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.

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.

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.

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.

THYROID FUNCTION AND METABOLIC SYNDROME: A CROSS-SECTIONAL STUDY IN OBESE AND OVERWEIGHT PATIENTS.

OBJECTIVE: Metabolic syndrome (MetS) is associated with increased risks of developing cardiovascular disease and type 2 diabetes. Thyroid dysfunction is also a known cardiovascular risk factor. In obese patients, serum thyroid-stimulating hormone (TSH) levels tend to be higher than in lean controls. The objective of this study was to assess potential associations between serum TSH levels and MetS as well as individual components of MetS. METHODS: This was a cross-sectional observational study of obese and overweight patients seen for initial evaluation at the Boston Medical Center weight-management clinic between February 1, 2013 and February 1, 2014. Demographic, anthropometric, and laboratory data including serum TSH, insulin, glucose, hemoglobin A1c, and lipid levels were obtained from electronic medical records. Associations between serum TSH levels and presence of MetS and its components were assessed. RESULTS: A total of 3,447 patients, 75.6% female and 38% African American, without known thyroid dysfunction, were included. Mean ± SD age was 46.74 ± 15.11 years, and mean ± SD body mass index was 36.06 ± 9.89 kg/m(2). Among 1,005 patients without missing data, the prevalence of MetS was 71.84%. In patients with MetS, the median serum TSH was 1.41 µIU/mL, compared with 1.36 µIU/mL in patients without MetS (P = .45). In multivariate models, there was no significant association between serum TSH levels and the presence of MetS, adjusting for age, sex, race, education, socioeconomic status, and smoking. There were also no significant associations between serum TSH and individual components of the MetS. CONCLUSION: Serum TSH level does not appear to be a potentially modifiable risk factor for MetS in obese and overweight individuals.

Changes in body weight after treatment of primary hypothyroidism with levothyroxine.

OBJECTIVE: Surprisingly few studies have examined weight change in hypothyroid patients after initiation of levothyroxine (LT4) therapy. Our study aimed to investigate weight change after initiation of LT4 treatment for primary hypothyroidism. METHODS: Using electronic medical records from Boston Medical Center, Boston, Massachusetts, we performed a retrospective cohort study between January 1, 2003, and February 1, 2011. Adults ≥18 years of age with newly diagnosed primary hypothyroidism with an initial thyroid-stimulating hormone (TSH) level ≥10 mIU/L were identified. Patients with postsurgical hypothyroidism, thyroid cancer, and a history of radioactive iodine or head/neck irradiation, congestive heart failure, anorexia nervosa, end-stage renal disease, cirrhosis, pregnancy, or use of prescription weight-loss medications were excluded. TSH and weight at diagnosis and up to 24 months after LT4 initiation were collected. Weight change was assessed at the first posttreatment serum TSH level <5 mIU/L. RESULTS: A total of 101 patients (mean age, 48 ± 15 years; 71% women) were included. Initial median TSH was 18.3 mIU/L (range, 10.1 to 710.5 mIU/L) and initial median weight was 79.6 kg (range 41.5 to 167.5 kg). Posttreatment median TSH level was 2.3 mIU/L (range, 0.04 to 5 mIU/L), and weight change at a median of 5 months (range, 1.1 to 25.6 months) was -0.1 kg (range, -20.6 to 7.7 kg). Initial median body mass index (BMI) of 95 of the patients was 29.3 kg/m2 (range, 19.5 to 56.1 kg/m2), and the median change in BMI was -0.1 kg/m2 (range, -7.1 to 3.3 kg/m2). Only 52% of patients lost weight, with a mean weight loss of 3.8 ± 4.4 kg. Gender, race, education, insurance type, age, initial TSH level, time to normalization of TSH, and initial weight were not associated with changes in weight or BMI. CONCLUSION: Contrary to popular belief, our study of 101 patients with primary hypothyroidism showed that no significant weight change occurs after initiation of LT4 treatment.

Iodine content of U.S. weight-loss food.

OBJECTIVE: The recommended iodine intake is 150 µg/day in adults, 220 µg/day during pregnancy, and 290 µg/day during lactation. Individuals exclusively consuming restricted diets as part of a weight-loss program may be at risk for mild to moderate iodine deficiency. The purpose of this study was to assess the iodine content in meals and snacks from 3 U.S. commercial weight-loss programs, all of which are intended to be the sole source of dietary intake during the desired weight-loss period. METHODS: The iodine contents in the products representing 1 week of all meals and snacks from 3 U.S. commercial weight-loss programs were measured by spectrophotometry. The measured total iodine content in 1 week's worth of food from each program is reported as an average level per day. RESULTS: A total of 53 total items were analyzed (29 different items [7 breakfasts, 7 lunches, 7 dinners, 6 snacks, 2 desserts] from Jenny Craig®, 21 different items [7 breakfasts, 7 lunches, 7 dinners] from Nutrisystem®, and 3 different items [1 breakfast, 1 lunch, 1 dinner; each to be intended to be eaten daily for 1 week] from Medifast®). Daily iodine content (mean ± SD) of meals and snacks from the weight-loss programs were 34.2 ± 1.2 (Jenny Craig®), 12.2 ± 0.7 (Nutrisystem®), and 70.1 ± 1.1 (Medifast) µg/day. CONCLUSION: These results indicate that the dietary content in the foods from 3 U.S. commercial weight-loss programs is far less than the recommendations for iodine intake of 150 µg/day in nonpregnant, nonlactating adults. Individuals following each weight-loss program should be advised to take a multivitamin containing 150 mg of iodine daily.

Steady-State Serum T3 Concentrations for 48 Hours Following the Oral Administration of a Single Dose of 3,5,3'-Triiodothyronine Sulfate (T3S).

OBJECTIVE: Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3. METHODS: Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 µg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration. RESULTS: At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported. CONCLUSION: (1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion.

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.

Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women from Greece.

OBJECTIVE: Thyroid hormone, requiring adequate maternal iodine intake, is critical for neurodevelopment in utero. Perchlorate and, less so, thiocyanate decrease uptake of iodine into the thyroid gland by competitively inhibiting the sodium/iodide symporter (NIS). It remains unclear whether environmental perchlorate exposure adversely affects thyroid function in first-trimester pregnant women. DESIGN: Cross-sectional. PATIENTS: 134 pregnant women from Athens, Greece, at mean ± SD 10·9 ± 2·3 weeks' gestation. MEASUREMENTS: Urinary iodide, perchlorate, and thiocyanate and thyroid function tests were measured. RESULTS: The median urinary iodide was 120 µg/l. Urinary perchlorate levels were detectable in all women: median (range) 4·1 (0·2-118·5) µg/l. Serum thyroperoxidase antibodies (TPO Ab) were detectable in 16% of women. Using Spearman's rank correlation analyses, there was no correlation between urinary perchlorate concentrations and serum TSH, although inverse correlations were seen between urine perchlorate and free T3 and free T4 values. In univariate analyses, urine thiocyanate was positively correlated with serum TSH, but was not associated with serum free T3 or free T4. Urine perchlorate was positively correlated with gestational age. In multivariate analyses adjusting for urinary iodide concentrations, urine thiocyanate, gestational age, maternal age and TPO Ab titres, urine perchlorate was not a significant predictor of thyroid function. CONCLUSIONS: Low-level perchlorate and thiocyanate exposure is ubiquitous, but, in adjusted analyses, is not associated with alterations in thyroid function tests among mildly iodine-deficient Greek women in the first trimester of pregnancy.

Neonatal thyroxine, maternal thyroid function, and child cognition.

CONTEXT: Thyroid hormone is essential for normal brain development. Limited data are available regarding whether thyroid function in neonates influences later cognitive development. OBJECTIVE: Our objective was to study associations of newborn T4 levels with maternal thyroid function and childhood cognition. DESIGN AND SETTING: We studied participants in Project Viva, a cohort study in Massachusetts. PARTICIPANTS: We studied a total of 500 children born 1999--2003 at 34 wk or more. MAIN OUTCOME MEASURES: We determined cognitive test scores at ages 6 months and 3 yr. RESULTS: Mean newborn T4 at a mean age of 1.94 d was 17.6 (sd 4.0) microg/dl, and levels were higher in girls [1.07 microg/dl; 95% confidence interval (CI) 0.38, 1.76] and infants born after longer gestation (0.42 microg/dl; 95% CI 0.17, 0.67 per wk). Newborn T4 levels were not associated with maternal T4, TSH, or thyroid peroxidase antibody levels. On multivariable linear regression analysis, adjusting for maternal and child characteristics, higher newborn T4 was unexpectedly associated with poorer scores on the visual recognition memory test among infants at age 6 months (-0.5; 95% CI -0.9, -0.2), but not with scores at age 3 yr on either the Peabody Picture Vocabulary Test (0.2; 95% CI -0.1, 0.5) or the Wide Range Assessment of Visual Motor Abilities (0.1; 95% CI -0.2, 0.3). Maternal thyroid function test results were not associated with child cognitive test scores. CONCLUSIONS: Newborn T4 concentrations within a normal physiological reference range are not associated with maternal thyroid function and do not predict cognitive outcome in a population living in an iodine-sufficient area.

Role of pendrin in iodide balance: going with the flow.

Pendrin is expressed in the apical regions of type B and non-A, non-B intercalated cells, where it mediates Cl(-) absorption and HCO3(-) secretion through apical Cl(-)/HCO3(-) exchange. Since pendrin is a robust I(-) transporter, we asked whether pendrin is upregulated with dietary I(-) restriction and whether it modulates I(-) balance. Thus I(-) balance was determined in pendrin null and in wild-type mice. Pendrin abundance was evaluated with immunoblots, immunohistochemistry, and immunogold cytochemistry with morphometric analysis. While pendrin abundance was unchanged when dietary I(-) intake was varied over the physiological range, I(-) balance differed in pendrin null and in wild-type mice. Serum I(-) was lower, while I(-) excretion was higher in pendrin null relative to wild-type mice, consistent with a role of pendrin in renal I(-) absorption. Increased H2O intake enhanced differences between wild-type and pendrin null mice in I(-) balance, suggesting that H2O intake modulates pendrin abundance. Raising water intake from approximately 4 to approximately 11 ml/day increased the ratio of B cell apical plasma membrane to cytoplasm pendrin label by 75%, although circulating renin, aldosterone, and serum osmolality were unchanged. Further studies asked whether H2O intake modulates pendrin through the action of AVP. We observed that H2O intake modulated pendrin abundance even when circulating vasopressin levels were clamped. We conclude that H2O intake modulates pendrin abundance, although not likely through a direct, type 2 vasopressin receptor-dependent mechanism. As water intake rises, pendrin becomes increasingly critical in the maintenance of Cl(-) and I(-) balance.

Colostrum iodine and perchlorate concentrations in Boston-area women: a cross-sectional study.

OBJECTIVE: To measure levels of colostrum iodine, which has not been previously measured, and perchlorate and cotinine (a surrogate for thiocyanate derived from cigarette smoke) in women up to 60 h postpartum. Perchlorate and thiocyanate are environmental inhibitors of iodide transport into the thyroid and lactating breast. DESIGN: Cross-sectional. PATIENTS: Ninety seven postpartum women in Boston, Massachusetts, USA. MEASUREMENTS: Colostrum iodine and perchlorate, and spot urine iodine, perchlorate, cotinine and creatinine concentrations were measured. RESULTS: Sufficient colostrum was obtained to measure iodine in 61 samples and perchlorate in 46 samples. Median colostrum iodine content was 51.4 micromol/l (range 21.3-304.2 microg/l). Perchlorate was detectable in 43 of 46 colostrum samples (median 2.5 micromol/l; range, < 0.05-188.9 micromol/l). Median urine iodine in 97 samples was 82.2 micromol/l (range, 10.3-417.1 micromol/l). Perchlorate was detectable in all 97 urine samples (median 2.6 micromol/l; range, 0.2-160.6 micromol/l). Colostrum iodine content was not significantly correlated with levels of colostrum perchlorate or concentrations per litre of urinary iodine, perchlorate, or cotinine. Colostrum perchlorate concentrations were not significantly associated with urinary iodine, perchlorate, or cotinine levels. Urinary cotinine levels were not significantly associated with urinary iodine or perchlorate levels. There was no association between maternal urinary iodine and urinary perchlorate levels. CONCLUSIONS: Iodine is present in human colostrum and thus available for breastfeeding infants immediately after birth. Perchlorate was also present in 93% of samples measured, but the concentrations did not correlate with colostrum iodine concentrations.

Free T4 immunoassays are flawed during pregnancy.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracies of 2 free thyroxine immunoassays during pregnancy. STUDY DESIGN: Serum was collected from healthy, thyroid peroxidase antibody-negative women during each trimester and nonpregnant controls. Thyrotropin, total T4 (TT4), free T4 index (FT4I), and 2 different FT4 immunoassays were studied. RESULTS: As expected, TT4 was elevated in all 3 trimesters compared to controls (P < .001). FT4I was elevated in the 1st trimester as compared with controls (P < .05) and returned to the nonpregnant range in the 2nd and 3rd trimesters. In contrast, 1st trimester FT4 immunoassay values were either comparable or lower than controls and by the 2nd and 3rd trimesters had decreased to approximately 65% of controls. CONCLUSION: Neither FT4 immunoassay accurately reflects established free T4 changes during pregnancy. TT4 and the FT4I retained an appropriate inverse relationship with TSH throughout pregnancy and appear to provide a more reliable free T4 estimate.

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.

Thyroid function and lipid subparticle sizes in patients with short-term hypothyroidism and a population-based cohort.

CONTEXT: Relations between thyroid function and lipids remain incompletely understood. OBJECTIVE: Our objective was to determine whether lipoprotein subparticle concentrations are associated with thyroid status. DESIGN AND SETTING: We conducted a prospective clinical study and cross-sectional cohort analysis at a university endocrine clinic and the Framingham Heart Study. SUBJECTS: Subjects included 28 thyroidectomized patients with short-term overt hypothyroidism and 2944 Framingham Offspring cohort participants. MAIN OUTCOME MEASURES: Fasting subclass concentrations of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) particles were measured by nuclear magnetic resonance spectroscopy. TSH values were also measured. RESULTS: Total cholesterol and LDL-C were increased during short-term overt hypothyroidism. Large LDL subparticle concentrations increased during hypothyroidism (917+/-294 vs. 491+/-183 nmol/liter; P<0.001), but more atherogenic small LDL was unchanged. Triglycerides marginally increased during hypothyroidism, small VLDL particles significantly increased (P<0.001), whereas more atherogenic large VLDL was unchanged. Total HDL-C increased during hypothyroidism (76+/-13 mg/dl vs. 58+/-15 mg/dl; P<0.001). There was no change in large HDL-C particle concentrations, whereas small (P<0.001) and medium (P=0.002) HDL-C particle concentrations decreased. Among Framingham women, adjusted total cholesterol and LDL-C were positively related to TSH categories (P