Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway.

INTRODUCTION: Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported. METHODS: After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association. RESULTS: We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves' disease was seen in three patients, Hashimoto's disease in two patients and thyrotoxicosis in one patient. CONCLUSION: Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.

Iodine Nutrition in Weaning Infants in the United States.

BACKGROUND: As iodine is a requisite micronutrient for infant brain development, infants are at risk for iodine deficiency during the weaning period when their diet transitions from milk (breast-milk, infant formula, or follow-on formula) to solid food. Dietary iodine intake during this weaning period is likely minimal, as the iodine content of commercial baby food is not regulated, and the addition of salt to baby food is not recommended. This study reports the current status of iodine nutrition among weaning infants in the United States. METHODS: Subjects (n = 60; 50% Caucasian, 30% black) were infants <12 months of age who were fed any combination of formula and/or baby food. Samples of all formula and food consumed in the previous 24 hours and a spot urine sample from each infant were obtained for the measurement of iodine. The estimated quantities of ingested formula and baby food were summed from a food diary recorded by the infants' parents. RESULTS: The mean age of the infants was 6.3 ± 3.5 months. The median urinary iodine concentration (UIC) was 117 µg/L (range 26.9-1302.8 µg/L). Estimated daily iodine intake obtained from the measured iodine content in infant formula/foods was 89 µg (range 0-288 µg). There was a positive correlation between the infants' UIC and the iodine content in the consumed foods (r = 0.4, p < 0.001). CONCLUSIONS: Although the median UIC of infants fed a combination of infant formula and baby food would meet the criteria for iodine sufficiency in a larger sample, those consuming the lowest quartile of iodine-containing nutritional sources had a median UIC <100 µg/L.

Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: a cohort study.

BACKGROUND: Iodine is important for thyroid hormone synthesis, and iodine deficiency in pregnancy may impair fetal neurological development. As perchlorate and thiocyanate inhibit sodium-iodide symporter reducing the transport of iodine from circulation into the thyroid follicular cells, environmental exposure to these substances in pregnancy may impair maternal thyroid hormone synthesis. We aimed to explore the impact of perchlorate and thiocyanate exposure on thyroid status in a cohort of pregnant mothers from South West England. METHODS: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks gestation. Samples were analysed for urinary concentrations of iodine (UIC), perchlorate (UPC) and thiocyanate (UTC). Blood samples were taken for free T4 (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab). Baseline data included age, parity, smoking status, ethnicity and BMI at booking. Following delivery, data on offspring's sex, gestational age at birth and birthweight were collected. RESULTS: Participants had a mean (SD) age 31 (5) years, median (IQR) BMI 24.4 (22.0, 28.3) kg/m2, 42% were primiparous, 10% were smokers, and 96% were Caucasian. Median UIC was 88 µg/l, and 174/308 (57%) women had UIC < 100 µg/l. Log transformed UPC negatively correlated with FT4, but not with TSH, in the whole cohort (r = - 0.12, p = 0.03) and in the subgroup of women with UIC < 100 µg/l (r = - 0.15, p = 0.04). Regression analysis with the potential confounders (TPO-Ab status, UIC and UTC) identified UPC to be negatively associated with FT4 (p = 0.01). There was no correlation between UTC and FT4 or TSH. Maternal UPC or UTC was not associated with offspring birthweight. CONCLUSION: Environmental perchlorate exposure is negatively associated with circulating FT4 levels in third trimester pregnant women. This may have an adverse impact on neurocognitive development of the fetus.

Maternal Plasma per- and Polyfluoroalkyl Substance Concentrations in Early Pregnancy and Maternal and Neonatal Thyroid Function in a Prospective Birth Cohort: Project Viva (USA).

BACKGROUND: Prenatal exposure to some per- and polyfluoroalkyl substances (PFASs) may disrupt maternal and neonatal thyroid function, which is critical for normal growth and neurodevelopment. OBJECTIVES: We examined associations of PFAS exposure during early pregnancy with maternal and neonatal thyroid hormone levels. METHODS: We studied 732 mothers and 480 neonates in Project Viva, a longitudinal prebirth cohort in Boston, Massachusetts. We quantified six PFASs, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and maternal thyroid hormones [thyroxine (T4), Free T4 Index (FT4I), thyroid stimulating hormone (TSH)] in plasma samples collected at a median 9.6 wk gestation and neonatal T4 levels from postpartum heel sticks. We estimated associations of PFAS concentrations with thyroid hormone levels using covariate-adjusted linear regression models and explored effect measure modification by maternal thyroid peroxidase antibody (TPOAb) status and infant sex. RESULTS: PFAS concentrations were not associated with maternal T4, but PFOA, perfluorohexane sulfonate (PFHxS), and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) were inversely associated with maternal FT4I [e.g., -1.87% (95% confidence interval (CI): -3.40, -0.31) per interquartile (IQR) increase in PFOA]. PFAS concentrations [PFOA, PFOS, and perfluorononanoate (PFNA)] were inversely associated with TSH levels in TPOAb-positive women only. Prenatal PFOS, PFOA, and PFHxS concentrations were inversely associated with T4 levels in male [e.g., PFHxS, quartile 4 vs.1: -2.51µg/dL (95% CI: -3.99, -1.04 )], but not female neonates [0.40µg/dL (95% CI: -0.98, 1.79)]. CONCLUSIONS: In this study, prenatal exposure to some PFASs during early pregnancy was inversely associated with maternal FT4I and neonatal T4 in male infants. These results support the hypothesis that prenatal exposure to PFASs influences thyroid function in both mothers and infants. https://doi.org/10.1289/EHP2534.

Determination of Thresholds of Radioactive Iodine Uptake Response With Clinical Exposure to Perchlorate: A Pooled Analysis.

OBJECTIVE: To conduct a more robust examination of perchlorate exposure on iodide uptake inhibition (IUI) using pooled data from four clinical studies of perchlorate exposure. METHODS: To establish a response threshold for IUI, data were analyzed using segmented linear regression and benchmark dose (BMD) analysis. RESULTS: Segmented linear regression applied to data for 69 subjects representing nine doses identified a breakpoint corresponding to a change in the slope of the dose-response relationship of 3.0 mg/d perchlorate. The estimated BMD for a 20% decrease in iodine uptake was 2.3 mg/d, with a lower 95% confidence interval limit of 1.6 mg/d. CONCLUSIONS: A threshold dose for IUI from perchlorate exposure of 1.6 to 3.0 mg/d (0.021 to 0.038 mg/kg d) was estimated using two modeling approaches. These estimates are slightly higher than the lowest observed effect level of 0.02 mg/kg d from the Greer Study.

Urinary Iodine, Perchlorate, and Thiocyanate Concentrations in U.S. Lactating Women.

BACKGROUND: Iodine is an essential micronutrient for thyroid hormone production. Adequate iodine intake and normal thyroid function are important during early development, and breastfed infants rely on maternal iodine excreted in breast milk for their iodine nutrition. The proportion of women in the United States of childbearing age with urinary iodine concentration (UIC) <50 µg/L has been increasing, and a subset of lactating women may have inadequate iodine intake. UIC may also be influenced by environmental exposure to perchlorate and thiocyanate, competitive inhibitors of iodine transport into thyroid, and lactating mammary glands. Data regarding UIC in U.S. lactating women are limited. To adequately assess the iodine sufficiency of lactating women and potential associations with environmental perchlorate and thiocyanate exposure, we conducted a multicenter, cross-sectional study of urinary iodine, perchlorate, and thiocyanate concentrations in healthy U.S. lactating women. METHODS: Lactating women ≥18 years of age were recruited from three U.S. geographic regions: California, Massachusetts, and Ohio/Illinois from November 2008 to June 2016. Demographic information and multivitamin supplements use were obtained. Iodine, perchlorate, and thiocyanate levels were measured from spot urine samples. Correlations between urinary iodine, perchlorate, and thiocyanate levels were determined using Spearman's rank correlation. Multivariable regression models were used to assess predictors of urinary iodine, perchlorate, and thiocyanate levels, and UIC <100 µg/L. RESULTS: A total of 376 subjects (≥125 from each geographic region) were included in the final analyses [mean (SD) age 31.1 (5.6) years, 37% white, 31% black, and 11% Hispanic]. Seventy-seven percent used multivitamin supplements, 5% reported active cigarette smoking, and 45% were exclusively breastfeeding. Median urinary iodine, perchlorate, and thiocyanate concentrations were 143 µg/L, 3.1 µg/L, and 514 µg/L, respectively. One-third of women had UIC <100 µg/L. Spot urinary iodine, perchlorate, and thiocyanate levels all significantly positively correlated to each other. No significant predictors of UIC, UIC <100 µg/L, or urinary perchlorate levels were identified. Smoking, race/ethnicity, and marital status were significant predictors of urinary thiocyanate levels. CONCLUSION: Lactating women in three U.S. geographic regions are iodine sufficient with an overall median UIC of 143 µg/L. Given ubiquitous exposure to perchlorate and thiocyanate, adequate iodine nutrition should be emphasized, along with consideration to decrease these exposures in lactating women to protect developing infants.

IODINE CONTENT OF ENTERAL AND PARENTERAL NUTRITION SOLUTIONS.

OBJECTIVE: Iodine is essential for thyroid hormone synthesis, and iodine deficiency may result in thyroid disorders including goiter and hypothyroidism. Patients on long-term enteral nutrition (EN) or parenteral nutrition (PN) may be at risk for micronutrient deficiencies. The recommended daily allowance for iodine intake is 150 µg for nonpregnant adults. However, there is no current consensus among scientific societies regarding the quantity of iodine to be added in adult EN and PN formulations. The objective of this study was to determine the iodine content of U.S. adult enteral and parenteral nutrition solutions. This study also aimed to determine whether adult patients in the United States who are receiving long-term artificial nutrition may be at risk for iodine deficiency. METHODS: Ten enteral nutrition solutions and 4 parenteral nutrition solutions were evaluated. The iodine contents of these solutions were measured spectrophotometrically and compared to the labeled contents. RESULTS: Measured and labeled EN iodine contents were similar (range 131-176 µg/L and 106-160 µg/L, respectively). In contrast, PN formulas were found to contain small, unlabeled amounts of iodine, averaging 27 µg/L. CONCLUSION: Typical fluid requirements are 30 to 40 mL/kg/day for adults receiving either total EN (TEN) or total PN (TPN). Adults on long-term TEN likely consume enough servings to meet their daily iodine requirements. However, patients on long-term TPN would require on average 5.6 L PN/day to meet the recommended daily allowance of iodine. This volume of PN is far in excess of typical consumption. Thus, U.S. patients requiring long-term TPN may be at risk for iodine deficiency. ABBREVIATIONS: EN = enteral nutrition; PN = parenteral nutrition; TEN = total enteral nutrition; TPN = total parenteral nutrition; UIC = urinary iodine concentration.

Associations between urinary diphenyl phosphate and thyroid function.

Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer with widespread human exposure. Data on health effects of TPHP are limited. Recent toxicological studies suggest TPHP may alter thyroid function. We used repeated measures to assess the temporal variability in urinary concentrations of the TPHP metabolite, diphenyl phosphate (DPHP), and to examine relationships between DPHP concentrations and thyroid hormones. We sampled 51 adults at months 1, 6, and 12 from 2010 to 2011. Urine samples were analyzed for DPHP. Serum samples were analyzed for free and total thyroxine (fT4, TT4), total triiodothyronine (TT3), and thyroid stimulating hormone (TSH). We assessed variability in DPHP using intraclass correlation coefficients (ICCs) and kappa statistics. We used linear mixed-effects models to examine associations between DPHP and thyroid hormones. DPHP was detected in 95% of urine samples. Mean DPHP concentrations were 43% higher in women than men. DPHP showed high within-subject variability (ICC range, 0.13-0.39; kappa range, 0.16-0.39). High versus low (≥2.65 vs. <2.65ng/mL) DPHP in all participants was associated with a 0.43µg/dL (95% confidence interval: 0.15, 0.72) increase in mean TT4 levels. In sex-stratified analyses, high versus low DPHP was associated with a 0.91µg/dL (95% CI: 0.47, 1.36) increase in mean TT4 in women. The association was attenuated in men (ßeta=0.19; 95% CI: -0.15, 0.52). We found no significant associations between DPHP and fT4, TT3, or TSH. We found evidence that TPHP exposure may be associated with increased TT4 levels, especially in women.

Population Survey of Iodine Deficiency and Environmental Disruptors of Thyroid Function in Young Children in Haiti.

Context: Iodine deficiency is the leading cause of preventable neurodevelopmental delay in children worldwide and a possible public health concern in Haiti. Objective: To determine the prevalence of iodine deficiency in Haitian young children and its influence by environmental factors. Design: Cross-sectional study, March through June 2015. Setting: Community churches in 3 geographical regions in Haiti. Participants: 299 healthy Haitian children aged 9 months to 6 years; one-third each enrolled in a coastal, mountainous, and urban region. Main Outcome Measures: Urinary iodide, serum thyrotropin (TSH), goiter assessment, and urinary perchlorate and thiocyanate. Results: Mean age was 3.3±1.6 years, with 51% female, median family income USD 30/week, and 16% malnutrition. Median urinary iodide levels were normal in coastal (145 µg/L, interquartile range [IQR] 97 to 241) and urban regions (187 µg/L, IQR 92 to 316), but revealed mild iodine deficiency in a mountainous region (89 µg/L, IQR 56 to 129), P < 0.0001. Grade 1 goiters were palpated in 2 children, but TSH values were normal. Urinary thiocyanate and perchlorate concentrations were not elevated. Predictors of higher urinary iodide included higher urinary thiocyanate and perchlorate, breastfeeding, and not living in a mountainous region. Conclusions: Areas of mild iodine deficiency persist in Haiti's mountainous regions. Exposure to two well-understood environmental thyroid function disruptors is limited.

Iodine Supplementation in Women During Preconception, Pregnancy, and Lactation: Current Clinical Practice by U.S. Obstetricians and Midwives.

BACKGROUND: Iodine deficiency is a major public-health problem throughout the world, especially for pregnant women, and it is considered the most common cause of preventable intellectual impairment. In the United States, iodine status in pregnant women is considered mildly deficient. Therefore, the Endocrine Society, the American Thyroid Association, the Teratology Society, and the American Academy of Pediatrics recommend that women receive prenatal vitamins containing 150 µg of iodine daily during preconception, pregnancy, and lactation. The objectives of this study were to evaluate awareness of iodine nutrition among obstetricians and midwives in the United States, and to document current clinical practice regarding recommendations for iodine supplementation for women during preconception, pregnancy, and lactation. METHODS: All midwife members of the American College of Nurse-Midwives (ACNM) and all obstetrician members of the American Medical Association (AMA) were invited to participate in a web-based survey. RESULTS: A total of 199 midwives and 277 obstetricians participated in the survey. One third of both obstetricians and midwives considered iodine status in U.S. pregnant women to be deficient. Although almost all obstetricians and midwives would recommend prenatal multivitamins, most reported rarely or never recommending iodine-containing multivitamins for women planning pregnancy (68.7% and 70.2%, respectively), pregnant women (66% and 67.1%), or lactating women (68.7% and 71.7%). Of the respondents who did report prescribing iodine-containing supplements, 85% recommended supplementation during the first trimester and 75-80% during the second and third trimesters. However, of those who did recommend iodine supplementation, only 45% would prescribe the recommended 150 µg of iodine daily during pregnancy. Overall, 75% of U.S. obstetricians and midwives do not recommend or would recommend an inadequate amount of iodine during preconception, pregnancy, and lactation. CONCLUSIONS: Despite the important consequences of iodine deficiency for pregnant women and the recommendations of many medical societies, the majority of U.S. obstetricians and midwives who participated in this survey do not recommend iodine-containing vitamins in women planning pregnancy, during pregnancy, and during lactation.

Iodine deficiency amongst pregnant women in South-West England.

INTRODUCTION: Iodine deficiency in pregnancy may impair foetal neurological development. The UK population is generally thought to be iodine sufficient; however, recent studies have questioned this assumption. Our study aimed to explore the prevalence of iodine deficiency in a cohort of pregnant mothers from South-West England. METHODS: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks' gestation. Samples were analysed for urinary iodine concentrations (UIC). Baseline data included age, parity, smoking status, ethnicity, body mass index (BMI) at booking, prenatal vitamin use and a dietary questionnaire. There was no difference in median UIC between women with (n = 156) or without (n = 152) a breech presentation (P = 0·3), so subsequent analyses were carried out as a combined group. RESULTS: Participants had a mean (SD) age 31(5) years, median (IQR) BMI 24·4 (22·0, 28·3) kg/m2 ; 42% were primiparous, 10% smoked during pregnancy, and 35% took iodine-containing vitamins. Ninety-six per cent were Caucasian. Median (IQR) UIC was 88·0 (54·3, 157·5) µg/l, which is consistent with iodine deficiency by WHO criteria. A total of 224/308 (73%) of women had UIC values <150 µg/l. Increasing milk intake was associated with higher UIC (P = 0·02). There was no difference in median (IQR) UIC between those women who took iodine-containing vitamins (n = 108) and those who did not (n = 200): 88 (54, 168) vs 88 (54, 150) µg/l, P = 0·7. CONCLUSION: Iodine deficiency in pregnancy is common in South-West England. Measures to develop optimum prevention and treatment strategies are urgently needed.

Polybrominated diphenyl ether exposure and reproductive hormones in North American men.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are flame retardant chemicals that are persistent organic pollutants. Animal experiments and some human studies indicate that PBDEs may adversely affect male reproductive function. OBJECTIVES: To assess the association between PBDE exposure and reproductive hormones (RHs) in a North American male adult cohort. METHODS: From 2010-11, we collected three serum samples from 27 healthy adult men. We assessed associations between PBDEs and RHs using mixed effect regression models. RESULTS: PBDEs were inversely associated with inhibin-B. In older men, increased concentrations of BDE-47 and BDE-100 were significantly associated with a decrease in inhibin-B, and an increase in follicular stimulating hormone (FSH). CONCLUSIONS: These findings suggest PBDE exposure may affect RHs in older men. We did not measure other parameters of male reproductive function and therefore these results are preliminary.

Hyperthyroidism.

Hyperthyroidism is characterised by increased thyroid hormone synthesis and secretion from the thyroid gland, whereas thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones, irrespective of the source. The most common cause of hyperthyroidism is Graves' disease, followed by toxic nodular goitre. Other important causes of thyrotoxicosis include thyroiditis, iodine-induced and drug-induced thyroid dysfunction, and factitious ingestion of excess thyroid hormones. Treatment options for Graves' disease include antithyroid drugs, radioactive iodine therapy, and surgery, whereas antithyroid drugs are not generally used long term in toxic nodular goitre, because of the high relapse rate of thyrotoxicosis after discontinuation. ß blockers are used in symptomatic thyrotoxicosis, and might be the only treatment needed for thyrotoxicosis not caused by excessive production and release of the thyroid hormones. Thyroid storm and hyperthyroidism in pregnancy and during the post-partum period are special circumstances that need careful assessment and treatment.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.