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Thyroid hormone (TH) plays a key role in regulating body temperature in mammals. Cold exposure stimulates the hypothalamus-pituitary-thyroid (HPT) axis at the hypothalamic level by activating hypophysiotropic thyrotropin-releasing hormone (TRH)-producing neurons, ultimately resulting in increased plasma TH concentrations. Importantly, the local TH metabolism within various cold-responsive organs enables tissue-specific action of TH on heat production and adaption to cold independently of the circulating TH levels. In addition to these neuroendocrine effects, TRH neurons in the hypothalamus also have neural connections with brown adipose tissue (BAT), probably contributing to regulation of thermogenesis by the autonomic nervous system. Recent studies have demonstrated that intrahypothalamic TH has profound metabolic effects on BAT, the liver, and the heart that are mediated via the autonomic nervous system. These effects originate in various hypothalamic nuclei, including the paraventricular nucleus (PVN), the ventromedial nucleus, and recently reported neurons in the anterior hypothalamic area, indicating a potential central function for TH on thermoregulation. Finally, although robust stimulation of the thermogenic program in BAT was shown upon TH administration in the ventromedial hypothalamus, the physiological relevance of these neurally mediated effects of TH is unclear at present. This review provides an overview of studies reporting the role of TH in cold defense, with a focus on recent literature evidencing the centrally mediated effects of TRH and TH.

Thyroid hormones play an essential role in regulating whole-body homeostasis. Deiodinases are known to convert thyroid hormone from the prohormone thyroxine (T4) to the bioactive hormone tri-iodothyronine (T3) and convert both T4 and T3 toward their inactive metabolites 3,3’,5’-tri-iodothyronine (rT3) and 3,3’-di-iodothyronine (3,3’-T2). Deiodinases are thus important for the regulation of intracellular thyroid hormone concentrations. This is known to be crucial both during development and adult life in regulating thyroid hormone-related gene transcription. This review discusses the importance of liver deiodinases in determining serum and liver thyroid hormone concentrations, liver metabolism and liver disease.

Introduction: Newborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm. Materials and Methods: RIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives. Results: Analyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56–118 nmol/L), TSH (<2.6 mIU/L), TBG (116–271 nmol/L), and the T4/TBG ratio (>20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood). Discussion/Conclusion: Established DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level.