Week 36 - Vitamin D Deficiency

If PTH is high, and calcium and/or phosphorous is low, what does that suggest about deficiency?

If PTH is high, and calcium and/or phosphorus is low, that would be suggestive of deficiency. If PTH is very low, and serum calcium and/or phosphorus is high, that would be suggestive of toxicity. I put this in a table on this slide, which you can print out to make it easier to reference.

What is the relationship between Vitamin D/K2/A?

One final thing: it's crucial to remember that fat-soluble vitamins have a synergistic relationship. I've written elsewhere that vitamin D raises the toxicity threshold of vitamin A significantly, but it is also true that adequate vitamin A and vitamin K2 protect against vitamin D toxicity. Therefore, just as the lower end of the 25(OH)D range should vary based on 1OHase genetics and the amount of PTH required to convert calcidiol to calcitriol, the upper end of the 25(OH)D range should depend on vitamin A and vitamin K2 status.

What is the breakdown of how different skin types absorb Vitamin D?

As a general rule, full-body exposure to midday summer sun will produce roughly 10,000 IU of vitamin D in about half the time it takes for your skin to turn pink. Now, depending on skin tone, this could be as little as 15 minutes in someone with pale skin, types I to III on the chart on the slide, but these numbers are best-case scenario. At higher latitudes, with less skin exposed, and with darker skin color such as types IV through VI, much less vitamin D will be produced.

What is the treatment protocol for Vitamin D?

Okay, so these are the next steps based on the patient's 25(OH)D levels. If their 25(OH)D level is below 25 ng/mL, then you would begin treatment. If their level is between 25 and 35, then you could use PTH, parathyroid hormone, to determine whether treatment is necessary, and if their level is above 35, no treatment is necessary in most cases. They can just continue their diet and lifestyle protocol for maintaining adequate 25(OH)D levels.

Why is Vitamin D important?

Vitamin D is critical for health. It promotes calcium absorption in the gut and maintains calcium and phosphate levels in the blood, which in turn enables proper mineralization of bone and protects against osteoporosis, rickets, and fracture. Vitamin D plays a number of other important roles in the body, including regulating cell growth and neuromuscular and immune function.

How is Vitamin D status determined?

Vitamin D status is determined by measuring a form called 25(OH)D in the blood. In the U.S., the lab reference range for 25(OH)D is 30 to 74 ng/ mL, with some labs. LabCorp goes from 30 to 100 ng/mL, so this, of course, depends on which lab is used. Vitamin D advocacy organizations such as the Vitamin D Council suggest a higher range of 40 to 80 ng/mL, with a target level of 50 ng/mL. However, there is little evidence that raising levels above 50 ng/mL is beneficial, and there is some evidence that that may cause harm.

What is the recommended 25(OH)D range for those with autoimmune conditions?

Also note that phototherapy, or UV exposure, is superior to supplementation for patients with autoimmune disease. As mentioned, UV exposure has many benefits that vitamin D and food or supplements don't have, including production of cGRP, substance P, ACTH, MSH, calcitriol, and beta-endorphin. One study found that multiple sclerosis severity score had a stronger inverse association with frequent sunlight exposure than vitamin D consumption.

What is one possible estimate of biological Vitamin D activity?

Also, it may be possible to get a better estimate of biological vitamin D activity, which is the most important measurement that we're looking at, by combining calcidiol and calcitriol levels. This can be done by using a formula such as 25(OH)D plus 1,000 x 1,25(OH)2D, where both markers are expressed in the same units, or by simply adding them when 25(OH)D is expressed as ng/mL and when 1,25(OH)2D is expressed as pg/mL. When you use these formulas, black and white girls from the study earlier in the presentation have nearly identical circulating vitamin D activity.

What is another possible mechanism behind What is the mechanism behind genetic variation in the activation of 25(OH)D?

Another possibility is that nonwhites require less PTH to convert calcidiol to calcitriol. American whites consume almost two times as much calcium as blacks. However, blacks may require less PTH to active calcidiol in states of calcium deficiency, again as the charts on this slide suggest.

Why are whole food nutrients preferred in absorption of food?

As you surely know by now, food is the best source of nutrients, and the reason for that is that there are various cofactors that are required for the absorption of certain nutrients that are present in food that are not present in synthetic supplements.

Is there new technology being developed that can assist with one's UV exposure within a narrow UVB spectrum?

At the time of this recording, new technology is being developed to provide UV exposure in a narrow UVB spectrum of 300 to 302 nm. This is a spectrum with maximum benefit and minimal risk. You'd spend two minutes in the booth and get a month's worth of vitamin D and sun exposure benefit with the risk that is associated with only 53 seconds of actual sun exposure. These booths may end up in your doctor's office or CrossFit gyms, nursing homes, and even drugstores, so stay tuned to my blog for updates.

What happens to calcitriol levels when calcidiol levels are extremely high?

Confusing the issue further, when calcidiol or 25(OH)D levels are extremely high, calcitriol levels can fall to undetectable levels, and this happens because PTH and FGF23 suppress the conversion of calcidiol into calcitriol in an attempt to protect against hypercalcemia and hyperphosphatemia. When 25(OH)D is high and 1,25(OH)2D is low, it could actually be vitamin D toxicity, or it could be vitamin D deficiency. This is why it is so important to use other markers such as PTH, serum calcium, and serum phosphorus to clarify the diagnosis.

What would current reference ranges suggest about vitamin D deficiency in the presence of normal PTH and calitriol?

Current reference ranges that are globally applied to all without regard to ethnicity would say yes, but this more complete understanding of vitamin D metabolism and research on calcidiol and calcitriol levels, ethnicity, and bone density would say no.

What is the recommended sun exposure criteria?

During the late spring, summer, and early fall, spend half as much time as it takes your skin to turn pink in the sun at least three times a week. During the late fall, winter, and early spring, you have to measure vitamin D levels and see where they are. If they are deficient, and if you live at a latitude where the solar angle is unlikely to provide much benefit, consider spending half as much time as it takes your skin to turn pink three to seven times a week, depending on the solar angle. Unfortunately, in some cases, sunlight isn't a viable route of UV exposure for various reasons, such as people who work indoors, latitude, or season.

What did one study label as the optimal level of Vitamin D?

For example, one study showed that the optimal level of vitamin D is between 20 and 36 ng/mL. Those with levels below 10 were 88 percent more likely to suffer from acute coronary syndrome or early death. Those with levels between 10 and 20 were 25 percent more likely, and those with levels above 36 were 13 percent more likely.

What is the link between malignant melanoma and the use of sunscreen?

Furthermore, sunscreens prevent sunburn generated by excess exposure to UVB, but they still allow UVA skin damage to occur, and this is the primary reason sunscreen use is a contributing factor to malignant melanoma, which is the deadliest form of skin cancer.

What is the functional range for Vitamin D levels?

Given everything we have discussed in this presentation, I've set my functional reference range for vitamin D at 35 to 60 ng/mL. This will undoubtedly catch several people who have so-called low levels of 25(OH)D who are not biologically deficient, but we can use PTH to clarify these situations, and I'd rather err on the side of caution given the association of low 25(OH)D with so many diseases.

What do studies around sun-exposure related Vitamin D toxicity assume defines the threshold of toxicity?

However, these studies essentially define harm from vitamin D as elevated serum calcium, and it's possible and even probable that elevated vitamin D can cause problems before serum calcium goes out of range. For example, at least two studies have linked kidney stones to latitude, with an increasing incidence of stones at lower latitudes. One study also directly linked kidney stones to sunlight. A Saudi Arabian study found kidney stones were more common in the summer, and 11 of 45 lifeguards in Israel had kidney stones, which is 20 times the rate of the general population. On the other hand, a large study of over 45,000 men 14 years of age or older, for a total of 477,000 person-years of follow-up, found no increased risk of kidney stones with vitamin D intake, but they did not look at sun exposure or 25(OH)D levels.

In the absence of 25(OH)D, what can we use to identify pathological Vitamin D deficiency?

In the absence of a 25(OH)D reference range based on ethnicity or a biological vitamin D activity reference range that we talked about on the last slide, we can use markers such as PTH and calcitriol to help us clarify when low 25(OH)D is pathological versus when it is just normal physiology, and here is how that works.

Is 25(OH)D always going to be out of the lab range for hyperparathyroidism?

Note that 25(OH)D is not always out of the lab range in hyperparathyroidism, and, in fact, it can even be normal or low. In those cases, 25(OH)D deficiency or low levels of 25(OH)D can obscure hyperparathyroidism, which doesn't become evident until vitamin D is repleted through sun exposure or supplements. Elevated serum calcium is the most important indicator of hyperparathyroidism, and we'll talk a little bit more about that when we talk about calcium.

Where do people on an industrialized diet get the majority of their Vitamin D?

Note that people on an industrialized diet get a majority of their vitamin D from cutaneous production. This means that serum vitamin D level is primarily a measurement of sun exposure and supplementation, not food sources. Dietary vitamin D contributes only 10 to 20 percent of vitamin D status in most people, and we'll talk about how to increase this percentage later

What are the 5 important conclusions about Vitamin D?

Now collectively, this suggests five important conclusions. First, although 25(OH)D is the best marker for measuring the available substrate from diet, supplements, and ultraviolet light for conversion to calcitriol, it's not the best marker of biological vitamin D activity. Second, people with nonwhite ancestry may be adapted to a lower optimal 25(OH)D than people with white ancestry. According to the research, we can be most confident that this is true for the traditional Inuit and African Americans and less confident that it is true for Asians. Third, many people who are considered deficient by the current U.S. lab range may not be. Fourth, giving them vitamin D, these people who are borderline deficient, may not only be unnecessary, it may actually be harmful given what some studies show about the U-shaped curve of vitamin D. The fifth conclusion arises naturally from the first four, which is that the reference range for 25(OH)D should probably be different for nonwhites and whites.

What is the mechanism behind genetic variation in the activation of 25(OH)D?

Okay, now let's get back to the question at hand. Recall that blacks have lower calcidiol levels than whites but better bone density. How could this be? One possibility is the genetic variation in the activation of 25(OH)D to calcitriol. In other words, blacks convert calcidiol to calcitriol more effectively, and they require less calcidiol to achieve the necessary amount of calcitriol.

What is the link between infant sunlight exposure and diabetes?

One study determined low infant sun exposure was associated with a twofold increase in type 1 diabetes. Seasonal variation and duration of sun exposure are both correlated to disease activity in patients with rheumatoid arthritis. The duration of sun exposure is inversely correlated to the incidence and severity of disease activity in Crohn's disease patients, and another study with MS patients discovered higher levels of reported sun exposure rather than 25(OH)D levels were associated with less depressive symptoms and less fatigue.

What foods are high in Vitamin D?

Only a few foods such as cold-water fatty fish or shellfish are rich in vitamin D, whereas the vitamin D content of the vast majority of other foods is small, or even zero.

What is the relationship between PTH and Vitamin D deficiency?

Put a different way, if you see a 25(OH)D level that is low-normal, let's say 32 or even slightly below the lab range such as 27 or 26, and you test PTH and it's below 30, then that would suggest that this patient is not actually vitamin D deficient from a biological perspective and that supplementation, diet, and lifestyle change aren't required. However, if you see a low or borderlinelow level of 25(OH)D, and you test PTH and it's above 30, then that would suggest that they are biologically deficient. The higher the PTH is above 30, the more biologically deficient they are.

What conditions are linked to Vitamin D overload?

Researchers have linked higher ranges with decreased bone density, heart attack and stroke, kidney stones, and other health problems. Despite the significant impact that vitamin D has on human health, research examining the effects of vitamin D supplementation has yielded inconsistent and sometimes conflicting results. In most studies, taking vitamin D supplements does not decrease the risk of death, cardiovascular disease, or other diseases, though some studies such as the one I mentioned on the last slide have shown some benefit.

What are the effects of too much Vitamin D (Hypercalcemia)?

So far, we've been mainly discussing the low end of the 25(OH)D range and the effects of vitamin D deficiency, but what about vitamin D toxicity? The hallmark of vitamin D intoxication is hypercalcemia, which is due to intestinal calcium hyperabsorption and calcium resorption from bone. Excess vitamin D also causes hyperphosphatemia. Hypercalcemia and hyperphosphatemia cause mineralization of various soft tissues, including the kidneys, heart, aorta and other blood vessels, and cutaneous tissue, and this can lead to kidney stones and increased risk of cardiovascular disease, among other problems. Vitamin D-intoxicated patients suffer from headache, nausea, vomiting, diarrhea, anorexia, weight loss, polyuria, and polydipsia, and excess vitamin D intake has also been shown to contribute to several documented deaths.

What is step three in the Vitamin D repletion protocol?

Step three is to retest 25(OH)D levels and PTH levels after 60 days. This, unfortunately, is a step that many clinicians omit, and it's really crucial to see what effect your treatment is having and also to check in with the patient and make sure they are not taking excess vitamin D because this, as I mentioned earlier, can lead to toxic levels of vitamin D, and it's something I'm seeing increasingly frequently in my practice. When you do the retest, your suggested action for what you do after that depends, of course, entirely on what their level is on the retest. If they are still below 15 after everything you did in the last step, it's very likely that they have an absorption problem, especially if you use micellized vitamin D and their level didn't come up. That's extremely rare. I've only seen it a couple times in almost a decade. In that case, the patient may need vitamin D injections, or they may need UV exposure from one of these new devices that are coming online soon in the next couple of years if they are unable to absorb oral vitamin D, or they have really severely impaired absorption.

If the patient has below 25 ng/ml of 25(OH)D, what is the next step?

The next step is to begin treatment if their level was below 25, and what treatment you do depends on what their level was. If their level was below 15, which is a pretty significant deficiency, you would advise them to eat one pound of cold-water fatty fish such as salmon, herring, mackerel, or sardines; six to eight egg yolks per week, pasture-raised; one teaspoon of extra-virgin cod liver oil; UV exposure, as possible; and then 10,000 IU per day of micellized vitamin D, which is the most absorbable form. It's a liquid form that is predigested.

What are two ways to increase calcitriol?

The two potential ways of increasing calcitriol are increasing the supply of calcidiol through sun exposure, supplements, or diet or increasing demand for calcitriol via parathyroid hormone. With more substrate from diet, supplements, or sun, more calcidiol is available for the enzymatic conversion to calcitriol. With higher levels of PTH, the kidney produces more of the enzyme that converts calcidiol to calcitriol, so maintaining adequate substrate or supply of calcidiol protects bone health, since it shifts the burden of maintaining serum calcium away from PTH-dependent bone and kidney mechanisms and toward maximizing intestinal absorption of calcium.

How does the parathyroid impact 25(OH)D?

This conversion of 25(OH)D to calcitriol is tightly regulated by parathyroid hormone. Parathyroid hormone, or PTH, increases calcitriol formation, and it helps it increase serum calcium by acting on kidney and bone. On the other hand, 25(OH)D is only loosely regulated. If the calcitriol level and related measures such as PTH and bone health remain normal, even when calcidiol or 25(OH)D levels drop into the deficiency range, does that mean the person is really deficient in vitamin D?

How does Vitamin D metabolism work?

To understand this, we need to do a short review of vitamin D metabolism. Vitamin D can be obtained from diet, supplements, and endogenous synthesis in response to ultraviolet light exposure. Once vitamin D is in the circulation, it is converted by hepatic hydroxylase into 25(OH)D, and this is what is typically measured on a blood test. As needed, 25(OH)D is converted into 1,25(OH)2D, which is also known as calcitriol. By the way, 25(OH)D is known as calcidiol. This is the biologically active form of vitamin D, calcitriol or 1,25(OH)2D. Calcitriol increases the level of calcium in the blood by increasing the uptake of calcium from the gut, decreasing renal excretion of calcium, and possibly increasing the release of calcium into the blood from the bone, although that is not yet well understood

What is the comparison between Inuit and Danish whites in terms of PTH meditated conversion of calcidiol to calcitrol?

We see a similar phenomenon in Inuit when compared to Danish whites and even a difference between Inuit on a traditional diet and Inuit on a Western diet. As the charts on the slide indicate, the traditional Inuit needs the least PTH to achieve higher calcitriol levels. The Inuit on the Western diet is next, and then the Danes need the most PTH to activate calcidiol into calcitriol.

What is important to consider about high Vitamin D levels in light of 1,25(OH)2D levels?

We should note that these studies don't prove causality. It's possible that high 25(OH)D levels may occur as a result of low 1,25(OH)2D levels, which could indicate deficient vitamin D actions at the cellular level. In other words, it is possible that increased mortality and disease are caused by a deficiency of active 1,25(OH)2D even though 25(OH)D levels are elevated.

Is Vitamin D toxicity from sun exposure possible?

What about toxicity of vitamin D from sun exposure? Again, there is some controversy here. Most studies suggest no reports of vitamin D intoxication from sun exposure alone. The argument is that the daily skin synthesis of 25(OH)D reaches a plateau after 15 percent of the precursor 7- dehydrocholesterol is converted into 25(OH)D, and after that, vitamin D inactive substances such as lumisterol and tachysterol are produced.

What are the Vitamin D supplementation recommendations?

First is that vitamin D is fat soluble, which means that it should be taken with a meal that contains fat to improve absorption. Second, there are two supplemental forms of vitamin D available: D2 and D3. Some research suggests that D3 supplements are more effective at raising and maintaining 25(OH)D levels. Third is that individual response to vitamin D supplements varies. I've found in my practice that some people efficiently absorb vitamin D from supplements, while others, particularly those with digestive issues, absorb very little and thus need a higher dose to stay in the optimal range. Vitamin D dosage should also be adjusted by weight. Those who are obese may need to increase the doses that I recommend by as much as 50 percent in order to achieve the target 25(OH)D level. Fourth, the increase in serum vitamin D is similar regardless of whether you take a smaller dose of oral vitamin D daily or a larger dose once a week. However, super-large monthly or semiannual doses are not recommended, so choose whichever dosing schedule the patient is more likely to follow through with.

What is to explain for the contradictory data in optimal Vitamin D levels in the serum?

How do we explain this contradictory data? The first important concept to understand, which is not yet widely known, is that the optimal physiologically appropriate 25(OH)D level may vary from population to population based on ethnicity. People with nonwhite ancestry, for example, may be adapted to a lower optimal 25(OH)D than people with white ancestry. Blacks have lower 25(OH)D than whites in the U.S., yet their bone mineral density is typically higher, as the chart on this slide indicates. Other studies have found that non-Caucasians have lower 25(OH)D levels than Caucasians, even at their ancestral latitudes.

What does the Institute of Medicine argue about 25(OH)D levels in patients taking supplements?

However, the Institute of Medicine has argued that 25(OH)D levels above 50 ng/mL when a patient is taking supplements may be cause for concern. This is based on several observational findings indicating the values above this level are associated with a higher risk of all-cause mortality and specific types of cancer. There is evidence for a U-shaped association of circulating 25(OH)D levels with allergy risk, indicating a high risk at both circulating 25(OH)D levels below 10 mg/dL and above 54 mg/dL.

What are the next steps for those with low levels of Vitamin D, but not severe (<25ng/ml)?

If their level was 15 to 25, then you would do everything that I just mentioned except you would use 5,000 IU of vitamin D3 in micellized form. If their level was 26 to 35, and their PTH was above 30, that would indicate deficiency, but it would be milder than the previous two cases, so you could just try extra-virgin cod liver oil, diet, and UV exposure and see if you can bring it up that way. If the level is 26 to 35 with PTH below 30, or above 35, then no treatment is necessary, and you can continue diet and lifestyle for maintaining adequate vitamin D levels.

What is the typical level of Vitamin D intake in those with Crohn's and other GI conditions?

In the absence of effective food fortification programs, dietary vitamin D intake does not exceed 3 to 5 mg per day for most people. This is particularly true for patients with Crohn's disease, ulcerative colitis, celiac disease, or other conditions that cause fat malabsorption, since vitamin D is a fat-soluble vitamin.

What is important to consider about Vitamin D toxicity due to supplementation?

It's important to be aware that in most cases of vitamin D toxicity due to supplements, 1,25(OH)2D is not elevated, and this is because calcitriol is tightly regulated by PTH and FGF23, both of which respond to changes in serum calcium and phosphate. Detoxicity leads to hypercalcemia and hyperphosphatemia and depresses calcitriol. This means that if you see a high calcidiol level, and calcitriol levels are normal, that does not rule out vitamin D toxicity.

What is the problem with sunscreen?

Just as it can be difficult to find the right dose of vitamin D that keeps 25(OH)D in the optimal range without the risk of toxicity, it can be hard to find just the right dose of UV exposure or sunlight without the risk of sunburn and skin cancer. There is no doubt that excess sun exposure can lead to sunburn and is linked to skin cancer. In an effort to reduce the incidence of skin cancer, many dermatologists are recommending the use of sunscreen. Unfortunately, sunscreen also prevents the cutaneous production of vitamin D3 and other beneficial effects of sun exposure.

Do Vitamin D levels have a bell curve?

Other studies have shown that bone mineral density peaks at 45 ng/mL and then falls again as 25(OH)D levels rise above 45 ng/mL. Still other studies have shown that the risk of kidney stones and cardiovascular disease increases with high 25(OH)D levels above 60 or 70 ng/mL due to elevated serum calcium levels that accompany excess vitamin D. These studies and many other similar studies explain why the Institute of Medicine recommends a much more conservative range of 20 to 50 ng/mL based on an exhaustive review of over 1,000 published studies.

What do studies with inflammatory bowel disease patients demonstrate about Vitamin D?

Studies with inflammatory bowel disease patients demonstrate that vitamin D status is linked to sun exposure, and dietary supplementation is inadequate to raise serum levels. Cutaneous synthesis of vitamin D is the most bioavailable source for those with fat malabsorption caused by inflammatory diseases.

What are the benefits of sunlight?

Substances that are made from chemical reactions with sunlight are called photoproducts. When human skin is exposed to sunlight, it produces several peptides and hormones that contribute to systemic wellness. These include calcitonin gene-related peptide, or cGRP; neuropeptide substance P; adrenocorticotropic hormone, ACTH; melanocyte-stimulating hormone, MSH; calcitriol; and beta-endorphin.

Which disease states does the presence of sunlight in one's lifestyle improve?

Sun exposure has been shown to improve hypertension, a wide variety of immune diseases, skin conditions, anxiety and depression, and more, independently of its effect on vitamin D production. In addition, while higher vitamin D levels created by the sun are useful in preventing disease, the research on vitamin D supplementation, as I said before, is mixed. Some studies have shown benefit, but many others have not, and the long-term effects of vitamin D supplementation are understudied. As we've seen, vitamin D toxicity may develop at levels of 25(OH)D that are lower than the upper end of the current laboratory reference range.

What is the PTH reference range at most labs?

The PTH reference range at most labs is 10 to 65 pg/mL, but studies that have looked at various populations have found that normal, average PTH is 37 pg/mL in Danes who are following a Western diet, 30 pg/mL in Inuit following a Western diet, and only 22 pg/mL in Inuit who are following a traditional diet. A meta-analysis of the suppressive effects of vitamin D supplementation on PTH found the greatest effect with baseline levels of PTH over 49. In that case, vitamin D supplementation suppressed PTH by 21 pg/mL. When PTH was between 38 and 49, vitamin D supplementation suppressed PTH by 17 pg/mL, and then when PTH levels were between 6 and 38, vitamin D supplementation only dropped PTH by 2 pg/mL. This suggests that a PTH level above 30 pg/mL would corroborate concerns about low 25(OH)D levels in proportion to its upward divergence from 30.

What are the mortality risks of Vitamin D deficiency?

Using the lower end of the reference range in the U.S. of 30 ng/mL, studies have found that as many as 70 percent of Americans are deficient, and vitamin D deficiency nearly doubled a person's risk of dying, whereas correcting the deficiency with supplements reduced the risk of death by 60 percent. Deficiency of vitamin D has been linked to a wide range of problems, including increased risk of heart attack, increased risk of cancer, higher severity and frequency of asthma symptoms, greater susceptibility to autoimmune diseases such as MS and rheumatoid arthritis, increased risk of type 2 diabetes, and increased risk of death from all causes.