THE PUZZLE OF VITAMIN D
It was very exciting to study about Vitamin D metabolism while we were medical students. Called Sunshine Vitamin it was manufactured in the skin from the Sunshine it was exposed to. Then there were two conversion once in the liver and then the active form in the kidney.
When the assays for Vitamin D became widely available two patterns emerged.
multiple large epidemiological studies have shown that persons with low serum vitamin D levels are at increased risk of multiple adverse health outcomes including osteoporosis, obesity, inflammatory bowel disease, incident diabetes, cardiovascular disease, cancer, and autoimmune disease.
That made me think, if for example for some reason the measurements were wrong, all the people who are sick with anything will have low vitamin D levels and one would see association with low vitamin D levels and various diseases.
Of course separately they also found out that vitamin D does affect the microbiomes and the probiotic industry was very happy about that.
Secondly, this is a sunshine vitamin so people who live in countries should not have problems with this vitamin. But their rates of deficiency was no different from colder countries or poorer countries.
Obviously we are measuring something wrong or there is a common factor in the conversion from the skin to the Liver to Kidney.
In the meantime, debates were raging how much vitamin D supplementation should be given and In what form.
A recent large randomized controlled trial of vitamin D supplementation of over 25,000 adults demonstrated no benefit in preventing cardiovascular events or cancer.
My feeling about Vitamin D was a gut feeling, sorry for the pun. I could believe that it affected the microbiome but which vitamin D the measured one or some other active form and the problem was with the conversion of measured one into the active form ?
The answer arrived from a recently published study .
Vitamin D metabolites and the gut microbiome in older men
- Robert L. Thomas, Lingjing Jiang, John S. Adams, Zhenjiang Zech Xu, Jian Shen, Stefan Janssen, Gail Ackermann, Dirk Vanderschueren, Steven Pauwels, Rob Knight, Eric S. Orwoll & Deborah M. Kado
volume
11, Article number: 5997 (2020)
The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith’s Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH)2D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25 (OH)2D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH)2D and/or the hormone-to-prohormone [1,25(OH)2D/25(OH)D] “activation ratio.” Men with higher levels of 1,25(OH)2D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health.
Because the serum 25(OH)D correlates with overall vitamin D storage, it is the preferred clinical measure to assess vitamin D sufficiency. Clinically, serum 25(OH)D levels ≥20 ng/ml are considered adequate while 25(OH)D levels <20 ng/ml are defined as vitamin D deficiency. However, it is the active form of vitamin D, 1,25(OH)2D, that interacts specifically with the vitamin D receptor (VDR) and transacts gene expression. Under tight feedback control, 1,25(OH)2D also induces the expression of catabolic 24-hydroxylase that converts 25(OH)D to 24,25(OH)2D and 1,25(OH)2D to 1,24,25(OH2D) metabolites13. Ratios of vitamin D activation (1,25(OH)2D/25(OH)D) and catabolism (24,25(OH)2D/25(OH)D) quantify the proportion of vitamin D stores that are being processed (activated or catabolized) and can serve as a measure of vitamin D mobilization for use in endocrine signaling, or vitamin D flux. These ratios relative to total vitamin D stores based upon 25(OH)D levels may be better predictors of clinically important outcomes including incident hip fracture and earlier mortality
Renal 1α-Hydroxylation
25(OH)D must be further hydroxylated to gain hormonal bioactivity. This occurs in the convoluted and straight portions of the proximal kidney tubule. Hydroxylation at position 1α by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1; hereafter referred to as 1α-hydroxylase) converts 25(OH)D to 1,25(OH)2D, the active, hormonal form of vitamin D.
In clinical settings we have been measuring 25 OH-vitamin D and they set arbitrary limits of what is deficiency and what is normal value. At one time values lower than 30 ng/ml were considered abnormal but for clinical purposes single digit numbers attract my attention for immediate action and the values 10-20 for further action.
Someone from the American University at Beirut had written:
despite its abundant sunshine the Middle East, a region spanning latitudes from 12°N to 42°N allowing vitamin D synthesis year round, registers some of the lowest levels of vitamin D and the highest rates of hypovitaminosis D worldwide. This major public health problem affects individuals across all life stages including pregnant women, neonates, infants, children and adolescents, adults, and the elderly.
So there has to be a rethink in the world of Vitamin D.. what is the normal level for good metabolic function? And how do we measure it ? And should we be giving so much supplementation on people who may not need supplementation?
It would be nice to do do 25 0h vitamin D levels as well as 1 25 OH vitamin D levels and see how this would influence our treatment of this “fictitious” laboratory illness or be proved wrong.
Let us give it a try.
The metabolism and biologic function of vitamin D. During exposure to sunlight, 7-dihydrocholesterol (7-DHC) is photolyzed to previtamin D3 (preD3). Body heat converts preD3 to vitamin D3. Vitamin D2 and vitamin D3 in the diet and vitamin D made in the skin enters the circulation and either is stored in the body’s fat adipocytes or enters the liver and is converted to 25-hydroxyvitamin D [25(OH)D]. For regulation of calcium metabolism, 25(OH)D is converted in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D interacts with its vitamin D receptor (VDR) in the small intestine and on osteoblasts to regulate calcium and phosphorus metabolism. 25(OH)D is metabolized in various tissues and cells for regulating cellular proliferation and differentiation as well as inducing cathelicidin D(CD) in macrophages. The induction of 1,25(OH)2D in the macrophage is controlled by the 2/1 toll-like receptors (TLR) and its interaction with lipopolysaccharide (LPS). In addition, circulating concentrations of 1,25(OH)2D may help increase insulin production and decrease renin production and alter adipocyte lipogenesis. thanks to Michael Hollick.
