Bence Szabó Gál

Bence Szabó Gál

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It has been suggested that it would be important to measure calcitriol levels to determine vitamin D status, as this would give a more complete picture than measuring calcidiol (25-OH-D3) levels alone. There are certain erroneous suggestions stating that it is only good if calcitriol levels also increase with vitamin D3 supplementation.  

The calcidiol (25-OH-D3) test alone is commonly used to measure vitamin D levels. The positive effects observed in the research correlate only with this, not with calcitriol, so it is not clear why it would be interesting to measure it from a health point of view. It is well known that calcitriol does not give an accurate picture of the body's vitamin D intake, but there is also no evidence that it is beneficial to measure calcitriol levels to determine vitamin D intake.   

The calcidiol (25-OH-D3) test is the best test currently available for determining vitamin D levels, which is why it is used in all research looking at the effects of different vitamin D levels. For example, studies that have found that low vitamin D levels increase the risk of several chronic diseases derived this result from measuring calcidiol levels, without knowing the calcitriol levels. The half-life of calcitriol is only a few hours, and there are several ways our body controls its levels to stay within certain limits. With its increased production, its removal and degradation is also increased, [1] so it is not a good one to rely on to determine vitamin D levels. In severe kidney disease/insufficiency, the activity of the enzyme responsible for converting calcidiol into calcitriol in the kidneys is reduced, so unfortunately they can no longer actually produce enough calcitriol, and in this rare case calcitriol therapy is used. [2] There is no reason to believe that the reduced activity of the enzyme responsible for calcitriol conversion affects a significant proportion of the population.  

Research on vitamin D also tends to point out that calcidiol levels are an accurate indicator of vitamin D status, and specifically warns against measuring calcitriol levels, stressing that they give a false picture. [3] Reversing the results of this research: as a person develops a vitamin D deficiency, the concentration of parathyroid hormone increases, which increases the production of calcitriol in the kidneys, so the concentration of calcitriol in the blood can be normal or even elevated. The study also shows that neither sun exposure nor vitamin D supplementation increases calcitriol levels. [4-6] Even taking 50,000 IU of vitamin D3 per day for 2 months did not increase calcitriol levels. [7] In comparison, the book tells us how important it is to measure calcitriol levels and to try to increase them. 

Even though most studies have looked at vitamin D intake and its effects based solely on calcidiol (25-OH-D3) levels, I have managed to find two that have also measured calcitriol levels alongside calcidiol and looked at its effects from the view of the risk of certain diseases.  

The first looked at the effect of vitamin D levels on cardiovascular and all-cause mortality. [8] They followed 3258 people for 8 years and categorised them into 4 groups based on their calcidiol and calcitriol levels. They concluded that both calcidiol (25-OH-D3) and calcitriol levels were correlated with cardiovascular problems and all-cause mortality. One might think that this would prove that it is worth measuring calcitriol, but the research shows that calcidiol alone showed this correlation, and calcitriol levels did not provide any additional useful information. In addition, the following sentences are available in the research, meaning that: the correlation between calcidiol and calcitriol levels is very weak. A person in a particular calcidiol (25-OH-D3) group can have both low and high calcitriol levels. 

The other study is much more interesting, because the description shows that the researchers were wondering whether it was worth measuring calcitriol levels, which is the active form of vitamin D. Here, 5066 people were followed and the effect of different vitamin D levels on the risk of developing hypertension was investigated. [9] Similar to the previous study, the participants were categorised into 4 groups based on their vitamin D levels, and finally the data collected was analysed. The higher a person's calcidiol (25-OH-D3) level, the lower their risk of hypertension, but what the researchers didn't expect was that the opposite was true for calcitriol levels: the higher a person's calcitriol level, the more likely they were to develop hypertension. Among the 4 categories, those with the lowest calcitriol levels had a 30% lower risk of developing hypertension than those with the highest calcitriol levels, after controlling for other risk factors. So it was best if someone's calcidiol (25-OH-D3) level was as high as possible and calcitriol level was as low as possible, which is mentioned in this study as being quite common. This research, in line with other studies of vitamin D levels, refutes the simplistic model that calcitriol levels should be measured alongside calcidiol, and that efforts should be made to increase them, on the basis that it is the more active form. Several serious diseases increase calcitriol levels and calcification, [10] while in the kidney disease mentioned above, levels will be low, [2] because the conversion itself does not occur. In one study, vitamin A reduced the rapid rise in blood calcium levels caused by calcitriol. [11] Other studies have also shown that vitamin A protects against calcification caused by vitamin D. [12] The hypertension study mentioned above also suggests that higher calcitriol levels may have been harmful because they may have increased calcification, [9] so it is also worth ensuring adequate vitamin A intake.  

Summary 

So, if you want to get an idea of your vitamin D status, it's perfectly fine to measure your calcidiol levels, but if you want to do the expensive calcitriol measurement, it's good to know, that the lower the calcitriol/calcidiol ratio the better, i.e. if you notice that your calcitriol levels are also increasing, not just calcidiol, then something is wrong and you might want to increase your retinol intake. Retinol deficiency is much more common than we think and it is important to do something about it, otherwise D3 supplementation can easily be counterproductive, so don't avoid liver or you should supplement retinyl palmitate in an amount of at least similar to D3. 

  1. Vitamin D 2nd Edition: Editors: David Feldman J. Wesley Pike Francis Glorieux eBook ISBN: 9780080543642 Imprint: Academic Press Published Date: 23rd December 2004 

  2. Melamed ML, Thadhani RI. Vitamin D therapy in chronic kidney disease and end stage renal disease. Clin J Am Soc Nephrol. 2012 Feb;7(2):358-65. doi: 10.2215/CJN.04040411. Epub 2011 Dec 22. PMID: 22193236; PMCID: PMC3280034. 

  3. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004 Mar;79(3):362-71. doi: 10.1093/ajcn/79.3.362. Erratum in: Am J Clin Nutr. 2004 May;79(5):890. PMID: 14985208. 

  4. Adams JS, Clemens TL, Parrish JA, Holick MF. Vitamin-D synthesis and metabolism after ultraviolet irradiation of normal and vitamin-D-deficient subjects. N Engl J Med. 1982 Mar 25;306(12):722-5. doi: 10.1056/NEJM198203253061206. PMID: 7038486.   

  5. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204-10. doi: 10.1093/ajcn/77.1.204. Erratum in: Am J Clin Nutr. 2003 Nov;78(5):1047. PMID: 12499343.  

  6. Reinhold Vieth, Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety, The American Journal of Clinical Nutrition, Volume 69, Issue 5, May 1999, Pages 842–856, https://doi.org/10.1093/ajcn/69.5.842  

  7. Calcium Absorptive Effects of Vitamin D and Its Major Metabolites 1 Heaney, Robert P., Barger-Lux, M. Janet, Dowell, M. Susan, Chen, Tai C., Holick, Michael F. Journal of Clinical Endocrinology & Metabolism1997 / 12 Vol. 82; Iss. 12 

  8. Dobnig H, Pilz S, Scharnagl H, et al. Independent Association of Low Serum 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Intern Med. 2008;168(12):1340–1349. doi:10.1001/archinte.168.12.1340 

  9. van Ballegooijen AJ, Gansevoort RT, Lambers-Heerspink HJ, de Zeeuw D, Visser M, Brouwer IA, Kema IP, de Borst MH, Bakker SJ, Joosten MM. Plasma 1,25-Dihydroxyvitamin D and the Risk of Developing Hypertension: The Prevention of Renal and Vascular End-Stage Disease Study. Hypertension. 2015 Sep;66(3):563-70. doi: 10.1161/HYPERTENSIONAHA.115.05837. Epub 2015 Jul 20. PMID: 26195480. 

  10. Moosgaard B, Vestergaard P, Heickendorff L, Mosekilde L. Plasma 1,25-dihydroxyvitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate and renal function. Clin Endocrinol (Oxf). 2007 Jan;66(1):35-42. doi: 10.1111/j.1365-2265.2006.02680.x. PMID: 17201799. 

  11. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001 Oct;16(10):1899-905. doi: 10.1359/jbmr.2001.16.10.1899. PMID: 11585356. 

  12. Fu X, Wang XD, Mernitz H, Wallin R, Shea MK, Booth SL. 9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice. J Nutr. 2008 Dec;138(12):2337-41. doi: 10.3945/jn.108.093724. 

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