacientes näo aderiam ao tratamento proposto, faltando aos retornos (36 por cento dos casos) e/ou näo seguido corretamente a prescriçäo médica (66 por cento dos casos). Os níveis de TSH foram controlados em 77 pacientes ao término do estudo, independente da formulaçäo de tiroxina prescrita (X2 de pacientes controlados?grupo: NS). Dezesseis pacientes apresentaram níveis de TSH diminuídos no 1§ retorno, sugerindo que usavam doses inferiores às prescritas antes do medicamento ser-lhes fornecido. Concluímos que podemos controlar portadores de hipotiroidismo adequadamente com qualquer uma das apresentaçöes disponíveis no mercado nacional quando o paciente adere ao esquema terapêutico proposto.

Thyroid function during pregnancy.

BACKGROUND: This Case Conference reviews the normal changes in thyroid activity that occur during pregnancy and the proper use of laboratory tests for the diagnosis of thyroid dysfunction in the pregnant patient. CASE: A woman in the 18th week of pregnancy presented with tachycardia, increased blood pressure, severe vomiting, increased total and free thyroid hormone concentrations, a thyroid-stimulating hormone (TSH) concentration within the reference interval, and an increased human chorionic gonadotropin (hCG) beta-subunit concentration. ISSUES: During pregnancy, normal thyroid activity undergoes significant changes, including a two- to threefold increase in thyroxine-binding globulin concentrations, a 30-100% increase in total triiodothyronine and thyroxine concentrations, increased serum thyroglobulin, and increased renal iodide clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy produces an overall increase in thyroid activity, which allows the healthy individual to remain in a net euthyroid state. However, both hyper- and hypothyroidism can occur in pregnant patients. In addition, two pregnancy-specific conditions, hyperemesis gravidarum and gestational trophoblastic disease, can lead to clinical hyperthyroidism. The normal changes in thyroid activity and the association of pregnancy with conditions that can cause hyperthyroidism necessitates careful interpretation of thyroid function tests during pregnancy. CONCLUSION: Assessment of thyroid function during pregnancy should be done with a careful clinical evaluation of the patient's symptoms as well as measurement of TSH and free, not total, thyroid hormones. Measurement of thyroid autoantibodies may also be useful in selected cases to detect maternal Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal consequences of maternal thyroid dysfunction.

Pharmacological effects of propylthiouracil on corticosterone secretion in male rats.

BACKGROUND: We investigated the direct effects of propylthiouracil (PTU) on corticosterone secretion both in vivo and in vitro. METHODS: Male rats were divided into 4 groups and then injected subcutaneously with saline, PTU, PTU plus thyroxine (T4), or T4 once daily for 2 weeks. After 2 weeks, rats were decapitated or received adrenocorticotropic hormone (ACTH), intravenously. Zona fasciculata-reticularis (ZFR) cells from normal, saline-, PTU-, PTU plus T4-, or T4-treated rats were incubated with ACTH, forskolin, 8-Br-cAMP, deoxycorticosterone (DOC) +/- PTU (1, 2, or 5 mg/mL) at 37 degrees C for 2 hours. Corticosterone concentrations in plasma and cell media, and 3':5'-cyclic adenosine monophosphate (cAMP) production in ZFR cells were determined by radioimmunoassay. The effects of PTU on the activities of steroidogenic enzymes in ZFR cells were measured by the amounts of intermediate steroidal products separated by thin-layer chromatography. RESULTS: The basal and ACTH-stimulated levels of plasma corticosterone in PTU-treated rats were lower as compared to saline-treated animals. Both basal and ACTH-stimulated corticosterone secretion were inhibited by PTU > 2 mg/mL in rat ZFR cells. The cAMP production induced by forskolin was lower in PTU, PTU plus T4, or T4-treated rats than in saline-treated animals. Chronic administration of PTU or PTU plus T4 inhibited the 3 beta-hydroxysteroid dehydrogenase, 21 beta-hydroxylase, and 11 beta-hydroxylase activities. Administration of PTU (1, 2, and 5 mg/mL) suppressed the basal, ACTH, 8-Br-cAMP, forskolin, and DOC-stimulated corticosterone secretion in rat ZFR cells. Likewise, PTU > 2 mg/mL inhibited the ACTH and 8-Br-cAMP-stimulated levels of intracellular cAMP in rat ZFR cells. CONCLUSIONS: These results suggest that PTU counteracts both basal and ACTH-induced adrenal steroidogenesis through their attenuation of the activity of 11 beta-hydroxylase and cAMP production in rat ZFR cells.

Effects of diabetes on rodent cardiac thyroid hormone receptor and isomyosin expression.

Previous studies show that diabetes induces marked transformations in cardiac myosin heavy chain (MHC) gene expression that are somehow linked to the cellular action of thyroid hormone 3,5,3'-triiodothyronine (T3). In this study, we tested the hypothesis that diabetes induces a reduced expression of thyroid hormone receptors (TRs), which are known to be important transcription factors interacting with thyroid response elements (TREs) in the promoter region of both alpha- and beta-MHC genes. Adult female rats were randomly assigned to either a normal control (NC) or diabetic (D) group. Three and/or six weeks after induction of diabetes via streptozotocin injection, the hearts of the animals were analyzed for MHC and TR mRNA isoforms expression, nuclear T3 binding, and nuclear extract interaction with a palindromic TRE. Results showed that diabetes induced significant alteration in alpha- and beta-MHC expression. Northern blot analyses indicated no diabetes-associated differences in TR isoform mRNA signals. Cardiac nuclear T3 binding studies suggested no differences in either the binding capacity or the equilibrium binding constant among the two groups, indicating no changes in either the number of nuclear TRs or their affinity for T3. Furthermore, gel mobility shift assays detected no difference between NC and D groups for cardiac nuclear extract binding to palindromic TRE. Collectively, these findings suggest that, whereas diabetes exerts a profound effect on cardiac isomyosin gene expression, the underlying mechanism, although dependent on factors linked to T3 function, does not involve alterations in TR expression.

Sex steroids modulate the pituitary parameters involved in the regulation of TSH secretion in the rat.

The sex-related differences observed in the regulation of TSH secretion was further investigated by determination of the densities of T3 nuclear and TRH membrane receptors as well as the activity of 5'-deiodinase (5'D) in the anterior pituitary gland of adult male and female rats. The respective modulatory roles of androgens and estrogens on these parameters were evaluated by similar determinations carried out in castrated and in estrogen-treated male rats. The density of pituitary T3 and TRH receptors and the activity of 5'D type II were significantly greater in the female than in the male rats. The E2-treated male rats disclosed a female profile, viz. also greater densities of T3 and TRH receptors when compared with control male rats (2.3 +/- 0.2 vs 1.8 +/- 0.2 fmol T3/mg gland and 9.4 +/- 0.8 vs 6.0 +/- 0.8 fmol TRH/mg gland, mean +/- SEM), whereas no changes were found in the castrated rats. The E2-treated rats and the castrated rats exhibited an increased pituitary activity of 5'D, type II (0.87 +/- 0.10 and 0.66 +/- 0.05, respectively, vs control 0.34 +/- 0.07 pmol rT3.h-1.(mg protein)-1), suggestive of a stimulatory effect of E2 and of an inhibitory effect of androgens on this parameter. In contrast, no differences in hepatic 5'D were found between all groups, illustrating the well-known tissue-specific regulation of 5'D. These results demonstrate that the sex difference in the density of pituitary T3 and TRH receptors and the activity of 5'D in the adult rat is mainly due to a modulatory effect of estrogens, which may be responsible for the sex-dependent regulation of TSH secretion.

Influence of sex and age on T3 receptors and T3 concentration in the pituitary gland of the rat: consequences on TSH secretion.

A reduced secretion of thyroid hormones with age has been documented in humans and animals with no substantial increase in TSH secretion, which may be indicative of an age-related impairment of the pituitary sensitivity to the negative control exerted by thyroid hormones. We have evaluated in rats the influence of sex and age on pituitary T3 nuclear receptors--known to be determinant in the regulation of TSH secretion--as well as on T3 concentration in the pituitary gland. As regards sex, the density of T3 receptors and the concentration of T3 in pituitary gland and plasma were greater in females than in males whereas pituitary and plasma TSH concentrations were less. As for age, the density of T3 receptors was greater in old male rats than in young ones with no changes in pituitary T3 and plasma TSH concentrations. In old female rats in contrast, there was no significant increase in T3 receptors but pituitary T3 was less and plasma TSH greater than in young female rats. In both sexes plasma thyroid hormones and pituitary TSH were reduced with age whereas TSH response to TRH was not altered. These results illustrate sex and age differences in pituitary T3 receptors and pituitary T3 concentration as well as in TSH secretion. In young animals of both sexes an inverse correlation is observed between the density of pituitary T3 receptors and plasma TSH. In contrast, in old animals the absence of this correlation is suggestive of an age-related impairment of T3 action on the thyrotrophs or of changes pertaining to other factors modulating TSH secretion.