Vitamin D and the Free Hormone Hypothesis: Lessons From Surgical Stress

Introduction:

Vitamin D is a versatile signaling molecule with a well-established role in the regulation of calcium homeostasis and bone health. The spectrum of vitamin D target-organs has expanded and it has been suggested that vitamin D influences the immune system, endocrine organs such as pancreas, testis and ovary and multiple other organs (Blomberg Jensen 2014). More recently attention has been paid to surgical patients suggesting hypovitaminosis D to increase postoperative morbidity. (Turan A et al, Zaloga et al). However, the perioperative literature is hindered by a mixture of acute and chronic diseases indicating surgery, different types of surgery and different time of vitamin-D assessments (pre- vs post-operatively) (Turan A et al Zaloga et al).

Vitamin-D is a protein-bound steroid hormone and interpretation of vitamin-D surgical studies require knowledge about the effect of clinical surgical trauma per se on vitamin-D physiology, as has been demonstrated with cortisol, thyroid hormones and other steroid hormones (Kehlet, Brandt, Rem). Unlike other steroid hormones vitamin D depends on a two step activation process before it is able to bind and activate the vitamin D receptor (VDR). First by 25-hydroxylation (CYP2R1) in the liver, which forms 25-hydroxyvitamin D (25-OHD). 25-OHD is also biologically inactive but used clinically to determine vitamin D status because serum 25-OHD levels are associated with rickets, bone health and calcium homeostasis. Circulating 25-OHD is bound to vitamin D binding protein (DBP) (Prosser and jones 2004). This complex is filtered in the glomerulus and subsequently transported into the proximal tubules cells by megalin-mediated uptake (Nykjær 1999). Here, 25-OHD undergoes 1α-hydroxylation (CYP27B1) and the resulting 1,25(OH)2D3 binds and activates the vitamin D receptor (VDR). The fact that the protein bound fraction is taken up by megalin differs from the metabolic clearance and/or activation of other steroid hormones and questions whether the free hormone hypothesis is applicable to the vitamin D system. The fact that binding proteins are lost during surgical stress indicates that this patient group is ideal for studying total versus free hormone concentrations and possible secondary changes for instance in serum PTH and calcium due to functional hormonal aberrations.

Aim of study:

The purpose of this study is to describe changes in vitamin D parameters before, during and after a well-defined elective surgical trauma (knee arthroplasty) and to compare these changes to another steroid hormone (testosterone and oestrogens). The hypothesis is that profound changes in free and total vitamin D will occur as a result of changes between intravascular vs extravascular protein compartments during surgical trauma.