We are, for most of us or soon to be, past the age where we could die at a young age (though with optimal doses and blood levels I think what constitutes young age will have to be reconsidered). Thus, this is coming back to hurt us. That is inadequate vitamin D3.
Inside the cells the Madison-HannaH (MH) effects occurs, (the active-slow state of the special cells in the three organs kidneys, small intestines and skeletal bone as well as all cells) through the genomic effect in the cell nucleus not on cell surface.
These MH effects are only activated once there are high enough concentration of the blood form of vitamin D3-calcifediol. These effects are independent of the hormonal effects and are not involved in controlling blood calcium levels.
Thus, the MH effects through the genomic VDR only once the blood forms concentration is high enough to assure the bodies calcium metabolism through hormonal effects are fully supplied. It appears the vitamin D binding protein must somehow regulate this.
Indirectly as perhaps at these higher concentrations of calcifediol-the blood form of vitamin D3, the free concentration of the blood form of vitamin D starts to increase. As there is either not enough DBP or there is a limit to how high a concentration of DBP the blood will support.
Thus, the free concentration (that is no longer bound to the DBP) of the blood form of vitamin D increases. It then diffuses into the cells where either the 1-alpha hydroxylase enzyme acts on it and creates the active form. Or the blood form despite its low affinity for the VDR is enough to activate these genes.
Though I doubt there would be VDR in the cells if the active form of vitamin D was not the molecule intended to interact with it. Perhaps it is both the active and blood form of vitamin D that activates the MH effects as surely both are involved it is just a matter of the ratio. Then either the active form cannot diffuse through the cell membrane back out into the blood.
Thus, preventing it from interfering with the hormonal system. Or so very little diffuses out as the majority is used in the cell before it can diffuse out. Maybe a combination of the two most of the active form is used in the cells and poor diffusion.
So, is it the blood form at higher doses that over rides the body’s control of the hormonal system or the loss of the active form from inside the cells that is causing this and hypercalcemia? From the research it appears it is the high concentrations of the blood form-calcifediol as typically with vitamin D3 associated hypercalcemia the concentration of the active form was normal or only slightly elevated. 1 Only one study showed that the active form and this case it was vitamin D2 not D3 was elevated. 2
Then with MH effects they only appear once the higher concentrations of the blood form of vitamin D3 are reached. So, is it a cumulative effect where enough cells are activated, or the system is suddenly switched on? Not clear which if either.
Though, that the blood form must reach a certain concentration before the MH effects occur indicates that there is some type of control. As these appear to be active-slow response genomic effects whereas the calcium/hormonal effects are nongenomic active-fast response.
Most of the blood form- calcifediol is carried in the blood by the vitamin D binding protein (DBP). Perhaps this is where the control comes in to play. As perhaps the DBP must be at a high enough concentration before it can diffuse into these other cells and initiate the MH effects.
So again, back to calcium. What happens if the blood calcium level becomes too high? The dumping of calcium in the kidneys is not enough because of parathyroid hormone. Then in comes the protein hormone calcitonin. This hormone works to lower the level of calcium but also phosphorus in the blood.
- Sheperd MR, Deluca, HF. Plasma concentrations of vitamin D3 and its metabolites in the rat as infused by vitamin D3 intake. Arc. Biochem. Biophys. 1980202,43-53.
- Mawer EB, Hann JT, Berr JL, et al. Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin. Sci. (Lond) 1985, 68, 135-141.
*The information posted above is for educational purposes only. Always check with your doctor before initiating any changes in your medical treatment. If you do not, then The Two-Minute Health Fact, Dr. Judson Somerville, nor The Optimal Dose is responsible!