Vitamin D, Thyroid Hormones and Cardiovascular Risk: Exploring the Components of This Novel Disease Triangle

Abstract

The role of thyroid hormones (THs) in the cardiovascular (CV) system, through several direct and indirect effects is recognized. Even very small modification in TH levels (as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome) may adversely affect the CV system, whereas thyroid hormones benefit the CV system and improve the prognosis. There is also evidence of vitamin D effects on cardiometabolic disease (e.g., through modulation of endothelial and smooth muscle cell activity, renin-angiotensin-aldosterone system, nitric oxide, oxidative stress, and inflammatory response), as well as an association between vitamin D [25(OH)D] deficiency and autoimmune thyroid diseases or cancer, and a relationship between vitamin D concentration and titers of antibodies and thyroid autoimmunity replacement. Interestingly, experimental data indicate a direct effect of vitamin D on Type 2 deiodinase expression causing subsequential peripheral conversion of T4 into T3. However, the functional links among THs, vitamin D and the cardiovascular system, and clinical effects of coexisting abnormalities in this new troublesome triad, have not yet been reviewed. The main aim of this review is to discuss pathophysiology of this relationship, proposing new mechanistic insights involving vitamin D in the modulation of cardiometabolic disease and thyroid profile.

Keywords: 25(OH)D; cardiovascular system; pathophysiology; thyroid hormones; vitamin D.

FIGURE 1

Main interactions between deficiency of vitamin D and THs on the CV system creating a complex network in a adverse vicious circle. Under the effect of underlying common mechanisms related to oxidative stress, inflammation, hypocalcemia and immune system worsening, Vitamin D deficiency induces VSMC proliferation, endothelial dysfunction, facilitates vascular calcification, and promotes insulin resistance, RAAS activation, thrombosis, PLT aggregation, and fibrosis to the CV system, and increased thyroid volume, TSH and T4/T3 impairment to thyroid, whereas THs deficiency also induces fibrosis, mitochondrial dysfunction, apoptosis, endothelial dysfunction, reduces chronotropic and inotropic effects, increasing MI size in experimental models, and reducing eNOS expression and activity, angiogenesis, cellular growth and differentiation, and cardiac remodeling at cardiovascular level. VSMC vascular smooth muscle cells, eNOS endothelial nitric oxide synthase, RAAS renin–angiotensin–aldosterone system, MI myocardial infarction, TSH thyroid stimulating hormone, T3 triiodothyronine, T4 thyroxine.

FIGURE 2

Multiple action of vitamin D affecting TH levels. The pituitary gland secretes TSH that stimulates the thyroid to produce thyroxine (T4) and triiodothyronine (T3). Moreover T3 may be produced in peripheral organs by deiodination from circulating T4. Vitamin D fits in the complex mechanisms of regulation of THs. In fact, vitamin D could increase TRH-induced-TSH secretion by pituitary thyrotroph cells. However, it is also possible that the finding of low TSH in the presence of a high vitamin D could be due, almost in part, to increased THs caused by the stimulatory effect of vitamin D on thyrocytes, and the activation of the negative feedback control that the THs exert over the hypothalamus and pituitary gland, thus finely modulating the release of TRH, TSH, and the TH themselves. TRH Thyrotropin-releasing hormone, TSH thyroid stimulating hormone, T3 triiodothyronine, T4 thyroxine, DIO deiodinase.

FIGURE 3

Values of fT3/fT4 according to 25(OH)D status in 124 AMI patients (ANOVA; severe hypovitaminosis D versus normal vitamin D p ≤ 0.001). Median, interquartile, outliers, and extremes of fT3/fT4 are given.