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 hormone has recently been recognized as an important determinant of innate immune cell function. Highly specialized cells of the innate immune system, including neutrophils, monocytes/macrophages, and dendritic cells, are capable of identifying pathogens and initiating an inflammatory response. They can either phagocytose and kill microbes, or recruit other innate or adaptive immune cells to the site of inflammation. Innate immune cells derive from the hematopoietic lineage and are generated in the bone marrow, from where they can be recruited into the blood and tissues in the case of infection. The link between the immune and endocrine systems is increasingly well established, and recent studies have shown that innate immune cells can be seen as important thyroid hormone target cells. Tight regulation of cellular thyroid hormone availability and action is performed by thyroid hormone transporters, receptors, and the deiodinase enzymes. Innate immune cells express all these molecular elements of intracellular thyroid hormone metabolism. Interestingly, there is recent evidence for a causal relationship between cellular thyroid hormone status and innate immune cell function. This review describes the effects of modulation of intracellular thyroid hormone metabolism on innate immune cell function, specifically neutrophils, macrophages, and dendritic cells, with a special focus on the deiodinase enzymes. Although there are insufficient data at this stage for conclusions on the clinical relevance of these findings, thyroid hormone metabolism may partially determine the innate immune response and, by inference, the clinical susceptibility to infections.

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.

Background: Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods: This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, and Beckman Coulter). Retrospective data (2008–2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2 to 20 years by 2-year categories and decade categories between 20 and 100 years. Results: We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits were higher in early childhood and decreased toward adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onward. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion: This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data are less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2–3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4–TSH–thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.