The MP treatment plan was originally designed to treat an inflammatory condition known as sarcoidosis. The treatment consists of using the drug Benicar, combined with the avoidance of all sources of vitamin D, and eventually adding various antibiotics, especially minocycline. After being used by sarcoidosis patients for some years, it was then theorized and claimed that the treatment could treat other inflammatory conditions. Eventually it was also claimed that it could treat fibromyalgia and CFS, conditions which are not recognized by the medical literature as being inflammatory in nature.
Sarcoidosis is an inflammatory disease, which is characterized by the presence of granulomas. Granulomas often occur as an immune response to certain types of infections and foreign bodies. However, no specific cause for sarcoidosis has yet been found. Many suspect an infectious cause, and studies are ongoing to find the infection. Others believe that while an infection may trigger the disease, that genetic and immune factors can significantly affect the course of the disease. Several articles state that over 50% of sarcoidosis patients eventually undergo remission without any treatment. The other patients develop a chronic form, which requires treatment to resolve. Steroids (glucocorticoids) that suppress the immune system are the main drugs that are used to treat sarcoidosis. Other immune suppressant drugs and antibiotics are also being used. However, many cases are hard to treat, and symptoms can last for years. Given the scarcity of traditional treatment options, it’s not surprising that someone has found an alternative way to treat it.
One of the main beliefs of the
MP is that an infection is the cause of all the conditions that the MP claims
it can treat, and that an excess of vitamin D prevents the body from properly
fighting the infection. In the early
years of the MP, one of the main beliefs was that an excess of the active form
of vitamin D, 1,25(OH)2D, was the problem.
However, the medical literature only mentions a few specific diseases
where this production contributes noticeable amounts of 1,25(OH)2D to the
circulating levels. Sarcoidosis is one of those diseases.
In conditions such as sarcoidosis, activation of immune cells, i.e. macrophages and T cells, results in the production of 1,25(OH)2D. The MP claimed that this was also occurring in unrelated conditions, such as CFS, fibromyalgia, and chronic Lyme. However, many people with those other conditions were not found to have elevated 1,25(OH)2D. This was eventually explained by the belief that the inactive form of vitamin D, 25(OH)D, is capable of reducing inflammation and blocking the production of 1,25(OH)2D. The MP claims that if people lower their 25(OH)D levels, by avoiding vitamin D intake, that this would result in elevated levels of 1,25(OH)2D, and this would prove that inflammatory, or “TH1 production” of 1,25(OH)2D was occurring. Furthermore, the MP also believes that 25(OH)D actually blocks 1,25(OH)2D from attaching to the vitamin D receptor, preventing 1,25(OH)2D from properly stimulating the immune system. The MP claims that this blocking prevents the body from fighting the infection. Thus, they now believe that 25(OH)D is also harmful, and they recommend avoiding vitamin D, in order to reduce 25(OH)D to below normal levels. The MP has continued to include new theories, such as the possibility that a substance from bacteria is also blocking the vitamin D receptor. None of this these theories have yet to be tested in any lab studies.
Positive Results from the MP Do Not Prove the MP’s Vitamin D Theories.
Does vitamin D really hinder these diseases? The medical literature does not support this claim, nor does it support the belief that 25(OH)D blocks the effects of 1,25(OH)2D. Indeed, a 2009 study has shown just the opposite, that 25(OH)D has agonistic activities similar to that of 1,25(OH)2D: And in fact, the avoidance of vitamin D in the MP treatment, has really never been properly studied, to see what, if anything, it contributes to the effects of the treatment. The treatment was designed for sarcoidosis, and was then applied to other conditions, without testing to see whether avoidance of vitamin D is actually of any benefit for those other conditions. Perhaps any benefits from the MP for other conditions, are due to the other aspects of the treatment. For example, other treatment plans that simply use only antibiotics, have been successful at treating inflammatory conditions. Indeed, there are even cases of sarcoidosis being successfully treated simply by antibiotics. Additionally, minocycline, which is the primary antibiotic use by the MP, may be especially potent in inhibiting granulomas.
And what about Benicar? Is Benicar helping sarcoidosis in the way that the protocol theorizes? ARBs such as Benicar have many useful effects on the body. Benicar not only has positive effects on the vascular system, but also has both anti-inflammatory and antioxidant effects. It may also be capable of increasing insulin sensitivity and affecting calcium metabolism. Studies about new effects of ARBs are constantly being published. Benicar could be helping sarcoidosis in one way, while helping other conditions in totally different ways. Indeed, it has been shown that the the angiotensin II "AT1 receptor activity is essential for the unrestricted development of full-scale innate immune response.” Thus, blocking the AT1 receptor, which ARBs such as Benicar do, will reduce the immune system’s innate response to infections. This is ironic, given that the MP claims tthat it’s treatment restores the innate immue system’s response.
The MP claims that Benicar acts as a vitamin D agonist, but there is no lab study that supports this claim. If Benicar was a VDR agonist, it would of great use, as many companies are trying to produce such an agonist. Yet, there has been no sign that the company that makes Benicar, believes that it has any affect on the VDR. Additionally, Benicar has not been studied at the high doses used by the MP, for the conditions that the MP treats. The more complete blocking of angiotensin II receptors at such high doses, might have even more positive effects than are presently known. And it might just be, that Benicar’s many positive effects, are capable of offsetting the negative effects of the vitamin D deficiency that results from the MP treatment.
Thus, there is no clear evidence that a reduction of vitamin D has any significant positive effects in the MP. Both Benicar and antibiotics are known to have many positive effects, for many different conditions. However, there is no proof in the medical literature, that reducing 25(OH)D to below normal levels, has any positive effects.
And what about the negative reactions to the MP treatment, that the MP claims is the body’s response to the killing of the infectious bacteria by the treatment. Are these reactions actually that, or are they simply side effects from the treatment?
The MP has yet to conduct any lab tests to support their theories. They have run computer simulations to support their beliefs about interactions of vitamin D metabolites, Benicar, and other substances, with the vitamin D receptor (VDR), but there is no guarantee that such simulations can accurately predict what actually happens in the body. For example, the author of the MP predicted that some of the statin drugs could interact with VDRs. But actual lab tests showed no such interaction. Indeed, the idea that statins have vitamin D type properties, was originally proposed by a non-MP researcher, and he has written that the MP author “is perhaps over-optimistic in suggesting that modern molecular biology can give precise answers to questions about actions of drugs because knowledge is inevitably incomplete.” Perhaps the lack of proof that Benicar affects the VDR, is the reason why, in some published articles by people involved with the MP, that they mention that their treatment uses a “VDR agonist”, without specifically mentioning that it is Benicar.
Since learning about the MP, I have tried to read as many medical studies as I could, that discuss sarcoidosis, ARBs, and vitamin D, and have learned many facts that I’ve not seen discussed elsewhere. Therefore, I’m presenting that information here, for anyone who is interested in the MP.
The intent of this web page is not to dissuade people from using the MP treatment. Instead, the intent is to question the validity of the theories connected with the treatment. These theories are often presented as being facts on MP web pages. Perhaps this is due to cognitive dissonance. Whatever the reason, many people who read those web pages end up believing that these theories are facts, when they are not. I have therefore decided to write this web page, in order to separate fact from theory, and to also point out when the MP theories are not supported by known facts. Given that the MP itself has changed some of its own views, such as recognizing that not everyone needs to avoid sunlight, we believe that it’s reasonable to question some of the other beliefs also.
The MP believes that excess
1,25(OH)2D production is occurring in many diseases, but the MP defines the
limit for normal 1,25(OH)2D to be 45 pg/ml, while lab tests and studies define it to be 60-65 pg/ml.
Flaws in MP 2009 Study “Vitamin D Metabolites as Clinical Markers in Autoimmune and Chronic Disease”
The MP believes that vitamin D metabolites play a role in sarcoidosis and many other diseases.
Vitamin D is a substance which the skin creates due to sunshine exposure. It is also found in supplements and certain foods. Vitamin D can either be stored in the body, or metabolized by the liver into 25(OH)D, which then circulates in the bloodstream and tissues. Only later is it then converted to the metabolite 1,25(OH)2D, which is the form that has hormonal active properties.
1,25(OH)2D both stimulates and
inhibits the immune system. 1,25(OH)2D enhances the activity of immature
immune cells (cell-lines, bone marrow cells), while it inhibits the activity of
more mature cells (peripheral blood monocytes and peritoneal macrophages).
Some researchers believe that this dual effect allows 1,25(OH)2D to stimulate the immune system, while providing a mechanism for preventing overstimulation.
One of the ways that this comes into play, is when immune cells produce 1,25(OH)2D themselves. For example, when macrophage immune cells are activated by the TH1 (inflammatory) cytokine IFN-gamma, they are able to produce 1,25(OH)2D. This type of production is far different from the more common renal production of 1,25(OH)2D, which is controlled by the presence of calcium. Renal 1,25(OH)2D production controls calcium levels in the body. Thus, if you increase calcium intake, it will decrease the need for 1,25(OH)2D, and renal 1,25(OH)2D production will be reduced.
However, TH1 production of 1,25(OH)2D does not respond to calcium. And in certain conditions, where excess inflammation occurs, excessive amounts of 1,25(OH)2D can be generated, which is then reflected by increasing serum levels. However, this requires immune cells to be activated, and this has not been shown to be occurring in conditions such as CFS and fibromyalgia. Furthermore, IFN-gamma is a necessary requirement for unregulated immune 1,25(OH)2D production to occur. IFN-gamma levels are increased in inflammatory conditions such as sarcoidosis, which helps to explain the excess 1,25(OH)2D that occurs in those conditions. However, IFN-gamma is not increased in CFS and fibromyalgia. In fact, in CFS, IFN-gamma may actually be decreased. Thus, there is a lack of evidence that 1,25(OH)2D TH1 production occurs in those other conditions.
The MP believes that an excess of 1,25(OH)2D impairs the immune system in sarcoidosis, preventing it from properly fighting pathogens called Cell Wall Deficient bacteria, or CWD. (Note: CWD are not mycoplasmas.) Some researchers have theorized that CWDs play a role in a number of diseases. For example, lab studies have shown the possibility that CWD may alter the way the immune system responds to an infection, However, there still is much controversy regarding whether CWD have any significant effects in human disease, and studies have yet to confirm that CWDs play a role in sarcoidosis. For a more detailed critique of the MP’s theories on bacteria, click here to another person's web page.
In any event, if 1,25(OH)2D is somehow a factor in preventing a proper immune response against a pathogen, it would be important to know if significant TH1 1,25(OH)2D production was occurring. One way would be to simply test serum 1,25(OH)2D. The MP believes that if the serum level of 1,25(OH)2D is above 45 pg/ml, then it is abnormally high. They obtained this figure from the Merck manual. However, the Merck’s normal range of 1,25(OH)2D was defined decades ago, and is most likely based on older laboratory testing assays, which were known to have problems. The MP recommends using Quest laboratories to test 1,25(OH)2D levels. However, Quest themselves defines the normal range to be 15-60 for adults (27-71 for younger than 17 years). These values have been confirmed by studies. For example, in a study which showed that 1,25(OH)2D levels decrease with obesity, the average 1,25(OH)2D level for the study population was 108.2 pmol/L (41.6 pg/ml), with a standard deviation upper limit of 56.4 pg/ml.. However, for subjects with the lowest BMI (body mass index), the average 1,25(OH)2D was 45.8 pg/ml, with a standard deviation upper limit of 62.1 pg/ml. A previous similar study showed even higher levels, i.e. an average 1,25(OH)2D level of 44 pg/ml for obese subjects, versus 52 pg/ml for nonobese subjects The MP gives no clear reason why they believe that the upper limit should be according to Merck. Thus, many people are being told by the MP that they have elevated 1,25(OH)2D, when it might not necessarily be so.
In a 2009 study on
1,25(OH)2D by people involved with the MP, entitled "Vitamin D metabolites
as clinical markers in autoimmune and chronic disease", it was stated
that “the threshold for elevated 1,25-D was selected as 110 pmol/L based
on the observation that all healthy patients in a clinical care setting showed
levels under this range”. This
conflicts with the studies mentioned above, where 110 was shown to be at or
even below the average level. Other
studies also support a higher average level.
For example, one recent study in the
the MP study tested 1,25(OH)2D levels in patients with various diseases, and
they declared that anyone with levels above 110 pmol/L had “elevated
levels”. Besides the fact that
this threshold is much lower than many other studies show, the characteristics
of the healthy and patient populations were not stated in the study.. There is no indication that they were
similarly matched. This is necessary,
because besides the fact that obesity can affect 1,25(OH)2D serum levels, there
are many other factors that affect 1,25(OH)2D serum levels, such as age, as
1,25(OH)2D levels decrease with age.
Hormone replacement therapy, diuretics, or pharmacological
doses of calcium, can also affect 1,25(OH)2D levels. And for postmenopausal women, 1,25(OH)2D
levels are dependent on 25(OH)D levels, as shown by the previous
The MP article also made reference to studies that show “deleterious or no beneficial effect of vitamin D supplementation on certain diseases”. Interestingly, the first referenced study, regarding prostate cancer vitamin D, did not actually involve vitamin D supplementation, but simply tested 25(OH)D levels. This and some other studies, have shown a possible increased risk of certain types of cancer at high 25(OH)D levels. One possible reason for this, has been proposed by the long time vitamin D researcher Professor Vieth. He believes that any possible deleterious effects from high levels of 25(OH)D, may be caused by varying 25(OH)D levels that occurs due to the seasons. The change of sunlight during the different seasons, changes serum 25(OH)D levels. However, the regulation of tissue production 1,25(OH)2D may not immediately respond to the change in serum 25(OH)D levels. There may be a delay before the tissues adjust enzyme levels. Thus, when 25(OH)D level decrease, 1,25(OH)2D production at the tissue levels may be inadequate, until enzyme levels adjusted. Most studies on cancer so far, have not actually used high levels of vitamin D supplementation. Such supplementation would sustain high levels of 25(OH)D throughout the year, and this might provide year round positive effects to prevent cancer.
Testing Methods used by the
MP for Dysregulated 1,25(OH)2D Production are flawed,
due to the fact that serum 1,25(OH)2D is affected by Calcium, Phosphate, PTH, and other factors.
For many years, the MP also believed that excess production of 1,25(OH)2D could be proven by computing the ratio of serum 1,25(OH)2D to 25(OH)D. A high ratio was believed to indicate the presence of TH1 1,25(OH)2D production, and this meant that your condition could be treated by the MP. The MP now states that this test is often unreliable. Instead, they now use absolute levels of 1,25(OH)2D and 25(OH)D. But 1,25(OH)2D can be significantly influenced by many factors that have nothing to do with TH1 production of 1,25(OH)2D, so that neither the D-ratio nor the absolute test are reliable ways to prove TH1 production of 1,25(OH)2D. And it is because of the fact that 1,25(OH)2D levels can be influenced by many factors, that 25(OH)D is the main test used by the medical community to determine a vitamin D deficiency, and not 1,25(OH)2D.
The conversion rate of 25(OH)D to 1,25(OH)2D can vary due to a number of factors. For example, 1,25(OH)2D levels can vary significantly during the menstrual cycle. Also, a study has shown that women with PMS have high serum levels of 1,25(OH)2D, and low levels of 25(OH)D. This is partially due to a direct influence of estrogen on renal 1,25(OH)2D production. Estrogen supplementation has been shown to increase 1,25(OH)2D levels. Using the MP criteria, some of these women with PMS would be deemed by the MP to have TH1 1,25(OH)2D production, when they did not.
Although the D ratio test is used less, the MP web page still states that “a D-ratio that is higher then 2 is a sign of inflammation. A normal ratio in a healthy person is between 0.75 to 1.75.” However, in practice, normal people do have a ratio of 2 or higher. For example, a recent study on postmenopausal women aged 45-58, showed that the average ratio was 1.98. Additionally, this study compared women who had different forms of the vitamin D binding protein (DBP). DBP binds to vitamin D metabolites in the serum and tissues. Different genetic forms exist. The D ratio was found to be different for women who had different forms of the DBP. This is theorized to be due to the fact that the different forms have different metabolic rates. For women with one specific form, the D ratio was found to be an amazing 2.49. Thus, the D ratio test is flawed, yet it was used for many years to diagnose people with a TH1 condition. Therefore, it’s unknown how many people who have tried the MP during those years, really had a TH1 condition.
The most obvious flaw in measuring 1,25(OH)2D, is the fact that serum 1,25(OH)2D is significantly affected by dietary calcium. Taking more calcium will decrease 1,25(OH)2D levels. Thus, one possible way to see if elevated 1,25(OH)2D is due to insufficient calcium, rather than due to TH1 production, is simply to significantly increase one’s calcium intake. If a decrease of 1,25(OH)2D occurs, then the elevated 1,25(OH)2D would likely be due to a calcium deficiency. A lack of calcium could simply be caused by a low calcium diet. Calcium insufficiency is very common in many countries, including the US. A lack of calcium could also be due to an undiagnosed gastrointestinal disease. For example, in celiac disease, one study showed serum 1,25(OH)2D levels as high as 80 pg/ml. Indeed, it is possible that some people on the MP who initially had high levels of 1,25(OH)2D, may simply have not been taking or absorbing enough calcium. And in fact, some people on the MP have eventually added calcium supplementation, which has then lowered both their PTH and 1,25(OH)2D levels. One wonders how many people who started the MP due to high 1,25(OH)2D levels, had high levels simply due to not taking enough calcium. Note however, that it is possible to have calcium insufficiency, yet still have normal PTH levels, so that testing for PTH is not necessarily a good indicatorr of calcium status.
1,25(OH)2D production is also dependent on dietary phosphate Thus, in addition to calcium, phosphate also affects 1,25(OH)2D levels. Any changes in dietary phosphate, intestinal phosphate absorption, or renal phosphate reabsorption, can affect serum levels of 1,25(OH)2D. In fact, some people with CFS and fibromyalgia may actually have phosphate diabetes, a condition that depletes phosphate.
Another problem with the ratio test is the following requirement listed on an MP web page: “The D ratio is not a sufficient indicator of vitamin D dysregulation, especially when 25-D levels rise above 15 ng/ml.” The reason for this is the belief that 25(OH)D reduces inflammation and therefore blocks the TH1 production of 1,25(OH)2D. The problem with that statement, is that even in healthy people, at the levels of 25(OH)D that the MP recommends, a significant rise in PTH levels occurs, which results in increased levels of 1,25(OH)2D. Therefore, a high ratio of 1,25(OH)2D to 25(OH)D at those levels of 25(OH)D, can have nothing to do with increased inflammation, and thus cannot be used as an indicator of inflammation.
Interestingly, there is no proof that higher levels of 25(OH)D, can significantly reduce TH1 1,25(OH)2D production. For example, there is a study on sarcoidosis patients whose levels of 25(OH) D were on average 25 ng/ml, and giving them oral vitamin D still resulted in a significant increase of 1,25(OH)2D production. In that study, oral Vitamin D.(100,000 IU) was given to people with and without sarcoidosis. People without sarcoidosis had no change in their 1,25(OH)D levels due to this dose. However, in sarcoidosis patients, this dose caused the 1,25(OH)2D levels to significantly rise, during which 25(OH)D levels rose to almost 50 ng/ml, well past the point at which the MP claims that 25(OH)D starts to block 1,25(OH)2D. But there was no sign of reduced 1,25(OH)2D production from 25(OH)D. Instead, in all patients, an approximate doubling of 25(OH)D levels, resulted in a doubling of 1,25(OH)2D levels, no matter what their initial 25(OH)D levels were.
Similarly, a study on rheumatoid arthritis has shown evidence of TH1 1,25(OH)2D production. This was done by giving patients a single dose of 250 µg of 25(OH)D. Before the dose was given, initial levels of 25(OH)D and 1,25(OH)2D were measured, both in the serum and the synovial fluid of the inflamed joints. These measurements showed that synovial 25(OH)D levels directly correlated with synovial 1,25(OH)2D. This implies that immune cells in rheumatoid arthritis joints are producing 1,25(OH)2D. The study also showed that serum 25(OH)D levels correlated with 25(OH)D synovial levels, which implies that serum 25(OH)D can directly affect immune production of 1,25(OH)2D. However, there was no sign that high serum levels of 25(OH)D were able to suppress TH1 1,25(OH)2D production, as the MP claims. 1,25(OH)D production in the joints increased at the same rate even in patients whose 25(OH)D serum levels were significantly greater than 20 ng/ml. Additionally, serum 1,25(OH)2D were unaffected by 25(OH)D levels. Serum 1,25(OH)2D levels of patients were similar to that of a healthy control group. Thus, there was no evidence that serum 1,25(OH)2D levels were significantly affected by TH1 production of 1,25(OH)2D in rheumatoid arthritis.
Thus, unlike sarcoidosis, the amount of TH1 1,25(OH)2D produced in rheumatoid arthritis is usually not great enough to have a significant effect on serum levels. This is likely true also of other conditions. Sarcoidosis is one of only a few known conditions where TH1 production of 1,25(OH)2D significantly affects 1,25(OH)2D serum levels. This could possibly be due to the location of the disease. Or perhaps it’s due to the type of immune cells that produce the 1,25(OH)2D. In sarcoidosis, the main source of 1,25(OH)2D is believed to be macrophages, while in most other diseases, T cells are believed to be the major source of 1,25(OH)2D.
In any event, there is no evidence that circulating levels of 1,25(OH)2D are affected by inflammation in most of the conditions that the MP claims to treat. However, there are many other influences that can affect 1,25(OH)2D levels, such as a deficiency of calcium. And different factor from s are present in different diseases. In sarcoidosis, 1,25(OH)D serum levels often rise with increasing disease activity, but the opposite is true for rheumatoid arthritis. Therefore, using the D ratio is an invalid way of testing for TH1 1,25(OH)D production. The proper way to test for this, is by administering a large dose of either of vitamin D or 25(OH)D, and then seeing if 1,25(OH)2D levels increase.
When one lowers 25(OH)D levels below 20ng/ml, as recommended by the MP, this will likely increase PTH levels. This is because it’s been found that PTH inversely correlates with 25(OH)D serum levels. The lower the 25(OH)D, the higher the PTH. 20 ng/ml has long been defined by the medical literature to be the lower limit of the normal vitamin D range. This limit was decided, based on where PTH started to significantly rise. However, that limit is most likely much lower than it should have been. Recent research has shown that PTH continues to drop at higher levels of 25(OH)D. This information, combined with results from other studies, has caused many doctors to recommend that 25(OH)D levels should at least be 32 ng/ml.
However, the MP web pages further states that “It is desirable for the D-25 level to be 12 ng/ml or lower”. At this level, PTH levels will be very significantly elevated. Such low levels of 25(OHD are a definite risk for bone loss. In fact, in a case where hyperparathyroidism and sarcoidosis occurred simultaneously, bone loss lab markers were almost reduced to normal after the hyperparathyroidism was treated, even though 1,25(OH)2D levels were still above normal. The researchers concluded that “PTH but not 1,25(OH)2D may primarily be involved in the stimulation of bone turnover.” Indeed, 1,25(OH)2D levels do not appear to be a risk factor for osteoporosis, but low levels of 25(OH)D are associated with an increased risk of osteoporosis.
It is elevated PTH, and not elevated 1,25(OH)2D, which causes bone loss. Many MP pages say the opposite, that 1,25(OH)2D causes bone loss. I.e. “As 1,25-D rises above a certain range (around 43 pg/ml), it stimulates bone osteoclasts, or cells that remove minerals from the bone. Stimulated osteoclasts dissolve bone material, causing it to be reabsorbed into the bloodstream - leading to osteoporosis and osteopenia.” Not only is there no proof that this occurs, but studies have shown that 1,25(OH)2D can actually be used to treat osteoporosis. The MP goes on to say that “Vitamin D does not reverse osteoporosis.” The problem with this statement is that’s it’s based on many studies in which the level of vitamin D supplementation had been too low. For example, they state: “The study of more than 36,000 middle-aged and older women – the largest ever to test the health benefits of vitamin D – found that calcium and vitamin D had essentially no benefit on the bone density of the women involved.” However, the problem with this study is that it only used 400 IU of vitamin D. Such low doses are simply not capable of achieving normal levels of 25(OH)D that are necessary to have an effect on osteoporosis. Thus it’s little wonder that this and other studies have shown little benefit from vitamin D on osteoporosis.
It should be noted that even if one’s PTH levels do not increase as the result of lowering one’s 25(OH)D levels, this doesn’t mean that one is healthy. The tumble level PTH response could be blunted due to other conditions. For example, magnesium deficiency has recently been recognized as a reason for the inhibition of PTH. If your PTH levels aren’t increasing, that could mean that you have a significant magnesium deficiency, which by itself could be the cause of many health problems.
Another reason that PTH levels can be low, is that it is being suppressed, due to excessive calcium serum levels that results from bone loss. This is known to occur in rheumatoid arthritis. In rheumatoid arthritis, PTH and 1,25(OH)2D serum levels have been found to decrease as disease activity increases. A recent study has shown one possible reason for this effect, which is that free serum ionized calcium is elevated in many rheumatoid arthritis patients, and this excess free calcium causes the suppression of PTH and 1,25(OH)2D production. This explanation has been overlooked in the past, because total serum calcium was found to be normal in these patients. However, this is deceiving, because albumin levels are decreased in rheumatoid arthritis, and calcium in the serum is bound to albumin. The reduced albumin levels are most likely caused by the increased inflammatory cytokines. This lack of albumin results in less bound calcium and more free ionized calcium.
In a 2008 article, the MP challenges the new FDA recommendations for increased vitamin D supplementation. That article claims that the new level of 25(OH)D, that vitamin D experts and the FDA are now recommending, is too high, In support of their claim, the article cites a study by Dr. Pollack on the “serum parathyroid hormone concentrations in African American women”. That study found that “a serum concentration of 40–50 nmol/L 25(OH)D is needed to prevent a rise in PTH concentrations in calcium-sufficient African American women in midlife.” This 25(OH)D level is much lower than the 75–80 nmol/L range presently being recommended as the optimal level. However, what the MP article doesn’t mention, is in that study, Dr. Pollack states that “we ultimately reject the clinical utility of the threshold as a way of identifying optimal vitamin D,” Indeed the point of the study was not that the optimum 25(OH)D levels should be lower, but that the optimum level cannot simply be judged by when PTH stops increasing. And in fact, Dr. Pollack states in a later study, that there is an “emerging consensus that 25(OH)D concentrations > 75 nmol/L may be optimal for bone health and extra skeletal effects.”
Dr. Pollack also states that “It is quite possible that African Americans (and others) may require less vitamin D for skeletal health but may require greater intake for prevention of these noncalcemic disorders.” Indeed, 25(OH)D production is affected by pigmentation in the skin For example, according to one article, the “median vitamin D intakes of American blacks are below recommended intakes in every age group, with or without the inclusion of vitamin D from supplements. Despite their low 25(OH)D levels, blacks have lower rates of osteoporotic fractures. This may result in part from bone-protective adaptations that include an intestinal resistance to the actions of 1,25(OH)2D and a skeletal resistance to the actions of parathyroid hormone (PTH). However, these mechanisms may not fully mitigate the harmful skeletal effects of low 25(OH)D and elevated PTH in blacks, at least among older individuals. Furthermore, it is becoming increasingly apparent that vitamin D protects against other chronic conditions, including cardiovascular disease, diabetes, and some cancers, all of which are as prevalent or more prevalent among blacks than whites.”
On the other hand, for other patient groups, PTH levels can be used to support the recommendation for a higher 25(OH)D level. For example, in a study on the “Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy”, it concludes that there is a significant “increase in serum PTH at 25(OH)D concentrations less than 29.8 ng/ml” (74.5 nmol/L). Additionally, there are other parameters that also can be used to support a higher level of 25(OH)D. For example, in a study on glucose metabolism, as measured by HbA1c (A1C), it was found that “There was a nonlinear association between 25(OH)D and A1C: a steep linear decrease in A1C by 25(OH)D until 65 nmol/l and only smaller decreases with further increases”. Also, in a study on healthy postmenopausal women, 1,25(OH)2D levels were shown to fall below 80 nmol/L, The study concluded that for that study group, “the conversion of 25OHD to active vitamin D depends on the substrate concentration”, and that “vitamin D insufficiency should be considered at P-25OHD levels below 80 nmol/L”. Thus, there is definite evidence for the new higher 25(OH)D recommended levels.
The MP article also states that due to vitamin D supplementation, that it is “very difficult to find a population which can be studied in order to ascertain what the level of natural metabolic homeostasis for 25-D might actually be. Two studies do provide a glimpse, however. The first found a high prevalence of vitamin D deficiency in Chilean healthy postmenopausal women. The average level of serum 25-D sampled from 90 healthy ambulatory women showed that 27% of premenopausal, and 60% of postmenopausal women, had 25-D levels under 50 nmol/L. A study showing hypovitaminosis D is common in both veiled and nonveiled Bangladeshi women, found a 25-D level less than 40 nmol/L in approximately 80% of the healthy young women. These studies show a wide variation in levels of 25-D being generated by populations whose diets have probably not yet been significantly altered by ’The Sunshine Vitamin’, indicating that the unsupplemented metabolic homeostasis is probably in the range 23–60 nmol/L, and that it falls with advancing age.”
However, vitamin D researchers have pointed out what’s wrong with this reasoning. For example, Dr. Hollis has written: “Past attempts to define "normal" circulating 25(OH)D were seriously flawed. To properly define "normal" 25(OH)D status in humans, it makes more sense to measure 25(OH)D in "healthy subjects" who are sunbathers, fieldworkers, construction workers, or other individuals who work outside, who are not overly clothed, and who are without sunblock. Humans did not evolve in today’s sun-shy culture, so "normal" with respect to circulating 25(OH)D levels should not be defined by the current average or median population level. In sun-rich environments where clothing or cultural practices do not prevent sun exposure, circulating 25(OH)D ranges from 135 to 225 nmol/L (54–90 µg/L) (1,14,15). Thus, we must be very careful how we define "normal" or adequate or sufficient with respect to circulating 25(OH)D.”
Other studies confirm that high levels of 25(OH)D occur in unsupplemented people in sunny locations. For example, in a Brazilian study, where “the control group consisted of 30 healthy men and the mean age was 34.6 years”, the mean level of 25(OH)D was 82 ± 25 nmol/L". Another study confirms these high levels: In a group of “(49 men and 72 women) aged 17-33 years, mean age 24.7 ± 2.7 years”, “mean serum 25OHD concentration was 78.7 ± 33.1 nmol/L for the group as a whole.” During the summer, the levels reached as high as 97.8 +/- 33.5 nmol/L.
The MP article additionally states the belief that vitamin D studies need to test not just 25(OH)D levels, but also 1,25(OH)2D levels. The MP believes that a low level of 25(OH)D is not necessarily the consequence of insufficient vitamin D, but may actually be due to the downregulation of 25(OH)D, resulting from extra production of 1,25(OH)2D. In support of this theory, they give the following example: “Just a few months ago, a commentary in Journal of Nutrition was uncertain how to explain the results from a comprehensive clinical study showing that at the end of their pregnancies, even though 90% were taking prenatal vitamins, ‘‘vitamin D deficiency’’ was still common in the cohort of pregnant women. The commentary suggested that maybe this might be due to lack of compliance on the part of women in the cohort, or perhaps they just needed even more supplementation than twice the daily reference intake (DRI), the amount they were being given. Surely, when the model fails to describe the data, it is time to question the model, not the data.”
However, it must be noted, that this study was the “first pregnancy study that used the 80-nmol/L cut-point to define vitamin D insufficiency.” It’s no wonder then, that vitamin D insufficiency was found to be common, as the vitamin D supplement in the study was only 400 IU. That dose is the recommended dose based on the older lower level of 25(OH)D from 1997, and would of course be insufficient for many people to achieve the newer level of 25(OH)D. In fact, according to some studies, that dose is insufficient to cause any significant changes in 25(OH)D. For example, to quote one study: “What effect does a daily dose of 400 IU vitamin D for an extended time (months) have in adults? The answer is little or nothing. At this dose (10 µg/d) in an adult, circulating 25(OH)D concentrations usually remain unchanged or decline.” Therefore, much higher doses would be necessary to significantly raise 25(OH)D levels. For example, in the previously mentioned study on African American women, in order to achieve concentrations >75 nmol/L, a dose of 2800 IU was deemed necessary for those with 25(OH)D, >45 nmol/L and a dose of 4000 IU would be necessary for those with a concentration <45 nmol/L. Thus, despite what the commentary in the journal said, there really is no mystery why vitamin D deficiency was still common.
The MP article and web pages claim that low 25(OH)D levels could be “due to the downregulation of 25(OH)D, due to extra production of 1,25(OH)2D.” High levels of 1,25(OH)2D have been shown to be able to suppress production of 25(OH)D. This is a fact that’s been well known since 1984. However, according to one vitamin D researcher, “the physiologic significance of this is not clear”. This researcher points to a study he conducted on phosphate deprivation, which caused an serum 1,25(OH)2D, but did not suppress 25(OH)D levels. Conversely, a study on phosphate ingestion, which decreased 1,25(OH)2D, did not alter 25(OH)D. Many other studies have shown little or no correlation between 1,25(OH)2D and 25(OH)D levels. For example, in a study where ketoconazole was used to block the production of 1,25(OH)2D, 1,25(OH)2D levels decreased from 113 to 70 pmol/L, but 25(OH)D only increased a very small amount, from 52 nmol/L to 55 nmol/L. Also, in a study on Crohn’s disease, patients who had significantly elevated 1,25(OH)2D compared to controls (57.8 vs. 42.1 pg/ml), still only had slightly less 25(OH)D levels (24.2 vs. 27.0 ng/ml). The MP article did not provide any studies to support their claim that extra production of 1,25(OH)2D can play a significant role in decreasing 25(OH)D levels. Presently, it appears that 1,25(OH)2D can only significantly suppress production of 25(OH)D, when levels of 1,25(OH)2D are definitely abnormally high, such as which occurs in sarcoidosis and hyperthyroidism.
The MP article further states: “Arnson et al.(52) noted that ‘‘on the whole, vitamin D confers an immunosuppressive effect’’ in autoimmune disease. That immunosuppression was confirmed by Waterhouse et al.(12) They joined Barnes et al.(50) in noting that correlation between the 25-D and active 1,25-D metabolites seemed strongest in disease, and weakest in health.” The Waterhouse article is written by MP authors, and they used the Vitamin D ratio to support their claim that elevated 1,25(OH)2D production in people was occurring in people who were using the MP treatment. However, no properly matched control groups were used to define what is the “normal” D ratio. In their article, the “normal” D ratio was defined by selecting several studies, neither of which had patients who were matched by gender, age, location, and race, to the people using the MP treatment. Nor was it confirmed that the vitamin D testing procedures were the same, which could be significant, since some tests show less 1,25(OH)2D, while others show more. And, as the MP has pointed out, improper storing of blood samples can reduce observed levels.
As for the Barnes study, this was a study that compared the levels of 25(OH)D and 1,25(OH)2D in male and female multiple sclerosis patients and control volunteers. They found that the absolute values were no different between the two groups. However, while there was a significant positive correlation between 25(OH)D and 1,25(OH)2D, this was only true in females, but not males, which indicates that some sort of gender effect was involved, perhaps unrelated to multiple sclerosis Or, perhaps it is due to a gender effect related to MS, as it has been found that there is renal dysfunction in MS females, but not in males. Thus, it could be that a renal dysfunction plays a role in the production of 1,25(OH)2D in women with MS.
Interestingly, the mean 25(OH)D serum levels of the multiple sclerosis females was 79.1 nmol/L, which is above the range that the MP article claims is normal. And these women were not taking any vitamin D supplements, so this is yet another study that supports the new higher recommended 25(OH)D levels. Additionally, we are surprised that the MP article selected this study to support their views. This is because, the 25(OH)D levels of these women is much higher than the point at which the MP claims that 25(OH)D is supposed to be able to block 1,25(OH)2D production by the immune system. Thus, such high levels should be very significantly suppressing such production, so that very little unregulated 1,25(OH)2D would be present. Any association between 1,25(OH)2D and 25(OH)D at that point would be unrelated to 1,25(OH)2D immune production.
any event, it is also worth noting that in another study on multiple sclerosis,
a possible association between low 25(OH)D levels and MS relapses has been
shown: “25(OH)D serum levels were lower and intact PTH (iPTH) serum levels were
higher during MS relapses than in remission. The study was conducted in
As an aside, the MP article also states “Our own work has shown that restoring VDR competence, with a VDR agonist, induces an immunopathologic response when patients suffering from chronic inflammatory diseases are challenged with bacterial protein synthesis inhibitors.” The VDR agonist that is referred to here is the angiotensin receptor blocker Benicar. The MP theorizes that it is also a VDR agonist, but no actual lab study has confirmed this. “Chronically ill subjects, whose conditions have not previously responded to antibiotics, sometimes experience unrestrained immunopathology when a VDR agonist is administered concurrently with the antibacterials. An initial uncontrolled, observational study has shown that recovery often accompanies reduction of the putative bacterial load.” The MP has not presented any data showing that bacteria levels have decreased, nor have they presented a study which shows that “unrestrained immunopathology” is an indication that bacteria are being more effectively killed.
In conclusion, we do not believe that the studies quoted by the MP article, supports the MP’s claim that the new vitamin D recommendations are too high or harmful.
The MP believes that vitamin D is improperly labeled as a vitamin, as it really is a steroid hormone precursor. This is essentially true. However, it is because of this fact, that some vitamin D researchers believe that the normal level of 25(OH)D levels should be much higher than is presently recommended. Quoting from the vitamin D council web page:
“Unlike other steroid hormones, vitamin D has very unusual metabolism in most modern humans, called first-order, mass action, kinetics. All this means is that the more vitamin D you take, the higher the 25(OH)D level in your blood, and the higher the 25(OH)D level in your blood, the higher the levels of activated vitamin D in your tissues. No other steroid hormone in the body behaves like this. Think about it, would you like your estrogen level to be dependent on how much cholesterol you ate? Or your cortisol level?” “No, the body must tightly regulate powerful steroid hormones through substrate inhibition, that is, if an enzyme turns A into B, when the body has enough B, B inhibits the enzyme and so limits its own production.”
“Not so with vitamin D, at least at modern human vitamin D levels.” “Why would the kinetics of vitamin D be different from all other steroids?” “Maybe they are not.” “Maybe vitamin D levels are so low in modern humans that its metabolic system is on full blast all the time in an attempt to give the body all the vitamin D metabolites it craves.” Dr. Hollis has asked, “Is vitamin D's metabolism different in populations in the upper end of 25(OH)D levels (a population of sun-exposed people and a group of women prescribed 7,000 IU per day)? “
According to Dr. Hollis’s study, “vitamin D's kinetics can be normalized, made just like all other steroid hormones in the body, but you have to get enough sunshine or take enough vitamin D to get your 25(OH)D level above 50 ng/ml, and 60 ng/ml would be better. Then your body starts to store cholecalciferol in the body without much further increase in 25(OH)D levels. The reaction becomes saturable. This is a remarkable discovery and it implies levels of 30 and 40 ng/ml are usually not sufficient. It also implies actual vitamin D levels (cholecalciferol levels), not just 25(OH)D levels, may be useful in diagnosing and treating deficiency. Note, that not all of the sun-exposed individuals or women prescribed 7,000 IU/day achieved such levels. That's because the sun-exposed individuals were tested after an Hawaiian winter and because prescribing and taking are two different things. So my answer to "How much should I take if I have cancer?" is take enough to get your 25(OH)D level above 60 ng/ml, summer and winter.”
The fact that PTH levels respond to serum 25(OH)D, points to a fundamental difference in how the medical community views 25(OH)D, versus what the MP believes in. The medical community believes that serum 25(OH)D is very important, while the MP does not. The reason that serum 25(OH)D is believed to be important, is that while serum 1,25(OH)2D affects bone metabolism, many other tissues actually respond to serum 25(OH)D. This is because other tissues contain the enzyme 25(OH)D-1-alpha-hydroxylase, which is capable of converting 25(OH)D to 1,25(OH)2D. This explains why PTH is significantly affected by 25(OH)D levels. The parathyroid gland first converts the 25(OH)D to 1,25(OH)2D, and it then responds to that.
The conversion of 25(OH)D to 1,25(OH)2D occurs in many tissues, as long time vitamin D researcher Professor Reinhold Vieth describes: “Vitamin D nutrition probably affects health beyond just bone. The mechanisms involved in mediating the non-classic (i.e. non-bone) effects of vitamin D are probably, through 1,25(OH)2D produced locally, using circulating, 25(OH)D as the substrate. Many tissues possess, 25(OH)D-1-alpha-hydroxylase, including the skin (basal, keratinocytes, and hair follicles), lymph nodes, (granulomata), pancreas (islets), adrenal medulla, brain, pancreas, and colon. An even wider range of tissues, possess receptors for 1,25(OH) 2D (VDR). All of this reveals a system for paracrine regulation of tissue processes that involves the local production of 1,25(OH)2D. Sufficient vitamin D nutrition, and hence, appropriate 25(OH)D concentration is essential to this local, paracrine role of 1,25(OH)2D that is not generally reflected in the circulating level of 1,25(OH)2D. The paracrine components of the vitamin D endocrine/paracrine systems account for the many effects of vitamin D nutrition and/or UVB light on health and disease prevention.”
It is not surprising that many tissues and cells in the body rely on serum 25(OH)D to obtain 1,25(OH)2D, rather than serum 1,25(OH)2D. 1,25(OH)2D circulates in a very small amount in the serum, and thus may have little ability to affect vitamin D receptors in all tissues. As one recent article states, the immune responses to 1,25(OH)2D in vitro (lab studies) require concentrations of 1−100 nmol/l, despite circulating levels of the hormone being approximately 0.1 nmol/l. Thus, the amount of circulating 1,25(OH)2D likely does not affect immune functioning. This makes logically sense, since serum 1,25(OH)2D levels are heavily influenced by many factors, such as calcium intake. It doesn’t make sense that immune functioning would be dependent on serum 1,25(OH)2D. By generating 1,25(OH)2D themselves, tissues have the ability to control how much 1,25(OH)2D is present, rather than relying on serum levels. For example, upon stimulation from pathogens, macrophage immune cells upregulate the expression of 25(OH)D-1-alpha-hydroxylase, leading to increased conversion of 25(OH)D to 1,25(OH)2D, which then stimulates the production of the antimicrobial peptide cathelicidin.
Another possibly important role of 25(OH)D, is it’s ability to influence certain forms of cancer. For example, 1,25(OH)2D has been found to inhibit the growth of certain forms of cancer cells, such as in the prostate. However, serum levels of 1,25(OH)2D that are required to achieve significant effects, are often above toxic levels. On the other hand, certain prostate cells are capable of converting 25(OH)D to 1,25(OH)2D. Because of this, it’s been found that 25(OH)D itself, is capable of also inhibiting cancer prostate cell growth, and that the effects are attainable using safe doses of vitamin D.
And regarding studies on vitamin D and cancer, it should be noted that some studies are flawed, in that all they do is to test 25(OH)D levels at a single time, and use that level to see if there is any correlation between vitamin D and cancer rates. These studies are of only limited use, because cancer often develops over many years, so that it’s important to know what the 25(OH)D levels were during those years. Additionally, many cancer studies involving vitamin D supplementation are also flawed, because they have used doses than are lower than are presently being recommended by many vitamin D experts. This is why the study from June 2007, that showed a decrease in all cancers, was so interesting, as it used a relatively high dose of 1100 IU over several years. This study also combined vitamin D with a high dose of calcium, which may be important, as some forms of cancer appeared to respond to a combination of vitamin D and calcium supplementation.
Several articles by the MP reference a 2007 study on breast cancer and vitamin D, which showed that while breast cancer rates decreased during the first 5 years, that this trend diminished over time. The MP uses this to support their claim that 25(OH)D only affects symptoms during the early stage of a disease, and doesn’t treat the actual cause, which is why trend disappears. However, it should be noted that vitamin D intake was estimated in this article. Neither 25(OH)D, nor 1,25(OH)2D levels, were measured. Indeed, the MP has strongly stated that testing for 1,25(OH)2D is very important. Thus, it’s ironic that the MP uses a study to support their view, even though 1,25(OH)2D levels were not measured. Indeed, a 2009 study on breast cancer risk, which did measure both 25(OH)D and 1,25(OH)2D levels, found a significant decreased risk of breast cancer with low levels of 25(OH)D, but found no association with 1,25(OH)2D levels.
Given the importance of 25(OH)D, it is thus very controversial that the MP claims that 25(OH)D blocks the action of 1,25(OH)2D. According to the vitamin D MP web page: “1,25-D is the only metabolite that turns the VDR on. Everything else turns it off, or at least modifies its capabilities. So exogenous Vitamin D and 25-D both bind into the VDR and block it from working properly. They will displace any 1,25-D from the receptor in a dose-dependent manner. The higher the concentration of Vitamin-D or 25-D competing with the endogenous 1,25-D the more of that 1,25-D will be displaced from the VDR.”
This theory is the basis for the reason of why the MP recommends a low amount of 25(OH)D. It’s not necessarily to lower 1,25(OH)2D levels. It is because they claim that 25(OH)D interferes with the activities of 1,25(OH)2D. This is also the basis of why they claim that 25(OH)D levels have to be low for the vitamin D ratio test to be valid. They believe that 25(OH)D blocks 1,25(OH)2D’s ability to create an adequate TH1 response. A lowered TH1 response would result in reduced inflammation, and reduced inflammation would then mean less 1,25(OH)2D being produced by the TH1 immune system. To quote again from the vitamin D MP web page: “Vitamin D supplementation can increase levels of 25-D high enough to actually shut down the inflammatory production of 1,25-D. When the concentration of 25-D rises above about 25 ng/ml it displaces 1,25-D from the active site in the VDR (Vitamin D Receptor), deactivating the VDR and reducing the body's ability to mount a Th1 immune response”.
However, the medical literature is filled with studies that show that it’s 1,25(OH)2D that has the ability to reduce inflammation, not increase it. In fact, one of such studies is posted on one of the MP’s own web pages. If 25(OH)D could block the effects of 1,25(OH)2D, then according to the medical literature, that would cause an increase in inflammation, not a decrease.
The claims by the MP, of the effects from 25(OH)D and 1,25(OH)2D, drastically opposes the fundamental viewpoints of many vitamin D researchers. To understand their views of vitamin D, I highly suggest you click here to read a chapter in a book on vitamin D, that was written by long time vitamin D researcher Professor Reinhold Vieth. Any unreferenced statements that I make in the following paragraphs are taken from that chapter.
Firstly, the levels of 25(OH)D which results from supplemental vitamin D, at the dose which is recommended in the US, is much lower than that which can be produced from sunshine. The highest claimed safe oral dose (which few people take) is 2000 IU. However, sunshine can create up to 5 times that amount. The current US RDA for vitamin D, for adults under 50, is only 2% of what a person with white skin can naturally produce in 20 minutes of summer sun. Thus, “natural” production of vitamin D, according to the theory on the MP web pages, would severely affect VDR activity much much more than oral sources. However, there are no studies that show that this happens. If inactive forms of vitamin D were able to affect VDR activity, it would affect serum calcium levels, and the body would then have to offset that by changing the levels of 1,25(OH)2D levels. But this does not happen. Inactive levels of vitamin D can vary significantly, but under normal circumstances, active levels will usually stay the same.
Secondly, no study that I’ve yet found, mentions that inactive forms of vitamin D adversely affects VDR functioning. Unmetabolized vitamin D has not been found to directly affect the VDR, in a study on the effects of different forms of vitamin D on calcium absorption And in molecular studies on VDRs, the binding ability of 25(OH)D is believed to be 500 times lower than 1,25(OH)2D. In another article, that number is quoted as being 1000 times lower. On the other hand, the amount of 25(OH)D in the blood stream is hundreds times greater than active D, which might lead one to speculate that this greater amount of 25(OH)D might offset it’s lower binding ability. making 25(OH)D just as likely to attach to VDRs. However, this is not totally the case, because in that same article, it’s pointed out that 25(OH)D is much more tightly bound to proteins in the plasma, by a factor of at least 10. Not only that, but the storage capability in plasma for vitamin D is huge. Unlike many other steroids, such as glucorticoids, where the binding proteins circulate at the same order of magnitude as the steroids themselves, the vitamin D binding protein circulates at a level that is 50 times more than the vitamin D metabolites themselves. Thus, under normal situations, the bloodstream is meant to store lots of 25(OH)D.
The body’s processes that handle vitamin D, appear to be much better suited for handling excess amounts of vitamin D, than a deficiency. This is likely due to the fact that our ancestors were out in the sun for much longer periods of time, with less clothing, and in tropical zones, so that the body had to deal with large amounts of vitamin D production, rather than a limited amount. Large amounts of vitamin D production can be easily handled. However, when toxic levels do occur, such as due to intoxication, Vieth has theorized that it’s the 1,25(OH)2D which is the source of toxic side effects such as hypercalcemia, and not the 25(OH)D. This is because the 25(OH)D binds more easily to the binding protein in the plasma blood, and this then leaves less amounts of the protein for 1,25(OH)2D to bind to. The unbound “free” amount 1,25(OH)2D in plasma increases, making it more available to VDRs in tissues. This theory has been confirmed in a study on patients with vitamin D toxicity, where the level of free vitamin D was found to be significantly increased, due to excessive amounts of 25(OH)D.
Given the strong binding ability of 1,25(OH)2D on VDRs, and that 25(OH)D levels can be easily increased due to natural production, most researchers do not credit 25(OH)D with being able to significantly affect VDRs. In fact, in a study on sarcoidosis, radioactive 1,25(OH)2D was bound to VDR receptors on T-lymphocytes (T cells), and it was found that 25(OH)D was unable to displace it, yet it could be displaced by normal 1,25(OH)2D. “Lavage T-lymphocytes from patients with tuberculosis or with sarcoidosis, but not those from normal control subjects, expressed 1,25(OH)2D3 receptors as demonstrated by binding of [3H]1,25(OH)2D3, which was inhibited by the presence of excess unlabeled 1,25(OH)2D3, but not by the presence of unlabeled 25(OH)D3.” Thus, this does support the theory that 25(OH)D can displace or block the effects of 1,25(OH)2D.
The MP claim about 25(OH)D could be easily tested for, and if it was true, it probably should have been noticed by at least one study in the medical literature as it would be appear to be a fundamental effect of 25(OH)D. For example, if 25(OH)D blocks 1,25(OH)2D stimulation of VDR, then PTH should be stimulated, not suppressed by 25(OH)D, as 25(OH)D would be blocking the suppression effects of 1,25(OH)2D. As another example, it’s known that 1,25(OH)2D can reduce rheumatoid arthritis symptoms. But 25(OH)D doesn’t appear to block these effects of 1,25(OH)2D, as shown by the fact that increased 25(OH)D levels are also associated with reduced symptoms rather than less. There are multiple such examples in the literature. For example, in a test on super high doses of vitamin D for multiple sclerosis (from 28 000 to 280 000 IU/wk), 25(OH)D reached twice the top of the physiologic range, yet there were no adverse effects. If 25(OH)D really does block 1,25(OH)2D at lower levels, then such high doses of 25(OH)D surely should block almost all 1,25(OH)2D activity, with dire effects. Instead, this study concluded that “vitamin D intake beyond the current upper limit is safe by a large margin.”
The only proof that the MP has presented for their theory that 25(OH)D blocks 1,25(OH)2D, is a computer simulation. However, no actual lab studies have been presented. In fact, on the MP discussion web page, when a person asked for a real study that shows that 25(OH)D is an antagonist to the VDR and blocks 1,25(OH)2D, the response was “I just can't recall any single paper which shows that, as it is a pragma which forms the underpinning of all the drug discovery in Vitamin D analogs, and has been proven many, many times by individual drug discovery groups.” However, this is not true. Indeed, an analog of 25(OH)D has also been shown to be a Vitamin D agonist analog. Not only that, but a 2009 study has shown that 25(OH)D has agonistic activities: That study concludes that the “synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important. In conclusion, 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties.
For more information about vitamin D, I highly suggest to click here to read the information on the Vitamin D council site.
The MP’s original claim about vitamin D, was that excess production from 1,25(OH)2D in sarcoidosis is a major cause of the inflammation. Indeed, a few researchers have hypothesized that 1,25(OH)2D might play a significant role in granulomas formation. This is mainly based on the fact that 1,25(OH)2D has the ability to promote the creation of immune cells that granulomas are created from. If this theory was found to be true, then that would at least explain why the MP works for sarcoidosis. But that explanation would not apply to other conditions that don’t involve granulomas. Granuloma formation is a complex immune process that is more than just a group of white cells. One cannot generalize what the effects of 1,25(OH)2D will be for any given condition, based on what its effects are on sarcoidosis. Indeed, even other granulomatosis diseases may respond differently to 1,25(OH)2D, as exemplified by the fact that 1,25(OH)2D has been found to be beneficial for tuberculosis.
In any event, the medical literature doesn’t support the belief that 1,25(OH)2D can significantly affect the progression of sarcoidosis. For example, drugs such as ketoconazole, that are able to lower the production of 1,25(OH)2D, have been given to sarcoidosis patients. However, while they are able to reduce the elevated 1,25(OH)2D levels, and decrease hypercalcemia, there is no evidence that they can control any of the other symptoms in sarcoidosis, or the course of the disease. Additionally, lab tests have shown that granuloma formation can occur even in animals lacking the vitamin D receptor (VDR). In fact, the granulomas formed in such animals, were actually significantly larger than in normal animals. Thus, even though elevated vitamin D has known to be associated with sarcoidosis for almost 2 decades, no study has yet proven that 1,25(OH)2D is a major cause of the chronic inflammation seen in sarcoidosis.
On the other hand, since the original MP claim on 1,25(OH)2D, new studies were published that documented the fact that 1,25(OH)2D has infection fighting properties. This had always been suspected, given the long held belief that sunshine helps to treat tuberculosis. Studies have shown that vitamin D supplementation can help treat tuberculosis. The receptor TLR2 on immune cells responds to tuberculosis mycobacterium, which causes an increase in VDR expression and 1,25(OH)2D production. This leads to increased levels of the cathelicidin antimicrobial peptide (LL-37), which is capable of killing tuberculosis mycobacterium.
Perhaps because of these facts, and the fact that many other inflammatory conditions do not have elevated 1,25(OH)2D, that the main focus of the MP eventually became that 25(OH)D was the main problem, and that it was blocking proper stimulation of the vitamin D receptor (VDR).
However, note that no proof has been shown that 25(OH)D blocks this process. Indeed, the addition of 25(OH)D has been shown to increase the production of LL-37. This is because the rate of conversion of 25(OH)D of 1,25(OH)2D is upregulated when the TLR2 receptor detects infections. This process provides increased levels of 1,25(OH)2D. Furthermore, the study on LL-37 stated that “African Americans have significantly decreased serum 25(OH)D3 levels and are known to have increased susceptibility to M. tuberculosis infection, as well as more rapid and more severe course of disease. We observed that serum levels of 25(OH)D3 in African Americans were significantly lower than in a Caucasian cohort. Strikingly, when these serum samples were used to support TLR2/1 activation, the induction of cathelicidin mRNA was significantly lower in the presence of serum from African American than the Caucasian individuals. Finally, supplementation of the African American serum with 25(OH)D3 to a physiologic range restored TLR induction of cathelicidin mRNA.”
MP web pages have declared that the vitamin D receptor is at the heart of human innate immunity. While VDR activation has been shown to increase production of LL-37, this only occurs in epithelial cells. Not only that, but it only occurs in certain epithelial cells. For example, it does not occur in colon epithelial cells. Additionally, other processes are capable of producing LL-37, without the help of the VDR. And while LL-37 does have potent antimicrobial properties, many bacteria have developed methods to avoid the effects of LL-37.
The MP then came up with yet another theory. They believe that bacteria secrete or induce substances which block the VDR’s ability to fight infections. For example, it’s known that the substance caspase-3 is capable of reducing the functioning of the VDR. Caspase-3’s function is to induce the cell death, a process known as apoptosis. Several bacteria are capable of activating caspase-3, which in certain situations can lead to chronic inflammation. The MP cites a study that shows that the pseudomonas aeruginosa. bacteria can activate caspase-3. However, a study was conducted to see if 1,25(OH)2D could induce LL-37 via the VDR in cells infected with either pseudomonas aeruginosa, or another bacteria called bordetella bronchiseptica. In both cases, 1,25(OH)2D was capable of killing approximately the same percentage of each bacteria, even though it is known that other bacteria, bordetella bronchiseptica, does not induce caspase-3. The MP also mentions that the helicobacter pylori bacteria upregulates caspase-3. However, the production of LL-37 in pylori infections has been found to be significantly increased. This implies that the production of LL-37 by the VDR is not being suppressed. Thus, these studies do not support the belief that caspase-3, induced by bacteria, is capable of reducing the antibacterial actions of the VDR. Indeed, in many granulomatosis and some inflammatory diseases, there is decreased apoptosis, rather than increased apoptosis. This is possibly one cause of the persistance of the inflammatory immune system. And in fact, some of the drugs that are used to treat those diseases, such as Infliximab and visilizumab, are believed to be helpful, due to the fact that they induce apoptosis via caspase-3.
Another substance which is produced by certain bacteria, known as capnine, is believed by the MP to be capable of blocking the VDR. Capnine is a substance produced by the Cytophaga-Flavobacterium bacteria family, which are capable of “gliding”. This means that they are to move over surfaces. The MP claims that capnine blocks the VDR, but this claim is only based on a computer simulation. The MP believes that the bacteria creates such substances in order to avoid the innate immue system. However several studies appear to suggest that capnine is actually involved in the ability of the bacteria to glide. For example, when capnine is blocked from being produced, the bacteria is no longer able to glide. Additionally, when the bacteria come in contact with a surface, a different form of capnine is formed. Thus, capnine’s function may be related to the bacteria ability to glide, and is not to produced to avoid the innate system.
The MP claims that capnine producing bacteria have been found in patients with hip replacements, and they use this as proof-of-concept that bacteria can block the VDR . However, capnine has only been found to be produced by Cytophaga-Flavobacterium bacteria family. And the hip replacement study referred to by the MP, did not find any capnine producing gliding bacteria. Instead the study found an unrelated gliding bacteria called Lysobacter, which doesn’t produce capnine. Many unrelated bacteria can glide, and they use different methods to do so. Thus, finding a gliding bacteria, does not imply that capnine is present. And in fact, capnine in it’s pure form,is only found in significant amounts in the bacteria species known as Capnocytophaga. Indeed, perhaps because of that fact, in a published study by the MP that mentioned the theory of capnine, they did not directly refer to the hip replacement study, or mention the specific bacteria that was found. Instead, they simply referred to other, unpuslished MP articles.
Capnine producing bacteria infections in humans are uncommon, as they mainly occur in significantly immunocompromised individuals, or due to animal bites. And when such infections due occur, they are quite severe, because these bacteria have many methods of avoiding detection by the immune system, that are unrelated to the production of capnine. Thus, it appears highly unlikely that capnine is present in any of the chronic conditions that the MP claims to treat. Combining that with the fact that capnine has yet to even be proven in a lab test to affect the VDR, we do not believe that there is proof-of-concept yet that bacteria produce substance that block the VDR, as claimed in the 2009 MP article ““Reversing Bacteria-induced Vitamin D Receptor Dysfunction Is Key to Autoimmune Disease".
In that MP article, they also continue to cite studies that they claim supports their belief that 25(OH)D interferes with the VDR. For example, they cite a study which found that “higher levels of 25-D blunted the favorable effect of calcium on bone density.” There are a couple of problems with this study though. First, it used oral 25(OH)D, rather than oral vitamin D, so the effects could be different Instead, they estimated the calcium intake in the 25(OH)D supplemented group. Thus, it’s unclear whether the 25(OH)D was blunting the effects of calcium, or whether some aspect of a higher calcium diet blunted the effects of the 25(OH)D, is unclear. . Plus also only compared the effects from 25(OH)D supplementation vs calcium supplementation. It did not include a group of patients that combined the two supplements.
In contrast to the above study, a 5 year study on elderly women found no difference in effects on BMD at high levels of 25(OH)D, comparing patients taking a calcium supplement with vitamin D, versus those only taking a calcium supplement. The medium baseline 25(OH)D levels was 68 nmol/l for the whole study group. They compared the study results for the groups of patients below and above that level. Above that level, neither treatment had any effect, while below that level, the calcium plus vitamin D group was more effective in the long run, compared to calcium alone. They concluded that “at the clinically important hip site, calcium therapy with an additional 1200 mg of calcium as calcium carbonate a day, although initially successful at stopping bone loss, was not different from placebo at 3 or 5 yr”” and that “the addition of 1000 IU vitamin D to calcium supplementation maintained hip BMD constant for 5 yr, especially in individuals with low 25OHD levels at baseline.” At the end of the treatment, the median level of 25(OH)D for whole group, rose to approximately 110 nmol/l. This was about the same level as that of the previous study, referred to by the MP. Thus, this study not only showed that that high levels of 25(OH)D were not detrimental, but it also showed that in the long term, that a combination of vitamin D and calcium was significantly more effective than calcium alone.
The above studies were older men and women. For other age groups, the results are sometimes different. For example, a study based on published data for adults older 20 years, found the following: That “higher calcium intake was significantly associated with higher BMD (p value for trend: p = 0.005) only for women with 25(OH)D status <50 nM, whereas calcium intake beyond the upper end of the lowest quartile (>566 mg/d) was not significantly associated with BMD at 25(OH)D concentrations >50 nM. Among men, there was no significant association between a higher calcium intake beyond the upper end of the lowest quartile (626 mg/d) and BMD within all 25(OH)D categories. Among both sexes, BMD increased stepwise and significantly with higher 25(OH)D concentrations (<50, 50-74, 75+ nM; p value for trend: women < 0.0001; men = 0.0001). Among men and women, 25(OH)D status seems to be the dominant predictor of BMD relative to calcium intake. Only women with 25(OH)D concentrations <50 nM seem to benefit from a higher calcium intake.”
The production of hormonally
active 1,25(OH)2D involves several steps.
It starts with the unmetabolized form of vitamin D which is in
supplements and foods, and which is also created in the skin due to sunshine
exposure. Once in the body, it is either
stored in tissues, eliminated from the body, or metabolized by the liver into
25(OH)D. 25(OH)D binds to a protein and
circulates through the serum and tissues.
As an aside, several MP web pages make the mistake of claiming that all
of the vitamin D is metabolized and stored as 25(OH)D. This is incorrect. It is the unmetabolized vitamin D which is stored in various
tissues in the body 25(OH)D only
lasts in the body for about 2-3 weeks.
Unmetabolized vitamin D lasts for several months. The latter is used as a source of vitamin D
by the body during the winter, in areas where the sun is not high enough to
stimulate vitamin D production (i.e. which includes about half the
25(OH)D is mainly converted into the hormonally active metabolite 1,25(OH)2D. This primarily occurs in the kidneys, where it's used to control calcium levels. 1,25(OH)2D usually lasts in the body for less than a day. Many other tissues can also convert 25(OH)D to 1,25(OH)2D. This non-renal production is believed to be used for local tissue effects. It usually results in the production of much smaller amounts of 1,25(OH)2D, compared with renal production. Such extrarenal production usually does not contribute much to serum levels, except in conditions such as sarcoidosis.
It’s recently been found that 1,25(OH)2D can also be directly created in the skin due to sunshine. The MP uses this fact to support their claim that “any and all 25-D which is made from sunlight is energetically converted to 1,25-D” The MP believes that this production is upregulated in TH1 conditions, such that “sunlight is not usually a significant contributor to the 25-D levels of Th1 patients.”
But the researchers who discovered that the skin could directly produce 1,25(OH)D, do not believe that this process could result in a significant amount of 1,25(OH)2D. Instead, in the conclusion of the study, they stated that “the photoproduced 1,25(OH)2 D3 quantities in vitro are very minute though. We measured 1,25(OH)2 D3 quantities of 175-177 fmol/106 cells in cellular homogenates and medium of BM15766-pretreated cells after UVB irradiation.” “This implies that only 0.005% of the intracellular 7-DHC is converted into 1,25(OH)2 D3” “cutanous 1,25(OH)2 D3 photoproduction probably does not contribute to the systemic effects of 1,25(OH)2 D3 . Indeed, the low 1,25(OH)2 D3 levels in hepatectomized or nephrectomized animals suggest that epidermal 1,25(OH)2 D3 production cannot compensate for the lost 1-hydroxylase activity in these animals and therefore that epidermal 1,25(OH)2 D3 photoproduction maximally accounts for a small fraction of total systemic 1,25(OH)2 D3 levels.”.
One of the researchers who authored that study, is Professor Roger Bouillon. He has been studying vitamin D since the 1970s, and is a strong believer that vitamin D deficiency is a wide spread problem. In fact, he has recently stated his belief that over one billion people may be suffering from a vitamin D deficiency.
The small production of 1,25(OH)2D in the skin, is likely there to create a local effect, such as protecting the skin against the damages of sunshine exposure. Localized production of vitamin D is a common scenario in the body. 1-hydroxylase, the enzyme that creates 1,25(OH)2D, has been found in many different tissues in the body. However, there is no study to support the claim that the activity of this enzyme is up regulated in the skin in TH1 conditions. In fact, one study that did measure the skin levels of 1-hydroxylase in sarcoidosis, did not find elevated levels. According to that study, in skin from patients with sarcoidosis, “1-hydroxylase was normally expressed in basal keratinocytes of the epidermis.”
Some people on the MP who avoid sunlight and wear sunglasses for a long period of time, and who then develop rapid negative symptoms when they are then exposed to the sun, often attribute this due to 1,25(OH)2D production. It is a fact that healthy people with lower 25(OH)D and 1,25(OH)2D levels, will produce greater amounts of 25(OH)D and 1,25(OH)2D, when exposed to either sunlight or vitamin D supplementation, compared to people with higher levels of 25(OH)D and 1,25(OH)2D. Thus, the lower your 25(OH)D levels, the more sensitive one will be to the effects of sunshine and vitamin D. Therefore, it’s not surprising that people who avoid sunlight and vitamin D, will become more sensitive to it’s effects.
Also, we have read several other statements on that MP web site, that are also incorrect regarding the ability of sunshine to produce vitamin D. For example, one web page states that people can get sufficient amount of vitamin D via sunshine, “in only a fraction of the amount of time they spend driving each week." However, this is not so, as a study has shown that when driving in a car with one’s windows closed, in direct sunshine, only 11% of the sun’s ultraviolet rays are able to get through. When the car is in shade, 0% gets through. Thus, people in a car, are exposed to a very limited amount of the sun rays that are necessary to produce of vitamin D.
Even if one does not have an elevated vitamin D ratio, the MP believes that having a bad reaction to Benicar, means that you have a TH1 dominant condition, and that you can then be treated by the MP. The MP believes that Benicar has almost no side effects in normal people, and so that any bad effect is due to the body reacting to bacteria dying off, and that these bacteria are the real cause of TH1 conditions. This method of using of Benicar to diagnose a TH1 condition is described by the MP as a “therapeutic probe”. To quote one MP web page: “A therapeutic probe is a method of determining a diagnosis that might be difficult to decide by other means.” “For example, if someone has pain in their great toe but blood tests are nonconclusive, the doctor may have the patient take a medication for gout. If the pain goes away, the patient is presumed to have gout and the medication is continued to prevent future episodes.”
However, there are several problems with these statements. First, the term "therapeutic probe" is not a standard medical term. In fact, the term is only found on a handful of web pages on the whole internet, and on just about all of them, the term is used to refer to a real physical probe. Secondly, the analogy with gout is flawed, due to the fact that in the case of the MP, a negative effect is expected from the medicine, while in the case of gout, a positive benefit is expected. Giving a medicine to see if a person will get better from it, and then continuing that medicine due to the fact that a positive benefit occurred, is of course extremely common. However, giving a medicine specifically to see if a person will get worse from it, and then continuing that medicine because this occurred, is quite rare. While it’s true that many medicines will first cause side effects before the positive benefits occur from it, these side effects are almost never considered to be a sign that the medicine is the proper medicine to use to treat a person.
And lastly, the gout example is simply wrong. Gout attacks are treated using normal anti-inflammatories, not gout specific medicines. Gout specific medicines are only useful to prevent gout attacks. However, since gout attacks often takes months or years to reoccur, one would have to use gout medicine for a very long time, before seeing the results. Thus, this is not a practical way in which gout is diagnosed. Instead, gout is diagnosed by taking samples of the synovial fluid of the joint, and by excluding other possible diagnoses based on other lab tests and symptoms.
In any event, the MP states that “persons without TH1 inflammation would note only a mild reduction in blood pressure if they took Benicar 40mg every eight hours. A positive response to a therapeutic probe with the Benicar blockade would be any reaction, either a reduction in symptoms or an increase in symptoms.” However, there is no proof that a lowering of blood pressure is the only thing that will happen to healthy people at such a high dose. Benicar has not been studied at this dose in either healthy people, or people with inflammatory diseases. Even at lower doses, many negative effects from Benicar have been reported by people taking Benicar for hypertension. Headaches, chest pain, muscle pain, and coughing, are just a few of the side effects that people experienced. However, when these same effects are experienced by people on the MP, they are explained as being reactions to bacteria dying off, and that experiencing these symptoms indicates that the person has a TH1 condition.
Many of the side effects from Benicar are due to the effects of blocking angiotensin II, and the decrease in aldosterone levels. These changes can lead to a decrease of blood pressure and volume, which can aggravate orthostatic related problems. People with CFS and fibromyalgia are prone to having orthostatic problems, and they may experience symptoms from Benicar that other people may not experience.
Benicar can significantly lower aldosterone. Decreased aldosterone can cause fatigue, headaches, muscle weakness, and constipation, all symptoms that have been reported by people on the MP who have taken Benicar. People who are prone to dehydration, or who have kidney problems, are more susceptible to symptoms that result from decreased aldosterone levels. Also, certain drugs can inhibit the production of aldosterone, and thus could potentiate the effects of Benicar. For example, some NSAIDS can reduce aldosterone levels. Potassium channel blockers, such as the anti-diabetic drug glyburide, can also block inhibit the production of aldosterone. Thus, ARBs may be able to lower kidney functioning in people who are susceptible to this problem. This may especially be true, given the very high doses of Benicar that are used by the MP.
However, it should also be noted that the effect of ARBs on aldosterone levels can be highly variable, and often such an effect can take many weeks and months before it occurs. In a study on long-term use of an ARB, aldosterone decreased in about half the patients, while in the other half it increased. This increase occurred due to an effect known as “aldosterone escape” or “aldosterone breakthrough”, where the body uses other ways to produce aldosterone. For ARBs, this effect possibly could be due to the stimulation of the AT2 angiotensin II receptor, which is not blocked by Benicar. Whatever the reason, it's obvious that Benicar’s effect on aldosterone might be patient specific, and thus it’s impossible to generalize about what Benicar's effects will be for any one person.
Some of people on the MP have reported abnormal kidney tests, such as high BUN levels. They are told by the MP that this is due to the die off of bacteria, which then affects kidney functioning. None of these claims are supported by any study, though. Instead, there is a much more simple explanation, which is that this effect is due to a condition known as “type 4 renal tubuluar acidosis”. This condition can be caused from taking ARBs. In fact, the initial side effects of acidosis, such as fatigue, muscle weakness, and headaches, are commonly reported by people on the MP. It’s possible then, that in some cases, these reported symptoms are actually due to temporary acidosis. Indeed, some people on the MP have discovered that they can offset these effects by taking remedies that decrease acidosis.
Benicar can decrease ACE levels. Decreased ACE levels can lead to increased bradykinin levels, and this effect is believed to be the cause of some of the side effects that can with drugs that inhibit ACE. Specifically, coughing is a common side effect of ACE inhibitors , and some people on the MP had reported coughing after starting Benicar.
One MP web page claims that Benicar is a “is a very weak anti-hypertensive agent”, and that “its effects are so minimal that doctors don’t use it very often.” No reference for this claim was provided. However, the medical literature has documented that Benicar has been shown to be effective at lowering blood pressure in both stage 1 and stage 2 hypertension. In fact, several studies have shown that Benicar is as or more effect than other ARBs. According to one study, “Olmesartan efficacy was consistently at the highest end of the range of efficacy of ARBs studied.”
That MP web page then goes on to minimize any effects from low blood pressure. They state that ““Marshall Protocol patients with extremely low blood pressure (85/55 or lower) have been able to continue taking Benicar.” ““The NIH has created no medical standards that define low blood pressure, or a range in which low blood pressure is considered dangerous.” However, studies do show negative effects from low blood pressure. A 2007 review article has stated that “A number of studies have provided strong evidence for reduced cognitive performance in hypotension, particularly in the domains of attention and memory. EEG studies have demonstrated that the hypotension-related poorer mental ability is also reflected in diminished cortical activity. Contrary to convention, more recent research has suggested a deficient regulation of cerebral blood flow in persons with low blood pressure. In addition to reduced tonic brain perfusion, studies demonstrated insufficient adjustment of blood flow to cognitive requirements. Altogether, these findings suggest that more attention should be allocated to chronic hypotension in both research and clinical practice.”
If Benicar is unavailable, then the MP says that minocycline can be used to test for a TH1 disease. According to an MP web page: “Minocycline almost always provokes a Herxheimer reaction in a patient with Th1 inflammatory disease.”
The Jarisch-Herxheimer Reaction, is a reaction that is known to sometimes occur when taking antibiotics for infections, However, the Jarisch-Herxheimer Reaction is only known to occur with specific types of infections, usually complex organisms such as syphilis and Lyme. It only occurs very soon after the first dose of an antibiotic. But the medical literature states that it definitely does not occur in everyone. Thus, any test that is based on whether this reaction occurs or not, is unreliable. The lack of such a reaction does not rule out the presence of an infection.
On the other hand, minocycline is known for having many major side effects, which is why other tetracycline antibiotics, such as doxycycline, are often preferred for certain conditions (i.e. Lyme disease). For example, minocycline can produce major vestibular side effects, the most common being dizziness and nausea, but other symptoms have also been noted. However, these symptoms are known to occur in healthy people, so they are not a reaction to bacteria dying off. Additionally, even more serious problems have been known to result from minocycline, such as intracranial pressure, and various pulmonary complications such as pulmonary lupus, hypersensitivity pneumonitis, and eosinophilic pneumonia. The latter problems are especially worth being aware of, since their symptoms could easily be mistaken for sarcoidosis symptoms.
The MP further states that if neither Benicar nor minocycline cause a negative reaction, then “if the level of a person's 25-D is above about 25 ng/ml then their immune system may not be able to kill the bacteria, even with the help of antibiotics, and the probe would fail.” We question how it is possible that 25(OH)D can block the killing effects of minocycline on the bacteria. Even in patients who have a greatly compromised immune system, antibiotics are still able to effectively treat infections.
In any event, because of this belief, people on the MP are often told that they must reduce their 25(OH)D, by avoiding all possible food sources of vitamin D, avoiding sunlight, and wearing NOIR sunglasses, before trying a therapeutic probe. In fact, the avoidance of vitamin D by itself is considered to be a “mini” therapeutic probe, so that having a bad reaction due to reduced vitamin D levels, is supposedly a sign of a TH1 condition. However, the reduction of 25(OH)D could create negative effects by itself, irrespective of supposed killing of bacteria, due to decreased anti-inflammatory effects from reduced 1,25(OH)2D tissue levels. However, some of the effects from reduced 25(OH)D can be due to less obvious reasons. For example, a reduction of 25(OH)D will often increase parathyroid hormone (PTH) levels, and elevated PTH can cause fatigue, concentration problems, irritability, depression, sleep problems, headaches, and palpitations. Few people realize that PTH is capable of many direct effects, that are independent of PTH’s effects on calcium levels. Additionally, the change in life style and diet, and the light deprivation, that are recommended in order to lower vitamin D, can have numerous negative effects of their own, independent of the negative effects that occur from a reduction of 25(OH)D levels.
The MP has started to avoid referring to negative reactions from the MP as being Herxheimer reactions. Instead, they are now being referred to as being symptoms of “immunopathology”. Immunopathology refers to the body’s immune system’s reactions to diseases. The MP believes that this term more correctly describes the reactions. However, the MP is still using this new term in a unique way. With regard to infections, the term is usually used to describe the symptoms caused by the body fighting an infection. The MP however is using it to describe symptoms that it believes are due to the body’s reactions to the dying off of the bacteria. Not only that, but the MP believes that almost any negative symptom can be attributed to this phenomena. According to one MP web page, “The following is only a partial list of possible herxheimer symptoms: fatigue, muscle weakness, rash, headache, photosensitivity, pain anywhere, numbness, nausea, diarrhea, constipation, ringing in the ears, toothache, sinus congestion, nasal stuffiness, fever/chills, flu-like bodyache, cough, irritability, depression, sleep disturbances and ‘brain-fog.” In essence, practically any negative symptom that one experiences on the MP, can be considered as an “immunopathology” symptom. The MP almost never believes that a negative effect is a side effect of the medicine. This is quite unusual, considering that most treatments for serious medical problems have some significant side effects. The MP thus has a whole different paradigm for looking at the source of side effects, than traditional medical medicine. As written on their web page, “The Marshall Protocol is a curative therapy and it is normal to feel worse before we feel better. The knowledge and remembering that, helps us and our family to manage that both physically and mentally to continue on the MP.”
Not only that, but the MP basically states that there is no way to avoid these negative reactions, and that anything you do to reduce these symptoms will reduce the efficacy of the treatment. To quote the administrator of the MP web page , “the concept that you can recover without herxheimer is just plain wrong. As the white cells die you will suffer. At least a little. Anything you take which reduces that suffering is almost certain to be reducing the pace, and certainty, of your recovery.”
If all these negative symptoms are the result of the body’s reaction to white cell die off, and it is so strong that it is impossible to offset their effects, surely this is something that could be measured in some way by a lab test. Instead, the MP relies on the presence of almost any negative reaction as being an indicator that white cells are dying off. We find this curious, given the fact that the MP prides itself on being based on the latest discoveries and molecular medicine, yet it cannot provide a more selective method of screening patients for who might benefit from their treatment. Indeed, their criteria have become less selective over the years, and they now have a long list of unrelated diseases which they claim to be able to treat.
As an aside, the administrator of the MP web page has also written: “In my work with Sarcoidosis patients, it is my experience that recovering MP patients understand and welcome the Herxheimer reactions even when they must endure temporary increased suffering. They accept it as the price that they must pay in order to get well and they even seem to find it gratifying to experience tangible evidence of bacterial elimination.” Given this very strong expectation by patients that negative effects on the MP are a good sign, one wonders how often it is that reported “herxing” symptoms, are actually perceived symptoms. It is well known that placebos can cause side effects in people, a phenomena known as the nocebo effect. If people can experience side effects from a placebo, how much more likely might such negative effects occur, if such effects are believed to be a good sign?
This is not to say that the effects which people are experiencing are not real. However, because they are told that their symptoms will get worse, they could simply be concentrating more than usual on their symptoms, and thus end up believing that they have become worse. Or they could be having a flareup of their symptoms for other reasons. Whatever the case, there simply is no way of truly knowing whether reported negative effects are real or not, given the power of expectation.
In conclusion, the tests used by the MP are vague and non-specific, and not supported by the medical literature. Thus, there is no reason why such tests should be relied upon. Unless a more reliable test can be created, perhaps people who are interested in the MP, should simply try it, and see if it works or not.
The MP believes that Benicar has the ability to lower 1,25(OH)2D, and that this is partially the reason why Benicar can treat TH1 conditions They say that they have observed that 1,25(OH)2D levels are reduced by Benicar. It’s unclear how they can make this claim, given that people who are taking Benicar, are also avoiding vitamin D at the same time. How can one tell if the decrease of 1,25(OH)2D is actually due to the Benicar itself, rather than the avoidance of vitamin D?
However, since ARBs such as Benicar can reduce inflammation and lower TH1 activity, it is possible that this would then lower TH1 1,25(OH)2D production. But the MP has recently been claiming a different reason for why Benicar can lower 1,25(OH)2D. Based on a computer simulation, the inventor of the MP has claimed that Benicar and other ARBs can significantly interact with the vitamin D receptor (VDR), and it is postulated that this is one of the reasons why Benicar can treat TH1 conditions. In a published paper, on the basis of the computer simulation, it was concluded that “the ARBs Olmesartan, Irbesartan and Valsartan … are likely to be useful VDR antagonists at typical in-vivo concentrations.”
On the other hand, since the paper was published, the author has changed his conclusion, and now believes that Benicar is at least a partial agonist of the VDR. As stated on the MP web page: “when Benicar docks into the VDR displacing 25-D and 1,25-D it at least partially activates the VDR.” However, no actual lab study has been done to prove this claim. And while computer simulations are useful, they still are not a substitute for an actual study. Indeed, this same author, using computer simulations, has also stated that statin drugs have a significant ability to interact with the VDR: *simvastatin is capable of exerting a direct effect on the VDR at a normal therapeutic dose, although lovastatin would do so at higher doses.” However, an actual study has disputed this claim, by showing that “statins do not directly activate vitamin D receptor.” Real studies on VDR agonists require real lab studies, using real VDR and cells. We wonder why no one has yet bothered to do this for ARBs. A huge amount of money has been invested by companies attempting to create vitamin D agonists and antagonists. If ARBs had a significant direct effect on VDRs, this would be a revolutionary discovery, and it would a boon to ARB drug companies. We await real studies, and confirmation of the MP’s claims, by vitamin D researchers.
Another reason that the MP states to support their theory that Benicar interacts with a non-angiotensin II receptor, is that they believe that Benicar is only useful if it is given at very high doses, doses that are much higher than the doses that are normally recommended to reduce blood pressure. They believe that this indicates that some other type of receptor is being activated by Benicar. However, this assumes that AT1 receptors are saturated at the doses that are given to reduce blood pressure. But this is not the case. People who have high blood pressure, often have high systolic pressure, but normal diastolic pressure. Doses of Benicar above 40mg, results in only small additional decreases of systolic blood pressure, and this is the reason why higher doses are not given for hypertension. On the other hand, diastolic pressure continues to significantly decrease at higher doses, even at 80mg. And as plotted on a graph, the rate of decrease at the 80mg dose, is very similar to that at10mg, so that even higher doses might likely still have additional effects. Thus, there is no indication that AT1 receptors are totally saturated by high doses of Benicar, even at 80mg.
Other studies also support this assertion. For example, angiotensin II plays an important role in wound healing. Thus, in theory, an ARB could reduce the rate at which a wound heals. And indeed, at high doses, this was shown to occur. However, at doses normally given for hypertension, the effect was minimal. Thus, this shows that AT1 receptors are not saturated at such doses, and that the effects from higher doses of Benicar could still simply be due to a more efficient blocking of AT1 receptors.
However, if ARBs can lower 1,25(OH)2D, there is another explanation for such an effect. It is based on the fact that angiotensin II itself can affect calcium metabolism. Indeed, in a recent lab study, angiotensin II was found to accelerate osteoporosis by activating osteoclasts, and Benicar was shown to block this affect. Thus, if one blocks angiotensin II via ARBs, this could change calcium levels, which would then affect the amount of 1,25(OH)2D produced by the kidneys.
This has actually been shown to
occur. In a study on hypertension, it was found that the use of ACE inhibitors resulted in a
decrease in 1,25(OH)2D levels. The study concluded:
"This therapeutic group acts by blocking angiotensin II synthesis. Consequently, it has a beneficial effect on the skeleton because there is a decrease in angiotensin concentration. It has been hypothesized that angiotensin can indirectly act on bone cells by regulating the flow of bone marrow capillaries or directly by binding to AT1 receptors located on osteoblasts, thus promoting the mediator release that would activate the osteoclasts." "The reduction of angiotensin II levels has a beneficial effect of inhibiting bone resorption and promoting mineralization."
"Angiotensin II can interfere with calcium metabolism. The administration of this peptide in a group of healthy volunteers caused a decrease in ionic calcium levels and an increase in PTHi levels. The decrease of calcemia was not related to an increase in calciuria, but it could be caused by an increase in calcium uptake by vascular smooth muscle cells. In our patients, ACE inhibitors increased the level of calcium, although the concentration of PTHi was not modified. These data suggest a beneficial effect on the blockage of the synthesis of angiotensin in calcium metabolism.”
If angiotensin II can directly affect calcium levels, then this might explain a study on sarcoidosis which showed that serum ACE levels were found to correlate with serum ionized calcium levels, independent of any effect from 1,25(OH)2D. And this could also help explain why hypercalcemia often occurs in sarcoidosis, but rarely occurs in Crohn's disease, even though 1,25(OH)2D is elevated in both diseases. The difference could be that ACE is rarely found to be elevated in Crohn's disease,
A more recent study on the lowering effect of ACE inhibitors on 1,25(OH)2D levels has shown that the effect occurs mainly in people with the gene that is associated with higher levels of ACE. This supports the claim that angiotensin II is directly responsible for the elevation of 1,25(OH)2D. In this new study, they present another possible theory for this effect, which is that angiotensin II may be able to increase the production of 1,25(OH)2D, due to its ability to upregulate the TLR4 receptor in renal immune cells. Stimulation of the TLR4 receptor on other immune cells is known to produce 1,25(OH)2D. So perhaps angiotensin II directly upregulates 1,25(OH)2D production on immune cells by upregulating TLR4 expression, rather than indirect via an angiotensin II effect on calcium. However, this theory is presently only based on studies of different cell lines. Nevertheless, it's an intriguing theory, due to the fact that nonbacterial substances that are up regulated by inflammation, are known to be able to stimulate the TLR4. Thus, in theory, inflammation due to raised ACE, may be able to affect 1,25(OH)2D levels, even in the absence of an infection.
While ARBs have not yet been studied, to see if they also affect 1,25(OH)2D levels, one could easily speculate that ARBs would have at least a strong, if not stronger effect, than ACE inhibitors, given ARB’s better ability to block the effects of angiotensin II.
Indeed, in further support of this theory, is the fact that it’s been shown that an ARB was capable of suppressing the expression of both TLR2 and TLR4 in monocytes. This effect seems likely to be due to the blocking of the angiotensin II receptor (and not via the VDR, as the MP claims), as monocytes without the AT1 receptor had significantly increased expression of the TLR receptors. If this effect is confirmed, this would give a clear explanation as to why Benicar could lower 1,25(OH)2D, as lowering the response to TLR2 or TLR4 is capable of lowering TH1 production of 1,25(OH)2D.
ARBs might also be capable of affecting 1,25(OH)2D levels via other pathways. For example, angiotensin II is capable of upregulating growth hormone (GH). Surprisingly this has received only scant interest in the medical literature even though it’s a proven effect in humans, and the effect can be blocked by an ARB. This property might be relevant for people on the MP, as GH is a known stimulator of kidney production of 1,25(OH)2D, via an action independent of PTH. Blocking angiotensin II might lower 1,25(OH)2D production, due to a reduction of GH. Interestingly, serum GH levels have been found to be elevated in patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia. The author’s theory is that elevated GH levels can cause pain and inflammation in muscles and joints.
Yet another effect of angiotensin II is the ability to increase PTH levels. This has been shown to occur in at least one study. This study also showed that atrial natriuretic peptide (ANP) can also suppress PTH, and a second study has shown that blocking angiotensin II can directly increase ANP. Thus, another reason why Benicar might be able to lower 1,25(OH)2D levels, is that it is blocking the angiotensin II induced release of PTH. Lowering PTH decreases renal 1,25(OH)2D production. However, this effect on PTH might be masked by the MP, due to the protocol’s avoidance of vitamin D. Avoiding vitamin D intake would lower 25(OH)D levels, which would then lower calcium absorption, prompting the body to produce more PTH. But this attempt possibly could be offset by the opposite action of Benicar, so that little change in PTH may be noted.
A direct effect of angiotensin II on PTH may explain a curious phenomenon in sarcoidosis. In some patients, PTH is normal or elevated, even though 1,25(OH)2D levels are increased. For example, one study has shown that PTH was two or three times higher than people without sarcoidosis. This is unexpected, because one would have expected that the increased 1,25(OH)2D levels in sarcoidosis would suppress PTH. Perhaps this increased PTH, is due to elevated ACE. Increased angiotensin II production might be increasing PTH in some patients.
Some people have questioned whether the MP is simply reducing inflammation without really treating the real cause of diseases. They additionally wonder if perhaps the MP is over suppressing the immune system in conditions that aren’t not necessarily TH1 conditions. While the MP claims that it can treat conditions such as CFS and chronic Lyme disease, the medical literature does not recognize these conditions as being TH1 dominant. In fact, there is some evidence that CFS may be a TH2 dominant condition. Chronic Lyme is theorized to possibly be a state of immunosuppressed tolerance to the infection. If Benicar can reduce TH1 responses, could this have negative effects on infections, in conditions where TH1 cytokines are not elevated, and may actually be suppressed?
Recent studies are now showing that angiotensin II may have profound effects on the immune system’s innate response to infections. As we previously mentioned, a study has shown that ARBs are capable of lowering the expression of receptors that detect bacteria. Yet another study has shown that angiotensin II receptors are essential for the development of the full innate immune and stress responses to bacterial endotoxin..
Unfortunately, there are few studies that look at the use of ARBs in actual infectious conditions. ARBs are mainly used for lowering blood pressure, and for cardiac and kidney disease. The single study that I did find, was a lab study on rats, in which an ARB was used for a kidney infection, in order to reduce the scarring associated with the infection. It accomplished this, but it was also observed that bacterial counts were significantly higher. Another study showed that injecting angiotensin II increased the host resistance to a bacterial infection. They concluded: “As AII acted on the host as an immunomodulator rather than on the bacteria, resistance to the effects on this molecule may not occur. This would be an advantage over antimicrobials, which allow the development of resistant strains. This observation should benefit not only individuals with normally functioning immune systems (as described here) but those with impaired immune systems as well, including patients undergoing immunosuppressive therapy (e.g., chemotherapy [antirejection drugs after transplantation]) or patients with human immunodeficiency virus infection”.
One of the positive effects found in this study, was that angiotensin II increased respiratory burst activity. The respiratory burst “is a process that produces reactive oxygen intermediates which, along with toxic nitrogen intermediates and a cocktail of proteinases and other enzymes, are used to acidify lysosomes (vacuoles) within the macrophages, which usually fuse with, and kill, any ingested bacteria.” Thus, in theory, reducing angiotensin II could decrease anti-bacterial activity. Additionally, it’s interesting to note that 1,25(OH)2D also increases this burst activity, So a combination of reducing 1,25(OH)2D and angiotensin II may significantly downgrade this immune response.
As an aside, the MP does not believe that chronic Lyme disease is due to Lyme bacteria. It believes it is due to cell wall deficient bacteria. This is one of the reasons why the MP does not use the same types or levels of antibiotics that are used by many people who treat Lyme. Additionally, some studies indicate that resolution of Lyme disease is associated with a strong TH1 response. It is because of such reasons, that have led people to question whether the MP can proper treat the actually source of chronic Lyme disease, or whether it is simply treating the symptoms, without actually affecting the bacteria.
Benicar may also have immunosuppressive effects against viral infections. Angiotensin II blockers are capable of reducing the activity of cytotoxic T cells. Cytotoxic T cells (CTLs) are able to search out and kill specific types of virus-infected cells. When CTLs find cells carrying the viral peptide they are looking for, they induce these cells to secrete proteins that attract nearby macrophages. These macrophages then surround and destroy the infected cells. CTLs are important in the body's response to viruses and cancer. Can ARBs reduce the activity of CTLs, enough to reduce the immune system’s response to viral infections? This is unknown at the present time.
The MP recommends vigorously avoiding sunshine, and some people on the MP have reported that they feel worse when they are exposed to sunshine. Since sunshine produces vitamin D, some people have concluded that it is the increase in vitamin D that is causing their symptoms. However, since sunshine has many different effects, a number of possible reasons can be given for sensitivity to sunshine. Sunshine is definitely known to be an immunosuppressive. It has well known suppressive effects on the skin immune system, which is one of the reasons why skin cancer occurs due to overexposure to the sun. It can also suppress skin reactions to antigens that the skin comes in contact with.
But there are some researchers who believe that sunshine can have other effects on the systemic immune system, in ways that have nothing to do with vitamin D. For example, one study has shown that exposure to sunlight caused an increase of the serum level of inflammatory cytokines IL-8 and TNF-alpha. This is probably due to the fact that these cytokines are known to be produced in the skin due to sunlight exposure. Whether it’s possible that a significant amount of these cytokines can enter the serum and cause systemic effects is still debatable, as another study using shorter exposure to sunlight, showed that there was no rise in cytokines after sunlight exposure. However, there might be more subtle changes to the immune system that have not yet been studied. For example, one study has shown a change in the number of a certain type of immune cell in the serum, due to sunshine exposure.
But whether cytokines are elevated or not, the effect of sunlight on melatonin production is definitely a significant effect. Light suppresses melatonin production, and avoidance of sunshine would raise melatonin production. Melatonin is known to have significant effects on the immune system. Anecdotal reports in the medical literature of sarcoidosis being treated with melatonin have been known for many years, and a 2006 open pilot study has shown that melatonin can indeed be an effective treatment for sarcoidosis.
Melatonin is a potent antioxidant. For example, a recent lab study has shown that it can reduce inflammatory injury from colitis, via the inhibition of NF-kappaB. Melatonin has also been found to help conditions such as IBS, CFS, and fibromyalgia.
The MP not only recommends avoiding sunlight, but also recommends wearing noir sunglasses, even indoors. Since melatonin production is mainly affected by exposure of light on the eyes, such a protocol could easily be expected to significantly alter melatonin levels.
On the other hand, the effects from melatonin are complex, as both stimulating and suppressing effects on the immune system have been observed. If indeed melatonin can help a condition such as sarcoidosis, it would be pure speculation as to how it might be able to help, due to a lack of data. Indeed, it’s possible that melatonin might help some conditions, while it might hurt others. Thus, the increase in melatonin might be the reason why some people feel worse when they start the MP and avoid bright lights.
However, for those people who like to speculate, here’s an interesting thought. Melatonin is produced from tryptophan. And since tryptophan levels are low in sarcoidosis and other conditions, due to IDO being elevated, perhaps melatonin levels are also decreased because of that.
It’s also possible that some people with certain conditions are more susceptible to suppression of melatonin. A recent study has shown that people who experience migraines, are supersensitive to the effects of light. In response to light, their melatonin levels decrease much more than in the average person. This is believed to be due to the hyperexcitability state of their nervous system. It would be very interesting to see if sensitivity was altered in TH1 and other chronic conditions. Unfortunately, no studies on this have been done. If sensitivity was found to be elevated, it might explain the light sensitivity that people on the MP have reported.
Sensitivity to light may also be due to a magnesium deficiency. Light sensitivity has long been claimed to be a symptom of a magnesium deficiency. Some people believe that light sensitivity that occurs during a hangover, is due to the drop in magnesium levels that occurs due to alcohol. A magnesium deficit would increase excitability of the nervous system, which could in theory cause light sensitivity.
One researcher has postulated further that light sensitivity, magnesium depletion, and disturbed melatonin production, are all related, and that this condition could possibly be treated with a combination of magnesium supplementation and darkness therapy. This is. however, speculation. Nevertheless, magnesium deficiency is a more common problem than many people realize, and high level magnesium supplementation has been found to be very useful in chronic conditions such as fibromyalgia and CFS. The MP, however, does not make use of it. Perhaps if it did, light sensitivity and other symptoms might be reduced.
The MP claims that it’s treatment can normalize low thyroid levels. The MP also claims it can treat Hashimoto's thyroiditis, an autoimmune form of hypothyroidism, where autoantibodies react against the thyroid gland. Considering that increased levels of thyroid autoantibodies and cases of Hashimoto’s have been found in sarcoidosis patients, there might indeed be a connection between these autoantibodies and sarcoidosis. Immune increasing therapies such as IL-2 and IFN-alpha, which have been known to trigger sarcoidosis, have also been known to trigger autoimmune hypothyroidism. Thus, increased cytokines may play a role in autoimmune hypothyroidism, just as it does in sarcoidosis. Indeed, excess TH1 production is a characteristic of Hashimoto’s, and reducing the TH1 response can help Hashimoto’s. Thus, it may be possible that a therapy that treats sarcoidosis by reducing the TH1 response, may also have a positive effective on Hashimoto's thyroiditis,.
However, it's also possible that lowering inflammation, may help to normalize low thyroid levels, even in cases of hypothyroidism that don’t involve autoantibodies. That's because the cytokine IL-6 has been shown to correlate with lower levels of the T3 thyroid hormone in inflammatory conditions, which is possibly due to the fact that IL-6 has been shown to inhibit the conversion of T4 to T3. If the MP is capable of lowering inflammatory cytokines, then it might be capable of lowering IL-6. In support of this theory, is the fact that angiotensin II is known to increase IL-6 levels, and some studies show that Benicar can lower IL-6 levels. Thus, Benicar might be able to increase levels of T3.
Thus, there are some possible valid reasons why the MP could affect thyroid levels. However, the MP has made further claims that vitamin D is capable of interacting with thyroid receptors. This claim is based solely on the results of a computer simulation program, and not a real lab test. Also, this simulation showed that vitamin D only affects the alpha-1 thyroid receptor. But this particular receptor is not significantly involved in the regulation of TSH, the hormone that stimulates the production of thyroid hormones: Thus, even if vitamin D could interact with this thyroid receptor, it would not likely have an effect on TSH or thyroid levels. Indeed, studies on commonly accepted therapeutic dosages of 1,25(OH)2D, do not show any effect on TSH levels:
On the other hand, it should be noted that extremely high levels 1,25(OH)2D may increase TSH levels: This effect, however, is not related to thyroid receptors, but is due to an increase in TSH production, in response to stimulation from TRH, the hormone created by the hypothalamus which triggers the pituitary gland to release TSH. Indeed, other studies have found that 1,25(OH)2D was capable of increasing prolactin, another hormone controlled by TRH.
But these studies involved using very high doses of 1,25(OH)2D. Most people, including patients using the MP, do not have such high levels. This would explain why there are no case studies of elevated levels of 1,25(OH)2D being associated with elevated levels of TSH. This result seems logical, when you consider the fact that 1,25(OH)2D circulates at a much lower level than most hormones. For example, free levels of the T3 thyroid hormone circulates at a level of 1/200 of the level of free 1,25(OH)2D, so it seems unlikely that such low doses of 1,25(OH)2D could affect thyroid receptors. And in fact, the amount of 1,25(OH)2D that the thyroid receptors would be exposed to, is probably even much less, given that much of the free 1,25(OH)2D would be attaching itself to vitamin D receptors instead of thyroid receptors. Thus, even if 1,25(OH)2D was capable of interacting with thyroid (or other hormone) receptors, it’s very unlikely that 1,25(OH)2D could be present in an amount great enough to significantly interact with those receptors
The MP states that Benicar is the most useful in treating inflammatory conditions. This has actually been confirmed in a lab study on the use of ARBs in experimental arthritis (non-bacterial form). ARBs were shown to reduce the severity of the arthritis, by their ability to reduce TH1 responses. And Benicar was shown to be the best at doing this. This study also showed that constant high doses were necessary to achieve significant results. This is also in agreement with the protocol, which states that it's important that Benicar be constantly taken.
Such an effect might be important for certain inflammatory conditions. For example, in rheumatoid arthritis, it’s been found that ACE levels in the synovial fluid are greatly increased, and may be contributing to joint destruction. Thus, Benicar may be useful in treating such arthritic conditions, by blocking angiotensin II.
Benicar may be particularly useful for certain inflammatory diseases, because out of several ARBs, it appears to be especially effective at reducing advanced glycation end products, an effect which is believed to be independent of it’s ability to block angiotensin II. Additionally, Benicar is capable of blocking advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression RAGE has been found to play a role in a number of inflammatory diseases, including rheumatoid arthritis and sarcoidosis. RAGE may also be involved in fibromyalgia.
The MP believes that Benicar works the best because of some special property that it has that other ARBs don’t have. Besides the VDR theory, another MP theory is that it is interacting with receptors on cell wall deficient bacterium, which the protocol believes is the cause of many inflammatory conditions, including sarcoidosis. Some cell wall deficient bacterium have been found to have receptors that respond to angiotensin II. However, these receptors are definitely not angiotensin II specific receptors, as they also respond to angiotensin I. Not only that, but they also react to other, totally unrelated proteins. On the other hand, they have not responded at all to several ARBs that were tested. This is not surprising, considering that ARBs were designed to only interact with one particular type of angiotensin II receptor, AT1. ARBs interact very little with other angiotensin II receptors, such as AT2. Their binding potencies to AT2 are often thousands times less when compared to AT1. And while Benicar has not been tested with these bacterium, there’s no evidence that it would interact with them. This is especially true, considering that Benicar was designed to interact with AT1, much more specifically that any other ARB. And while some of the other ARBs are known to partially interact with other non-angiotensin II receptors, no real study has shown this to be the case with Benicar. Thus, Benicar appears to be the least likely ARB to interact with a totally different type of receptor, such as the one found in these bacterium.
The study of ARBs on experimental arthritis did not involve bacterium at all. ARBs worked due to the suppression of TH1 responses. Benicar was found to be the most potent at doing this. Thus, this appears to be the more likely reason why Benicar has been found to work the best in the protocol.
ARBs such as Benicar appear to have multiple benefits for inflammatory conditions. As previously mentioned, at least one study has shown that ARBs can reduce TH1 inflammatory effects. One possible reason for this may be the previously discussed ability of angiotensin II to stimulate IFN-gamma production in T cells. ARBs would thus reduce this effect, leading to a reduction of macrophage activation.
However, another property of
angiotensin II, which is being intensely studied, is it's effect on adipose fat
fat cells have only been recently been recognized as possibly playing a
significant role in many inflammatory conditions. These cells, known as adipocytes, secrete a
group of substances known as adipocytokines. Some of these adipocytokines
are well known inflammatory cytokines such as TNF-alpha and IL-6. Others
are unique substances, such as the hormone adiponectin. This hormone is
the most abundant hormone in the blood stream, at a level that is 3 times
higher than any other hormone.
One of adiponectin's main effect appears to be to an ability to control insulin sensitivity. Adiponectin levels inversely correlate with insulin sensitivity and obesity. Adiponectin also appears to have anti-inflammatory properties, which may play a role in the vascular inflammation that is associated with obesity. Adiponectin has been shown to have anti-inflammatory effects on both adipocytes and macrophages, causing suppressed production of TNF-alpha and IL-6. The factors that control adiponectin levels are still being studied, but one class of drug that appears to increase adiponectin levels are ARBs. ARBs have been found to elevate adiponectin levels, and at the same time reduce insulin resistance,
An improvement of insulin sensitivity and glucose control have been well noted by people on the MP. This effect alone may be significant to some people. For example, a significant number of people with fibromyalgia have found improvement of symptoms on low carbohydrate diets, possibly due to such diets reducing the effects from insulin resistance. ARBs ability to treat insulin resistance may be an important property from many chronic diseases.
Benicar has been shown to be capable of significantly
increasing adiponectin levels. Thus,
this could be yet another significant anti-inflammatory effect of Benicar.
On the other hand, some studies have indicated a pro-inflammatory effect from adiponectin. This apparent conflict may have been resolved by a recent study which showed that indeed adiponectin did cause an increase in pro-inflammatory cytokines production by macrophages. However, "pre-treatment of macrophages with adiponectin and subsequent re-exposure to it resulted in the development of tolerance. This effect of adiponectin appears to be much more fundamental since it made macrophages also tolerant to other powerful pro-inflammatory stimuli." In other words, "adiponectin, by being constantly high in lean individuals, renders macrophages resistant to pro-inflammatory stimuli, including its own."
This complex property of adiponectin means that an increase in adiponectin does not necessary mean an immediate anti-inflammatory reaction. In fact, just the opposite, that initially an inflammatory reaction can occur. If an ARB was truly capable of causing an increase in adiponectin, this might initially cause a worsening of inflammatory symptoms. Therefore, this could explain why some people feel an initial bad reaction to taking Benicar, which the protocol theorizes is due to a herxing reaction.
This property might also explain the observation that ARBs need to be taken at a constant high dose in order to achieve a significant reduction in TH1 inflammatory responses. This may be due to the fact that adiponectin must be kept at a relatively constant, decently elevated level, in order to provide an anti-inflammatory response.
Adiponectin has been found to have a further ability, that of being able to bind to bacterial LPS and to neutralize it’s effect, and thus be capable of moderating the inflammatory response to infections.
Interestingly, the immune elevating therapy that is used in HIV, that is known for triggering autoimmune problems like sarcoidosis, just so happens to contain a class of drugs whose side effect is to reduce adiponectin levels. One could speculate that this might be a possible reason why such therapy can trigger inflammatory conditions.
The multiple effects of blocking angiotensin II, have caused ARBs to be used for some conditions, without it being known why they work. For example, ARBs have been found to be useful in preventing migraines, even though the reason why they work is still “a matter of speculation.”
ARBs also may have the ability to suppress the central nervous system's reactions to stress. This is likely due to the fact that angiotensin II is able to stimulate the sympathetic nervous system, and ARBs block this effect. Reducing this stimulation can not only reduce stress, but can indirectly affect the immune system, as stress increases levels of glucocorticoids and catecholamines, which influence the immune system. A stress reduction effect might be especially beneficial for fibromyalgia, as there is much evidence that shows that the sympathetic nervous system is in a hyperactive state in fibromyalgia. Reducing the sympathetic nervous system might also help to undo tense muscles in fibromyalgia. This effect appears to vary in different ARBs, as a study that compared several ARBs, showed that not all of them had the same level ability to reduce noradrenalin sensitivity, at comparable doses. Additionally, the study showed that the effect was dose dependent, sometimes requiring a high dose for the effect to be noticed. Benicar has not be studied for this effect, so it’s possible that Benicar has this potent ability at doses being used, and the high doses that the MP requires, might be because this effect is only noticeable at that level.
Certain ARBs are capable of increasing serum uric acid. Uric acid is a potent antioxidant, with the ability to scavenge peroxynitrite. Such an effect could be significant for many of the conditions that the MP claims to treat. One study has proposed that Benicar might be capable of increasing serum uric acid. However, this has yet to be proven in an actual clinical study. On the other hand, this effect might only be seen with very high doses of Benicar, as used by the MP. Additionally, there have been a few reports of people on the MP who have noticed increased serum uric.
ARBs also are able to enhance blood flow in muscles, by blocking the vasoconstriction effects of angiotensin II. And ARB’s ability to improve insulin sensitivity, can further help muscle functioning. Finally, ARBs also have an antiplatelet effect (via the release of nitric oxide). This might further help fibromyalgia (for information regarding this, see my web page on the guaifenesin treatment for fibromyalgia, as guaifenesin not only can relax muscles, and but it also happens to have an antiplatelet property, which could play a role in its treatment of fibromyalgia.)
The possibility that lowering angiotensin II might be of help in some people with fibromyalgia, CFS, and chronic Lyme, is supported by the fact that 2 alternative therapies use salt supplementation. Salt increases water retention, which reduces the production of angiotensin II. A popular remedy for fibromyalgia is a supplement known as Recuperat-ion. This is supposedly a mineral supplement, yet it basically only contains tiny amounts of magnesium and calcium, a very small amount of potassium, but a lot of sodium. Similarly, there is a popular treatment plan for Lyme, which uses vitamin C and a huge amount salt. The reason for using salt in that treatment, is the belief that salt helps to kill the Lyme bacteria (although no study has shown that a high salt diet is useful for against any known infection). We believe that it is too coincidental that 2 remedies are using salt for conditions that often overlap, and believe it likely that both treatments are effective for the same reason, namely salt’s well known effect on blood volume. Low blood volume is a problem for many people with fibromyalgia and CFS, so salt’s water retention ability could be the useful effect. However, the reduction in angiotensin II could just as well be the important effect, because that would have benefits for everyone, not just people with low blood volume. While the MP believes that lowering angiotensin II is not effective, and that only blocking it is useful, this belief was mainly based on experience with the MP for sarcoidosis. Simply lowering angiotensin II, may be useful for other conditions that are not autoimmune diseases.
Wearing noir sunglasses is part of the MP treatment. These glasses block both visible and nonvisible light, and the MP claims that they are necessary to reduce neurological symptoms associated with TH1 diseases. The MP says these symptoms include "fatigue, irritability, aggressiveness, lack of concentration, brain fog, photosensitivity, transient loss of memory, mood swings, confusion, anxiety, anger, neurosis and even psychosis."
Increased eye sensitivity to light, or photophobia, is often mentioned in the medical literature as being a symptom seen in sarcoidosis. This is not surprising, given that several different types of inflammatory eye conditions are frequently seen in conjunction with sarcoidosis. In fact, one article has stated that "ocular involvement may also be the initial manifestation of sarcoidosis in many patients." But sarcoidosis is not the only inflammatory disease that is associated with eye disorders. Ocular involvement is also seen in many other autoimmune diseases.
However, the medical literature does not recognize that these eye problems are associated with neurological symptoms. Indeed, the main reason for which the MP recommends NOIR glasses, is not due to any existing eye problem. Instead, the MP believes that photophobia and neurological symptoms occur due to the MP treatment itself, and that NOIR glasses must be worn before starting Benicar, in order to avoid these symptoms. This belief is so strong, that the MP has stated that not wearing the glasses was not an option. However, little proof was provided. Indeed, after many years of making this claim, the MP is now saying that not everyone develops photosensitivity, and that some people might even be able to do the MP treatment without having to avoid sunlight and bright light.
But how is it that the MP treatment can cause photophobia to occur in some people? The MP has given several theories as to why this eye sensitivity occurs. One is that "the eyes have a complete, self-contained, renin-angiotensin system in them." However, if angiotensin II was the cause of the problem, then high levels of Benicar would suppress the condition, not increase it. Another theory is that increased vitamin D production occurs due to light exposure on the eyes. However, while vitamin D receptors have been found in retinas, no study has shown evidence for production of vitamin D in the eyes. Besides which, even if either of these theories are correct, then eye inflammation should also be occurring, and that could then be detected by an eye exam.
However, the main theory given for the eye sensitivity to light, is that light causes "stimulation of the amygdala in the brain", and that this leads to the neurological symptoms. The amygdala is a portion of the brain that is involved in emotional responses, particularly in those relating to fear. Thus, stimulation of the amygdala could cause many neurological symptoms. And in fact, studies have shown a possible connection between panic and anxiety disorders, and amygdala functioning. However, why would light provoke a fear response from the amygdala? Humans are normally afraid of darkness, not light.
But studies do show that some people with panic disorders suffer from photophobia. Indeed, according to this study, “Light hypersensitivity has often been considered a possible factor of panic attack pathogenesis, and several studies suggest a neurobiological hypothesis to explain the relation between light and panic attacks.” Thus, light may indeed cause neurological problems in some people. However, even though this photophobia may be a true physiological problem, it was found that this symptom could be significantly reduced via cognitive behavioral therapy. Perhaps since light triggers panic attacks in these people, that light itself becomes something to fear, and this then causes light to be even a greater trigger for panic. Cognitive behavioral therapy then helps to overcome this fear, and reduce symptoms.
Thus, it is possible that the belief that light is dangerous, can lead to an increased fear response to light, which can then lead to increased neurological symptoms. A different example of this is found in the medical literature, where a boy became very afraid of light, due to the fact that it would trigger seizures. Using cognitive behavioral therapy, the boy was not only able to eliminate his fear of light, but to also greatly reduce his seizure response to light, to the point that the boy was able to discontinue his anti-seizure medicine.
If fear of light can be a factor in photophobia, then it seems possible to us that if someone believes in the MP’s theory that light was harmful, then this belief could lead to a fear of light. Perhaps this by itself would not lead to photophobia. However, it might be a significant factor, if this fear is also combined with the avoidance of sunlight and wearing NOIR glasses. These two actions would seem to likely cause the eyes to be less accustomed and more sensitive to bright light. Exposure to bright light would then become uncomfortable, so that this physical response, combined with the fear of light, could be a strong enough trigger to provoke photophobia and neurological symptoms.
Many people with the chronic diseases that the MP are helped by taking antibiotics. But are the infections that they treat, the cause of the condition, or are they the result of the condition? For example, significant immune hyporesponsiveness is present in sarcoidosis. Could this fact make people with sarcoidosis more susceptible to the immunosuppressive effects of 1,25(OH)2D. Sarcoidosis is well known to be "associated with anergy (poor response to antigens in vitro and in vivo)”, and this effect appears to be due to very high levels of regulatory CD4+CD25+ T cells. These T regulatory cells promote immune tolerance and protect against autoimmunity. One study on sarcoidosis has found very high serum levels of these cells. In fact, according to that study, “there is no clinical situation in which a T reg amplification of such magnitude (up to 21% of CD4+ T cells) has been found in the blood of patients.” A deficiency of these cells is believed to be a factor in some autoimmune diseases such as rheumatoid arthritis. On the other hand, an excess of these regulatory cells can suppress immune responses to infections, and may play a role in creating chronic infectious states. Because of this, the study on sarcoidosis concluded that people with sarcoidosis might be more susceptible to infections.
These CD25 regulatory cells are also able to inhibit the expression of inflammatory cytokines by T cells. However, they aren’t efficient at reducing levels of IFN-gamma and TNF-alpha, cytokines which are critical for the formation of granulomas. So while the granuloma immune response may not be significantly reduced by these regulatory cells, systematic immune responses in the rest of the body may be reduced by them in sarcoidosis. .
The formation of CD25 regulatory cells is critically dependent on the cytokine IL-2, and IL-2 is elevated in sarcoidosis. IL-2 is produced by activated T cells, and stimulates the growth of immune T cells, B cells, and natural killer cells. Because of these effects, IL-2 has been used to treat conditions that have suppressed immune systems, such as cancer and AIDS. However, macrophage immune cells also have IL-2 receptors, and IL-2 can increase macrophage production of IFN-gamma. Activation of macrophages and elevated IFN-gamma levels are well known and important characteristics of sarcoidosis. Thus, it’s not surprising that there has been a reported case of sarcoidosis reoccurring due to IL-2 cancer therapy. Indeed, there are examples of other immune upregulating therapies being able to trigger sarcoidosis. For example, interferon therapy for viral infections, which also increase IFN-gamma production, has also been known to trigger sarcoidosis. This implies that the state of the immune system can play a major role in the triggering and the resolution of sarcoidosis.
But the other half of the story is, of course, the effects of pathogens in sarcoidosis. New studies continue to be published that show evidence of mycobacterial infections in the granulomas of sarcoidosis. And there is new evidence that gram negative bacteria may be able to increase the levels of the cytokine IL-18 in sarcoidosis. This may be significant, since IL-18 can increase IFN-gamma production, and Il-18 levels have been found to be higher in sarcoidosis patients with disease progression. On the other hand, these studies show evidence not only for the presence of different strains of bacteria, but also for different forms of pathogens (i.e. fungi and viruses). The fact that no single pathogen has been identified as being associated with sarcoidosis, has led many researchers to theorize that while an infection is likely a trigger for sarcoidosis, that the true cause of sarcoidosis is a dysfunctional immune system. This conclusion is also based on the results of studies that show that the risk of sarcoidosis is strongly associated with genes that affect the immune system, and also that environmental and occupational risks factors increase the likelihood of sarcoidosis. This could explain why in some people, the disease resolves, simply due to the suppression of the immune system.
Nevertheless, in some people, infections could significantly affect the course of the disease. And the highly elevated levels of CD25 regulatory cells could increase the risk of secondary infections, confounding the situation. Indeed, one might speculate that secondary infections could be the reason why in some people, the disease does not easily resolve. And it could be the reason why antibiotic therapy could be effective in some people, as prescribed by the MP.
However, does 1,25(OH)2D significantly affect the immune system in sarcoidosis? The MP believes that it overly stimulates the immune system, but the medical literature extensively documents many immunosuppressive effects of 1,25(OH)D. If the latter is true, then the elevated levels seen in sarcoidosis, combined with the elevated CD25 levels, could lead to an immune system that was especially susceptible to infections. Regardless of what the effects of 1,25(OH)2D on sarcoidosis might be, the elevation of CD25 in sarcoidosis by itself, could be preventing proper immune responses to infections. This is one of many unique features found in sarcoidosis, which are not found in other inflammatory conditions. Any therapy that can effectively treat sarcoidosis, is thus treating a very unique condition. Such a treatment may not necessarily be as effective for other inflammatory conditions.
One possible reason for the lack of ability of CD25 to control sarcoidosis, is the elevated IL-6 found in sarcoidosis. Elevated IL-6 is known to be capable of suppressing the effects of CD25. And elevated IL-6 has been found to be associated with the chronic form of sarcoidosis. And, as we previously described, Benicar may be capable of lowering levels of IL-6. Thus, suppression of IL-6 by Benicar may be one way that the MP treatment specifically helps sarcoidosis. However, there are actually many unique ways that the MP treatment that could help sarcoidosis. But before I describe those, it will be helpful to first know about factors that influence granulomas.
The MP may not necessarily help all TH1 conditions, but there are reasons to believe that it has effects that may specifically help granulomatosis diseases.
Sarcoidosis is a granulomatosis disease with many complex features, the obvious one being the granulomas themselves. Knowing how granulomas are formed and sustained, can help one to better understand how ARBs and vitamin D affect sarcoidosis. The quotes below, describe some of what is known about the granuloma formation. While it’s a bit wordy, I think it’s worthwhile for people to read, to see how unique and complicated the granuloma process is. But feel free to skip to the next section. The quotes were taken from the following article:
Immunology Letters,Volume 92,
Issues 1-2 , 29 March 2004, Pages 135-142
T cell contributions to the different phases of granuloma formation
“Primarily, granuloma formation is a protective response to chronic infections with persistent pathogens. The function of the granuloma in infection is to contain the pathogen, thereby preventing dissemination of the organism and restricting the inflammation to protect surrounding healthy tissue. Nevertheless, chronic granulomatous inflammation can cause damage and fibrosis to surrounding tissue.”
“The process of granuloma formation can be divided into four phases: initiation, accumulation, effector, and resolution. Each of these phases involves T cells, which are absolutely required for the formation of the delayed type hypersensitivity (DTH) granuloma. During initiation, macrophages are attracted to the persistent inflammatory stimulus and begin to nucleate the granulomatous lesion. During accumulation, CD4+ T cells accumulate at the site and recruit other effector cells, including T cells, more macrophages and in some cases eosinophils. The accumulation phase is critical in granuloma formation, since without CD4+ T cells, the nascent lesion would not mature through the accumulation of effector cells. During the effector phase, various effector cells attempt to reduce the pathogen load through diverse mechanisms. Finally, once the threat from the pathogen has been reduced or eliminated, the infiltrating cell population is reduced and the formation of scar tissue is induced. “
“During the initiation phase, the basic structure of the granuloma is established by recruitment of specific cell types. Similarly, during the accumulation phase, effector cells are recruited to destroy the pathogen and strengthen the structure of the granuloma.” “Macrophages are a natural choice for the central mediator of initiation, since they are part of the innate immune system and are recruited early to the inflammatory site without the need for specific antigen recognition.“
“The involvement of T cells in initiation is more controversial, since it is generally expected that T cells require time for antigen presentation and subsequent activation before they can respond. In contrast to controlled experimental infections, T cells in an organism in the real world are constantly being activated in response to other antigenic challenges. Thus, it is possible that non-granuloma antigen-specific T cells may infiltrate and participate. Thus, while macrophages are likely to play the primary role in initiating granuloma formation, in a complex world of multiple infections, non-specific T cells may also play an auxiliary role. In summary, initiation is the least understood phase of granuloma formation. Whether different granulomas initiate by a common mechanisms or by different mechanisms such as frustrated phagocytosis, macrophage fusion or T cell induced macrophage activation remains to be seen.”
“In contrast to initiation, much more is known about the accumulation phase of the granulomatous response. While macrophages continue to have a significant role in inducing chemokines and adhesion molecules, CD4+ T cells are known to play the central role in recruiting and organizing effector cells at the site of granuloma formation”
“Intuitively, the accumulation of infiltrating cells at the developing granuloma is determined by the number of cells entering the granuloma balanced by the number of cells leaving the granuloma. Cells can be recruited to the granuloma from the circulation under the influence of chemokines and adhesion molecules. Recruitment is probably the major mechanism controlling the cellular composition of the granuloma, but survival may also contribute. “
“TNF has long been recognized for its important role in granuloma integrity. Recent evidence indicates that some of its effect may be mediated through regulation of cell recruitment. Severe combined immunodeficiency (SCID) mice, which lack B and T cells, are unable to form granulomas around schistosome eggs deposited during infection, but administration of exogenous TNF restores granulomas. This is likely to result from impaired chemokine secretion and recruitment of macrophages. In addition, though TNF has no chemoattractant ability of its own, it has been shown to cooperate with other chemokines in vitro to arrest the migration of T cells. Thus, TNF may aid in retaining T cells at the developing granuloma site.”
“While trafficking of cells to the granuloma is the main mechanism of accumulation in the granuloma, inhibition of apoptosis may also play a role. Granulomas are a site of intense inflammation where cells will eventually die, but the kinetics of death can be regulated by altering the apoptotic sensitivity for a population of granuloma-residing cells. This can contribute to the life span and character of the local inflammation.”
“Ideally, in an infection, the immune system specifically recognizes the invading pathogen and directs T cells specific for that pathogen to the inflammatory site. However, it is clear that, while initial T cell infiltration will be specific for local antigen, chronic inflammation, such as granulomas, will allow the recruitment of non-specific T cells. “ The data from various studies “favor a model of granuloma formation in which a few local antigen-specific T cell can initiate granuloma formation, followed by the arrival of non-specific T cells to the site. The proportion of local antigen-specific T cells can range from none to dominant in different granuloma models. In infectious granulomas where this is a strong systemic immune response, pathogen-specific T cells may dominate.”
“CD4+ T cells are essential to granuloma formation and function. In addition to their roles in the initiation and accumulation phases, CD4+ T cells are also thought to have important direct effector functions. In Th1 type granulomas as exemplified by tuberculous granulomas, CD4+ T cells are the main source of interferon-γ (IFN-γ) and augment the production of TNF by macrophages. IFN-γ is thought to activate macrophages to kill intracellular infections via acidification of the phagosomal compartment housing the infection and production of NO, which is thought to have potent bactericidal effects. CD4+ T cells must have roles other than NO induction, since CD4-deficient mice have poor granuloma formation and high mycobacterial loads despite near normal levels of IFN-γ and NO. IFN-γ appears to synergize with TNF to achieve bacterial control. Mice deficient in TNF form loose granulomas, which poorly control bacterial numbers. In summary, CD4+ T cells play an important role in the effector phase both by recruiting other effector cells and by secretion of effector cytokines.”
“Resolution of granuloma formation ends in fibrosis. Fibrosis serves to wall off the granuloma contents and is part of both the wound healing response and organ damage. Two cytokines have been implicated in granulomatous fibrosis, TGF-β and more recently, IL-13, both produced by a population of granuloma-homing T cells. TGF-β has also been found in fibrotic granulomas of human tuberculosis and sarcoidosis patients. “
Granulomas have a vital role in fighting severe forms of infections. But when granulomas don’t resolve on their own, or if the granuloma response is inappropriate for the presenting pathogen, or if the resulting inflammation is the source of severe effects, granuloma suppression is desirable. One then needs to use methods that lowers the immune system activity that drives granuloma formation.
One way of reducing granuloma activity is by blocking angiotensin II. Blocking of angiotensin II has been found to significantly decrease IFN-gamma production of T cells, by 30% in one study. This is significant, given that IFN-gamma is necessary for production of 1,25(OH)2D by macrophages in sarcoidosis. Interestingly, while it was known as far back as 1987 that angiotensin II can increase T cell production of IFN-gamma production, it's only been in the last few years that studies have been published regarding blocking this effect, in relation to treating inflammatory diseases.
There are several ways that T cells can become activated, which then leads to production of IFN-gamma. One way is due to the actions of dendritic immune cells (DCs).
Dendritic cells “are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes”. “Dendritic cells constantly sample the surroundings for pathogens such as viruses and bacteria. Once they have come into contact with such a pathogen, they become activated into mature dendritic cells.” They then are induced “to travel through the blood stream to the spleen or through the lymphatic system to a lymph node. Here they act as antigen-presenting cells: they activate helper T-cells and killer T-cells as well as B-cells by presenting them with antigens derived from the pathogen. Every helper T-cell is specific to one particular antigen. Only professional antigen-presenting cells (macrophages, B lymphocytes, and dendritic cells) are able to activate a helper T-cell which has never encountered its antigen before. Dendritic cells are the most potent of all the antigen-presenting cells.”
DCs may play an important role in autoimmune diseases such as sarcoidosis and Crohn’s, as studies show that DCs are present at the sites of inflammation in these diseases, rather than the spleen or lymph nodes. A recent study on sarcoidosis has concluded “unequivocally that DCs infiltrate into sarcoid granulomas in humans.” It was found that “the number of total blood DCs was significantly decreased in patients with sarcoidosis.” “A number of mature DCs infiltrated exclusively into the lymphocyte layer of the sarcoid granuloma. The decrease in immature blood DCs and the accumulation of mature DCs in the granuloma suggest that DCs experience a maturation process during or after their movement from the blood to the granuloma.” “It is hypothesized that the migrating DCs may regulate the T cell response in sarcoidosis”. “These findings suggest that the blood DC subsets may migrate into the affected tissues, contributing to the formation of the granulomas in sarcoidosis.”
Dendritic cells, like macrophages, produce ACE, and therefore angiotensin II. In fact, one study showed that DCs “expressed the highest level of ACE per cell among the human cells tested.” DCs also contain angiotensin II receptors. In a lab study, pre-incubation of DCs with angiotensin II increased the production of TNF-α by 80% and IL-6 by 50%. Thus, blocking angiotensin II can reduce TH1 cytokine production by DCs. Not only that, but angiotensin II can also affect the differentiation of DCs, so that blocking angiotensin II via ARBs, results in dendritic cells that are less active. A reduction of dendritic cell activity via Benicar may be able another way that it helps sarcoidosis.
1,25(OH)2D also plays a role in the activity of dendritic cells, but its effects are opposite to that of angiotensin II. 1,25(OH)2D affects the differentiation of DCs, both by preventing the generation of DCs from monocytes, and also redirecting already differentiated DCs toward a more immature stage, which promotes tolerance in the immune system, rather than activating T cells. However, the more mature a DC becomes, the less responsive it is to the effects of 1,25(OH)2D. It’s thus likely that the effects from angiotensin II, combined with other factors, offsets the effects of 1,25(OH)2D, resulting in the accumulation of mature DCs into granulomas, promoting their formation, and elevating TH1 responses and inflammation. And not only are mature DCs unaffected by 1,25(OH)2D, but they also produce 1,25(OH)2D themselves, just like macrophages do.
Another effect of 1,25(OH)2D is to increase the macrophage production of ICAM-1. ICAM-1 is “a cytokineinducible adhesion molecule that can be expressed on a variety of cells during inflammation. ICAM-1 is supposed to be of primary importance with regard to both cell recruitment and cell-cell interaction in the lung in various pulmonary diseases.” It “plays a major part in leukocyte homing to sites of chronic inflammation, which is a crucial step during the inflammatory response.” However, the study of 1,25(OH)2D’s effect on ICAM-1, demonstrated that “the expression of ICAM-1 on AM [alveolar macrophages] from patients with sarcoidosis is up-regulated and reflects disease activity in the pulmonary compartment. ICAM-1 plays a major role in granuloma formation.” ICAM-1 is very important in providing a proper granuloma immune response against infections. However, the study on ICAM-1 and sarcoidosis, concluded that “considering the role of ICAM-1 in cell-cell interaction, an increased release of 1,25-(OH)2D2 in granulomatous lung diseases may provide an amplifying loop in the immune response. It may contribute to the perpetuation of the alveolitis and subsequent formation of granulomata in sarcoidosis.”
Thus, in sarcoidosis, a reduction of 1,25(OH)2D could be specifically helpful, by reducing factors that promote granuloma formation.
The importance of T cells
in granuloma formation and inflammatory conditions, is well illustrated in AIDS
patients. Granulomas are rare in AIDS. The TH1 immune system is
depressed, with low amounts of the TH1 cytokine IL-12, and low levels of CD4 T
cells. Additionally, serum 1,25(OH)2D is often either severely depressed,
or totally non-existent (possibly due to certain HIV drugs that prevent
1,25(OH)2D production). Serum ACE is sometimes elevated, but this is most
likely due to the widespread renal disease that occurs in association with
However, autoimmune and inflammatory diseases in AIDS have been triggered by using therapies that increase the immune system, such as the HAART therapy. Cases of sarcoidosis, excess 1,25(OH)2D production, and hypercalcemia, have been known to occur in conjunction with HAART. These cases seem to occur when CD4 levels are raised to a certain level. However, even at that level, CD4 levels are still quite low. So how could such a strong immune response like sarcoidosis, occur in a suppressed immune system? I believe it is due to something that AIDS, sarcoidosis, and if Crohn's all have in common, which is that TNF-alpha is elevated, and that it plays a major role in all these diseases.
Elevated TNF-alpha is often a marker for activated macrophages. Macrophages are activated in AIDS, sarcoidosis, and other inflammatory conditions, and macrophages are a significant source of TNF-alpha.
TNF-alpha is also an essential component in granulomatous diseases, such as sarcoidosis. TNF-alpha is necessary for the formation of granulomas. One study has shown that the release of TNF-alpha by macrophages was much better at predicting the prognosis of the sarcoidosis, than ACE.
Crohn's disease is also associated with granulomas. Not only are intestinal granulomas quite commonly found, but granuloma skin lesions occur in a significant percentage of patients. These skin granulomas can occur, even when intestinal symptoms are not present. This is not surprising, given that TNF-alpha levels are still very high, even when the disease is in remission.
The TNF-alpha inhibitor drug Infliximab, has been successfully used to treat several diseases where excess TNF-alpha is present. However, TNF-alpha inhibitors do carry risks. For example, tuberculosis, which is another granulomatous disease, is due to a bacteria which often is not actually eradicated from the body, but is simply isolated inside granulomas, causing the disease to became latent. The inhibition of TNF-alpha, can lead to a breakdown of these granulomas, freeing the tuberculosis bacterium, and causing a reactivation of the disease. Proper testing for tuberculosis and other similar granuloma infections can avoid these risks. An increased risk of other types of infections have been noted. However, while the MP claims an increased risk of cancer from this type of treatment, the actual observed increased risk has been found to be very small.
Since anti TNF-alpha treatment can lead to the reactivation of tuberculosis, by releasing the bacteria from granulomas, one might speculate that the breakup of granulomas in sarcoidosis, would cause similar adverse effects, if pathogens resided in them. However, infliximab has been used successfully in sarcoidosis, without evidence of immune problems. In fact, infliximab has been able to treat sarcoidosis patients, who did not respond well to the normal treatment of corticosteroids and other immunomodulatory agents. And infliximab has allowed these patients to be able to reduce their use of these other drugs.
In pulmonary sarcoidosis, macrophages are believed to be the main source of TNF-alpha.
Sarcoidosis patients who are resistant to corticosteroid treatment,
often have significantly elevated TNF-alpha secretion from macrophages.
Lupus pernio, a skin condition that can sometimes occur with sarcoidosis,
has been found to respond to anti-TNF treatment. This
condition has been found to be significantly associated with patients who develop the chronic
form of sarcoidosis, rather than the form that undergoes remission.
But another factor that increases the level of TNF-alpha, is the number of immune cells. T cells such as CD4 are key to granuloma formation. Controlling apoptosis of T cells is apparently very important to proper treatment, as it's been found that the TNF-alpha inhibitors which are the most effective, are the ones that increase CD4 apoptosis.
It's interesting to compare
sarcoidosis with another granulomous disease, tuberculosis. In both
cases, 1,25(OH)2D is produced by the immune system. However, there are
some important differences. One is that a lack of vitamin D has been
associated with a greater risk of developing tuberculosis. Secondly,
decreased IFN-gamma levels in tuberculosis is often associated with more severe
symptoms, due to the fact that the immune system is not reacting strong enough
to contain the infection. Administration of IFN-gamma appears to have
beneficial effects on resistant forms of tuberculosis. On the other hand, therapies that increase
IFN-gamma, are known to worsen sarcoidosis.
So while both sarcoidosis and tuberculosis are granulomous diseases, in which macrophage production of 1,25(OH)2D occurs, treatment of them is drastically different. Treatment of one involves suppressing the immune system to reduce inflammation, while the other involves stimulating the immune system. One cannot assume that reducing 1,25(OH)2D would be beneficial for any given disease, simply based on the presence of TH1 production of 1,25(OH)2D. When excess 1,25(OH)2D levels occur, it is of course prudent to reduce it. But when that is not the case, it would only make sense to reduce it, if there is a clear indication of excess or dysfunctional macrophage activation.
It’s interesting to note, that in a study comparing sarcoidosis and tuberculosis, TNF-alpha was only significantly elevated in the serum and bronchial fluid of sarcoidosis patients, but not in tuberculosis. Additionally, unlike sarcoidosis, where blocking TNF-alpha has been found to be useful, TNF-alpha is essential for the immune system for fighting tuberculosis, and blocking it would worsen the infection. Since 1,25(OH)2D has been found to be useful in fighting tuberculosis, perhaps increased amounts of 1,25(OH)2D are only detrimental, for conditions when TNF-alpha levels are either elevated, and/or not helpful for recovery from the disease.
There are many studies indicating that angiotensin II increases TNF-alpha in many organs or cells, such as skeletal muscle, cardiac fibroblasts, monocytes, and the kidneys. ARBs can sometimes reduce TNF-alpha, and this effect appears to be more potent in ARBs than in ACE inhibitors (ACEIs). This might be one reason why the MP claims that only ARBs are useful, and not ACEIs. It would also explain why the protocol believes that Benicar helps to suppress the Jarisch-Herxheimer reactions that occur from bacteria die off. Elevation of TNF-alpha has been shown to occur in a Jarisch-Herxheimer reaction, and one study has shown that this reaction was suppressed by the anti-TNF drug Inflimixab. Thus, ARBs, and perhaps particularly Benicar, may have a strong ability to suppress TNF-alpha, and this could account for part of their usefulness.
Excess TNF-alpha, may be an
important factor in bone density loss seen in some TH1 conditions. For example, in a Crohn's study on patients
with elevated 1,25(OH)2D, there was a correlation between elevated 1,25(OH)2D
levels and decreased bone mass density (BMD). On the other hand, in
comparison to Crohn's, a study on BMD in sarcoidosis patients showed much less
significant effects from 1,25(OH)2D, except in patients who were older
women. Increased levels of 1,25(OH)2D
are much more common in sarcoidosis than in Crohn’s, so why the
difference? Here's one possible
explanation. TNF-alpha levels in
Crohn's, are far in excess of levels seen in any other condition (it's 640
times the normal level of TNF-alpha).
Excess TNF-alpha production in bone cells, causes bone loss, via several possible different mechanisms. Thus, serum TNF-alpha may have an effect on bone loss, especially if the levels are very high. In fact, a recent study has shown that the anti-TNF drug Inflimixab improves BMD in Crohn's patients. Additionally, the reason that decreased BMD in sarcoidosis mainly only occurs in older women, could possibly be due to the fact that older women are more likely to have decreased estrogen levels, and decreased estrogen is known to increase TNF-alpha production in bones.
Thus, perhaps it’s the TNF-alpha, and not elevated 1,25(OH)2D that is the major cause bone loss in these conditions. Indeed, according to a recent lab study, “exogenous 1,25(OH)2D3 increased serum calcium independent of PTH, not due to increased bone resorption, but likely due to increased intestinal calcium absorption in association with increased renal calcium reabsorption facilitated by enhanced expression of renal transporters. Endochondral bone formation was augmented, which emphasizes the important role for the active form of vitamin D in growth and which may indicate an important role for this sterol in facilitating the achievement of peak bone mass. Exogenous administration of 1,25(OH)2D3 also, independently of PTH, increased both cortical and trabecular bone.”
Additionally, the MP has attributed many sarcoidosis symptoms, such as pain and fatigue, to the elevated 1,25(OH)2D. However, the symptoms may be related to another problem commonly found in sarcoidosis, known as small fiber neuropathy, or SFN. SFN is a type of neuropathy which is easy to misdiagnose, which is why it's often been overlooked. Common symptoms of SFN are both pain and fatigue, but many other seemingly unrelated symptoms are often associated with it. There are several possible factors that play a role in SFN, and one of the prime factors is TNF-alpha. In fact, a patient with sarcoidosis and SFN, had her SFN successfully treated by anti-TNF alpha therapy. Thus, it’s possible that symptoms attributed to 1,25(OH)2D, are actually due to TNF-alpha..
Beyond the scope of this article, is the possibility that the antibiotics that are used by the MP, may be effective due to their anti-inflammatory and other effects. For example, minocycline is well known to have anti-inflammatory effects, and has been found to be useful in rheumatoid arthritis. It also has neuroprotective and analgesic effects. Zithromax also is known to have anti-inflammatory effects, and it has been found to beneficial for the lung disease cystic fibrosis.
Clindamycin may also have anti-inflammatory effects. Some studies show that its anti-inflammatory effects require very high concentrations. However, these effects might still be present in the MP, because clindamycin concentrations in lung macrophages has been found to be huge, due to an active transport process into the cells. Interestingly though, clindamycin’s ability to fight certain intracellular bacteria was shown to be very low. Perhaps it’s effectiveness in the MP, therefore, is not due to it’s ability to fight intracellular bacteria, but is due to other abilities, such as it’s anti-inflammatory effects.
Also, even if the anti-inflammatory effects of these antibiotics is individually low, perhaps the effect is much stronger when combined together, as recommended by the MP.
As an aside, the MP claims that using these 3 antibiotics together provides superior bacteria killing, because they act in different ways. It is true that combining antibiotics with different modes of action is often more effective than using a single antibiotic. Minocycline is a tetracycline antibiotic, while zithromax and clindamycin are two different forms of macrolides. They do indeed act somewhat differently, in that they bind to different areas of bacteria RNA. Nevertheless, their main mode of action is still similar, i.e. they act by inhibiting protein synthesis. And because of this similarity, if bacterial resistance to one of these drugs occurs, resistance to one of the drugs may also occur. This cross resistance not only occurs between macrolides, but it also occurs between macrolides and tetracyclines, “mostly because their major resistance determinants are carried on the same mobile element.” Indeed, for some infections, resistance to macrolides is much more likely to occur, when the macrolides are combined with tetracyclines. And even if cross resistance doesn’t occur, the overuse of macrolides is known to result in resistant bacteria. According to a recent article: “Macrolide use is the single most important driver of the emergence of macrolide resistance in vivo. Physicians prescribing antibiotics should take into account the striking ecological side-effects of such antibiotics.”
According to people’s experiences of the MP, as recorded on the web, the MP treatment does appear to help some people with sarcoidosis. It may also be helping other conditions, but if it does, there is no guarantee that it is working in the same way that it helps sarcoidosis. This is because Benicar has many effects that could be beneficial for a host of different conditions. And antibiotics have long been known to be beneficial for some of the conditions that the MP claims to treat. It may be possible that either one or both of these remedies may be the primary reasons for the benefits of the MP for some people. The lowering of vitamin D levels may not necessarily be a factor. However, there is no way of knowing this, given that people who start the MP are first told to reduce their vitamin D, before they start take Benicar and antibiotics.
Also, it is invalid to claim that feeling good on the MP proves that reducing vitamin D helps. This is because many of the effects of a vitamin D deficiency can be offset by simple measures. For example, the major negative effect of a vitamin D deficiency, which is reduced calcium absorption and increased PTH levels, can mostly be offset by supplementing with sufficient calcium. Other possible negative effects from a vitamin D deficiency, such as insulin resistance and increased cancer rates, might be offset by the positive effects which Benicar has on these conditions. And the reduced infection fighting ability of vitamin D, can be offset by the antibiotics that are used by the MP. Thus, the negative aspects of a vitamin D deficiency are likely being offset by the MP treatment. Therefore, the fact that some people are doing well on the MP, doesn’t necessarily mean that the decrease in vitamin D is necessary. And since everybody on the MP reduces their vitamin D level, there is no way of knowing whether this aspect of the treatment plan is necessary for every condition.
And now, congratulations to anyone who has actually read everything up to here. I’m glad someone found it interesting enough to read. If you have questions about any medical condition and treatments for them, I highly suggest that you not only learn how to use PUBMED, but also visit sites such as groups.yahoo.com,, where you can find many discussion groups on just about every known health condition out there, and where you might find people who used to be on the MP treatment.
Mark London MRL@PSFC.MIT.EDU