Serum TSH Values Research Articles

Lymphocyte respiration in children with Trisomy 21

BackgroundThis study measured lymphocyte mitochondrial O2 consumption (cellular respiration) in children with trisomy 21.MethodsPeripheral blood mononuclear cells were isolated from whole blood of trisomy 21 and control children and these cells were immediately used to measure cellular respiration rate. [O2] was determined as a function of time from the phosphorescence decay rates (1/τ) of Pd (II)-meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. In sealed vials containing lymphocytes and glucose as a respiratory substrate, [O2] declined linearly with time, confirming the zero-order kinetics of O2 conversion to H2O by cytochrome oxidase. The rate of respiration (k, in μM O2 min-1), thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming that oxidation occurred in the mitochondrial respiratory chain.ResultsFor control children (age = 8.8 ± 5.6 years, n = 26), the mean (± SD) value of kc (in μM O2 per min per 107 cells) was 1.36 ± 0.79 (coefficient of variation, Cv = 58%; median = 1.17; range = 0.60 to 3.12; -2SD = 0.61). For children with trisomy 21 (age = 7.2 ± 4.6 years, n = 26), the values of kc were 0.82 ± 0.62 (Cv = 76%; median = 0.60; range = 0.20 to 2.80), p<0.001. Similar results (p<0.000) were obtained after excluding the five trisomy 21 children with elevated serum TSH (values >6.1 mU/L). Fourteen of 26 (54%) children with trisomy 21 had kc values of 0.20 to 0.60 (i.e., <−2SD). The values of kc positively correlated with body-mass index (BMI, R >0.302), serum creatinine (R >0.507), blood urea nitrogen (BUN, R >0.535) and albumin (R >0.446).ConclusionsChildren with trisomy 21 in this study have reduced lymphocyte bioenergetics. The clinical importance of this finding requires further studies.

Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches

Although levothyroxine sodium is highly prescribed worldwide, the exact daily dosage, mode of assumption, and refractoriness to treatment are as yet matter of debate. Growing evidence highlighted that undertreatment with T4 has detrimental effects on several tissues and functions. This is even more proper during pregnancy, when an inadequate treatment may increase the likelihood of obstetric complications and may affect the neuropsychological performance during childhood [1]. In adult patients, subclinical hypothyroidism has been reported to be involved in impaired lipid metabolism and atherosclerosis as well as in cardiovascular disorders [2]. The need for an individually tailored dose potently emerges from these findings. Thyroxine treatment should no longer be prescribed according to the commercially available dose size, but rather related to the patient’s weight and age [3]. Two major issues are indeed crucial to obtain an optimal daily dose for a specific patient: an unbiased serum TSH value and an efficient absorption process of thyroxine. The assumption that serum TSH would be a reliable marker of pharmacologic euthyroidism in all tissues has been challenged since its value may be affected by a number of drugs, cosmetics, and pathophysiological conditions [4, 5]. Even the upper limit of normal serum TSH ( or [ 2.5 mU/l) has been questioned [5]. However, it still remains the best available marker, since the direct measurement of thyroxine absorption is not an easy task. Assuming an unbiased serum TSH value in each patient, the absorption process of T4 becomes key for a successful treatment. The daily dose required to obtain the desired TSH value/therapeutic effect is, in fact, not simply a mirror of the ingested dose of thyroxine. One of the major determinants on pharmacological thyroid homeostasis is, thus the incomplete absorption of oral thyroxine (60–80 % of the administered dose) which takes place at the intestinal level. Indeed, the absorbed dose of T4 may be considered the resultant of: (a) patient compliance; (b) some physiological (pregnancy, weight) and/or paraphysiological (behavioral, nutritional) or pharmacological conditions of increased or decreased T4 need; and (c) the presence of diseases which cause malabsorption of T4 (see [6] for review). Repeated failure to reach therapeutic target in response to an ‘‘adjusted’’ dose is a fairly common and frustrating experience. Larger doses of thyroxine are required to attain the desired serum TSH concentrations, leading to expensive and often inappropriate hormonal monitoring. Once attributed to pseudomalabsorption, the increased need for thyroxine may be also explained by an impaired absorption of levothyroxine. Recently, the modality of drug ingestion gained attention. There is now evidence that at least 1 h delay between T4 tablet ingestion and breakfast warrant the best therapeutic achievement [7]. According to Benvenga et al. [8], even the common use of coffee close to the T4 tablet ingestion results in an altered T4 absorption. According to these authors, coffee physically interacts with T4 tablets and retains thyroxine within the intestinal lumen thus making it less available for absorption [8]. This mechanism closely resembles the one suggested for the reduced absorption of thyroxine in patients with celiac sprue [9]. In these patients, the amount of active hormone available for the absorption may be M. Centanni Chief of Endocrinology Unit, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy

Hyperthyrotropinemia at 2 weeks of age indicates thyroid dysfunction and predicts the occurrence of delayed elevation of thyrotropin in very low birth weight infants

For preterm infants, transient hypothyroxinemia of prematurity and transient primary hypothyroidism, especially with delayed elevation of serum thyrotropin (TSH), are important. To address the above two issues, we performed thyrotropin-releasing hormone (TRH) stimulation tests at about 2 weeks of age for 31 preterm infants with a gestational age of 30 weeks or less. For basal TSH levels, 68% of infants (21 of 31) showed normal values (TSH < 10 mU/l) and 32% of infants (10 of 31) showed higher values (four infants: TSH 10-15 mU/l, six infants: TSH > 15 mU/l). Peak TSH values in response to TRH stimulation tests ranged from 9·76 to 114·8 mU/l. All infants showed a significant response to TRH stimulation tests. Only 9·5% of infants (two of 21) with normal basal TSH values showed a hyperresponse (peak TSH > 45 mU/l), whereas 80% of infants (eight of 10) who had higher basal TSH values showed a hyperresponse. All infants who showed mildly elevated basal TSH values (TSH 10-15 mU/l) and a hyperresponse to TRH stimulation tests showed delayed elevation of basal TSH values (TSH > 15 mU/l) later. Thyrotropin-releasing hormone stimulation tests at about 2 weeks of age suggested that the hypothalamic-pituitary-thyroid axis might be established even in extremely premature infants. Basal increased TSH levels (TSH > 10 mU/l) and a hyperresponse to TRH stimulation tests (peak TSH > 45 mU/l) suggested subclinical thyroid dysfunction. Serum TSH values at about 2 weeks of age could be useful for the prediction of delayed TSH elevation.

Incidence and Prevalence of Hypothyroidism in Patients Affected by Chronic Heart Failure: Role of Amiodarone

It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism. To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy. Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed. Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.

Monitoring Levothyroxine Dose during Pregnancy: A Prospective Study

Problem statement: Thyroid dysfunction in pregnant women can influence the outcome for mother and fetus at all stages of pregnancy. As the fetus is entirely dependent on maternal thyroid hormones for its development until about 13 weeks of gestation, it is important to ensure adequate thyroxine substitution in pregnant women during the first trimester. The aim of this prospective study was to explore whether hypothyroidic pregnant women are adequately levothyroxine (L-T4) substituted in early pregnancy. Approach: During March 2008 to July 2009, 93 pregnant females with thyroid diseases were followed at the outpatient department of INMAS. At the first visit 86 patients were on L-T4 substitution for hypothyroidism. Seven other patients had hyperthyroidism. The patients were regularly followed every 4-8 weeks during pregnancy for dose adjustment. Before each visit serum Free Thyroxine (FT4) and TSH concentrations were determined. Results: Of the 86 patients on thyroxine substitution for hypothyroidism 56 (65.12%) had serum TSH values within the reference range at their first TSH test. Thirty (34.9%) had TSH values outside the reference range. In 5 patients TSH was <0.27 μIU mL-1. Fifty (58.13%) of the patients had to increase their thyroxine dose during pregnancy. The initial L-T4 increase at the first evaluation during pregnancy was 17.46±30.8 μg day-1. In the 50 patients who needed to increase L-T4, 26% reached a definitive therapeutic dosage within 12th week of pregnancy, 24% within the 20th week and 50% within the 31st week. Conclusion/Recommendations: In 34.9% of pregnant women on L-T4 substitution for hypothyroidism, serum TSH values were abnormal when first tested and they had increased chances of fetal loss if not treated timely. Thyroid function in pregnant women on thyroxine substitution should be monitored as soon as pregnancy has been confirmed and carefully followed during pregnancy.

Personal Considerations on the 2011 American Thyroid Association and the 2007 Endocrine Society Pregnancy and Thyroid Disease Guidelines

ThyroidVol. 21, No. 10 Editorials and CommentaryPersonal Considerations on the 2011 American Thyroid Association and the 2007 Endocrine Society Pregnancy and Thyroid Disease GuidelinesDaniel GlinoerDaniel GlinoerSearch for more papers by this authorPublished Online:23 Sep 2011https://doi.org/10.1089/thy.2011.2110.ed2AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited ByPituitary Physiology During Pregnancy and LactationMaternal Serum TSH Value in Early Pregnancy and its Relation with Pregnancy OutcomeResearch Journal of Obstetrics and Gynecology, Vol. 7, No. 1 Volume 21Issue 10Oct 2011 InformationCopyright 2011, Mary Ann Liebert, Inc.To cite this article:Daniel Glinoer.Personal Considerations on the 2011 American Thyroid Association and the 2007 Endocrine Society Pregnancy and Thyroid Disease Guidelines.Thyroid.Oct 2011.1049-1051.http://doi.org/10.1089/thy.2011.2110.ed2Published in Volume: 21 Issue 10: September 23, 2011PDF download

Hypothyreose

Hypothyroidism is one of the most frequent endocrine disorders affecting 4.6% of the adult population. 90% of the cases represent subclinical hypothyroidism, defined by increased serum TSH but normal free thyroxine (fT4) values. General screening for hypothyroidism is not recommended because of lack of benefits for the patients. Search for hypothyroidism should therefore focus on patients with symptoms and signs and/or those presenting risk factors for development of hypothyroidism (e.g., autoimmune disorders, thyroid injury, post partum state). Because of the lack of specificity of sings and symptoms of this frequent disorder the diagnosis is based on measurement of TSH or TSH and fT4 in case of conditions that may affect TSH values such as non-thyroidal illness, or medications. Whereas primary hypothyroidism is due to lack of function of the thyroid itself and easy recognized by increased serum TSH, mild forms of secondary hypothyroidism may be difficult to detect because of the lack of function of the pituitary and thus absence of the best indicator of thyroid function. Here measurement of fT4 and a clinical assessment are the cornerstones for diagnosis of secondary hypothyroidism and monitoring of its treatment. In case of subclinical hypothyroidism defined as increased TSH but fT4 still within the normal laboratory range a TSH value above 10 mU/l is regarded as indication for treatment. For values between 4 and 10 mU/l an individualized pragmatic treatment approach based on the presence of clinical sings of hypothyroidism may be justified. Some patients however should be treated regardless of their clinical symptoms including women in childbearing age who want to become pregnant, patients with goitre, and patients with history of Graves disease. Treatment of hypothyroidism is best done with thyroxine (T4) alone; combination therapy of thyroxine with the active compound T3 does not have any advantage. The required L-T4 dose for optimal substitution (TSH between 0.5 and 2.5 mU/l) is in the range of 1.6 µg/kg body weight per day. In young subjects the starting dose should be close to the required dose i.e., 75 to 100 µg, elder patients and those with ischemic heart disease should start with lower doses (25-50 µg). Pregnant women under L-T4 substitution should increase the dose by 25% as soon as pregnancy is diagnosed.

Incidence of thyroid dysfunction in renal cell carcinoma (RCC) patients treated with pazopanib in prospective clinical trials.

4633 Background: Pazopanib is a small molecule, selective, multi tyrosine kinase inhibitor (TKI), targeting vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R). Pazopanib is approved for the treatment of advanced RCC and is given by oral daily dosing. Other TKIs for this indication induce thyroid dysfunction in up to 85% of patients (pts) (Rini, B 2007). The incidence and severity of thyroid dysfunction were explored in pazopanib-treated pts participating in 3 trials, where thyroid function tests were systematically assessed. Methods: Thyroid function data from 578 RCC pts participating in trials VEG102616 (phase II), VEG105192 (phase III), and VEG107769 (phase III extension) were analyzed. Serum TSH values were collected at baseline and every 12 weeks. Free T3 and T4 were assessed at baseline and when TSH was abnormal during treatment. Results: In 578 pts, the incidence of elevated TSH at baseline (>5 MU/L) was 37 (6%).167 (29%) pts had a TSH value of >5 MU/L during treatment; 97 (17%) pts had TSH values of >5-10 MU/L during treatment; 45 (8%) pts had TSH values of >10-20 MU/L, and 25 (4%) pts had TSH values of >20 MU/L. Hypothyroidism (TSH >5-10 MU/L and T4 <LLN) was observed in 19 (3%) pts. Hypothyroidism with TSH >10 MU/L and T4<LLN was diagnosed in 15 (3%) pts. Hyperthyroidism, defined as TSH <0.3 MU/L and T4>ULN, was seen in 8 (1%) pts. Thyroid replacement therapy was received by 20 (3%) pts with a TSH elevation. Hypothyroidism was reported as an AE in 26 (4%) pts (15 Grade 1, 10 Grade 2 and 1 unknown grade) by the investigators. Thyroid dysfunction was never reported as a severe adverse event in any pt. Conclusions: In clinical trials, pazopanib, the most recently approved treatment for advanced RCC, lead to a very low incidence of thyroid dysfunction. The low rate of hypothyroidism may partly explain the low incidence of fatigue (19%) and asthenia (14%) with pazopanib (Sternberg 2010), given these conditions can result from hypothyroidism. As fatigue has a profound detrimental effect on HRQoL in RCC pts (Larkin 2010), this data should be considered when making clinical treatment decisions in pts with advanced RCC.

Should we treat mild subclinical/mild hyperthyroidism? No

The management of a patient with subclinical hyperthyroidism or mild thyroid over-activity is controversial. Subclinical hyperthyroidism is defined as a serum thyrotrophin (TSH) below the reference range but a normal thyroxine (T 4) and triiodothyronine (T 3) level in a patient who is either asymptomatic or has only non-specific symptoms. Epidemiological studies report an overall prevalence of approximately 3%, with men and women over 65 years and those in iodine deficient regions having the highest prevalence. Approximately 50% of subjects are taking levothyroxine. The aetiology for those with endogenous subclinical hyperthyroidism is Graves' disease, toxic nodular goitre or rarely a solitary toxic adenoma or thyroiditis. Non-thyroidal illness is an important cause of false positive low serum TSH test results. Subjects with low but detectable serum TSH values (0.1–0.4 mU/L) usually recover spontaneously when re-tested. It has been estimated that in those with an undetectable serum TSH (< 0.1 mU/L) conversion to overt hyperthyroidism occurs at a rate up to 5% per year. Advocates of intervening for subclinical hyperthyroidism argue that early treatment might reduce mortality, prevent the later development of atrial fibrillation, osteoporotic fractures, and overt hyperthyroidism but data supporting improvement in outcomes are sparse. No appropriately powered prospective, randomised, controlled, double-blinded trial of intervention for subclinical hyperthyroidism exists. For the vast majority of patients adopting a “wait and see” policy rather than intervention may avoid unnecessary treatment or the potential for harm. Any potential benefits of therapy in subclinical hyperthyroidism must be weighed against the significant morbidity associated with the treatment of hyperthyroidism.

TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects

To examine the association between thyroid function and the components of the metabolic syndrome and insulin resistance in an Hispanic population. Cross-sectional study. Subjects with no history of thyroid disease or diabetes were included. Thyroid function was stratified as euthyroid or subclinical hypothyroidism (SCH) status and subsequently by free thyroxine (FT(4)) and TSH tertiles. The association of the metabolic syndrome components (defined by 2004 Adult Treatment Panel III criteria) and insulin resistance with thyroid status, TSH, and FT(4) were examined. A total of 3148 subjects were analyzed. The prevalence of SCH was 8.3%. The prevalence of the metabolic syndrome was similar in euthyroid and SCH patients (31.6 vs 32.06%, P=0.89). Total cholesterol was higher in patients with SCH (5.51+/-1.19 vs 5.34+/-1.05 mmol/l, P<0.032). Serum TSH values showed a positive correlation (adjusted for age and sex) with total cholesterol, triglycerides, and waist circumference. In contrast, FT(4) showed a positive correlation with high-density lipoprotein cholesterol, and an inverse correlation with waist circumference, insulin, and HOMA-IR. SCH is not associated with an increased risk for the metabolic syndrome (as conceived as a diagnostic category defined by the National Cholesterol, Education Program, Adult Treatment Panel III criteria). Despite this, low thyroid function (even in the euthyroid state) predisposes to higher cholesterol, glucose, insulin, and HOMA-IR levels. The combined use of TSH and FT(4), compared with the assessment based on only FT(4), is a more convenient approach to evaluate the association between thyroid function and metabolic variables.

Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in elderly patients

Results Serum TSH values was <0.5 fiUI/ml in 24 (32%, Group A), between 0.5 and 1 fiUI/ml in 22 (29.3%, Group B) and above 1 fiUI/ml in 29 (38.7%, Group C) patients. No significant difference was observed among the 3 groups for echocardiographic parameters. Holter registration showed : Heart Rate [HR (24 hours)] of 67.7 + 10.8 b/m in the group A, 71.8 + 8.9 b/m in the group B and 70.5 + 18 b/m in the group C; HR (Max) of 134.6 + 35.2 b/m in the group A, 124 + 22.8 b/m in the group B and 119.6 + 40.8 b/m in the group C; HR (Min) of 43.8 + 8.3 in the group A, 43.7 + 11 b/m in the group B and 45.8 + 14.6 b/m in the group C; Diurnal HR of 71 + 10 b/m in the group A, 75.3 + 8.9 b/m in the group B and 69.7 + 12 in the group C and Nocturnal HR of 68 + 11 b/m in the group A, 65.6 + 8.4 b/m in group B and 61.4 + 9.5 b/m in the group C. Persistent AF was observed in 17/24 (70.8%) patients in the group A, in 8/22 (36.4%) patients in the group B and in 9/29 (31.0%) patients in the group C. Conclusions In conclusion, the 24 h, the Maximal and the Minimal HR did not significantly differ among the 3 groups; the circadian HR variation was lost in group A patients, while it was present in the other groups; the frequency of persistent AF was significantly increased in group with serum TSH values <0.5 μU/ml.

Serum thyroid hormone profile in critically III children

To study thyroid hormone profile in critically ill children and its correlation to disease severity and clinical outcome. Total serum triiodothyronine (T3), thyroxine (T4) and TSH were estimated at admission and discharge from PICU/ just before death. Mean T3 levels in cases were significantly lower than controls and lower in patients who expired, both at admission and just prior to death. Mean T4 levels were lower in cases, and just prior to death. Mean TSH levels were not different in cases and controls; or in survived and expired cases. When both T3 and T4 are low, mortality risk increases 30 times. Serum T3, T4 and TSH values improved in patients who survived unlike in those who expired. Age, sex, duration of hospital stay, ventilation, inotropic support, and PICU stay did not show any correlation with patient outcome or thyroid hormone profile. PRISM score at 24 hours and T4 levels in the second sample were significant predictors of survival. T3 levels reflect the patient's clinical status, T4 levels can predict survival.

Enhanced proatherogenic inflammation after recombinant human TSH administration in patients monitored for thyroid cancer remnant

To evaluate the effect of recombinant human TSH (rhTSH) on biomarkers of vascular endothelial cell and platelet activation in patients monitored for thyroid carcinoma remnant. Circulating levels of soluble(s) intercellular adhesion molecule (sICAM)-1 and sE-selectin, as indices of vascular endothelial cell activation, of sP-selectin and sCD40 ligand (sCD40L), as indices of platelet activation, and of 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), as an index of lipid peroxidation, were evaluated in 20 patients (16 females, 48.0 +/- 13.6 years) at baseline and after intramuscular rhTSH injection (0.9 mg/day on two consecutive days). At baseline, serum TSH values were below normal whereas free T3 and free T4 were within the normal range. After rhTSH injection, serum TSH increased significantly but free T3 and free T4 remained unchanged. Concomitantly, plasma sICAM-1 concentrations increased significantly (from 155.9 +/- 39.1 to 183.6 +/- 38.1 ng/ml, P < 0.03), as did those of sE-selectin (from 74.8 +/- 15.4 to 91.4 +/- 12.2 ng/ml, P < 0.0006), sP-selectin (from 56.4 +/- 13.7 to 72.2 +/- 14.9 ng/ml, P < 0.002), sCD40L (from 2.1 +/- 0.9 to 2.8 +/- 1.1 ng/ml, P < 0.03) and total 8-iso-PGF(2alpha)(from 238.5 +/- 47.0 to 307.8 +/- 41.2 pg/l, P < 0.0001). Changes in circulating levels of sCD40L were directly correlated with changes in levels of plasma total 8-iso-PGF(2alpha) (r = 0.523, P < 0.02) and sP-selectin (r = 0.480, P < 0.03). Supraphysiological concentrations of rhTSH might exert proatherogenic effects by promoting activation of vascular endothelial cells and platelets probably through enhanced oxidative stress.

Pregnant Women on Thyroxine Substitution Are Often Dysregulated in Early Pregnancy

Thyroid hormones are important for normal fetal development. Maternal hypothyroidism during early pregnancy is associated with impaired neuropsychological development of children and other adverse outcomes. The primary aim of this prospective study was to determine whether thyroxine-treated pregnant women with hypothyroidism are adequately thyroxine substituted in early pregnancy. A secondary aim was to determine if fetal loss differed between females with thyrotropin (TSH) values within and outside the reference range at their first TSH test, scheduled for 1-2 weeks after verification of pregnancy. This was a prospective open-labeled study. During the years 1997-2002, 119 consecutive pregnancies in 101 females with thyroid diseases were followed at the Department of Endocrinology, Malmö University Hospital. At the first visit, 63 patients, median age 30 years (range 17-45 years), were on thyroxine substitution therapy for hypothyroidism. In these patients 83% were in their first trimester at the time of the initial test. Of the 63 patients on thyroxine substitution for hypothyroidism 32 (51%; Group A) patients had serum TSH values within the reference range at their initial test and 31 (49%; Group B) had serum TSH values outside the reference range. Twelve (19%) had TSH values of <0.40 mIU=L and 19 (30%) had TSH values of >4.0 mIU=l. The fetal loss was 2 of 32 (6%) in Group A compared to 9 of 31 (29%) in Group B ( p < 0.05). In 49% of pregnant women on thyroxine substitution, serum TSH values were outside the reference range when first tested, generally in the first trimester. Fetal loss was significantly greater in pregnant women with abnormal TSH values compared to those with normal TSH values. Thyroid function in pregnant women on thyroxine substitution should be monitored early in pregnancy and carefully followed during pregnancy. The thyroxine dose should be increased as needed early in pregnancy to avoid hypothyroidism.

Prohibitin Is Overexpressed in Papillary Thyroid Carcinomas Bearing the BRAFV600EMutation

Prohibitin (PHB) is a multifunctional protein that is localized in different intracellular sites. PHB may exert different roles in tumorigenesis, having either a permissive action on tumor growth or an oncosuppressor role, depending on the cellular context. The objective of this study was to evaluate PHB expression in normal thyroid tissues, thyroid follicular adenomas (FAs), and papillary thyroid carcinomas (PTCs). PHB expression was analyzed by immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Transfections in the BCPAP and TPC-1 thyroid cancer cell lines were used to evaluate the PHB promoter activity. In terms of protein and mRNA levels, normal tissues from patients with serum thyrotropin (TSH) values >0.8mU/L had PHB levels that were significantly reduced compared to specimens from patients with serum TSH values <0.5mU/L, suggesting that TSH exerts an inhibitory effect on PHB expression. Consistent with this was the finding that the presence of TSH was associated with low PHB levels in normal FRTL5 thyroid cells. Immunohistochemical analysis showed relatively low and high PHB expression in FAs and PTCs, respectively. PHB mRNA and protein overexpression, as assessed by quantitative RT-PCR and Western blot, was noted only in PTCs bearing the BRAF(V600E) mutation. Notably, cell transfection experiments suggested that presence of the BRAF(V600E) mutation may be associated to increase of the PHB promoter activity. PHB is overexpressed in PTCs bearing the BRAF(V600E) mutation. We postulate that the presence of the BRAF(V600E) mutation increases PHB promoter activity and therefore potentially mediates effects of this mutation on the behavior of BRAF(V600E) positive PTCs.

The Prevalence of Thyroid Dysfunction in Elderly Cardiology Patients with Mild Excessive Iodine Intake in the Urban Area of São Paulo

OBJECTIVES:To evaluate the prevalence of thyroid dysfunction in elderly cardiac patients in an outpatient setting.SUBJECTS AND METHODS:A total of 399 consecutive patients (268 women, age range 60–92 years) who were followed at Heart Institute were evaluated for thyroid dysfunction with serum free T4, TSH, anti-Peroxidase antibodies, urinary iodine excretion measurements and thyroid ultrasound.RESULTS:Hyperthyroidism (overt and subclinical) was present in 29 patients (6.5%), whereas hypothyroidism (overt and subclinical) was found in 32 individuals (8.1%). Cysts were detected in 11 patients (2.8%), single nodules were detected in 102 (25.6%), and multinodular goiters were detected in 34 (8.5%). Hashimoto’s thyroiditis was present in 16.8% patients, most of whom were women (83.6%). The serum TSH increased with age and was significantly higher (p= <0.01) in patients, compared to the normal control group. No significant differences in serum TSH and free T4 values were observed when patients with atrial fibrillation (AF) where compared with those without arrhythmia. The median urinary iodine levels were 210 μg/L (40–856 μg/L), and iodine levels were higher in men than in women (p<0.01). Excessive iodine intake (urinary iodine >300 μg/L) was observed in one-third of patients (30.8%).CONCLUSIONS:Elderly patients have a higher prevalence of both hypo- and hyperthyroidism as well as thyroid nodules when compared with the general population. About one-third of the older patients had elevated urinary secretion of iodine and a higher prevalence of chronic Hashimoto’s thyroiditis. It is recommended that ultrasonographic studies, tests for thyroid function and autoimmunity should be evaluated in elderly patients.

Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 3-amino-1,2,4-triazole based on the Organization for Economic Co-operation and Development draft protocols

We performed a uterotrophic assay, the Hershberger assay, and the 28-day repeated-dose toxicity study (enhanced OECD test guideline no. 407) of 3-amino-1,2,4-triazole based on the OECD draft protocols. In the uterotrophic assay, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay, the test chemical was orally administered at doses of 0, 40, 200, and 1,000 mg/kg/day to castrated male Wistar rats for 10 consecutive days beginning on postnatal day 56, and no androgen agonistic and antagonistic changes were observed. Alternatively, when the test chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid follicular epithelial cell hypertrophy with increased thyroid weights was detected in the male and female rats in 25 and/or 125 mg/kg groups, and hypertrophy of the anterior pituitary cells with increased pituitary weights in male and female rats was also observed in the 125 mg/kg group. Furthermore, serum T3 and T4 values decreased and serum TSH values increased in male and female rats in the 125 mg/kg group. Therefore, 3-amino-1,2,4-triazole was concluded to have anti-thyroid acting as endocrine-mediated effects, but no estrogenic or androgenic effects. In addition, decreased body weight, and abnormal biochemical parameters attributed to thyroid, liver or kidney dysfunction were observed in male and female rats in the 25 and/or 125 mg/kg groups.

Transient Congenital Hypothyroidism Caused by Biallelic Mutations of the Dual Oxidase 2 Gene in Japanese Patients Detected by a Neonatal Screening Program

Mutations in dual oxidase (DUOX2) have been proposed as a cause of congenital hypothyroidism. Previous reports suggest that biallelic mutations of DUOX2 cause permanent congenital hypothyroidism and that monoallelic mutations cause transient congenital hypothyroidism. To clarify the inheritance of hypothyroidism, we looked at the DUOX2 gene in patients with transient congenital hypothyroidism. DUOX2, thyroid peroxidase, Na+/I- symporter and dual oxidase maturation factor 2 genes were analyzed in eight patients with transient congenital hypothyroidism, using the PCR-amplified direct sequencing method. The eight patients were found by a neonatal screening program. Six of these patients belonged to two independent families; the other two were unrelated. Their serum TSH values varied from 24.8-233.0 mU/liter. Six of the eight patients had a low serum freeT4 level (0.19-0.84 ng/dl). Seven of the eight patients were treated with thyroid hormone replacement therapy, which ceased to be necessary by 9 yr of age. Eight novel mutations were detected in the DUOX2 gene. Four patients in one family were compound heterozygous for p.L479SfsX2 and p.K628RfsX10. Two patients in a second family were compound heterozygous for p.K530X and p.[E876K;L1067S]. The two remaining unrelated patients were also compound heterozygous, for p.H678R/p.L1067S and p.A649E/p.R885Q, respectively. All eight patients had biallelic mutations in the DUOX2 gene. We find that loss of DUOX2 activity results in transient congenital hypothyroidism and that transient congenital hypothyroidism caused by DUOX2 mutations is inherited as an autosomal recessive trait.

In vitro production of interferon-gamma by peripheral blood from patients with Graves' disease, Hashimoto's thyroiditis and rheumatoid arthritis

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.

Transient congenital hypothyroidism in an iodine-replete area is not related to parental consanguinity, mode of delivery, goitrogens, iodine exposure, or thyrotropin receptor autoantibodies

To assess transient congenital hypothyroidism (TCH) etiologies in two Iranian cities. Cord dried blood spot samples were collected from neonates in Tehran and Damavand. Serum TSH and T4 were measured in those with cord TSH > or =20 mIU/l. Normal serum values at 2-3 weeks of age confirmed transient hyperthyrotropinemia (THT), while persistently abnormal levels revealed congenital hypothyroidism (CH). Normal serum TSH and T4 4-6 weeks after levothyroxine replacement therapy discontinuation at 2-3 yr of age differentiated TCH from persistent CH. Among 50,409 screened newborns, 9 (1:5601 births) were diagnosed as TCH and compared to 88 full-term neonates (>/=37 weeks' gestation) with THT and 45 normal (cord TSH<20 mIU/l) neonates. At a median age of 11 days, median (range) serum TSH values in TCH, THT, and normal neonates were 36.8 (13-130), 3.6 (0.1-13.3), and 2.9 (0.7-8.0) mIU/l (p<0.0001) and serum T4 values were 97 (36-168), 142 (74-232), and 160 (79-228 nmol/l), respectively (p=0.002). Urinary iodine concentration (UIC) >220 microg/l was observed in 5 (55.6%) of TCH neonates. The occurrence of TCH was not associated with gender, parental consanguinity, mode of delivery, pre- or post-natal consumption of goitrogens and/or thyroid affecting medications, TSH receptor autoantibodies, or neonatal UIC. Elevated UIC was the most frequent finding in newborns with TCH but the distribution of excessive UIC was not significantly different among TCH, THT, and normal neonates. Since no other etiologies were found in TCH neonates without elevated UIC values, evaluation of other environmental and/or genetic factors is warranted.