TABLE 10.

Thyroid hormone production and metabolism during iodine insufficiency and sufficiency¹

Mechanisms of normal thyroid hormone production and metabolism

• Under conditions of iodine adequacy, adults accumulate ∼60 μg iodine/d in the thyroid gland to account for losses and thyroid hormone production

• A transmembrane protein in the basolateral membrane of the thyrocyte, referred to as the NIS, is responsible for transferring iodide into the thyroid gland (79) (see Fig. 1)

• Production of thyroid hormone is a multistep process that includes:

◦ Oxidation of iodide via the action of the enzymes TPO and hydrogen peroxide at the apical surface of the thyrocyte

◦ The product is attached to tyrosyl residues on thyroglobulin to produce MIT and DIT

◦ TPO then catalyzes the linkage of the phenyl groups of the iodotyrosines to form T4 (via linkage of 2 DIT molecules) and T3 (via linkage of an MIT and a DIT); T3 and T4 are therefore structurally identical except for an extra iodine

• Relevant features of T3/T4:

◦ 65% and 59% of the weights of T4 and T3 is iodine (see Fig. 2) (62)

◦ Thyroglobulin contains 0.1–1.0% of its weight as iodine and is stored extracellularly in the luminal colloid of the thyroid follicle

• Thyroglobulin that is digested undergoes endocytosis and subsequent digestion by endosomal and lysosomal proteases to release T4 and T3 into the circulation

• T4 and T3 are broken down in the periphery (the half-life of circulating T4 is 5–8 d; that of T3 is 1.5–3 d)

• The fate of the liberated iodine is to enter the plasma iodine pool for uptake by the thyroid or be excreted by the kidney

• More than 90% of ingested iodine is ultimately excreted in the urine (35), with only a small amount appearing in the feces

Mechanisms of response to dietary iodine insufficiency

• In non-pregnant, non-lactating adults, maintenance of intake above a threshold of ∼60 μg/d, even in the face of a decrease in circulating plasma inorganic iodine, allows the iodine content of the thyroid to remain within normal limits (∼10–20 mg)

• Below this threshold, despite high fractional clearance of plasma inorganic iodine, the iodine content of the thyroid is depleted, and the potential for development of goiter ensues

• Responses to low intake include:

◦ Marked modification of thyroid activity, triggered by increased secretion of TSH by the pituitary (see Fig. 3)

◦ Increased plasma iodine clearance by the thyroid; in otherwise healthy individuals, iodine intake below ∼100 μg/d results in increased TSH secretion resulting in increasing plasma inorganic iodide clearance by the thyroid through stimulation of NIS expression (8)

◦ The increased iodine clearance by the thyroid leads to a progressive reduction in renal iodide excretion

◦ TSH also stimulates breakdown of thyroglobulin and preferential synthesis and release of T3 into the blood

• The profile of thyroid hormones in iodine deficiency is:

◦ In areas of moderate-to-severe iodine deficiency, children will have a variably elevated TSH, a low serum T4, and a normal or high-normal T3

◦ A similar pattern is seen in adults, but less predictably, and it may not be present

◦ In conditions of low iodine intake, serum thyroglobulin concentration is typically elevated

◦ Thyroid failure and cretinism usually develop only in regions of chronic, severe iodine deficiency accompanied by low circulating T4 and T3 and dramatically elevated TSH (80)

¹DIT, diiodotyrosine; MIT, monoiodotyrosine; NIS, sodium/iodide symporter; T3, triiodothyronine; T4, thyroxine; TPO, thyroperoxidase; TSH, thyroid-stimulating hormone.