disease and papillary thyroid carcinoma. Iodine is efficiently absorbed within the gastrointest­inal tract and concentrated within the thyroid gland for T3 and T4 synthesis [69]. The sodiu­m–iodide symporter (NIS) is the intrinsic plasma membrane protein that couples move­ment of sodium and iodide into thyroid cells [70–72]. This energy dependent process, utiliz­ing the gradient created by the sodium-potas­sium-ATPase within the basolateral membrane, is the key first step in thyroid hormone synth­esis (Fig. 1.4). The structure of the NIS has been elucidated and much effort has been expended at understanding the mechanisms that regulate its activity. The primary regulation of this sym­porter is via TSH stimulation and serum iodine levels [73, 74]. The action of TSH on follicular cells, through multiple pathways, results in inc­reased biosynthesis of the NIS as well as increa­sed localization of the protein in the follicular plasma membrane. Increasing iodine levels will also stimulate uptake through the symporter. Wolff and Chaikoff demonstrated that progres­sively increasing levels of plasma iodine canreach a threshold that effectively stops organic binding of iodine and shuts down production [75]. After a period of adaptation the normal hormone synth­esis resumes. The Wolf-Chaikoff effect appears to be a regulatory mechanism to protect from iodide overload and the process is mediated by the reg­ulation of NIS activity. The NIS allows the con­centration of iodide within a TFC to be 20–40 fold greater than that of the serum and thus >90% of the total body iodide is contained within the thyroid. The function of the transporter is impor­tant not only in the normal gland but in thyrotox­icosis and thyroid cancer. NIS mediated uptake of radioactive iodine is a key feature in ablation of the gland and disruptions to the function of this symporter, through mutations or meta­bolism, limit uptake of iodide and can impair

I

-mediated ablation.

The mechanism of thyroid hormone action was revealed by Tata et al. in the 1960s, through changes in RNA transcription and protein synthesis [79]. It is now understood that the action of thyroid hormone on target cells is tissue specific and regulated through membrane transporter and intracellular enzymatic activity [80–83]. Firstly, thyroid hormone uptake into cells is controlled by unique hormone receptors on the plasma membrane of different cells [84]. Only recently have these transporters been characterized at the molecular level and they have been categorized into two groups as organic anion or amino acid transporters. Some transporters are found in a single tissue while others have a wide tissue distribution. The varying ability to uptake and utilize plasma levels of thyroid hormone represents the first mechanism controlling the effects of thyroid hormone on target cells. The second level of control is via a class of enzymes known as the iodothyronine deiodinases which can control the intracellular levels of T3 and T4 [81–85]. These enzymes, known as D1, D2 or D3 (or Type I, II or III, respectively) are integral mem­brane proteins that control the relative propor­tion of T3, T4 and rT3 within the cell and thus influence changes in thyroid hormone action. These three enzymes can activate or inactivate thyroid hormone depending on whether they act on the phenolic or tyrosil rings of the iodothyronines, respectively. Shown in Fig. 1.5 is a schematic diagram of some of the pathways for the conversion of prohormone T4 to T3 and its action on the nuclear receptors. D1 is a kine­tically inefficient enzyme that is known to inac­tivate or activate T4 on an equimolar basis. D2 is the principle enzyme responsible for conversion of T4 to T3. D3 inactivates T3 by converting it to T2 as well as converting T4 to rT3. While it is possible that cells may have all three of these enzymes, only one is typically expressed at a given time and some tissues may express none. D1 is the most common with a presence in most tissues with its highest levels in the liver, kidney and thyroid [2, 80]. D2 is found mostly within the pituitary gland and the brain and D3 is found primarily in placenta, brain and skin. In fact it is the peripheral deiodination of T4, and

hormone and DNA binding domains and are part of a superfamily of nuclear hormone recep­tors that include the steroid and vitamin D receptors. There are different isoforms of this nuclear receptor, TR- and TR-b with genes located on chromosome 17 and 3, respectively. It is the differential splicing of these genes that lead to the TR- and TR-b isoforms. Both iso­forms of the nuclear receptor have an equal affinity for T3 but the expression of each iso­form is tissue specific [80]. Thyroid nuclear receptors are unique among the steroid receptor class in that when it is unbound, it remains active and can bind the TRE and thus provide a level of basal repression of genes downstream. Thus in hypothyroidism the relative decrease in hormone may repress expression of certain genes as opposed to simply being inactive and not positively regulating transcription [80–83]. It is the net effect of thyroid hormone on the products of transcription that mediates its clin­ical effects. For example thyroid hormones may affect cardiac contractility by altering the rela­tive proportions of the various myosin heavy chains in cardiac muscle [64, 89]. It is important to note however that there may also be non­genomic effects of T3 and T4, via adenylate cyclase (see Fig. 1.5) and mitochondrial activity may be directly regulated by thyroid hormone as well. However, these alternative signaling pathways are not well understood.

mode of action is perhaps most useful physio­logically in times of stress such as pregnancy or early growth when bone remodeling and cal­cium release must be tightly controlled [91]. Disruption of bone resorption has also made calcitonin a useful treatment in bone disorders including Paget’s disease, osteoporosis, and hypercalcemia secondary to malignancy. How­ever excess levels of endogenous calcitonin, such as with medullary cancer does not cause hypocalcemia. Conversely, loss of C-cell mass by surgical removal of the thyroid also does not appear to disrupt calcium homeostasis. The clinical value of calcitonin is as a marker of disease burden in medullary thyroid carcinoma, and it can be measured with or without calcium and pentagastrin stimuli [91–93].