Impact of Thyroglobulin and Thyroglobulin Antibody Assay Performance on the Differential Classification of DTC Patients.

CONTEXT: Measurements of thyroglobulin (Tg) and Tg antibodies are crucial in the follow-up of treated differentiated thyroid cancer (DTC) patients. Interassay differences may significantly impact follow-up. OBJECTIVE: The aim of this multicenter study was to explore the impact of Tg and Tg antibody assay performance on the differential classification of DTC patients, as described in national and international guidelines. DESIGN: Four commonly used Tg and Tg antibody assays were technically compared to reflect possible effects on patients with DTC follow-up. Storage stability at different storage temperatures was also investigated for LIAISON® and Kryptor assays, as this is an underexposed topic in current literature. RESULTS: B.R.A.H.M.S. assays yield approximately 50% lower Tg values over the whole range compared to the DiaSorin and Roche assays investigated. These differences between assays may result in potential misclassification in up to 7% of patients if fixed cutoffs (eg, 1 ng/mL) are applied. Poor correlation was also observed between the Tg antibody assays when the method-specific upper limits of normal are used as cutoffs. Storage of Tg and Tg antibodies was possible for 3 to 4 weeks at -20°C and -80°C. Calibration of the assays, however, was found to be crucial for stable results over time. CONCLUSIONS: Technical aspects of Tg and Tg antibody assays, including interassay differences, calibration and standardization, and cutoff values, may have a significant clinical impact on the follow-up of DTC patients.

Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.

Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation.

OBJECTIVE: Monocarboxylate transporter 8 (MCT8) is an essential thyroid hormone (TH) transporter as humans with MCT8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block-and-replace treatment in an MCT8 patient. DESIGN: The TOP-R study is a cross-sectional nation-wide multicentre study. PATIENTS: Subjects with unexplained mental retardation (MR) were screened for MCT8 mutations. RESULTS: We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block-and-replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU, and eventually their complete normalization by administration of LT4 with PTU but not with methimazole. The frequency of MCT8 mutations in males with X-linked MR approximately 3·9%. CONCLUSIONS: We identified several MCT8 mutations in a cohort of subjects with unexplained MR. We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block-and-replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT8 mutations. Our study indicates that MCT8 mutations are a relatively frequent cause of X-linked MR.

Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age.

CONTEXT: Age-appropriate reference ranges for thyroid hormones are required for detecting pediatric thyroid dysfunction. Data on thyroid hormones and peripheral thyroid metabolism in short children born small for gestational age (SGA) before and during GH treatment are lacking. OBJECTIVES: Our objectives were to obtain pediatric thyroid hormone reference ranges; to investigate thyroid hormones in short SGA children before puberty, during puberty, and during postponement of puberty by GnRH analog; and to evaluate thyroid hormones during GH treatment. PATIENTS AND DESIGN: In 512 healthy children (225 females; 0-18 yr), free T(4) (FT(4)), TSH, total T(4), T(3), rT(3), and T(4)-binding globulin were determined. Reference ranges were calculated using the linearity, median, and skewness method. In 125 short SGA children (62 females; mean age 11.3 yr), thyroid hormones were analyzed before and after 2 yr of GH treatment and additional GnRH analog. RESULTS: Thyroid references showed wide ranges postnatally and age-specific patterns thereafter, similar in boys and girls. Untreated short SGA children had similar FT(4) and T(4) levels as the reference population but significantly higher T(3), rT(3), and T(4)-binding globulin levels. During puberty and during GH treatment, FT(4) and rT(3) significantly decreased, whereas T(3) significantly increased. CONCLUSION: Age-specific thyroid reference ranges are presented. Puberty and GH treatment both induce changes in peripheral thyroid metabolism, resulting in more biologically active T(3) at the expense of less inactive rT(3), possibly mediated by IGF-I. GH treatment induces altered peripheral thyroid metabolism but does not result in thyroid dysfunction.

Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study.

OBJECTIVE: Abnormalities in thyroid state may affect development and function of the brain and result in mental retardation (MR). Thyroid parameters have not been systematically investigated in institutionalized MR subjects. The objective is to measure thyroid parameters in a novel cohort of 946 institutionalized subjects. DESIGN: The TOP-R (Thyroid Origin of Psychomotor Retardation) study is a cross-sectional nation-wide multicentre study. PATIENTS: Subjects with unexplained MR. RESULTS: The majority of the MR subjects had thyroid parameters within the reference range used in our laboratory. Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102·1 ± 1·2 vs 83·9 ± 1·2 nmol/l, P < 1 × 10(-24) ; FT4: 18·0 ± 0·2 vs 16·1 ± 0·2 pmol/l, P < 1 × 10(-9) ; T3: 1·72 ± 0·02 vs 1·57 ± 0·02 nmol/l, P < 1 × 10(-9) ; and rT3: 0·37 ± 0·01 vs 0·27 ± 0·01 nmol/l, P < 1 × 10(-28) in subjects without vs with AEDs). The prevalence of unrecognized primary hypothyroidism and hyperthyroidism was 5·2% and 2·8%, respectively. CONCLUSIONS: We report thyroid parameters in a cohort of institutionalized subjects with MR. Our findings substantiate the fact that AEDs affect thyroid hormone levels. Future studies will be employed to investigate genetic causes of MR related to abnormalities in thyroid hormone homeostasis.

Mutations in the iodotyrosine deiodinase gene and hypothyroidism.

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.

Novel criteria for parathyroid hormone levels in parathyroid hormone-guided parathyroid surgery.

CONTEXT: Novel criteria for decrease of perioperative parathyroid hormone measurement may improve the accuracy of perioperative quick parathyroid hormone (qPTH)-guided parathyroidectomy. OBJECTIVE: To assess overall cure rate based on conventional criteria (50% decline of qPTH). Perioperative qPTH levels were evaluated to determine novel criteria for successful parathyroid surgery. DESIGN: Analysis of perioperative qPTH measurement findings of all consecutive patients undergoing parathyroidectomy for hyperparathyroidism (72 with primary hyperparathyroidism and 28 with secondary or tertiary hyperparathyroidism or multiple endocrine neoplasia I/IIa disease). RESULTS: Measurement of qPTH (based solely on the criterion of greater than 50% decline of parathyroid hormone) in 72 patients with primary hyperparathyroidism (77 procedures) showed true-positive results in 69, false-positive results in 4, and true-negative results in 4 procedures. In our series, false-positive and true-negative results were associated with high postexcision levels. However, when qPTH declines of greater than 70% and 80% were used in cases of postexcision qPTH levels of 100 to 200 ng/L and greater than 200 ng/L, respectively, no false-positive results were observed. CONCLUSIONS: Through adherence to these novel criteria, reexploration of the neck could have been prevented in 29% of patients with primary hyperparathyroidism due to multiple gland disease. These novel criteria demand future evaluation to establish their value.

The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men.

BACKGROUND: Variations in thyroid function within the normal range are associated with differences in metabolism and body composition. For instance, TSH is positively associated with body mass index (BMI). This could be due to alterations in thyroid hormone activity, or to direct effects of TSH, as the TSH receptor (TSHR) is also expressed in adipose tissue. The TSHR-Asp727Glu polymorphism is associated with lower serum TSH levels in vivo. In this study, we analysed whether serum thyroid parameters and the TSHR-Asp727Glu polymorphism were associated with glucose metabolism and insulin resistance. In addition, we analysed the Thr92Ala polymorphism in the type 2 deiodinase (D2), which was recently associated with insulin resistance. METHODS: Genotypes were determined in a population of 349 elderly men (age 77.7 +/- 3.5 years), for whom serum thyroid parameters and data on insulin resistance, such as fasting blood glucose, serum insulin and homeostasis model assessment (HOMA) values, were available. RESULTS: In nondiabetic, euthyroid subjects, TSH was positively associated with leptin levels, whereas FT4 and rT3 were significantly negatively correlated with insulin and HOMA. Carriers of the TSHR-Glu727 allele had a significantly higher glucose (P = 0.01), insulin (P = 0.001), glycated haemoglobin (HbA1c) (P = 0.002), HOMA (P = 0.001) and leptin (P = 0.008). The D2-Ala(92) allele showed a trend towards higher levels of insulin (P = 0.07) and a higher HOMA (P = 0.09). CONCLUSION: In this population of nondiabetic elderly men, serum thyroid parameters and the TSHR-Asp727Glu polymorphism were associated with relative insulin resistance. Our study suggests that genetic variation in TSHR plays a role in insulin resistance and thereby influences glucose metabolism.

Tissue thyroid hormone levels in critical illness.

CONTEXT: Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity. PATIENTS AND STUDY QUESTIONS: We therefore investigated, in 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, whether total serum thyroid hormone levels correspond to tissue levels in liver and muscle. Furthermore, we investigated the relationship between tissue thyroid hormone levels, deiodinase activities, and monocarboxylate transporter 8 expression. RESULTS: Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines. CONCLUSION: Our results suggest that, in addition to changes in the hypothalamus-pituitary-thyroid axis, tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone in critical illness.

Increased thyroxine sulfate levels in critically ill patients as a result of a decreased hepatic type I deiodinase activity.

INTRODUCTION: Marked changes in peripheral thyroid hormone metabolism occur in critical illness, resulting in low serum T3 and high rT3 levels. In this study, we investigated whether T4S levels are increased in patients who died after intensive care and whether T4S levels are correlated with liver type I deiodinase (D1) or sulfotransferase (SULT) activity. METHODS: A total of 64 blood samples and 65 liver biopsies were obtained within minutes after death from 79 intensive care patients, randomized for intensive or conventional insulin treatment. Serum T4S and the activities of hepatic D1 and 3,3'-diiodothyronine (T2)-SULT and estrogen-SULT were determined. RESULTS: No differences in T4S or hepatic SULT activities were found between patients treated with intensive or with conventional insulin therapy. T4S levels were significantly elevated compared with healthy references. Furthermore, hepatic D1, but not SULT activity, showed a strong correlation with serum T4S (R = -0.53; P < 0.001) and T4S/T4 ratio (R = -0.62; P < 0.001). Cause of death was significantly correlated with hepatic T2- and estrogen-SULT activities (P < 0.01), with SULT activities being highest in the patients who died of severe brain damage and lowest in the patients who died of a cardiovascular collapse. A longer period of intensive care was associated with higher levels of T4S (P = 0.005), and high levels of bilirubin were associated with low T2-SULT (P = 0.04) activities and high levels of T4S (P < 0.001). CONCLUSION: Serum T4S levels were clearly elevated compared with healthy references, and the decreased deiodination by liver D1 during critical illness appears to play a role in this increase in serum T4S levels.

Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage.

CONTEXT: Transient hypothyroxinemia is common in infants less than 30 wk gestation and is associated with neurodevelopmental deficits. Reductions in T4 and T3 levels with TSH unchanged are the key features of severe illness using surrogate indices of overall severity of illness, but these do not inform the impact of individual disease conditions or drug use. OBJECTIVE: Our objective was to investigate the contribution of postnatal factors to the variations in serum levels of iodothyronines, thyroid-binding globulin, and TSH. DESIGN: We recruited a cohort of infants (23-34 wk gestation; n = 780) between January 1998 and September 2001. SETTING AND PATIENTS: The study involved 11 level III Scottish neonatal intensive care units and included cohorts of infants delivered at 23-34 wk gestation. MAIN OUTCOME: We assessed serum levels of iodothyronines, thyroid-binding globulin, and TSH at 7, 14, and 28 d adjusted for the potentially significant postnatal influences (n = 31). RESULTS: Serum levels of TSH, free T4, T3, and T4 are variably but significantly associated with bacteremia, endotracheal bacterial cultures, persistent ductus arteriosus, necrotizing enterocolitis, cerebral ultrasonography changes, oxygen dependence at 28 d, and the use of aminophylline, caffeine, dexamethasone, diamorphine, and dopamine. CONCLUSIONS: There are many more associations of postnatal factors with transient hypothyroxinemia than had previously been considered in preterm infants. Alternative strategies should be considered for correction of hypothyroxinemia rather than sole reliance on the direct therapy of hormone replacement. A more oblique preventative approach may be necessary through reduction in the incidence or severity of individual illness(es). Similarly, alternatives to those drugs that interfere with the hypothalamic-pituitary-thyroid axis should be evaluated (e.g. other inotropics instead of dopamine).

Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities.

INTRODUCTION AND METHODS: Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment. Seventy-one patients died, and postmortem liver and skeletal muscle biopsies were obtained from 50 of them for analysis of deiodinase (D1-3) activities. RESULTS: Insulin treatment did not affect thyroid parameters. On d 1, rT3 was higher and T3/rT3 was lower in nonsurvivors as compared with survivors (P = 0.001). Odds ratio for survival of the highest vs. the lowest quartile was 0.3 for rT3 and 2.9 for T3/rT3. TSH, T4, and T3 were lower in nonsurvivors from d 5 until LD (P < 0.001). TSH, T4, T3, and T3/rT3 increased over time in survivors, but decreased or remained unaltered in nonsurvivors. Liver D1 activity was positively correlated with LD serum T3/rT3 (R = 0.83, P < 0.001) and negatively correlated with rT3 (R = -0.69, P < 0.001). Both liver and skeletal muscle D3 activity were positively correlated with LD serum rT3 (R = 0.32, P = 0.02 and R = 0.31, P = 0.03). CONCLUSION: In critically ill patients who required more than 5 d of intensive care, rT3 and T3/rT3 were already prognostic for survival on d 1. On d 5, T4, T3, but also TSH levels are higher in patients who will survive. Serum rT3 and T3/rT3 were correlated with postmortem tissue deiodinase activities.

Transient hypothyroxinemia in preterm infants: the role of cord sera thyroid hormone levels adjusted for prenatal and intrapartum factors.

CONTEXT: Transient hypothyroxinemia is common in infants less than 30 wk gestation and is associated with neurodevelopmental deficits; it has no consensus definition. We previously suggested that appropriate ranges for postnatal serum T4 values are at least cord levels corrected to an equivalent gestational age if the fetuses had remained in utero. OBJECTIVE: The study objective is to investigate the contribution of prenatal and intrapartum factors (n = 27) to the variations in cord levels of iodothyronines, T4-binding globulin, and TSH, and to provide an appropriate definition of transient hypothyroxinemia. DESIGN: The study design is a cohort study (n = 620) in 11 Scottish neonatal intensive care units. PATIENTS: Infants were delivered at 23- to 42-wk gestation and recruited between January 1998 and September 2001. RESULTS: Using -2 SD of adjusted T4 cord levels applied to postnatal d-7 values of equivalent gestational age, 14% of the 23- to 27-wk group, 1% of the 28- to 30-wk group, and 3% of the 31- to 34-wk group are hypothyroxinemic; using -1 SD, the respective figures are 41, 23, and 12%. CONCLUSIONS: In the absence of neurodevelopmental follow-up studies to quantify transient hypothyroxinemia, a pragmatic criterion is necessary for selection of extreme preterm infants into clinical trials of T4 supplementation. We suggest the use of serum T4 levels on postnatal d 7 that are below -1 SD of adjusted cord T4 levels of equivalent gestational age. This criterion avoids over-recruitment of the more mature infants in whom universal T4 supplementation is detrimental to neurodevelopmental outcome, but still allows selection of the least mature entrants on whom universal T4 supplementation is beneficial.

A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans.

The interaction between the GH-IGF-I axis and thyroid hormone metabolism is complex and not fully understood. T(4) stimulates IGF-I activity in animals in the absence of GH. On the other hand, GH replacement therapy results in an increase in serum T(3) and a decrease in T(4) and rT(3) levels, suggesting a stimulation of type I deiodinase (D1) activity. Recently, we demonstrated the association of two polymorphisms in D1 (D1a-C/T; T = 34%, and D1b-A/G; G = 10%) with serum iodothyronine levels. Haplotype alleles were constructed, suggesting a lower activity of the D1 haplotype 2 allele (aT-bA) and a higher activity of the haplotype allele 3 (aC-bG). In this study, we investigated whether genetic variations in D1 are associated with the IGF-I system. In 156 blood donors and 350 elderly men, the association of the D1 haplotype alleles with circulating IGF-I and free IGF-I levels was studied. In addition, potential associations with muscle strength and body composition were investigated in the elderly population. Finally, the relation between serum iodothyronine levels and IGF-I levels was studied. In blood donors, haplotype allele 2 was associated with higher levels of free IGF-I (302.9 +/- 22.9 vs. 376.3 +/- 19.1 pg/ml, P = 0.02). In elderly men, haplotype allele 2 also showed an allele dose increase in free IGF-I levels (P(trend) = 0.01) and an allele dose decrease in serum T(3) levels (P(trend) = 0.01), independent of age. Carriers of the D1a-T variant also had a higher isometric grip strength (P = 0.047) and maximum leg extensor strength (P = 0.07) as well as a higher lean body mass (P = 0.03). In blood donors, T(4) and free T(4) were negatively correlated with total IGF-I levels (R = -0.18, P = 0.03 and R = -0.24, P = 0.003), whereas T(3) to T(4) and T(3) to reverse T(3) ratios were positively correlated with total IGF-I (R = 0.31, P < 0.001 and R = 0.18, P = 0.03). Free IGF-I showed a negative correlation with T(4) (R = -0.26, P = 0.001) and T(4)-binding globulin (R = -0.31, P < 0.001) and a positive correlation with T(3) to T(4) ratio (R = 0.21, P = 0.01). In conclusion, a polymorphism that results in a decreased D1 activity is associated with an increase in free IGF-I levels. The pathophysiological significance of this association with IGF-I is supported by an increased muscle strength and muscle mass in carriers of the D1 haplotype 2 allele in a population of elderly men. The association of D1 haplotype allele 2 with serum T(3) levels in the elderly population suggests a relative increase in its contribution to circulating T(3) in old age.

Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness.

The purpose of this study was to relate severity of illness at 1, 7, 14, and 28 postnatal days in preterm infants groups, 23-27 (n = 73), 28-30 (n = 160), and 31-34 (n = 208) wk gestation, to the corresponding sera levels of T(4), free T(4), T(4)-binding globulin, TSH, T(3), rT(3), and T(4) sulfate. The British Association of Perinatal Medicine and Neonatal Nurses Association 1992 scoring categories (published elsewhere) were used as an index of illness severity: level 1 (maximal intensive care) was compared with level 2 (high-dependency intensive care) combined with level 3 (special care); infants were scored on 1, 7, 14, and 28 postnatal days. In level 1 infants, there were significant reductions in T(3) at 7 d (28-30 wk), 14, and 28 d (23-27 and 28-30 wk); T(4) at 7, 14, and 28 d (23-27 wk); at 14 and 28 d (28-30 wk); and at 7 d (31-34 wk); and free T(4) at 14 d (23-27 wk). TSH was unchanged in all groups at all ages and with reductions in T(4) and T(3) being the key features of severe illness in extreme preterm infants.

Developmental trends in cord and postpartum serum thyroid hormones in preterm infants.

The purpose of this study was first to clarify postnatal trends in sera T(4), free T(4) (FT(4)), T(4)-binding globulin, TSH, T(3), rT(3), and T(4) sulfate levels in cord and at 7, 14, and 28 d in groups of preterm infants at 23-27 wk (n = 101), 28-30 wk (n = 196), and 31-34 (n = 253) wk gestation, and second to compare these trends to those of term infants and also with cord sera levels of equivalent gestational ages (n = 812; 23-42 wk gestation). In all preterm groups, TSH and rT(3) decrease to below, T(4)-binding globulin increases to within, and T(3) and T(4) sulfate increase to above cord levels of equivalent gestational age. Term infants are hyperthyroxinemic relative to cord and nonpregnant adult levels of T(4). Postnatal T(4) increases are attenuated in 31- to 34-wk infants, absent in 28- to 30-wk infants (although levels are equivalent to gestational age), and crucially reversed in 23- to 27-wk infants. This immature group is hypothyroxinemic relative to other groups and to cord levels of equivalent gestational age. Compared with term infants, postnatal FT(4) increases are lower in 31- to 34-wk infants, attenuated in 28- to 30-wk infants, and absent in 23- to 27-wk infants. The 23- to 27-wk group is distinctive; they are hypothyroxinemic on T(4) levels, yet FT(4) levels are within the cord levels of equivalent gestational age.

Human fetal and cord serum thyroid hormones: developmental trends and interrelationships.

Thyroid hormone is essential for fetal and neonatal development in particular of the brain, but little is known about regulation of fetal thyroid hormone levels throughout human gestation. The purpose of this study was to clarify developmental trends and interrelationships among T(4), free T(4) (FT4), thyroxine-binding globulin (TBG), TSH, T(3), rT(3), and T(4) sulfate (T4S) levels in cord and fetal blood sera (n = 639, 15-42 wk gestation) and correlate infant levels (23-42 wk gestation) to maternal values (n = 428, 16-45 yr) and those of nonpregnant women (n = 233, 16-46 yr). In cord and fetal serum, T(4), T(3), and TBG levels increase with gestation until term; TSH, FT4, T4S, and rT(3) levels increase and peak in the late second/early third trimester and then decline to term; T(4)/TBG ratios increase until late second trimester and plateau to term. Term cord sera TSH, TBG, and all iodothyronine levels, except T(3), are higher than nonpregnant women. In the third trimester, cord serum FT4, TSH, rT(3), and T4S levels are also higher than corresponding maternal levels, but T(4), T(3), and TBG levels are lower than maternal values. The late second/early third trimester is a critical transition period in fetal thyroid hormone metabolism, which may be interrupted by preterm birth and contribute to postnatal thyroid dysfunction.

The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life.

The purpose of this study was to measure serum T4, free T4, TSH, T3, rT3, T4 sulfate, and thyroxine binding globulin at four time points within the first 24 h of life (cord and 1, 7, and 24 h) in infants between 24 and 34 wk gestation. The infants were subdivided into gestational age groups: 24-27 wk (n = 22); 28-30 wk (n = 26); and 31-34 wk (n = 24). The TSH surge in the first hour of postnatal life was markedly attenuated in infants of 24-27 wk gestation [8 compared with 20 (28-30 wk) and 23 mU/liter (31-34 wk)]. T4 levels in the most immature group declined over the first 24 h, whereas levels increased in the more mature groups [mean cord and 24-h levels: 65 and 59 (NS) vs. 70 and 84 (P < 0.002) vs. 98 and 125 (NS) nmol/liter]. Free T4 and T3 showed only small, transient increases in the most immature group and progressively larger and sustained increases in the other gestational groups. rT3 and T4 sulfate levels in cord serum were higher in the most immature infants, and in all groups levels decreased initially and then variably increased. The features of a severely attenuated or failed hypothalamic-pituitary-thyroid response to delivery critically define this 24- to 27-wk group as distinct from more mature preterm infants.

Molecular basis for the substrate selectivity of cat type I iodothyronine deiodinase.

The type I iodothyronine deiodinase (D1) catalyzes the activation of T4 to T3 as well as the degradation of T3 (rT3) and sulfated iodothyronines. A comparison of the catalytic activities of D1 in liver microsomal preparations from several species revealed a remarkable difference between cat D1 on one hand and rat/human D1 on the other hand. The Michaelis constant (Km) of cat D1 for rT3 (11 microm) is 30-fold higher than that of rat and human D1 (0.2-0.5 microm). Deiodination of rT3 by cat D1 is facilitated by sulfation [maximal velocity (Vmax)/Km rT3 = 3 and Vmax/Km rT3S = 81]. To understand the molecular basis for the difference in substrate interaction the cat D1 cDNA was cloned, and the deduced amino acid sequence was compared with rat/human D1 protein. In the region between amino acid residues 40 and 70 of cat D1, various differences with rat/human D1 are concentrated. By site-directed mutagenesis of cat D1 it was found that a combination of mutations was necessary to improve the deiodination of rT3 by cat D1 enzyme. For efficient rT3 deiodination, a Phe at position 65 and the insertion of the Thr-Gly-Met-Thr-Arg48-52 sequence as well as the amino acids Gly and Glu at position 45-46 are essential. Either of these changes alone resulted in only a limited improvement of rT3 deiodination. At the same time the combination of the described mutations did not affect the already quite efficient outer ring deiodination of rT3S nor the inner ring deiodination of T3S, whereas each of the described changes alone did affect rT3S deiodination. Our findings suggest great flexibility of the active site in D1 that adapts to its various substrates. The active site of wild-type cat D1 is less flexible than the active site of rat/human D1 and favors sulfated iodothyronines.