Vitamin D

One of the most common clinical concerns I encounter from patients is surrounding vitamin D status. People ask: are my vitamin D lab values normal? How often should I test? How much should I supplement? Can I get enough vitamin D from sunlight and foods without supplements? What if my lab values say I’m insufficient but I have horrible reactions to vitamin D supplements? What about the report from the Endocrine Society that says I should have serum levels far beyond what the current NIH standards suggest is adequate?

We’ll look at answers to all of these questions and concerns here today as well as explore some of the biochemistry behind how our individual bodies utilize vitamin D.

Vitamin D Biochemistry

Vitamin D is one of four fat-soluble vitamins; the others being vitamins A, E, and K. Vitamin D is unique among all of the vitamins in that most of us can synthesize it in its active form from UVB rays (wavelength 280-315 nm) beaming down from sunlight. Note that UVC (100-280 nm) and UVA (315-400 nm) rays do not gift us with the same ability. Of course, many of us have sub-optimal UVB exposure during parts of the year, as latitude - and thus, changing seasons - will affect our UVB exposure. The further away you are from the equator, the less time annually you spend basking in UVB-rich sun. Summer months typically experience the highest UVB output of all the seasons. (1)

Inadequate vitamin D status has been linked to everything from cancer, diabetes, impaired bone mineralization (leading to things like rickets and osteopenia or osteoporosis), and cardiovascular disease to autoimmunity, neurodegenerative disease (such as multiple sclerosis), IBS, and dermatitis (2). And because vitamin D receptors (VDRs) are found in nearly every tissue in our bodies, it suggests that we’ve only just begun to grasp the extent to which this vitamin influences physiological function. However, in the last decade as vitamin D has enjoyed increasing attention in the research spotlight, some practitioners and researchers are being accused of over-hyping the need to push serum levels higher and subsequently over-supplementing vitamin D. (3)

When UVB rays hit your skin or you consume foods such as fortified milk or fatty fish like salmon, you get the precursors to active vitamin D - but they aren’t the final active form of vitamin D your body needs to bind to the VDRs. Your body must pass these precursors through several enzymatic conversion steps before at last arriving in the active form. As skin encounters UVB rays, something called 7-dehydrocholesterol is converted to cholecalciferol (D3). The intensity of the UVB rays as well as the melanin content of the skin itself affect the rate of this D3 conversion.

Dietary sources of the precursors include D3 and ergocalciferol (D2). Both of these must first undergo conversion to 25-hydroxyvitamin D (25OHD), also known as calcidiol, in the liver followed by conversion to our final active hormonal form, 1,25-dihydroxyvitamin D (1,25(OH)2D), also known as calcitriol, in the kidney. As you might guess, liver and kidney disease may impair this conversion. Calcitriol, our final product, binds to the VDR, which in turn acts to influence DNA binding sites called vitamin D response elements (VDREs). These binding sites regulate hundreds of genes with high cellular specificity (4).

Genetic Variation

Genetic variation is a hallmark of adaptation and improves odds of survival in a dynamic and challenging ecosystem. Another term for a point of genetic variation is polymorphism. Genetic polymorphisms are variations - often small - in the genetic code, or DNA, that may confer altered function to the corresponding protein produced by that particular genetic sequence. Many proteins are involved in vitamin D metabolism, including enzymes involved in conversion steps and VDRs themselves. This means that changes in the genetic code relating to any of these proteins may alter vitamin D status (5).

Though we are still sorting out the details in the science and some of it remains conflicting, studies have revealed significant associations between VDR polymorphisms and prostate, breast, colorectal, and skin cancer. Other significant associations have been noted between vitamin D-related cytochrome system polymorphisms, vitamin D binding protein polymorphisms, and disease risk. It is suggested that most of these polymorphisms are not likely to be sole causes of disease, per se, but rather an important piece of a more complex landscape of neoplastic contributors (6).

Our Current Standard

While it’s true that the science of vitamin D status is evolving and will continue to shed new light on our current reference ranges - perhaps redefining them in the future, we need to know how to accurately interpret the current standards, which come from the National Institutes of Health (NIH) and Institute of Medicine (IOM). You may be amazed - or perhaps not - to learn how frequently the current standards are misinterpreted and misunderstood. To add to this confusion, falsely low or falsely high serum values for 25(OH)D may emerge, depending upon the lab and its assay. Liquid chromatography and antibody-based assays are typically used in the lab to assess a serum sample for 25(OH)D, but notable variability in assay-dependent results prompted creation of a standardization technique/material about 10 years ago, helping to improve results between and across labs.

The National Institutes of Health (NIH) currently states:

Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects. (7)

Now, take a minute to have second look at this, this time paying careful attention to the way there are TWO different units of measurement here: ng/mL and nmol/L. Based upon which unit of measure is used, the reference ranges differ significantly. I routinely encounter practitioners - even laboratories - who have marked a patient as “deficient” in vitamin D when he or she has a serum 25(OH)D level <30 ng/mL. Look at those units: ng/mL, not nmol/L. The NIH states that 97.5% of the population is considered to possess an adequate serum 25(OH)vitamin D level between 20 and 50 ng/mL. If we had in fact been measuring in nmol/L, that patient would have indeed been deficient at levels <30. But that wasn’t our unit of measure. Perhaps these practitioners or labs had mistakenly swapped their units of measure and reference ranges, looking at the range for nmol/L instead. That might be a clinically significant error. Watch those units!

The Controversy

In 2011, a report was issued by the esteemed Endocrine Society seeking to challenge the NIH standard. It said:

“Based on all the evidence, at a minimum, we recommend vitamin D levels of 30 ng/mL, and because of the vagaries of some of the assays, to guarantee sufficiency, we recommend between 40 and 60 ng/mL for both children and adults.” (8)

In 2012, the IOM published a thorough critique of the Endocrine Society’s data with a response there articulated:

Although the IOM committee welcomes efforts to identify the role of vitamin D in treating special and diseased populations outside the category of the general population, the guideline defines a number of population groups to constitute those at risk when such groups clearly were considered as part of the general population for establishing Dietary Reference Intakes. The guideline goes on to inappropriately conclude that the benefits of vitamin D for a large segment of our population occur only when serum levels are at 30 ng/ml 25OHD and above, and mistakenly concludes that all persons with serum 25OHD levels below 20 ng/ml are deficient in vitamin D. In turn, the guideline conclusion that at least half of our population requires routine testing represents a large, unnecessary cost. Finally, the guideline's recommendation for high levels of intake for a wide range of conditions in which benefits have not been demonstrated is disconcerting and does not reflect an evidence-based approach.

We support the Endocrine Society efforts to produce clinical practice guidelines targeted to persons with underlying health conditions, but this needs to be done using a systematic, evidence-based approach that assesses the strength of evidence for both benefits and risks of supplementation. The current guideline fails in both respects and therefore is in need of reexamination” (3)

In other words, The Endocrine Society’s data had failed to convince the IOM and larger scientific community.

Meanwhile, yet another very different debate was being launched by some of the leading epidemiologists and endocrinologists. In a published article in NEJM, these experts, several of whom had presided on the original IOM committee for establishing vitamin D standards, argued for a lowering of the current NIH standard to something closer to 12.5 ng/mL as the cutoff for insufficiency (as opposed to the current standard of 20 ng/mL). They strongly felt that the medical community was over-screening for vitamin D deficiency and over-treating. Furthermore, they had built this opinion from a huge amount of data gained from the National Health and Nutrition Examination Survey (NHANES) for 2007-2010 (8).

Dr. Monique Tello, a physician and author for the Harvard Health Publishing site wrote an article echoing many of these aforementioned points as well as highlighted a particular interview she undertook with the associate director of the Bone Density Center at Massachusetts General Hospital, Dr. Joel Finkelstein - himself possessing over 3 decades of research experience in the field. Dr. Finkelstein’s opinion is aligned with the NEJM article: we’ve over-hyped and over-blown the need for higher serum D levels. As he states in the interview, looking critically at the evolutionary perspective of vitamin D access:

“Vitamin D is actually quite hard to find in naturally occurring food sources. Yes, we can get vitamin D from the sun, but our bodies evolved to create darker skin in the parts of the world that get the most sun. If vitamin D is so critical to humans, why would we evolve in this way, to require something that is hard to come by, and then evolve in such a way as to make it harder to absorb?”(8)

So Now What?

As of right now, the scientific consensus on vitamin D status as reflected in the NIH standards represents the most rigorous meta-analysis of the present available data - controversies included. There is currently insufficient evidence to alter this, and certainly insufficient evidence to alter it in favor of pushing it higher yet. Still, with a reference range for adequacy being quite large, it remains possible that optimal individual levels vary within the normal range. The real question is: what will be optimal for you? A laboratory test can rarely perform with the precision that your body can in terms of letting you know what is or isn’t optimal for your unique biochemistry. You often just have to know how to ask your body the right questions and how to set up those questions in such a way so as to be able to get a clear read on the answers.

If you are at a level below 20 ng/mL (and definitely if you are below 12.5 ng/mL), it is possible you might be insufficient and in need of extra vitamin D support - ideally through a combination of food, supplements, and appropriate amounts of UVB-rich sun exposure. If you are between 20 and 50 ng/mL it becomes much less likely that you are starkly deficient. Here’s the guide I use when treating my patients and managing their vitamin D status:

Step 1: Get the test done just for a simple frame of reference to begin to establish trends for a given individual over time. It’s easy to do, insurance covers it. Many would argue that standard testing of vitamin D is not needed for most healthy people, but since nearly all of my patients fall into the “higher risk” categories of illness, I make testing standard. If a patient doesn’t have a history of testing for vitamin D, it can be helpful to establish an annual or bi-annual test from here going forward over the next 2 years or so. Reasons for this will be outlined below. If a patient does have a history of testing, I ask to know the details of those numbers.

Step 2: Do a full assessment of dietary factors contributing vitamin D, UVB-rich sun exposure frequency, and any supplementation of D, including dosages and frequency

Step 3: If the test shows a patient is between 40-50 ng/mL or higher (typically I only see this in those who have been aggressively supplementing; though not everyone who aggressively supplements will achieve those higher levels), I stop all supplementation immediately and manage D solely from a food and lifestyle (sun) perspective, monitoring symptom trends closely and retesting D in 4-6 months. If a patient is between 20-30 ng/mL, I continue to recommend food sources of vitamin D in accordance with dietary recommendations and tolerance as well as encourage the individual to get 5-10 mins of UVB-rich sun exposure about 3 days a week during peak seasonal times, considering supplemental levels of vitamin D during the winter and low-UVB times of year. The supplement dosage is a very tricky issue I’ll discuss below. If a patient is less than 20 ng/mL, I opt for the food and sun as mentioned above, and begin testing tolerance to supplemental vitamin D regardless of the time of year.

To Supplement or Not to Supplement?

Let’s talk about supplemental vitamin D. You need to be careful. I find that almost everyone has strong negative reactions to vitamin D supplements when the dosage reaches the amount their body deems “too much”. This negative reaction can occur at very low dosages for some sensitive individuals. As I discuss at length in a number of previous blog posts, all nutrients in excess are capable of causing a detrimental reaction. Excess doesn’t necessarily mean massive doses, or the “upper limit” or UL of a nutrient as defined by the dietary reference ranges. Excess is what your body says no to, regardless of how much you’re taking or what the number on a test shows you. And you must listen. Though I find it important as a frame of reference to view what an individual’s vitamin D labs show over time, I do not advocate “treating to the test”. That is, regardless of what the lab values show, I seek to manage an individual’s dosage of D based upon that individual’s tolerance - which can vary wildly among different people. You may wonder then, why test at all?

Testing certainly isn’t necessary in order to clinically manage vitamin D status sufficiently. However, it can be helpful in terms of noting what a given individual’s body “likes” to do, therefore managing clinical expectations in the future for both patient and practitioner. Sometimes a test can simply empower someone to speak up for themselves in a clinical setting.

Our Example

Amanda, 43 years old

After addressing and controlling for a number of other dietary and lifestyle variables over prior weeks, my patient Amanda and I have been working to now establish her tolerance for vitamin D supplements. Amanda’s lifestyle and location means that she is rarely out in the sun during peak UVB times. She enjoys eating some vitamin D-rich foods such as salmon a few times a week but also notices that she tends to feel even better when on a very small amount of vitamin D (1000 IU) twice a week. If she goes much beyond this in frequency or dosage, she’ll notice more skin breakouts and anxiety in direct correlation with the days she takes the extra D. This is her body’s individual way of showing intolerance and in my clinical experience, such symptom trend correlations are common.

These symptoms are then managed accordingly and respond well to finely tuned adjustments in this supplement (as well as other food factors that have been known to trigger the same response and are limited accordingly). When I first saw Amanda, her doctor had tested her 25(OH)D level and found it to be 23 ng/mL. Being considered deficient in the eyes of this doctor, Amanda was prescribed 10,000 IU of D daily for the first week, then 5000 IU of vitamin D daily thereafter. After a month, Amanda felt worse - not better. Yet she stayed the course, unsure of what was causing what and wanting to listen to her doctor. This doctor was clearly diagnosing Amanda based upon the Endocrine Society’s recommendations, which had not been fully substantiated to supplant the current NIH recommendation. And Amanda was not getting better.

When she and I began working together, we did an updated vitamin D test. At this point, Amanda had been on high dose D supplementation for over 3 months. Her 25(OH)D levels had barely inched up - now at 25 ng/mL despite hefty doses of vitamin D supplements. One of the first things I did was recommend she stop her supplemental D - after which, she felt better. However, she didn’t really begin to feel a lot better until we tackled the many facets of her diet that had been contributing to other metabolic imbalances and problems. Once these were addressed, Amanda and her doctor elected to remove the other medications she had been on (one for sleep and one for anxiety), since both of these symptoms had improved with other dietary and lifestyle alterations.

After ironing these pieces out, we tested the waters with vitamin D supplementation again to explore if there was a dose where Amanda might actually note any improvement beyond her current state - this time going very slowly with a much lower dose and monitoring symptom correlations closely. And what we found was that the answer wasn’t black or white here; she felt a little better with a little more vitamin D supplement but worse with too much. Either way, her serum 25(OH)D would hover between 22-24 ng/mL when she felt her best and wouldn’t drop below 20 (at one point in her past it had been as low as 14) unless she stopped all of her supplements and even dropped her D-rich foods down considerably (while also continuing with her life of low UVB exposure).

In Amanda’s case, we used the tests to mark where she was when she felt her best and gain a frame of reference for what was normal for her, but never used the tests as an ultimate guide for treatment - preferring to allow her body and symptoms to set the pace. Amanda could then use this frame of reference to appreciate how her body really was “normal” within the established NIH range for normalcy and at a level where some may have considered her deficient. Amanda may never be someone who will have vitamin D levels above 30 ng/mL (even if given higher doses of supplemental D) and - given the current science - there’s no reason to expect that she should be in order to feel healthy enough to live her life well, minimizing disease risk.

Perhaps some would suggest that Amanda’s inability to achieve higher serum 25(0H)D despite high doses of supplemental D might have something to do with potential vitamin D polymorphisms that alter how she metabolizes higher amounts of D3. However, we don’t have nearly enough evidence currently to assert this with confidence. And unless that assertion is followed by novel types of gene therapy that show great promise to not only accurately diagnose such a so-called functional deficit but treat it effectively - it’s moot. We can’t force her body beyond a point, genetic diversity and all. We must work with what we have, all of us. For Amanda, this means not pushing her body to process higher amounts of D3 than she likely won’t tolerate.

Amanda is just one example of the many cases I see where vitamin D tests and subsequent high-dose supplement recommendations have not improved outcomes but possibly only worsened them in patients. As clinicians, we need to stay abreast of the science the best we can - controversy and all - and remember the importance of treating someone with more finesse and nuance than these current tests provide insight into. As individuals, it can sometimes feel complicated to untangle the cause-and-effect web of symptom translation. Taking concentrated isolated dosages of supplements daily is not recommended in most cases, as this disallows our ability to see contrast and thus, disallows our ability to see cause-and-effect more clearly. If you are wondering if your vitamin D supplement is right for you, I encourage you to consult with a qualified healthcare practitioner who understands the research mentioned in this article and can help you navigate your own symptoms and dosages if you decide to take vitamin D.

References:

(1) Solar UV Index, A Practical Guide. A joint recommendation of the World Health Organization, World Meteorological Organization, United Nations Environment Programme, and the International Commission on Non-Ionizing Radiation Protection. https://www.who.int/uv/publications/en/UVIGuide.pdf. Published 2002. Accessed 8/11/19.

(2) Oregon State University, Linus Pauling Micronutrient Information Center. https://lpi.oregonstate.edu/mic. Accessed 8/14/19.

(3) Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK. IOM Committee Members Respond to Endocrine Society Vitamin D Guideline. JCEM. 2012; 97(4): 1146-1152

(4) Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014. 21(3): 319-329

(5) Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta. 2006; 371(1-2): 1-12

(6) Gandini S, Gnagnarella P, Serrano D, Pasquali E, Raimondi S. Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol. 2014. 810: 69-105

(7) Vitamin D Fact Sheet for Professionals. National Institutes of Health. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Updated 8/7/19. Accessed 8/12/19.

(8) Vitamin D: What’s the “right” level? Harvard Health Blog. https://www.health.harvard.edu/blog/vitamin-d-whats-right-level-2016121910893. Published 12/19/16. Updated 12/26/18. Accessed 8/12/19.