Image credits: Ionuț Ștefan
As we’re heading into the winter months and the sun becomes but a distant memory of a rosier past, as Christmas decorations and pesky jingles fill out the crisp November (!) air, among pumpkin spice and energy crises and cozy blankets and warm candles, there is yet another slightly ominous warning: “make sure you get that vitamin D in!”. But this little slogan has been repeated so many times that most of its meaning has been lost. Especially over the last years, we’ve been drowning in vitamin D headlines: “It helps against Covid!”, “It doesn’t actually…”, “It helps with Parkinson’s, Alzheimer’s, and will even walk your dog!”, “It doesn’t actually…” So in this post we thought we’d go back to the roots and work our way up from there to see why vitamin D is important, with what it can actually help, and who should take supplements.
Disclaimer: this random post on the Internet is in no way, shape or form a substitute for professional medical advice. If you have questions about your health, please talk to your doctor.
(Not so) basic biochemistry
Don’t worry, we won’t make you memorize complicated molecular structures or ugly biochemical terms. But there are a couple of biochemical fun facts about vitamin D which can help us better understand why vitamin D and the sun are linked and why studies on vitamin D could have conflicting results.
Fun fact #1: vitamin D is not actually a vitamin, but a hormone. Surprised? I was too. But here’s the deal: vitamins cannot generally be synthesized by the body. They need to be taken in through diet. In contrast, only ~20% of our vitamin D comes from our diet, with the remaining ~80% synthesized in the body from sterols (for those interested: 7-dehydrocholesterol; side note here: plants and fungi can also synthesize their own vitamin D from ergosterol). And in its active form, vitamin D functions as a signaling molecule which acts far away from its place of synthesis. Again, this fits the (albeit loose) definition of a hormone (if you’d like to read more about that, check out this post).
Fun fact #2: vitamin D is an umbrella term for a bunch of molecules, especially in popular language. We’ve mentioned above that vitamin D is synthesized from two sterols. Each of these leads to two types of vitamin D, namely D2 (derived from ergosterol in plants and fungi) and D3 (from 7-dehydrocholesterol in humans). The conversion from sterols to vitamin D is the step that needs the sun and which happens in the skin (D3) or surfaces exposed to the sun (D2). But vitamin D’s journey isn’t over there.
From the skin, D3 continues to the liver, where it is transformed into yet another “vitamin D”. This one goes by several formal names (such as 25-hydroxycholecalciferol or 25-hydroxyvitamin D), but the easiest to remember is calcifedol. And calcifedol also takes a little trip through the body, landing in the kidneys, where finally calcitriol, the “real vitamin D” hormone is formed.
Fun fact #3: lack of standardized vitamin D laboratory tests is still a major challenge. This is problematic because the lack of standardization means that results cannot be readily compared across studies.
Initially, I wanted to offer an in-depth explanation of how such tests are standardized and what is standing in the way of doing that for vitamin D testing. But as I read more and more about it, I began realizing that my superficial knowledge of the field of biochemistry, and more particularly of immunoassays, might cause me to overlook or misinterpret some important details. So instead, I will resume myself to a brief overview and direct you towards the reading at the end of this article.
In brief, a gold standard method (such as high-performance liquid chromatography) is used to determine the reference value of a molecule of interest in a sample. But as this method is expensive and takes some time to deliver results, it is not routinely employed in clinical practice. Instead, cheaper and faster methods such as immunoassays are used there. But due to the way in which these assays work, results based on kits from different manufacturers and different laboratories cannot be directly compared. This comparison is only accurate if the immunoassays were previously calibrated based on the reference value given by the gold standard method.
So if this standardization is important, why hasn’t it happened yet for vitamin D? Well, it is happening, but it’s a process which requires a lot of time. And practically speaking, it appears that vitamin D testing quickly rose to popularity in recent years, much quicker actually than how fast the methods could be standardized.
Vitamin D effects
Now that we have an understanding of its basic biochemistry, it’s time to see what vitamin D does for us and why it’s such a big deal that we don’t synthesize enough during the winter months. In particular, we will talk about two types of effects: skeletal and extraskeletal.
Skeletal effects of vitamin D are the most well-known. More importantly, they are the only ones for which we also have a confirmed causal link. Vitamin D’s actions on the skeletal system are indirect. The molecule acts by binding to vitamin D receptors located in the nucleus of cells. In turn, this leads to the inhibition of secretion of another hormone, namely the parathyroid hormone or PTH. PTH is normally secreted in response to low calcium levels in the blood and it leads to bone remodelling and release of calcium from the bones. Vitamin D, on the other hand, also helps increase calcium levels, but it does so by increasing its absorption in the small intestine. In short, vitamin D maintains normal calcium levels and indirectly protects your bones. The consequences of low vitamin D are rickets in children and osteomalacia in adults. Basically, the bones become soft and weak, which in turn leads to all sorts of complications.
Extraskeletal effects of vitamin D are much more interesting, but the findings are also quite controversial and come mainly from observational studies (remember: correlation does NOT equal causation). Studies suggest that vitamin D is associated, among others, with proper immune system function, lower mortality from certain types of cancer, good cardiovascular health, and proper metabolic function.
Regarding the nervous system, we know that vitamin D receptors are widespread throughout the brain, particularly in regions such as the hippocampus, hypothalamus, cortex, thalamus, and substantia nigra. We also have evidence that vitamin D plays a role in the differentiation and maturation of neurons. On top of that, some studies suggest that vitamin D deficiency is related to various neurological and neuropsychiatric disorders, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, major depressive disorder, and schizophrenia. At the same time, other studies have found no associations in these cases.
A wealth of randomized clinical trials are currently underway to test whether vitamin D is actually beneficial in these situations and also to determine optimal vitamin D values in these cases. But until results actually come in and until we get a better understanding of how vitamin D can exert these beneficial events, I cannot stress enough that what we have so far is correlational evidence. What’s more, it is a terribly bad idea to start gobbling up vitamin D like there’s no tomorrow because excess has its downsides, including fatigue, high blood pressure, and muscle weakness, among others.
Who needs vitamin D?
With those cautionary words in mind, we finally come to the practical implications, which boil down to one question: do you need to take vitamin D or not?
Ideally, the answer to this question would be based on a simple blood test that could tell you whether you suffer from a deficiency or not. If you’re deficient, of course you take supplements. And if you’re not, there’s no need for that. But in the real world, as resources are finite, we can’t all get tested for potential vitamin D deficiencies. Instead, doctors recommend them in cases where clinical symptoms indicate a potential deficiency.
Still, what if you only have a minor deficiency which doesn’t lead to severe symptoms, so you never see a doctor about it? In this case, the best course of action is to follow the recommendations of health authorities in your country. For example, in the UK, the NHS recommends that people take 10 micrograms of vitamin D per day in winter months, and additionally, that those who don’t spend much time outdoors or are dark-skinned keep the same supplementation level throughout the rest of the year. In contrast, in Germany, the recommendation is of 20 micrograms per day, but limited only to high-risk individuals or those suspected of a deficiency. In general, these recommendations are based not only on the amount of sunlight that people are likely to be exposed to, but also on estimates of vitamin D deficiency prevalence in a particular population.
To sum up, vitamin D is an interesting hormone with a wealth of potential health effects. However, there is still a lot of work to be done in terms of standardizing tests, conducting large-scale clinical trials and establishing whether causal links are present in so many disorders, as well as identifying the underlying mechanisms which contribute to these effects. And in terms of vitamin D supplementation, you should follow the recommendations of health authorities in your country and also keep in mind that there is such a thing as too much vitamin D intake.
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Altieri, B., Cavalier, E., Bhattoa, H. P., Perez-Lopez, F. R., Lopez-Baena, M. T., Perez-Roncero, G. R., … & Holick, M. F. (2020). Vitamin D testing: advantages and limits of the current assays. European journal of clinical nutrition, 74(2), 231-247.
Bivona, G., Agnello, L., Bellia, C., Iacolino, G., Scazzone, C., Lo Sasso, B., & Ciaccio, M. (2019). Non-skeletal activities of vitamin D: from physiology to brain pathology. Medicina, 55(7), 341.
Bouillon, R., Manousaki, D., Rosen, C., Trajanoska, K., Rivadeneira, F., & Richards, J. B. (2022). The health effects of vitamin D supplementation: Evidence from human studies. Nature Reviews Endocrinology, 18(2), 96-110.
Bouillon, R., Marcocci, C., Carmeliet, G., Bikle, D., White, J. H., Dawson-Hughes, B., … & Bilezikian, J. (2019). Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocrine reviews, 40(4), 1109-1151.
Khundmiri, S. J., Murray, R. D., & Lederer, E. (2011). PTH and vitamin D. Comprehensive Physiology, 6(2), 561-601.
Meulenberg, E. P. (Ed.). (2012). Antibodies applications and new developments. Bentham Science Publishers.
Moretti, R., Morelli, M. E., & Caruso, P. (2018). Vitamin D in neurological diseases: a rationale for a pathogenic impact. International journal of molecular sciences, 19(8), 2245.
Parker, G. B., Brotchie, H., & Graham, R. K. (2017). Vitamin D and depression. Journal of affective disorders, 208, 56-61.
Wise, S. A., Camara, J. E., Sempos, C. T., Lukas, P., Le Goff, C., Peeters, S., … & Cavalier, É. (2021). Vitamin D Standardization Program (VDSP) intralaboratory study for the assessment of 25-hydroxyvitamin D assay variability and bias. The Journal of steroid biochemistry and molecular biology, 212, 105917.
4 thoughts on “Vitamin D in the Brain and Beyond”
Obese people tend to have suboptimal levels of serum Vitamin D3 because its less readily available from their dermis. This may play a factor in certain health vulnerabilities of obese people.
This is interesting, I didn’t know. Thanks for the addition!
The “gold standard is…” HPLC – High Pressure Liquid Chromatatography 🙂
Oh, I missed that! Thanks a lot, just corrected it!