Mild Hypothyroxinemia Research Articles

Graves' Disease in Hypopituitarism Due to Pituitary Apoplexy.

Central hypothyroidism and autoimmune hyperthyroidism are contrasting pathologies requiring careful hormone monitoring for restoring euthyroidism. Their coexistence is rare and challenging for clinicians [1, 2]. We have, herein, presented the case of a 41-year-old female patient with an unremarkable clinical history except for chronic autoimmune thyroiditis in euthyroidism. At the 21st week of gestation, she experienced a spontaneous abortion. The patient underwent an assessment of the uterine cavity, which was complicated by bleeding and hypotensive shock. In the postoperative course, the patient presented worsening headache, and after an MRI, the diagnosis of pituitary apoplexy due to an ischemic-hemorrhagic base was made. Laboratory tests showed anterior panhypopituitarism. Multiaxial replacement therapy was initiated with hydrocortisone, levothyroxine (LT4), and subsequently estrogen-progestin and GH. After two years of good recovery with stable LT4 dosage, the patient experienced palpitations and fine tremors; blood tests showed hyperthyroidism with suppressed Thyroid-stimulating Hormone (TSH) levels and elevated free thyroid fractions and anti-TSH receptor antibodies. Diagnosis of Graves' disease was made, and therapy with methimazole was initiated. During antithyroid therapy, TSH remained persistently suppressed, consistent with the underlying central hypothyroidism. This condition required close follow-up, with monitoring based solely on free thyroid hormone levels. After six months of antithyroid therapy, disease remission was achieved, with negative antibodies and mild hypothyroxinemia. Therefore, methimazole was discontinued and replacement therapy gradually resumed until optimal hormone levels were reached. This case is unique demonstrating autoimmune hyperthyroidism to coexist with central hypothyroidism, rendering TSH a misleading disease progression indicator. Consequently, managing Graves' disease has become more complex and challenging.

Thyroid Function in Patients with Cystic Fibrosis: No Longer a Concern?

Development of goiter and hypothyroidism has been reported in patients with cystic fibrosis (CF) since the 1970s, especially when treated with iodine-based expectorants. With iodine-containing expectorants no longer in routine use, the prevalence of thyroid dysfunction in CF patients is unknown. This cross-sectional study assessed thyroid function status in a large cohort of CF patients. Sera from ambulatory subjects were obtained from an Institutional Review Board (IRB)-approved biorepository of patients seen at the Emory CF Center between January 1, 2011, and December 31, 2014. Sera from hospitalized subjects were obtained from banked specimens from an IRB-approved inpatient clinical trial. Demographics, forced expiratory volume in one second (FEV1), and medication use were assessed from medical records. Thyroid function tests were measured from the stored sera. Multivariate regression models assessed associations between covariates and thyrotropin (TSH), free thyroxine (fT4), and thyroid dysfunction risk. A total of 89 subjects (54% male, 91% white, Mage = 24.4 years, median FEV1 63%) were included in the analyses. One subject was on thyroid hormone replacement, 93% were on pancreatic enzyme replacement, and 68% received antibiotics within six months. None had computed tomography scans with intravenous contrast within six months. One patient had positive thyroid peroxidase (TPO) antibodies. Of the 87 subjects with measured TSH values, seven (8%) had abnormal levels (range 0.2-7.6 μIU/mL; one overt, four subclinical hypothyroidism, and two subclinical hyperthyroidism). Of the 56 subjects with measured fT4 values, 19 (34%) had slightly low levels (range 0.49-0.79 ng/dL; 17 isolated mild hypothyroxinemia). A positive correlation between age and body mass index (BMI; p < 0.001) and a negative correlation between age and FEV1 (p = 0.041) were seen. Age, sex, race/ethnicity, BMI, FEV1, hospitalization status, use of pancreatic enzyme or thyroid hormone replacement, recent antibiotic use, and TPO antibody positivity were not predictive of TSH, fT4, or thyroid dysfunction risk. Stratified analyses by hospitalization did not predict TSH or fT4. Although 24 (27%) of the patients had abnormal serum thyroid function tests, overt thyroid dysfunction was rare in this cohort of 89 patients with CF. The degree of hypothyroxinemia was marginal, likely due to nonthyroidal illness. There were no significant predictors of thyroid dysfunction.

Modeling mixtures of thyroid gland function disruptors in a vertebrate alternative model, the zebrafish eleutheroembryo

Maternal thyroxine (T4) plays an essential role in fetal brain development, and even mild and transitory deficits in free-T4 in pregnant women can produce irreversible neurological effects in their offspring. Women of childbearing age are daily exposed to mixtures of chemicals disrupting the thyroid gland function (TGFDs) through the diet, drinking water, air and pharmaceuticals, which has raised the highest concern for the potential additive or synergic effects on the development of mild hypothyroxinemia during early pregnancy. Recently we demonstrated that zebrafish eleutheroembryos provide a suitable alternative model for screening chemicals impairing the thyroid hormone synthesis. The present study used the intrafollicular T4-content (IT4C) of zebrafish eleutheroembryos as integrative endpoint for testing the hypotheses that the effect of mixtures of TGFDs with a similar mode of action [inhibition of thyroid peroxidase (TPO)] was well predicted by a concentration addition concept (CA) model, whereas the response addition concept (RA) model predicted better the effect of dissimilarly acting binary mixtures of TGFDs [TPO-inhibitors and sodium-iodide symporter (NIS)-inhibitors]. However, CA model provided better prediction of joint effects than RA in five out of the six tested mixtures. The exception being the mixture MMI (TPO-inhibitor)-KClO4 (NIS-inhibitor) dosed at a fixed ratio of EC10 that provided similar CA and RA predictions and hence it was difficult to get any conclusive result. There results support the phenomenological similarity criterion stating that the concept of concentration addition could be extended to mixture constituents having common apical endpoints or common adverse outcomes.

Thyroxine Levels During Pregnancy in Healthy Women and Early Child Neurodevelopment

The fetus depends on maternal thyroid hormones during pregnancy for normal brain development. Little is known about the effects of subclinical hypothyroidism and mild hypothyroxinemia during pregnancy on neurodevelopment of the child. We evaluated a population-based birth cohort in Spain. A total of 1761 children and their mothers were included in the main analyses. Serum levels of free thyroxine and thyrotropin were measured in pregnant women. Mental and psychomotor development of their children was assessed using the Bayley Scales of Infant Development during the second year of life. Low free thyroxine levels (<5th percentile) and self-reported prepregnancy thyroid disorder without medical treatment were associated with a decrease of mental scores (Beta = -3.4 [95% confidence interval= -6.7 to -0.2]) and -5.5 [-8.9 to -2.0], respectively). No association between thyrotropin levels and mental scores or psychomotor scores was observed. Low free thyroxine levels in healthy pregnant women are related to a moderate delay in child neurodevelopment. The impairment is similar in magnitude to that observed in mothers with untreated prepregnancy thyroid disorder. The value of screening pregnant women for thyroid function requires further assessment, particularly in mildly iodine-deficient areas.

Maternal Thyroid Function during the Second Half of Pregnancy and Child Neurodevelopment at 6, 12, 24, and 60 Months of Age

Although evidence suggests that maternal hypothyroidism and mild hypothyroxinemia during the first half of pregnancy alters fetal neurodevelopment among euthyroid offspring, little data are available from later in gestation. In this study, we measured free T4 using direct equilibrium dialysis, as well as total T4 and TSH in 287 pregnant women at 27 weeks' gestation. We also assessed cognition, memory, language, motor functioning, and behavior in their children at 6, 12, 24, and 60 months of age. Increasing maternal TSH was related to better performance on tests of cognition and language at 12 months but not at later ages. At 60 months, there was inconsistent evidence that higher TSH was related to improved attention. We found no convincing evidence that maternal TH during the second half of pregnancy was related to impaired child neurodevelopment.

Delayed Neurobehavioral Development in Children Born to Pregnant Women with Mild Hypothyroxinemia During the First Month of Gestation: The Importance of Early Iodine Supplementation

Maternal hypothyroxinemia, due to gestational iodine deficiency, causes neurological dysfunctions in the progeny. Our aim was to determine the effects of delayed iodine supplementation (200 microg KI per day) to mildly hypothyroxinemic pregnant women at the beginning of gestation (i.e., having circulating free thyroxine [FT(4)] within the 0th-10th percentile interval and normal thyrotropin [TSH]) on the neurobehavioral development of their children. Using the Brunet-Lézine scale, we evaluated the neurocognitive performance at 18 months of age in three groups of children. Group 1 included children of women with FT(4) above the 20th percentile at 4-6 gestational weeks and at full-term. Group 2 included children of mildly hypothyroxinemic women diagnosed during the first 12-14 gestational weeks and with FT(4) above the 20th percentile at full-term. Group 3 included children born to mildly hypothyroxinemic women at full-term, without iodine supplementation during gestation. Women of all groups were iodine supplemented from the day of enrollment until the end of lactation. Before iodine supplementation, 33.0% of the women (114 out of 345) were hypothyroxinemic, with FT(4) below normal in 28 of them (8.1%). None were found to be hypothyroxinemic at full-term after supplementation. The mean (+/-SD) developmental quotient of children was 101.8 +/- 9.7 in group 1 (n = 13) vs. 87.5 +/- 8.9 in group 3 (n = 19; p < 0.001) and 92.2 +/- 5.4 in group 2 (n = 12; p < 0.05). The difference between groups 2 and 3 was not statistically significant. Delayed neurobehavioral performance was observed in 36.8% and 25.0% of children in groups 3 and 2, respectively, compared with no children in group 1. Differences (p < 0.001) were found on gross and fine motor coordination and socialization quotients. No statistically significant differences were found on language quotients. A delay of 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny. Public health programs should address the growing problem of iodine deficiency among women of gestational age in developing and industrialized nations.

Embarazo y déficit de yodo. Situación actual

Several studies performed in Spain have reported iodine deficiency in pregnant women but data from Valencia are lacking. The aim of the present study was to determine the degree of implantation of iodine supplementation in pregnant women in our health area.A total of 232 pregnant women were studied in the first trimester of pregnancy. Thyroid-stimulating hormone (TSH), free thyroxine, and antiperoxidase antibodies were measured. A survey was performed on intake of iodized salt and pharmacological iodine supplements. Neonatal TSH concentrations were measured, based on screening of metabolopathies, in the newborns of participating women.Then mean age was 30.5+/-4.4 years. A total of 60.8% of the women consumed iodized salt, 51.3% took iodine polyvitamins and only 14.2% consumed potassium iodide. The median urinary iodine concentration was 100 microg/l; 66% had urinary iodine concentrations below the recommended level (150 microg/l). A positive association was found between pharmacological iodine intake and urinary iodine (p=0.016). Ten percent of the women had mild hypothyroxinemia, while 5.7% of the newborns had elevated TSH levels.Iodine intake in pregnant women in our health area is low, despite current recommendations. Our data support the need to promote the use of iodized salt in every home and to systematically administer potassium iodide supplements in all pregnant women.

A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the Developing Rat Brain

Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis as encompassed in conditions of subclinical hypothyroidism and hypothyroxinemia, however, has not been established. The present investigation examined the effects of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain. Thyroid hormone insufficiency was induced by administration of propylthiouracil (PTU) to pregnant rats via drinking water from gestational day 6 until sacrifice of pups prior to weaning. In the first study a specialised microarray, the Affymetrix Rat Neurobiology array RN_U34, was used to contrast gene expression in the hippocampus of animals exposed to 0 or 10 ppm (10 mg/l) PTU, a treatment producing severe hypothyroidism. In the second study, a more complete genome array (Affymetrix Rat 230A) was used to compare gene expression in the neocortex and hippocampus of postnatal day (PN) 14 animals experiencing graded degrees of thyroid hormone insufficiency induced by delivery of 0, 1, 2 or 3 ppm PTU to the dam. Dose-dependent up- and down-regulation were observed for gene transcripts known to play critical roles in brain development and brain function. Expression levels of a subset of approximately 25 genes in each brain region were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data indicate that genes driving important developmental processes are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression is related to the degree of hormone reduction. Altered patterns of gene expression during critical windows of brain development indicate that thyroid disease must be viewed as a continuum and that conditions typically considered 'subclinical' may induce structural and functional abnormalities in the developing central nervous system.

Iodine supplementation during pregnancy: a public health challenge

Iodine deficiency remains the most frequent cause worldwide, after starvation, of preventable mental retardation in children. It causes maternal hypothyroxinemia, which affects pregnant women even in apparently iodine-sufficient areas, and often goes unnoticed because L-thyroxine (T4) levels remain within the normal range, and thyroid-stimulating hormone (TSH) is not increased. Even a mild hypothyroxinemia during pregnancy increases the risk of neurodevelopmental abnormalities, and experimental data clearly demonstrate that it damages the cortical cytoarchitecture of the fetal brain. The American Thyroid Association (ATA) recommends a supplement of 150 microg iodine/day during pregnancy and lactation, in addition to the use of iodized salt. We discuss the importance of iodine supplementation to ensure adequate T4 levels in all women who are considering conception and throughout pregnancy and lactation.