Calcium homeostasis, and clinical or subclinical vitamin D deficiency
– Can a hypothesis of “intestinal calcistat” explain it all?
Medical Hypotheses, Volume 81, Issue 2, August 2013, Pages 253–258
M.K. Garg a, mkgargs at gmail.com
Namita Mahalle b
a Department of Endocrinology, Command Hospital (Southern Command), Pune 411040, Maharashtra, India
b Biochemistry Division, Department of Pathology, Deenanath Mangeshkar Hospital and Research Center, Erandawane, Pune, India
The main physiological function of vitamin D is maintenance of calcium homeostasis by its effect on calcium absorption, and bone health in association with parathyroid gland. Vitamin D deficiency (VDD) is defined as serum 25-hydroxy vitamin D (25OHD) levels <20 ng/ml. Vitamin D insufficiency is called when serum 25OHD levels are between 20–29 ng/ml, though existence of this entity has been questioned.
Do all subjects with VDD have clinical disease according to this definition?
Analysis of published studies suggests that calcium absorption in inversely correlated with serum 25OHD levels and calcium intake.
We hypothesize that there exist an intestinal calcistat, which controls the calcium absorption independent of PTH levels. It consists of calcium sensing receptor (CaSR) on intestinal brush border, which senses calcium in intestinal cells and vitamin D system in intestinal cells. CaSR dampens the generation of active vitamin D metabolite in intestinal cells and decrease active transcellular calcium transport. It also facilitates passive paracellular diffusion of calcium in intestine.
This local adaptation adjusts the fractional calcium absorption according the body requirement. Failure of local adaptation due to decreased calcium intake, decreased supply of 25OHD, mutation in CaSR or vitamin D system decreases systemic calcium levels and systemic adaptations comes into the play. Systemic adaptations consist of rise in PTH and increase in active vitamin D metabolites. These adaptations lead to bone resorption and maintenance of calcium homeostasis.
Not all subjects with varying levels of VDD manifest with secondary hyperparathyroidism and decreased in bone mineral density.
We suggest that rise in PTH is first indicator of VDD is rise in PTH along with decrease in BMD depending on duration of VDD.
Hence, subjects with any degree of VDD with normal PTH and BMD should not be labeled as vitamin D deficient.
These subjects can be called subclinical VDD, and further studies are required to assess beneficial effect of vitamin D supplementation in this subset of population. This hypothesis further highlights pitfalls in treatment of hypoparathyroidism.
Fig. 1. Correlation between mean fractional calcium absorption and mean basal serum 25OHD levels in various studies shown in Table 1.
Fig. 2. Correlation between mean change in fractional calcium absorption and mean basal serum 25OHD levels in various studies.
Fig. 3. Correlation between mean change in fractional calcium absorption and mean increase in serum 25OHD levels in various studies with vitamin D supplementation.
Fig. 4. Correlation between mean fractional calcium absorption and mean calcium intake in various studies.
Fig. 5. Interaction between calcium, calcium sensing receptor (CaSR), vitamin D system in intestine.
CaSRs (blue) are located on intestinal cell brush border. Calcium (red with blue border) in intestinal lumen activates CaSRs, which modifies vitamin D system and calcium absorption. Under condition of low calcium intake (arbitrarily ∼250 mg): assuming total body calcium requirement of ∼200 mg, 80% of this calcium should be absorbed (maximal fractional calcium absorption has been reported as ∼80%). With decrease in occupancy of CaSR, the inhibition on vitamin D system will be removed. This will lead enhanced active transport of calcium (80%, ∼160 mg) which is vitamin D dependent, and rest by passive diffusion (20%, ∼40 mg). Passive diffusion is vitamin D independent and it is calcium dependent. Passive diffusion contributes to about 10–20% of total calcium intake. Here we have depicted it as 16% of total calcium intake. Under the condition of high calcium intake (arbitrarily ∼1000 mg): Assuming total body calcium requirement of ∼200 mg, and 16% of total calcium intake (160 mg) will be absorbed by passive diffusion. Hence, only 40 mg is required to be absorbed by active transport. This decrease in active transport will be mediated by dampening effect of activated CaSR on vitamin D system due to high occupancy of CaSRs by calcium. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 6. Total body BMD according to PTH quartile and VDD categories in adolescents.