Effects on the thyroid gland and thyroid hormone metabolism

Vitamin A (VA) deficiency (VAD) and the iodine deficiency disorders (IDD) affect > 30% of the global population and these deficiencies often coexist in vulnerable groups. VAD has multiple effects on the pituitary-thyroid axis; VA status modulates thyroid gland metabolism, peripheral metabolism of thyroid hormone, and production of thyrotropin (TSH) by the pituitary. Findings from Africa children indicate that VAD in severely-IDD-affected children increases TSH stimulation and thyroid size, and reduces risk for hypothyroidism. In children with VAD, the higher TSH concentrations in the face of higher circulating total thyroxine suggest central resistance to normal TSH suppression by thyroid hormone. In IDDand VAD-affected children receiving iodized salt, concurrent VA supplementation improves iodine efficacy. Recent VA and iodine depletion studies in rats indicate moderate VAD alone has no measurable effect on the pituitary-thyroid axis; however, concurrent iodine deficiency (ID) and VAD produce more severe primary hypothyroidism than ID alone. Repletion studies in VAand iodine-deficient animals suggest: 1) primary hypothyroidism in animals with concurrent moderate VAD and ID does not reduce the efficacy of high doses of oral VA; 2) VAD does not reduce the efficacy of dietary iodine to correct pituitary-thyroid axis dysfunction due to iodine deficiency; and 3) given alone, without iodine repletion, high-dose VA supplementation in combined VAD and ID may reduce thyroid hyperstimulation and reduce risk for goiter. DOI 10.1024/0300-9831.77.3.236 M.B. Zimmermann: Interactions of Vitamin A and Iodine Deficiencies 237 Int. J. Vitam. Nutr. Res., 77 (3), 2007, © Hogrefe & Huber Publishers [11,12], peripheral metabolism of thyroid hormone [13–18], and production of thyrotropin or thyroid-stimulating hormone (TSH) by the pituitary [19–22]. At the thyroid, VAD causes thyroid hypertrophy [11, 23] reduces thyroidal iodine uptake [24], impairs synthesis of thyroglobulin (Tg) and coupling of iodotyrosine residues to form thyroid hormone [12], and decreases intrathyroidal T3 and T4 [11, 12]. In the periphery, VAD increases total and free T4 and T3 [12, 13], reduces hepatic conversion of T4 to T3 [12, 25], and decreases T3 uptake and binding [14, 15]. Ingenbleek [12] fed rats iodine-deficient (ID), vitamin A-deficient (VAD), or iodineand vitamin A-deficient (ID + VAD) diets, and compared them to controls. Compared to controls, serum free and total T4 were increased in the VAD group, reduced in the ID group, and intermediate in the VAD+ID group. TSH and T3 concentrations were increased in the ID and the VAD + ID group. Overall, the data suggested ID + VAD produced greater impairments in thyroid metabolism than either ID or VAD alone [12]. Morley et al [16] gave pharmacologic doses of retinyl palmitate to rats and showed a decrease in thyroid gland size and serum TT4 and TT3, and an increase in thyroidal iodine uptake and hepatic conversion of T4 to T3. The effect of VAD on thyroid metabolism may be mediated at least partly through shared transport proteins. Thyroid-binding globulin (TBG) carries the majority of T4 and T3 in plasma (ca. 70%), while transthyretin (TTR) binds 10–15% [26]. TTR is also the primary indirect carrier of vitamin A in the plasma through its interaction with retinol-binding protein (RBP) [27]. RBP is secreted from the hepatocyte as a complex with TTR, and binding of RBP to TTR prevents glomerular filtration and renal clearance of RBP, thereby enhancing vitamin A delivery [28]. Although VAD decreases hepatic release of RBP, release of TTR and serum TTR concentrations is similar during vitamin A depletion and repletion in rats [29, 30]. Animal studies have suggested that the binding capacity and affinity of TTR for thyroid hormone may be modified by interaction with RBP [27, 31–33]. Effects on pituitary TSH production VAD may also affect thyroid metabolism through a central mechanism. Both the thyroid hormone-activated thyroid receptor and the retinoic acid-activated retinoid X receptor suppress transcription of the pituitary TSHβ gene by occupying half-sites on the promoter DNA of the gene [19–21]. Breen et al [22] found VAD in rats increased pituitary TSHβ mRNA levels 2-fold, and increased serum TT4; both returned to normal after treatment with vitamin A. They concluded the increased TSHβ mRNA expression, despite high serum TT4, implied VAD had made the pituitary thyrotrope relatively insensitive to feedback control by thyroid hormone. In pair-fed rats with VAD, Morley et al [13] also found an increase in hypothalamic thyrotropin-releasing hormone (TRH) and pituitary TSH despite high levels of circulating T3 and T4.