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INTRODUCTION

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Thyroid hormone is essential for normal development, especially of the CNS. In the adult, thyroid hormone maintains metabolic homeostasis and influences the functions of virtually all organ systems. Thyroid hormone contains iodine, which must be supplied by nutritional intake. The thyroid gland contains large stores of thyroid hormone in the form of thyroglobulin. These stores maintain adequate systemic concentrations of thyroid hormone despite significant variations in iodine availability and nutritional intake. The thyroidal secretion is predominantly the prohormone T4, which is converted in the liver and other tissues to supply the plasma with the active form, T3. Local activation of T4 also occurs in target tissues (e.g., brain and pituitary) and is increasingly recognized as an important regulatory step in thyroid hormone action. Similarly, local deactivation of T3 is an important regulatory step. Serum concentrations of thyroid hormones are precisely regulated by the pituitary hormone TSH in a negative-feedback system. The predominant actions of thyroid hormone are mediated via nuclear TRs that modulate the transcription of specific genes.

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Overt hyperthyroidism and hypothyroidism, thyroid hormone excess and deficiency, respectively, are associated with numerous clinical manifestations. Milder disease often has a subtler clinical presentation and may be identified based solely on abnormal biochemical tests of thyroid function. Maternal and neonatal hypothyroidism, due to iodine deficiency, remains a major preventable cause of mental retardation worldwide (Zimmermann, 2009). Treatment of the hypothyroid patient consists of thyroid hormone replacement (Biondi and Wartofsky, 2014). Treatments for hyperthyroidism include antithyroid drugs to decrease hormone synthesis and secretion, destruction of the gland by the administration of radioactive iodine, and surgical removal (Brent, 2008). In most patients, disorders of thyroid function can be either cured or controlled.

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Likewise, thyroid malignancies are most often localized and resectable (Haugen and Sherman, 2013; Haugen et al., 2016). Metastatic disease often responds to radioiodine treatment but may become highly aggressive. Radioiodine-refractory, progressive thyroid cancers may respond to targeted chemotherapies such as tyrosine kinase inhibitors.

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ABBREVIATIONS

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Abbreviations

ADME: absorption, distribution, metabolism, excretion

Akt: protein kinase B

BAT: brown adipose tissue

CNS: central nervous system

CYP: cytochrome P450

D #: type # deiodinase, where # = 1, 2, or 3

DIT: diiodotyrosine

EOI: enzyme-linked species

ERK: extracellular signal-regulated kinase

FT4: free thyroxine

HCN: hyperpolarization-activated, cyclic nucleotide–gated cation channel

HOI: hypoiodous acid

IP3: inositol 1,4,5-trisphosphate

KISS: potassium iodide saturated solution

LDL: low-density lipoprotein

L-T3: liothyronine

L-T4: levothyroxine

MAP kinase: mitogen-activated protein kinase

MCT: monocarboxylic acid transporter

MHC: myosin heavy chain

MIT: monoiodotyrosine

MMI: methimazole

NIS: sodium iodide symporter

NO: nitric oxide

OATP1C1: solute carrier organic anion transporter family, member 1C1

PI3K: phosphoinositide 3-kinase

PKC: protein kinase C

PLC: phospholipase C

PTU: propylthiouracil

RAIU: radioactive iodine uptake

rT3: 3,3′,5′-triiodothyronine, reverse T3

SCN: thiocyanate

SECIS: selenocysteine insertion sequence

SST:...

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