Vitamin D3 CholecalciferolPhysiology

Vitamin D Physiology

Different Forms of Vitamin D

To understand the vitamin D endocrine system one needs to be familiar with the different forms of vitamin D, namely cholecalciferol, calcidiol, and calcitriol.

Cholecalciferol

vitamin D3

Cholecalciferol is the naturally occurring form of vitamin D. Cholecalciferol is made in large quantities in your skin when sunlight strikes your bare skin. It can also be taken as a supplement.

Calcidiol

25(OH)D or 25D

Calcidiol (25-hydroxyvitamin D) is a prehormone in your blood that is directly made from cholecalciferol. When being tested for vitamin D deficiency, calcidiol is the only blood test that should be drawn. When someone refers to vitamin D blood levels, they are referring to calcidiol levels. Your doctor can order calcidiol levels but the lab will know calcidiol as 25-hydroxyvitamin D.

Calcitriol

1,25(OH)2D3 or 1,25D3

Calcitriol (1,25-dihydroxyvitamin D) is made from calcidiol in both the kidneys and in other tissues and is the most potent steroid hormone derived from cholecalciferol. Calcitriol has powerful anti-cancer properties. It is sometimes referred to as the active form of vitamin D. Calcitriol levels should never be used to determine if you are deficient in vitamin D.

Vitamin D Endocrine System

Cholecalciferol Forms In The Skin

Cholecalciferol is formed in the skin when ultraviolet light of the correct wavelength, UVB, strikes bare skin. Enormous quantities of cholecalciferol are rapidly made in the skin if: the sun is high in the sky (midday and the summer season), your skin is not covered by clothes or sunblock, you stay in the sun until your skin just begins to turn pink (not red), you are not behind glass. Glass blocks virtually all UVB, preventing vitamin D from being made.

Studies show that if you go out in the summer sun in your bathing suit until your skin just begins to turn pink, you make between 10,000 and 50,000 units of cholecalciferol in your skin. Professor Michael Holick of Boston University School of Medicine has studied this extensively and believes a reasonable average of all the studies is 20,000 units. That means a few minutes in the summer sun produces 100 times more vitamin D than the government says you need! As discussed in other pages, this is the single most important fact about vitamin D.

The skin does another amazing thing with cholecalciferol. It prevents vitamin D toxicity. Once you make about 20,000 units, the same ultraviolet light that created cholecalciferol, begins to degrade it. The more you make, the more is destroyed. So a steady state is reached that prevents the skin from making too much cholecalciferol. This is why no one has ever been reported to develop vitamin D toxicity from the sun, though it is possible when taken orally.

Animals Form Cholecalciferol In Their Fur

Fur bearing animals and many birds make cholecalciferol in their fur or feathers as sunlight can not get to their skin. Interestingly, mammals and birds then eat the cholecalciferol by licking their fur (grooming) or rubbing their beaks on their feathers (preening). So, when you take cholecalciferol by mouth, you are doing what a number of other mammals do!

Calcidiol Made in Liver

After it is made in the skin or taken by mouth, cholecalciferol is transported to the liver where it is metabolized into calcidiol or 25(OH)D. Calcidiol is now thought by some scientists to have steroid hormone properties. It certainly helps maintain your blood calcium levels. But calcidiol's main importance is that it is the storage form of vitamin D. Calcidiol is what fills your vitamin D gas tank. If your serum calcidiol level is less than 40 ng/mL, your tank is low, and you should fill it up and keep it full unless you have one of those rare medical conditions called vitamin D hypersensitivity.

In order to understand why you should keep your vitamin D tank full, you need to understand the next step in the metabolism of cholecalciferol. After your liver turns cholecalciferol into calcidiol, calcidiol follows one of two pathways. The first pathway takes priority, as your life literally depends on it, but the second pathway is causing all the excitement. However, if your tank is low, most of your calcidiol takes the first pathway.

Calcitriol Made in Kidneys

The first pathway leads to the kidney, where calcidiol is turned into calcitriol. Calcitriol is a potent steroid hormone, in fact, it is the most potent steroid hormone in the human body. A steroid hormone is simply any molecule in the body that is made from cholesterol and that acts to turn your genes on and off. They are always important to health, always need to be handled with care, and are often quite potent.

Calcitriol made by the kidney circulates in the blood to maintain your blood calcium levels. Calcium is vital to the function of the cells in the body, without enough calcitriol in the blood calcium levels will fall and illness will set in. Therefore, the first priority for calcidiol is to go to the kidney where it makes enough calcitriol to secrete into the blood in order to regulate serum calcium.

More Calcitriol Produced in Tissues

The second vitamin D pathway leads to your tissues and that is where all the action is. All of the amazing health benefits of vitamin D discovered in the last 10 years are from vitamin D going down the second pathway. If any calcidiol is left over—that is, if your tank is full and your kidneys are getting all the calcidiol they need to maintain serum calcium—then calcidiol is able to take another pathway, one that leads directly to the cells. This path is only now being fully understood and is causing excitement all around the world, especially concerning cancer. These are the autocrine (inside cell) and paracrine (around the cell) functions of the vitamin D system.

These functions are crucial to understanding why you should keep your vitamin D tank full. If you only have a small amount of calcidiol in your blood, virtually all of it goes to your kidney, which then makes extra calcitriol to keep your serum calcium levels from falling. Almost no calcidiol gets to your tissues to make tissue calcitriol.

Tissue Calcitriol A Cancer Fighter

But when your tank is full, the left over calcidiol goes to the many cells in the body that are able to make their own calcitriol to fight cancer—and they do so with gusto! In fact, they appear to make as much calcitriol as they can. The more calcidiol they get, the more calcitriol they make. The step is not rate limited by its product (calcitriol) and is thus uncontrolled. No other steroid hormone system in the body works this way; the manufacture of calcitriol in the tissues is unique. This is the second most important fact about vitamin D.

Other steroids limit their own production by inhibiting the very chemical reactions that make them. For example, a chemical reaction in the body turns cholesterol into progesterone, a female hormone. When enough progesterone is made, progesterone shuts down (inhibits) the chemical reaction so no more progesterone is made. This is called negative feedback. This occurs with all other steroids, somewhere in the metabolic process. If it didn't, the body would not be able to precisely regulate steroid hormone levels.

It does not appear to occur with calcitriol in the tissues! Throughout the entire range of normal calcidiol levels, tissue calcitriol levels continue to increase.

This is a crucial piece of information, because it has such profound implications for the normal state of human affairs. Just as modern humans have been living (and dying) with historically low levels of calcidiol in their blood, their tissues have been living (and dying) with historically low levels of calcitriol. And calcitriol is the most potent steroid hormone in the human body. It turns genes on and off at a dizzying rate, genes that are either making proteins that are essential to fighting cancer or genes that are making proteins that are promoting diseases like cancer.

Built‑in Toxicity Protection

What prevents tissue calcitriol levels from getting too high? Something has to or your tissues would make too much. One thing that helps is called catabolism or breakdown. The more calcitriol that is made, the more is metabolized and excreted in the bile. But that doesn't prevent too much from being made in the first place.

Lets go backwards for a minute. One possibe way of limiting calcitriol in the tissues is by limiting the amount of calcidiol in the blood. That is, maybe the chemical reaction that turns cholecalciferol into calcidiol in the liver is rate limited, or has a negative feedback loop?

No, it does not. In normal humans, the more cholecalciferol in the blood, the more calcidiol the liver makes. So, in the natural state, what limits the amount of cholecalciferol in the blood? What is the rate limiting step for the production of calcitriol in the tissues?

Your skin! How much you go into the sun. Remember, the body has a fool proof method of limiting cholecalciferol. Only about 20,000 units can be made in the skin every day because the same sunlight that makes it, begins to break it down. After your skin turns dark (tan) even less cholecalciferol is made, maybe 10,000 units. Humans have a natural system in the skin that prevents toxicity. Another way of saying this is that the rate-limiting step for the production of calcitriol in the tissues is your behavior: how often you go into the sun or how much cholecalciferol you take as a supplement. This makes vitamin D unique.

Block the Sun, Block Vitamin D

Remember, our ancestors lived naked in the sun for several million years. Then 50,000 years ago, some of us migrated north and south to places with less sun. Then we put on clothes, started working inside and living in cities where buildings blocked the sun. Then we started traveling in cars instead of walking or riding horses and glass blocked even more of the UVB in the sunlight. Then, only a few years ago, we started actively avoiding the sun and putting on sunblock. All this time we humans have been steadily reducing the tissue levels of the most potent steroid hormone in our bodies, one with powerful anti-cancer properties.

The really significant reductions in sunlight exposure have occurred since the industrial revolution, just the time the "diseases of civilization," like cardiovascular disease, diabetes and cancer, seem to have greatly increased. Pretty frightening when you think about it.