Vitamin D3 and the CYP24A1 genetic defect causing hypercalcemia-Vitamin D toxicity

For some reason I thought I had already done this blog post. It must have been that I wrote about it so many times that it seemed like I had already blogged on it. I had not. So here goes. The CYP24A1 gene is critical to the break down of the active form of vitamin D3. 

Those with a total deficit of this gene normally are ill as infants. Suffering severe hypercalcemia. Almost never is their initial issues with hypercalcemia, but it does happen. The more though still uncommon issue is when people have only one copy of the gene or two partially defective copies of the gene. 

The big bugaboo of taking higher doses of vitamin D3 is toxicity. No one wants to be toxic or ill. Have you ever found it curious that they never fully spell out exactly how much vitamin D3 is toxic? They do a better job of spelling out that too much calcium is bad and that is how vitamin D3 causes people to be ill. 

However Again they do not explain how much calcium or vitamin D3 is the problem. On the one hand I understand. However, I believe it is not spelled out as better to let people to use their imagination to scare them. 

Well hypercalcemia I believe after much thought that it is mainly due to CYP24A1. Not a complete deficit of both copies. What is the issue is those with only one copy of the gene, two partial defective genes. Traits the are inherited rarely but more common than both copies of the CYP24A1 genes being absent.  

As I noted in my book many physicians in the Kashmir region India prescribe 10,000,000 to 200,000,000 IU for one to three month period, yet despite this they rarely have people suffer from hypercalcemia due to these doses. I bet that the CYP24A1 genetic defect is rare in that population. 

Even in US the only cases are always from industrial mistakes where instead of hundreds of units per day1from the supplement they contain close to a million units and people are who are taking doses in the 60,000 IU a day and have a partial defect of the CYP24A1 gene. 

Even then not everyone who takes these high doses of vitamin D3 develop hypercalcemia. There are cases of people who were apparently handling vitamin D3 fine until adulthood. 1,2 So why are there these apparently normal people who develop hypercalcemia.

Hypercalcemia at doses of vitamin D3 at doses two to three orders of magnitude less yet those who do not take the same order of magnitude more? Well it probably must do with the CYP24A1 gene. This gene is crucial to breaking down vitamin D3. 

Particularly the active form of vitamin D3 1,25 dihydroxy vitamin D.3 Those who have defects in this gene can have problems breakdown this form of vitamin D3. This defect can present in several forms. If severe it usually presents in infancy with severe hypercalcemia and usual symptoms. 

Milder forms, those with only one functioning or partially functioning CYP24A1 gene (s), can often go asymptomatic until late in life when exposed to higher doses of vitamin D3. 4 In researching this I found a description of another genetic defect to the SLC34A1 gene that likewise causes an alteration in the destruction of the active form of vitamin D3. Though found in only one family. Thus, much rarer the CYP24A1 defect. 

As more interest and research occurs in vitamin D3 surely other genetic defects with the destruction of the active form of vitamin d3 are sure to be found. So, if you have never had an issue with vitamin D3 then you probably do not have a severe case of these or similar gene defects. 

1. Elston MS, Toit SD, Alkanderi S, et al. Variable Phenotypes See with a Homozygous CYP24A1 mutation: case Report. SN Compr. Clin. Med. 2, 995-1002. 2020. 
2. Cappellani D, Brancatella A, Kaufmann M, et al. Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature. Case Rep Endocrinol. 2019; 2019: 4982621. Published online 2019 Apr 8. doi: 10.1233jl155/2l019/4982621PMCID: PMC6476011 
3. De Bonis M, Minucc A, Scaglione GL, and Capoluongo E. CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype. Clinical Chemistry and Laboratory Medicine (CCLM) | Volume 57: Issue 11 Elisa De Paolis. ORCID iD: https://orcid.org/0000-0002-0780-0153 DOI: https://doi.org/10.1515/cclm-2018-1208 | Published online: 07 Jun 2019
4. Ibid (2)

*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!