Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

Abstract

Vitamin D₃ (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)₂D₃ (calcitriol). 1,25(OH)₂D₃ has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D₃ therapy in autoimmune diseases. The necessity of high doses of vitamin D₃ for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D₃ per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D₃ therapy.

Keywords: Coimbra protocol; autoimmune diseases; multiple sclerosis; vitamin D; vitamin D receptor (VDR).

Figure 1

Vitamin D metabolism and the sites of vitamin D resistance acquirement. Vitamin D₃ is mainly produced in the skin through solar ultraviolet-B (UVB) radiation and gets transported through blood by binding to vitamin D binding protein (DBP). The liver is the systemic production site of 25(OH)D₃ via the enzymes CYP2R1, CYP27A1 or CYP27B1. 25(OH)D₃ then gets converted to the active hormone 1,25(OH)₂D₃ by a second hydroxylation which occurs mainly in the kidneys or in other tissues through paracrine production. 1,25(OH)₂D₃ binds to the vitamin D receptor (VDR) to promote intestinal calcium (Ca) absorption and other Ca-mobilization pathways (e.g. in bone), so that ionized Ca levels in serum rise. The paraythroid glands sense Ca²⁺ levels, and secrete parathyroid hormone (PTH). PTH in turn promotes the production of 1,25(OH)₂D₃, e.g. by inhibiting CYP24A1 which catalyzes the first degradation step of 1,25(OH)₂D₃. Besides 1,25(OH)₂D₃, there are other vitamin D3-derived hydroxy-metabolites that exert hormone-like actions. For example, skin also expresses CYP11A1, which promotes the conversion of vitamin D₃ into 20(OH)D₃, which has non-calcemic biological effects, for example on immune cells. The blue flashes show where polymorphisms can interfere with normal vitamin D metabolism, building the basis for the development of acquired vitamin D resistance. Additional factors that impair vitamin D signaling are highlighted in blue boxes.

Figure 2

The etiology of acquired vitamin D resistance. Polymorphisms of genes within the vitamin D system constitute the basis for a susceptibitly towards developing vitamin D resistance, and hence autoimmune diseases. Partial blockades of the vitamin D receptor through pathogens, glucocorticoids (chronic stress) and – putatively – environmental toxins such as heavy metals may interact with such a susceptibility so that vitamin D resistance emerges. Finally, low sun exposure and aging, which correlate with autoimmune diseases as well, will exacerbate this situation further.

Figure 3

Longitudinal PTH measurements in a cohort of 41 relapsing-remitting multiple sclerosis patients treated by the corresponding author (DL) with the Coimbra protocol. Black lines indicate the median, blue crosses the mean. At three months follow-up, PTH levels had dropped significantly compared to the baseline measurement (Wilcoxon rank sum test, p<0.001), while there were no significant differences between any of the follow-up measurements. The reduction of PTH concentrations into the middle of the lower third of its laboratory-specific reference range is judged as an indicator for overcoming vitamin D resistance.