In patients with hyperthyroidism, the metabolic clearances of T4 and T3 are increased and the half-lives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors) increase the metabolism of both T4 and T3 (Table 38–3). Despite this change in clearance, the normal hormone concentration is maintained in the majority of euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients dependent on T4 replacement medication may require increased dosages to maintain clinical effectiveness. A similar compensation occurs if binding sites are altered. If TBG sites are increased by pregnancy, estrogens, or oral contraceptives, there is an initial shift of hormone from the free to the bound state and a decrease in its rate of elimination until the normal free hormone concentration is restored. Thus, the concentration of total and bound hormone will increase, but the concentration of free hormone and the steady-state elimination will remain normal. The reverse occurs when thyroid binding sites are decreased.
Mechanism of Action
A model of thyroid hormone action is depicted in Figure 38–4, which shows the free forms of thyroid hormones, T4 and T3, dissociated from thyroid-binding proteins, entering the cell by the active transporters (eg, monocarboxylate transporter 8 [MCT8], MCT10, and organic anion transporting polypeptide [OATP1C1]). Transporter mutations can result in a clinical syndrome of mental retardation, myopathy, and low serum T4 levels (Allan-Herndon-Dudley syndrome). Within the cell, T4 is converted to T3 by 5′-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 thyroid receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, α and β. Mutations in both α and β genes have been associated with generalized thyroid hormone resistance. Cigarette smoking and environmental agents (eg, polychlorinated biphenyls) also may interfere with receptor action. Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on these tissues.
Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis, eg, increased formation of Na+/K+-ATPase. This is consistent with the observation that the action of thyroid is manifested in vivo with a time lag of hours or days after its administration.
T4,T3
FIGURE 38–3 The hypothalamic-pituitary-thyroid axis. Acute psychosis or prolonged exposure to cold may activate the axis. Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary thyroid-stimulating hormone (TSH) release, while somatostatin and dopamine inhibit it. TSH stimulates T4 and T3 synthesis and release from the thyroid, and they in turn inhibit both TRH and TSH synthesis and release. Small amounts of iodide are necessary for hormone production, but large amounts inhibit T3 and T4 production and release. Solid arrows, stimulatory influence; dashed arrows, inhibitory influence. H, hypothalamus; AP, anterior pituitary.