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History of vitamin D

Vitamin D was misnamed when it was discovered in 1922. It’s not a true vitamin because an ongoing nutrient source is not required to sustain normal levels in the body. Vitamin D is properly classified as a secosteroid hormone precursor. A hormone is a chemical substance produced by one organ and then transported in the bloodstream to a target organ, where it causes a specific biological action.


This entertaining animated video explains the importance of vitamin D's connection to a range of vital systems in the human body.

Forms of vitamin D

Vitamin D has several natural forms (metabolites). For practical purposes, this explanation is limited to three of those forms: vitamin D3, 25(OH)D and 1,25(OH)2D.

Vitamin D3

Vitamin D3 is formed in the skin in response to exposure to sunlight. Vitamin D3 may also be obtained from naturally occurring dietary sources (e.g., fish, fish oils, liver, eggs, etc.), processed foods that are supplemented with vitamin D3 (e.g., dairy products, cereals, etc.) and vitamin D3 supplements. 

25(OH)D

Vitamin D3 is transported to the liver where it’s converted to 25(OH)D (also known as calcidiol or calciferol). 25(OH)D is not very active biologically. 25(OH)D is the major circulating form of vitamin D and the form that is usually measured to assess vitamin D status. It’s main purpose is conversion to 1,25(OH)2D, the biologically active form of vitamin D.

25(OH)D has a half life of 2-6 months and is stored as a safeguard for later use during months when sunlight is less available.

1,25(OH)2D

1,25(OH)2D (also known as calcitriol) is, primarily, formed in the kidneys but it’s also generated locally by many other body tissues. 1,25(OH)2D is a potent secosteroid paracrine (cell to cell) mediator and it affects almost all cellular activity.

Dietary requirement for vitamin D
 
There is no Recommended Daily Allowance (RDA) for vitamin D, because it is endogenously produced by humans in the presence of a few minutes of sunlight. The alternative Recommended Dietary Intake (RDI) of nutritional vitamin D is based on the absence of adequate sunlight.

Most humans, who have access to minimal sunlight several months of the year, will not become deficient in vitamin D.

Ten to 15 minutes of sunlight or daylight exposure to a small area of skin (e.g., the forearm or face) twice a week supplies all the 1,25(OH)2D necessary for health. Patients whose cutaneous tissues are infected with intracellular bacteria may produce excess 1,25(OH)2D locally when skin is exposed to sunlight.
 
Dysregulated vitamin D metabolism
 
Normally, production of 1,25(OH)2D is tightly controlled by the kidneys in response to a complex system of hormonal regulation. But if nucleated cells are infected with bacterial pathogens, 1,25(OH)2D is generated by the inflammatory response. This causes the level of 1,25(OH)2D to exceed the upper limit normally controlled by the kidneys.

It also results in a depletion of the precursor 25(OH)D which often leads to a misdiagnosis of vitamin D deficiency.

It is essential to measure both 25(OH)D and 1,25(OH)2D to rule out a vitamin D deficiency. The level of 25(OH)D doesn’t directly reflect the level of 1,25(OH)2D. Patients with Th1/Th17 inflammation (who have not been supplementing with vitamin D) often have a low level of 25(OH)D while the level of 1,25(OH)2D is high. Testing only 25(OH)D, as is usually done, may result in a false diagnosis of vitamin D deficiency. The key result is the level of 1,25(OH)2D because it is the active metabolite.

Long-term problems associated with dysregulated vitamin D metabolism include upset calcium homeostasis and bone loss. See Vitamin D Metabolism Dysregulation

Symptoms of elevated 1,25(OH)2D
 
Mildly elevated 1,25(OH)2D can cause a variety of inflammatory symptoms. Extremely high 1,25(OH)2D is known as hypervitaminosis-D. Hypervitaminosis-D may cause a variety of symptoms such as constipation, anorexia, dehydration, fatigue, irritability, vomiting, headache, weight loss, polyuria, polydipsia and hypercalcemia.

The effect of 25(OH)D on the immune system

A known effect of 25(OH)D is suppression of the immune system. Some have assumed this means 25(OH)D blocks the VDR. This is an incorrect assumption, as shown by researchers in a study published in the Journal of Steroid Biochemistry and Molecular Biology. 

However, in a study of a pro-inflammatory molecule, lipopolysaccharide (LPS), Lemire found elevated 25(OH)D reduced the inflammatory cascade. Low levels (below 30 ng/mL) failed to inhibit the LPS inflammatory cascade but higher levels (30 ng/mL) inhibited inflammatory signaling (the highest levels of inflammatory inhibition occurred at 50 ng/mL).

Also, 25(OH)D can be indirectly immunosuppressive by two methods. First, by being converted to excess 1,25(OH)2D. And second, by its effect on the VDBP (Gc protein). Gc protein is the precursor of GcMAF (group-specific component macrophage activating factor), a powerful molecule for immune activation. Gc protein has a high-affinity binding site for 25(OH)D. Unbound VDBP is known to be converted into GcMAF, by a combination of B and T immune cells. GcMAF presents a potent attack against bacteria and viruses so when more 25(OH)D is in circulation there may be less unbound VDBP to be altered into GcMAF to improve immune function. A 2007 study concluded, "On the whole, vitamin D confers an immunosuppressive effect."

Theoretically, immune system suppression allows parasitic microbes to persist and proliferate in host phagocytes, successfully compete for nutritional resources, and displace commensal organisms from their niche.

For these reasons, we believe that reducing 25(OH)D can improve the effectiveness of Inflammation Therapy (IT) by improving immune system function. In addition, avoiding elevated 25(OH)D also helps reduce 1,25(OH)2D somewhat, which may decrease inflammatory symptoms and help patients feel better.

Too low a 25(OH)D can also be detrimental. A 25(OH)D level of 20-30ng/mL appears to be enough to maintain normal, but not excessive, 1,25(OH)2D, in those with chronic inflammatory diseases.

Avoiding vitamin D

Sources of vitamin D must be avoided while treating inflammatory diseases caused by intracellular bacteria because 25(OH)D levels are elevated by the foods and supplements that contain vitamin D. 

People who increase their intake of vitamin D with food or supplements may feel better in the short-term if inflammatory symptoms are reduced but they will succumb to the chronic diseases caused by intracellular infection more rapidly in the long run.

See:

Vitamin D Supplementation

Vitamin D Supplementation and Chronic Disease

Vitamin D Supplementation news articles

Vitamin D Supplementation Risks

Reducing 25(OH)D
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We recommended patients avoid all ingested sources of vitamin D to reduce 25(OH)D to an optimal level (20-30ng/mL) to prevent too much production of 1,25(OH)2D which can cause an increase in inflammatory symptoms.

For some patients, it takes a long time to reduce levels of 25(OH)D even with strict dietary compliance and avoidance of natural light.
 
There is no advantage to waiting to start Inflammation Therapy until the level of 25(OH)D has been reduced by vitamin D deprivation. This could take many months in some cases and during that time, Benicar and antibiotic/s will enable the innate immune system to begin killing the intracellular bacteria.
 
Testing levels of vitamin D
 
It is helpful, but not essential, to measure 1,25(OH)2D before therapy is initiated. If the level is high, it confirms the diagnosis of a dysregulated vitamin D metabolism. If the level is not elevated, despite clinical signs of Th1/Th17 inflammation, the sample may have been mishandled. Measuring 1,25(OH)2D three to four  weeks following initiation of Benicar will usually show a dramatic reduction in elevated 1,25(OH)2D.
 
It is essential to measure 25(OH)D to determine its potential effect on the severity of immune system reactions. If it was elevated, retest at two-monthly intervals until it reaches a therapeutic level of 30 ng/mL or less. All patients will benefit by periodic testing to ensure it doesn't become too high during therapy.

Rising 25(OH)D

An increase in 25(OH)D is due to ingesting vitamin D. Patients should check the food they are eating which may be naturally high in vitamin D or supplemented with vitamin D (sometimes unlabeled). Any supplements being taken (herbal, vitamin or dietary) can be assumed to contain hidden vitamin D and should be discontinued if possible. Recheck the level in one month to make sure it is going in the right direction.

Updated April 22, 2016