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Concept: Thyroxine

168

Congenital hypothyroidism, usually of the primary and permanent variety, is an eminently preventable cause of growth retardation and mental handicap whose outlook has been transformed by newborn screening, usually involving the measurement of capillary TSH. Severe primary congenital hypothyroidism, due for example to athyreosis, may result in subtle cognitive, behavioural and sensori-motor deficits, but the extent to which these can be offset by optimal postnatal diagnosis and management remains uncertain. This is because the available adult follow-up data reflect the outcome of previous management in the 1970’s and 1980’s, and also because the accurate neuro-psychological assessment of children is difficult, particularly in the preschool population. There is an urgent need to develop new consensus guidelines and to ensure that the children managed according to such guidelines are systematically and prospectively assessed so that good quality outcome data become available. In this review, key recommendations in the management of congenital hypothyroidism include: screening at day 3 so that severely affected infants can begin treatment within the first 10 days of life; setting the thyrotropin (TSH) referral cut-off at 8-10 mU/L; adopting a disciplined diagnostic algorithm to evaluate referred cases, with measurement of venous free thyroxine (T4), TSH and thyroglobulin combined with dual ultrasound and radioisotope imaging; initial treatment with a T4 dose of 50 μg daily in infants weighing ≥ 2.5 kg and 15 μg/kg/day in infants weighing < 2.5 kg followed by weekly review until thyroid function is normalised; and maintenance of free T4 levels between 15-26 pmol/L and TSH between 0.5-5 mU/L thereafter to avoid both under- and overtreatment.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Thyroxine, Newborn screening, Congenital hypothyroidism

28

Childhood abuse is a powerful risk factor for developing postpartum depression in adulthood, and recently it has been associated to thyroid dysfunction in postpartum depressive women. The purpose of this study was to investigated the effects of childhood abuse on thyroid status and depressive symptomatology in two hundred and thirty-six (n=236) postpartum women 24-48h after delivery. The Early-Trauma-Inventory Self-Report was used to assess the presence of childhood abuse and the Edinburgh Postpartum Depression Scale (EPDS) to evaluate depressive symptomatology (EPDS≥11). Free thyroxin (fT4) and thyroid-stimulating hormone (TSH) were measured. Thyroid dysfunction (TD) was defined as altered TSH or TSH and fT4. Socio-demographic, reproductive, and psychopathological variables were also collected. Multivariate analysis shows that childhood physical abuse increases by four times the risk for TD (OR: 3.95, 95% CI: 1.23-12.71) and five times the risk for depressive symptomatology (OR: 5.45, 95% CI: 2.17-13.66) in the earlier postpartum. Our findings suggest that women with history of childhood physical abuse are particularly at-risk for thyroid dysfunction and depressive symptomatology 24-48h after delivery. The assessment of childhood abuse in the perinatal period is important to identify women at-risk for physical and mental health problems in this period.

Concepts: Pregnancy, Childbirth, Multivariate statistics, Child abuse, Bipolar disorder, Postpartum depression, Thyroxine, Physical abuse

27

Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Concepts: Immune system, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone, Triiodothyronine, Thyroxine

27

Abstract Background: Thyroid dysfunction is very common and is associated with neurodevelopmental impairments in preterm infants. Objectives: This study was conducted to determine the incidence and natural course of various thyroid dysfunctions and their impacts on neurodevelopmental outcomes among premature infants. Methods: A total of 177 infants were enrolled who were born at <34 weeks or whose birth weight was <1500 g and who underwent repeat thyroid function tests. We analyzed how various thyroid dysfunctions affected neurodevelopmental outcomes at 18 months of corrected age. Results: Thyroid dysfunction was noted in 88 infants. Hypothyroxinemia was observed in 23 infants, and their thyroid function was influenced by variable clinical factors. Free T4 levels were all normalized without thyroxine medication, and neurodevelopmental outcomes were not affected. In contrast, hyperthyrotropinemia was not associated with other clinical factors. Among 58 subjects who had hyperthyrotropinemia, only 31 infants showed normal thyroid-stimulating hormone (TSH) levels at follow-up tests. The remaining 27 infants had persistently high TSH levels, which significantly and poorly influenced the neurodevelopmental outcomes. Conclusions: Thyroid dysfunction is common among preterm infants. With the exception of persistent hyperthyrotropinemia, it generally does not affect neurodevelopmental outcomes. However, the beneficial effects of thyroid hormone therapy in patients with persistent hyperthyrotropinemia merits further study.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Thyroid, Thyroid hormone, Triiodothyronine, Thyroxine, Tyrosine, Thyroglobulin

27

PURPOSE: The role of thyroid function in biochemical markers of first trimester screening has not been assessed. The aim of the present study was to investigate if there were any relation between maternal thyroid hormones and free-beta subunit of human chorionic gonadotropin (fβ-hCG) and pregnancy-associated plasma protein A (PAPP-A) levels as the biochemical markers of the combined first trimester aneuploidy screening. METHODS: 375 pregnant women between 11 and 14 weeks of gestation who were offered routine first trimester prenatal aneuploidy screening and whose thyroid hormone levels (Thyroid stimulating hormone (TSH), free and total thyroxine, free and total triiodothyronine, anti thyroid peroxidase antibody) were measured were assessed. Correlation of free-β-hCG and PAPP-A with maternal thyroid hormones was analyzed. RESULTS: There was no statistically significant correlation between maternal TSH, free and total thyroxine, free and total triiodothyronine, anti-thyroid peroxidase antibodies and free-β-hCG and PAPP-A as biochemical markers of first trimester aneuploidy screening. CONCLUSION: Maternal thyroid function does not seem to affect secretion of fβ-hCG and PAPP-A.

Concepts: Pregnancy, Hormone, Thyroid, Thyroid hormone, Human chorionic gonadotropin, Triiodothyronine, Thyroxine, Thyroid peroxidase

25

To provide an overview of the clinical utility of thyroglobulin antibody (TgAb) measurements in the management of differentiated thyroid cancer (DTC), taking into consideration the methodological concerns associated with these measurements.

Concepts: Thyroid, Mean, Thyroxine

23

There is ample evidence demonstrating the importance of maternal thyroid hormones, assessed at single trimesters in pregnancy, for child cognition. Less is known, however, about the course of maternal thyroid hormone concentrations during pregnancy in relation to child behavioral development. Child sex might be an important moderator, because there are sex differences in externalizing and internalizing behavioral problems. The current study examined the associations between maternal thyroid hormone trajectories versus thyroid assessments at separate trimesters of pregnancy and child behavioral problems, as well as sex differences in these associations. In 442 pregnant mothers, serum levels of TSH and free T4 (fT4) were measured at 12, 24, and 36weeks gestation. Both mothers and fathers reported on their children’s behavioral problems, between 23 and 60months of age. Latent growth mixture modeling was used to determine the number of different thyroid hormone trajectories. Three trajectory groups were discerned: 1) highest and non-increasing TSH with lowest fT4 that decreased least of the three trajectories; 2) increasing TSH and decreasing fT4 at intermediate levels; 3) lowest and increasing TSH with highest and decreasing fT4. Children of mothers with the most flattened thyroid hormone trajectories (trajectory 1) showed the most anxiety/depression symptoms. The following trimester-specific associations were found: 1) lower first-trimester fT4 was associated with more child anxiety/depression, 2) higher first-trimester TSH levels were related to more attention problems in boys only. A flattened course of maternal thyroid hormone concentrations during pregnancy was a better predictor of child anxiety/depression than first-trimester fT4 levels.

Concepts: Hormone, Thyroid, Thyroid hormone, Puberty, Mother, Triiodothyronine, Thyroxine, Thyroglobulin

16

The carnivoran giant panda has a specialized bamboo diet, to which its alimentary tract is poorly adapted. Measurements of daily energy expenditure across five captive and three wild pandas averaged 5.2 megajoules (MJ)/day, only 37.7% of the predicted value (13.8 MJ/day). For the wild pandas, the mean was 6.2 MJ/day, or 45% of the mammalian expectation. Pandas achieve this exceptionally low expenditure in part by reduced sizes of several vital organs and low physical activity. In addition, circulating levels of thyroid hormones thyroxine (T4) and triiodothyronine (T3) averaged 46.9 and 64%, respectively, of the levels expected for a eutherian mammal of comparable size. A giant panda-unique mutation in the DUOX2 gene, critical for thyroid hormone synthesis, might explain these low thyroid hormone levels. A combination of morphological, behavioral, physiological, and genetic adaptations, leading to low energy expenditure, likely enables giant pandas to survive on a bamboo diet.

Concepts: Biology, Hormone, Thyroid, Thyroid hormone, Triiodothyronine, Thyroxine, Giant Panda, Carnivora

6

In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population.

Concepts: Cohort study, Thyroid, Thyroid hormone, Iodine, Macular degeneration, Triiodothyronine, Thyroxine, Tyrosine

6

The objectives of these GLP US EPA OPPTS 970.3800 and 970.3700 studies were to examine the effects of tetrabromobisphenol A (TBBPA) at oral doses of 10, 100 or 1000mg/kgBW/day over the course of 2 generations on growth as well as behavioral, neurological and neuropathologic functions in offspring. In a separate study the influence of oral TBBPA (0, 100, 300 or 1000mg/kgBW/d) was examined on embryonic/fetal development from gestation days (GDs) 0-19. In the reproductive study, exposure to ≥100-mg/kgBW/d TBBPA resulted in a decrease in circulating, peripheral thyroxine (T4) levels in rats that were not accompanied by any marked alterations in triiodothyronine (T3) and thyroid stimulating hormone (TSH). These findings are explainable on the basis of induction of rat liver catabolism, a phenomenon that may be species-specific and not relevant for humans. TBBPA at up to 1000mg/kgBW/d was not associated with any significant non-neurological effects on reproduction, growth and development. A subtle reduction, of unknown biological relevance, in the thickness of the parietal cortices of 11-day-old F2 pups in the 1000mg/kgBW/d group was noted. This change was not accompanied by evidence of micro-anatomic changes. No estrogenic effects sufficient to affect macro and micro anatomy, fertility, reproduction, development, survival or behavior were detected in the embryofetal development study or in the multigenerational study. No other TBBPA-related effects on developmental neurotoxicity/neuropathology were detected. In the developmental study no TBBPA related change in mortality rate was observed in any of the dams. No other significant test article-related effects were noted. The no observed effect level (NOEL) for maternal and developmental toxicity was 1000mg/kgBW/d, the highest dose evaluated.

Concepts: Human, Reproduction, Thyroid-stimulating hormone, Thyroid, Thyroid hormone, Triiodothyronine, Thyroxine, Development studies