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+ | **Type:** Presentation\\ | ||
+ | **Presenter: | ||
+ | **Conference: | ||
+ | **Location: | ||
+ | **Date: | ||
+ | **Related content:** [[https:// | ||
+ | |||
+ | |||
+ | |||
+ | ===== Transcript ===== | ||
+ | |||
+ | |||
+ | Hi. I hope your coffee break has you all alert enough that I won’t | ||
+ | put you to sleep. Actually, I think there is some exciting new | ||
+ | information here, and I hope it will interest you. | ||
+ | The title here refers to vitamins D, no that isn’t a typo, we use | ||
+ | vitamins D since there are many forms of vitamin D. Actually, it is | ||
+ | not really a true vitamin, since our bodies produce it, with the aid | ||
+ | of the sun. It is actually better, in our view, to think in terms of a | ||
+ | steroid hormone and it’s precursors. | ||
+ | |||
+ | You might ask, why is vitamin D important? As you probably know, | ||
+ | the Marshall Protocol or MP that we have been discussing at this | ||
+ | conference includes a reduction of vitamin D to help improve | ||
+ | immune function and bacterial killing. We need to discuss this in | ||
+ | detail because there are widespread misunderstandings about | ||
+ | vitamin D among people who are not aware of the true | ||
+ | importance of some recent discoveries. | ||
+ | |||
+ | There are some researchers that seem to be saying we all need to | ||
+ | take more vitamin D and we think this is wrong and this | ||
+ | presentation will explain why. | ||
+ | |||
+ | |||
+ | I’m going to talk mostly today about the material covered in a | ||
+ | book chapter, “High levels of active 1,25D despite low levels of | ||
+ | the 25D precursor — implications of dysregulated vitamin D for | ||
+ | diagnosis and treatment of chronic disease.” It should be coming | ||
+ | out in a month or so. | ||
+ | |||
+ | I will present research to back our view that Vitamin D | ||
+ | dysregulation due to Th1 inflammation is widespread and is a | ||
+ | result of macrophages becoming infected with cell wall deficient or | ||
+ | CWD forms of bacteria. I will present evidence and arguments to | ||
+ | counter many of the studies behind the push for increasing vitamin | ||
+ | D in certain diseases and show the potential harm from excess | ||
+ | vitamin D. I will also discuss the controversy over different views of | ||
+ | Vitamin D and some very new molecular modeling results. | ||
+ | |||
+ | I won’t have time for questions at the end of the talk, but you can | ||
+ | ask me questions afterwards individually or email me at | ||
+ | jcw@autoimmunityresearch.org. By the way, you should all have | ||
+ | handouts of the slides to make it a little easier. | ||
+ | |||
+ | |||
+ | Now, I’ll briefly go into some background information in simplified | ||
+ | form. In our view, the key to Th1 disease is bacteria-infected | ||
+ | macrophages leading to excessive inflammation and increased | ||
+ | 1,25D production. Th1 cells, a type of T helper lymphocyte, or | ||
+ | immune cell, produce the cytokine Interferon Gamma and | ||
+ | promote cell mediated inflammation. | ||
+ | |||
+ | Th1 cells can stimulate macrophage activity and these activated | ||
+ | macrophages also produce Interferon Gamma. The macrophages | ||
+ | are supposed to surround and internalize the bacteria in order to | ||
+ | destroy them, a process called phagocytosis. | ||
+ | |||
+ | Our understanding of Th1 disease is that the macrophages are | ||
+ | unable to destroy the CWD bacteria during phagocytosis and | ||
+ | instead the bacteria actually thrive inside the very macrophages | ||
+ | that are supposed to kill them, leading to chronic disease. | ||
+ | Although elevated Interferon Gamma can indicate Th1 disease, it | ||
+ | stays mainly in the tissue, and only circulates in the blood to a | ||
+ | limited degree. However, the 1,25D produced by the activated | ||
+ | macrophages, | ||
+ | Interferon Gamma. Thus, 1,25D, can serve as a useful marker or | ||
+ | indicator of Th1 disease and that is why we measure it, along with | ||
+ | 25D. | ||
+ | |||
+ | |||
+ | Now, on to vitamin D regulation. | ||
+ | |||
+ | This first part of the slide shows a simplified view of the vitamin D | ||
+ | situation in a healthy person. The precursor form of vitamin D, | ||
+ | 25D, is the form that most healthy people derive from the diet, | ||
+ | supplements and sun exposure. By the way, this shows the situation | ||
+ | without the inflammatory cytokines that cause the 25D from the | ||
+ | sun to convert directly to 1,25D in the skin. | ||
+ | |||
+ | The main point to emphasize here, is that in healthy people, the | ||
+ | kidneys tightly regulate the conversion of 25D to keep the 1,25D | ||
+ | active steroid hormone in a fairly narrow range. There are parts of | ||
+ | other molecules shown here — the vitamin D receptor around | ||
+ | here, but this is the vitamin D part. | ||
+ | |||
+ | But the only difference is where you add the hydroxyl group, which | ||
+ | is this little red oxygen. It’s actually an OH and this is added and it | ||
+ | makes all the difference. And here we have a nice picture of a | ||
+ | kidney. O.K. So we have the molecule transformed by adding | ||
+ | the hydroxyl group so it can now activate the vitamin D receptor. | ||
+ | Most doctors rely on the 25D precursor to decide how much | ||
+ | vitamin D is needed, without paying enough attention to the active | ||
+ | hormonal form. This only makes sense if one assumes 1,25D | ||
+ | levels are regulated by the kidneys with the aid of parathyroid | ||
+ | hormone. | ||
+ | |||
+ | O.K., Now for the vitamin D dysregulation. Dysregulation is | ||
+ | caused by activated macrophages, | ||
+ | |||
+ | 1,25D without the kidneys, at a high rate — there you can see the | ||
+ | macrophage. | ||
+ | |||
+ | So, the macrophages are the source of vitamin D | ||
+ | dysregulation in Th1 diseases, aka vitamin D hypersensitivity. | ||
+ | This extrarenal, meaning outside of the kidneys, production is well- | ||
+ | known in sarcoidosis and other diseases where aggregations of | ||
+ | macrophages form granulomas. And as I said before, in Th1 | ||
+ | disease, the 25D from the sun goes immediately to 1,25D in the | ||
+ | skin. | ||
+ | |||
+ | |||
+ | Now, you might ask, how does Vitamin D regulation break down? | ||
+ | Normally, there are feedback controls that would compensate for | ||
+ | overproduction. | ||
+ | |||
+ | Well, it turns out we know the enzymes and cytokines involved in | ||
+ | this failure to compensate for the macrophage’s production of | ||
+ | 1,25D. | ||
+ | |||
+ | Activated macrophages contain the enzyme 1 alpha hydroxylase | ||
+ | that causes the conversion of 25D to 1,25D. Abundant Interferon | ||
+ | Gamma, an inflammatory cytokine, can suppress the normal | ||
+ | feedback inhibition of 1 alpha hydroxylase that would otherwise | ||
+ | help regulate 1,25D production. The Interferon Gamma in the | ||
+ | region of inflamed tissue inhibits the enzyme 24-hydroxylase, | ||
+ | which is involved in 1,25D inactivation. | ||
+ | |||
+ | This effect of Interferon Gamma seems to extend to the kidneys, at | ||
+ | least in many granulomatous diseases, like sarcoidosis, | ||
+ | kidney can not effectively compensate for the unregulated 1,25D | ||
+ | production by macrophages. | ||
+ | |||
+ | Also, inflammatory cytokines cause increased conversion of 7- | ||
+ | dehydrocholesterol into 1,25D in the skin, thus providing | ||
+ | additional 1,25D that contributes to dysregulation. | ||
+ | And what is the result? Well when 1,25D is severely elevated, high | ||
+ | blood calcium levels can occur, which may be quite dangerous. | ||
+ | But even when 1,25D is moderately elevated, with normal serum | ||
+ | calcium levels, bone loss and a wide range of negative | ||
+ | consequences may occur. | ||
+ | |||
+ | |||
+ | Now, we’ll briefly cover some issues relating to measurement. We | ||
+ | think many labs reference ranges are inaccurate because they | ||
+ | include undiagnosed Th1 disease patients in their control | ||
+ | populations. | ||
+ | |||
+ | For this reason, we prefer Merck Manual’s upper limit of 45 pg/ml | ||
+ | for 1,25D, to the higher upper limits some labs use. | ||
+ | Blood serum for 1,25D tests should be frozen since 1,25D | ||
+ | degrades easily. The largest U.S. lab does it this way. | ||
+ | In D dysregulation, | ||
+ | conversion to the active hormone. So 25D may be low while | ||
+ | |||
+ | |||
+ | 1,25D may be high, thus one can see the need to measure both. | ||
+ | Low 25D, high 1,25D and/or a higher ratio of 1,25D to 25D, | ||
+ | known as the D ratio, can be used as an indicator of the level of | ||
+ | Th1 inflammation. The D-ratio from a large control population | ||
+ | that we use as “normal” is 1.3. | ||
+ | |||
+ | The FDA recommends measuring both types of vitamin D | ||
+ | when evaluating osteoporosis treatments. We think both | ||
+ | tests should also be much more widely done in chronic | ||
+ | disease. | ||
+ | |||
+ | Now, I am going to review literature that supports our view that D | ||
+ | dysregulation due to activated macrophages is actually | ||
+ | widespread in inflammatory diseases. | ||
+ | |||
+ | In most of these diseases there is also some evidence of bacterial | ||
+ | involvement and/or responsiveness to antibiotics. The first example | ||
+ | is Inflammatory Bowel Diseases. | ||
+ | |||
+ | Abreu et al found 1,25D levels were elevated above 60 pg/ml in | ||
+ | 40% of Crohn’s Disease and 7% of Ulcerative Colitis patients. The | ||
+ | elevated 1,25D was related to reduced bone mineral density that | ||
+ | was independent of glucocorticoid use. They also found elevated | ||
+ | levels of 1 alpha hydroxylase from colonic biopsies of Crohn’s | ||
+ | patients, indicating extrarenal synthesis, as in sarcoidosis. | ||
+ | The percentages are much higher if the Merck Manual cutoff for | ||
+ | elevated 1,25D, of 45 pg/ml is used — 68% for Crohn’s and 45% | ||
+ | for Ulcerative colitis. | ||
+ | |||
+ | Now, I will discuss a key experiment supporting extrarenal synthesis | ||
+ | of 1,25D in rheumatoid arthritis. | ||
+ | |||
+ | Mawer et al challenged 19 RA patients with a large dose of the | ||
+ | precursor, 25D, and found that patients generated peak serum | ||
+ | levels of 1,25D significantly higher than controls. | ||
+ | |||
+ | The 1,25D levels were particularly elevated in the joint fluid in | ||
+ | patients. This provides strong evidence for extrarenal synthesis of | ||
+ | 1,25D in patients with RA. | ||
+ | |||
+ | Another important point is that the median serum 1,25D at | ||
+ | baseline was not elevated in the RA patients — only 24 pg/ml. | ||
+ | Thus the extrarenal synthesis of 1,25D was not obvious from the | ||
+ | routine blood test. | ||
+ | |||
+ | So, although we do find Vitamin D tests helpful in diagnosis, this | ||
+ | study shows that they are not always enough. One may need to | ||
+ | look deeper to detect extrarenal synthesis in Th1 disease. | ||
+ | It is also the reason why a therapeutic probe with the Marshall | ||
+ | Protocol may be needed, when the clinical picture suggests Th1 | ||
+ | |||
+ | |||
+ | disease, but the vitamin D test results are unclear. A therapeutic | ||
+ | trial is when one uses the MP, and assess symptom changes — like | ||
+ | bacterial die off reactions — to determine if the protocol is | ||
+ | appropriate. | ||
+ | |||
+ | |||
+ | Some additional independent studies in RA are also relevant here. | ||
+ | In vitro studies of macrophages from synovial fluid or joint fluid in | ||
+ | RA also revealed synthesis of 1,25D and elevated D-ratios. Inaba | ||
+ | found elevated 1,25D to be related to elevation of IL-1 and IL-2. | ||
+ | These 2 inflammatory cytokines are correlated with disease activity. | ||
+ | IL-1 has also been implicated in increased bone loss. | ||
+ | Sambrook et al found little, if any bone loss near the wrist joint in | ||
+ | patients with RA with the lowest 1,25D. Those with higher 1,25D | ||
+ | had significant bone loss near their wrist joints. | ||
+ | In our view, these various findings argue against vitamin D | ||
+ | supplementation to prevent inflammatory damage or bone loss in | ||
+ | RA. The role of bacteria and antibiotics shown in several studies | ||
+ | further support our view that RA is similar to sarcoidosis in its | ||
+ | underlying bacterial cause. | ||
+ | |||
+ | |||
+ | O.K., as for lupus, two studies measuring vitamin D levels are | ||
+ | consistent with Vitamin D dysregulation, | ||
+ | 2.2, well above the 1.3 average for the healthy. | ||
+ | Interestingly, | ||
+ | associated with UVB solar radiation in a correlational study and we | ||
+ | believe this effect probably occurs through increasing 1,25D. | ||
+ | It is known that lupus patients have flares of symptoms in response | ||
+ | to UVB light, and sometimes even to fluorescent or UVA light, | ||
+ | something we observe in sarcoidosis. There was at least one study | ||
+ | that seems to support the role of bacteria. From all of this, we | ||
+ | conclude lupus (SLE) is a Th1 disease. | ||
+ | |||
+ | |||
+ | Only one study in fibromyalgia measured both vitamin D forms | ||
+ | and the D ratio was elevated at 1.7. | ||
+ | |||
+ | Several other studies showed a tendency to low levels of 25D in | ||
+ | these several chronic pain and fatigue states and this is consistent | ||
+ | with our hypothesis of extrarenal conversion by activated | ||
+ | macrophages depleting 25D. | ||
+ | |||
+ | Several researchers have linked chronic fatigue syndrome and | ||
+ | fibromyalgia with bacteria, including Borrelia and Mycoplasma. | ||
+ | Now, in Sjogren’s Syndrome, the D-ratio was 2.7 and the study | ||
+ | authors mentioned this indicated a disturbed vitamin D | ||
+ | metabolism. | ||
+ | |||
+ | |||
+ | O.K. Multiple Sclerosis. We have shown some vitamin D patterns | ||
+ | and how they relate to our view that bacterial infection causes | ||
+ | vitamin D dysregulation. In Multiple sclerosis or MS, vitamin D | ||
+ | data is lacking, but there are other types of studies that have been | ||
+ | used to try to link MS with a lack of vitamin D. And I will discuss | ||
+ | some of the problems we see with these studies. | ||
+ | The initial reason for the interest in vitamin D in MS is that a higher | ||
+ | rate of disease had been observed in higher latitudes — and it has | ||
+ | been claimed that this is due to less sun exposure producing less | ||
+ | vitamin D. | ||
+ | |||
+ | We will focus on one of the alternative explanations — that the | ||
+ | pattern is caused by the geographic distribution of bacterial | ||
+ | pathogens not solar radiation. An analysis by Fritzsche related the | ||
+ | geographical and seasonal pattern of MS to that of the tick that | ||
+ | carries the Lyme spirochete Borrelia burgdorferi. | ||
+ | |||
+ | Also, Chlamydiae pneumoniae is known to be more commonly | ||
+ | acquired in the winter and this may relate to geographical patterns | ||
+ | due to the greater amount of time spent indoors at higher | ||
+ | latitudes. Chlamydiae pneumoniae has been linked to progressive | ||
+ | MS by Munger et al. | ||
+ | |||
+ | Our view is that multiple bacterial pathogens are probably the | ||
+ | cause of MS and other Th1 diseases. This seems likely because | ||
+ | immune dysregulation initiated by the first pathogen would tend to | ||
+ | promote infection with other species. | ||
+ | |||
+ | There is also abundant direct evidence for the role of bacteria in | ||
+ | MS, for example, see Brorson et al and Mattman. Mattman has | ||
+ | some reviews of numerous studies. | ||
+ | |||
+ | |||
+ | Some studies have been done linking low vitamin D consumption | ||
+ | and serum 25D patterns to a greater rate of MS. One reason we | ||
+ | think low 25D might be observed to precede MS is increased | ||
+ | conversion of 25D to 1,25D by macrophages thus depleting 25D | ||
+ | in early stages of illness prior to being diagnosed — the low 25D | ||
+ | is thus not a cause but an early effect of MS. | ||
+ | |||
+ | There are other factors that may bias results and you can see the | ||
+ | book chapter for some examples. Since we know that correlation | ||
+ | does not imply causation, these types of observational studies, by | ||
+ | their very nature, can not prove a benefit of Vitamin D in | ||
+ | preventing MS. | ||
+ | |||
+ | But, if future randomized controlled trials were to show a | ||
+ | preventative effect of vitamin D for MS, this might be due to | ||
+ | enhancement of immune response to the initial phase of bacterial | ||
+ | infection through correction of very low levels of vitamin D in | ||
+ | certain individuals. There is some limited evidence for this in | ||
+ | Tuberculosis. But even if this preventative effect were proven, this | ||
+ | would not mean vitamin D supplementation would be beneficial in | ||
+ | patients already ill with MS, since, in our view, increased 1,25D | ||
+ | synthesis would be occurring once the illness is established. | ||
+ | |||
+ | |||
+ | |||
+ | Another type of study that has been done in MS involves short term | ||
+ | experiments in which some form of vitamin D is given. | ||
+ | Several studies have shown a benefit from elevated 1,25D in | ||
+ | prevention and treatment of experimental allergic | ||
+ | encephalomyelitis, | ||
+ | try to approximate MS. | ||
+ | |||
+ | Some of the pitfalls of studies of this type include differences in the | ||
+ | physiology of humans and mice and the short time span of the | ||
+ | experiment. There is also likely to be different disease causation | ||
+ | involved in EAE. Even if a given animal model, such as this one, | ||
+ | did apply to human MS, giving large amounts of 1,25D might be | ||
+ | able to halt the disease process in EAE only due to | ||
+ | immunosuppression. But the short time span of the experiment | ||
+ | would fail to detect a long-term worsening that might occur due to | ||
+ | bacterial increase occurring as a result of the immunosuppression. | ||
+ | Likewise, in studies in humans with MS, we view the short term | ||
+ | nature of the few studies that have been done as the likely reason | ||
+ | that benefit has sometimes been linked to vitamin D. | ||
+ | |||
+ | |||
+ | Now, I will discuss some new research on the mechanisms by | ||
+ | which we think too much of either form of Vitamin D may suppress | ||
+ | bacterial killing and harm long term health in Th1 disease. | ||
+ | Recent molecular modeling research indicates that high 25D levels | ||
+ | block innate immunity. Sophisticated computer modeling of the | ||
+ | molecules shows that the 1-alpha-hydroxy position is key to | ||
+ | activation of the Vitamin D Receptor or VDR. 25D can bind to the | ||
+ | VDR, but since it lacks the 1-alpha-hydroxy found in 1,25D, it will | ||
+ | bind to the VDR but fail to activate it. | ||
+ | The affinity constants show that 25D above approximately 20 | ||
+ | ng/ml can thus displace 1,25D, blocking VDR (Vitamin D | ||
+ | Receptor) activation and thus blocking innate immunity. This is | ||
+ | supported by our finding that bacterial killing increases for patients | ||
+ | on the Marshall Protocol when 25D goes below 20 to 25 ng/ml. | ||
+ | |||
+ | |||
+ | As for 1,25D, although it aids the immune response by stimulating | ||
+ | the vitamin D receptor, too much 1,25D suppresses the immune | ||
+ | system, inhibits bacterial killing and causes hormonal disruption. | ||
+ | New evidence indicates these negative effects of high 1,25D do | ||
+ | not occur through its binding to the VDR, but through its excessive | ||
+ | binding to thyroid, glucocorticoid and other receptors. Dr. | ||
+ | Marshall has recently presented molecular modeling evidence for | ||
+ | this at an FDA Visiting Professor presentation. | ||
+ | |||
+ | If, as we believe, a bacterial cause underlies these Th1 diseases, | ||
+ | then immunosuppression from high 1,25D is harmful in the long | ||
+ | |||
+ | |||
+ | O.K. Theses are not real portraits of the people — so, you don’t | ||
+ | need to go around looking for the silhouettes to match it. | ||
+ | Most of the data collected on hundreds of patients — prior to | ||
+ | starting the MP — is fitting the pattern of vitamin D dysregulation | ||
+ | that we described above, indicating increased production of | ||
+ | 1,25D by macrophages. Dr. Marshall presented slides of some of | ||
+ | this data on sarcoidosis, | ||
+ | Chicago Conference and elsewhere. | ||
+ | |||
+ | Today, I will just talk briefly about 4 of the 12 patients we discuss in | ||
+ | the book chapter to illustrate the pattern of vitamin D values in a | ||
+ | variety of illnesses. | ||
+ | |||
+ | In some cases, the 25D is somewhat elevated. Usually this is due | ||
+ | to vitamin D in food or supplements, | ||
+ | ratio downward. Patient 9 has MS, diagnosed 9 years ago. One | ||
+ | can see her 1,25D of 53 is above the Merck upper limit and her | ||
+ | 25D is rather high at 35 ng/ml and her ratio is a little elevated at | ||
+ | 1.5. She has a history of worsening on daily doses of 2000-4000 | ||
+ | IU vitamin D. And one symptom that had worsened while on the | ||
+ | vitamin D improved after stopping it prior to the Marshall Protocol. | ||
+ | Patient 10 has amyotrophic lateral sclerosis or ALS. He has an | ||
+ | elevated 1,25D of 58.9, a 25D of 36 ng/ml and a D ratio of 1.6. | ||
+ | Both patients 9 & 10 have had bacterial die-off reactions, also | ||
+ | called Jarisch Herxheimer reactions, as expected on the Marshall | ||
+ | Protocol, but it is too soon to know if they have improved. | ||
+ | Patient 11 has rheumatoid arthritis and had an initial 1,25D of 65, | ||
+ | 25D of 32, and a D ratio of 2. During 2 years on vitamin D | ||
+ | supplementation prior to the Marshall Protocol, her condition | ||
+ | worsened. Also, she failed to improve during several years on an | ||
+ | antibiotic-only protocol, but improved significantly on the Marshall | ||
+ | Protocol in less than 18 months. | ||
+ | |||
+ | Patient 12 has been disabled for 20 years by chronic fatigue | ||
+ | syndrome, fibromyalgia and Lyme disease. With her 1,25D at 64 | ||
+ | and her 25D at only 11, giving a ratio of 5.8, this patient is a | ||
+ | good example of 25D being depleted by conversion to 1,25D. | ||
+ | Sun exposure elevates her heart rate and worsens a number of | ||
+ | other symptoms. She has improved considerably on the MP. | ||
+ | |||
+ | |||
+ | O.K., as to the controversy on vitamin D. Why do some advocate | ||
+ | taking so much vitamin D and why do we think they are wrong? | ||
+ | To begin with, many vitamin D advocates focus on the issue of | ||
+ | secondary hyperparathyroidism, | ||
+ | is low, causing parathyroid hormone to increase, which can lead | ||
+ | to bone resorption and osteoporosis. The hyperparathyroidism | ||
+ | leads to a greater production of 1,25D by the kidneys, to try to | ||
+ | compensate for the low calcium. | ||
+ | |||
+ | |||
+ | This is why some researchers think it wrong to look at 1,25D levels | ||
+ | when considering whether a patient is deficient in vitamin D. Their | ||
+ | claim is that the 1,25D is meaningless, | ||
+ | compensating for a low 25D. | ||
+ | |||
+ | Of course, we agree that secondary hyperparathyroidism certainly | ||
+ | can lead to bone loss. However, in several Th1 diseases we have | ||
+ | discussed, sarcoidosis, | ||
+ | hyperparathyroidism was specifically ruled out as an explanation | ||
+ | for the patterns. Rather, the Vitamin D results were clearly related | ||
+ | to inflammation. We think that evidence points to inflammation as | ||
+ | the explanation of the vitamin D patterns in the other Th1 diseases, | ||
+ | as well. | ||
+ | |||
+ | To clarify a little further, secondary hyperparathyroidism occurs in | ||
+ | order to compensate for low calcium, not low 25D. The 1,25D | ||
+ | can increase the percentage of calcium absorbed, but is not even | ||
+ | necessary for its absorption, since when calcium is adequate, most | ||
+ | of the absorption is passive. | ||
+ | |||
+ | The role of calcium is shown in a study of patients who had | ||
+ | abundant calcium in their diet, and it was found that only 7% of | ||
+ | the variation in parathyroid levels was related to 25D. And there | ||
+ | was no link between bone mineral density and 25D. It turns out | ||
+ | that calcium intake below the recommended level is widespread | ||
+ | according to the NIH, varying from 44% to 87% depending on sex | ||
+ | and age. | ||
+ | |||
+ | And in our view providing adequate calcium is a safer way to | ||
+ | avoid secondary hyperparathyroidism than vitamin D | ||
+ | supplementation. MP patients maintain bone health by first | ||
+ | avoiding elevated 1,25D that stimulates bone loss through | ||
+ | osteoclast activity and by having adequate calcium and just | ||
+ | generally keeping 1,25D in the normal range. We have observed | ||
+ | no problems from even quite low 25D levels among MP patients. | ||
+ | |||
+ | Another area that needs to be clarified is the question of whether | ||
+ | extrarenal production of 1,25D is good or bad. The answer is it | ||
+ | depends on how much and what is the source. | ||
+ | |||
+ | There is now a theory that a lot of extrarenal production of 1,25D | ||
+ | in many tissues is important and must be fueled with a large level | ||
+ | of 25D. Now there are normally low levels of 1,25D production by | ||
+ | many types of cells and that is fine and normal. But we have been | ||
+ | referring to something different — to the excessive production of | ||
+ | 1,25D by macrophages in a Th1 disease. | ||
+ | |||
+ | Well, some say that even this increased 1,25D production by | ||
+ | macrophages is good — that it is an attempt to protect the body | ||
+ | from too much inflammation by suppressing the immune system. | ||
+ | But, we think this idea falls apart if we are dealing with a chronic | ||
+ | infection. We have presented evidence for several ways in which | ||
+ | high 25D and 1,25D can negatively affect the immune system’s | ||
+ | ability to fight CWD bacteria and thus lead to long term harm. | ||
+ | |||
+ | |||
+ | The success of the MP in treating patients is further evidence for | ||
+ | our view, since lowering vitamin D has been found to be beneficial | ||
+ | for bacterial killing. | ||
+ | |||
+ | Some vitamin D proponents believe that very high levels of vitamin | ||
+ | D are needed, levels that may exceed those found to cause harm | ||
+ | in some studies. How could it be that some seem to find a benefit? | ||
+ | In the light of what we know, it makes the most sense to us that the | ||
+ | reason they find a need for high intakes of vitamin D are two fold. | ||
+ | They may be unwittingly be relying on the immunosuppressive or | ||
+ | anti-inflammatory effect of high 25D, which may temporarily | ||
+ | correct problems with kidney, parathyroid function, or other | ||
+ | problems that are really associated with bacteria-induced | ||
+ | inflammation. The high 25D they achieve suppresses the bacterial | ||
+ | killing and associated die off reactions and may cause some short | ||
+ | term benefit, but long term harm. This explanation may even apply | ||
+ | to some elderly patients who seem to have improved muscle | ||
+ | strength when given vitamin D. | ||
+ | Another reason some vitamin D advocates may find they require | ||
+ | such high vitamin D intakes is that conversion to 1,25D by | ||
+ | macrophages continually depletes the 25D in Th1 disease, making | ||
+ | it harder to keep serum levels of 25D as high as they want them. | ||
+ | |||
+ | |||
+ | As for future research directions, there is a need for more data on | ||
+ | 25D and 1,25D levels. | ||
+ | |||
+ | But, as we have shown, the role of 1,25D production by | ||
+ | macrophages is not always obvious from simple blood tests. In the | ||
+ | less clear cut cases, as in rheumatoid arthritis, 1,25D elevation | ||
+ | may be at a lower level and more restricted to areas of inflamed | ||
+ | tissue and thus not show up in the blood test. | ||
+ | Despite our belief that the response so far to the MP is strong | ||
+ | enough to warrant immediate trials for many diseases, further | ||
+ | experiments on vitamin D might be useful. Experiments could be | ||
+ | done to detect increased synthesis of 1,25D by macrophages by | ||
+ | challenging with a dose of 25D and comparing responses with | ||
+ | controls — and then looking at levels of 25D and 1,25D in | ||
+ | inflamed tissues and so on, like the experiments discussed earlier | ||
+ | in RA. | ||
+ | |||
+ | |||
+ | What other diseases might be good candidates for this type of | ||
+ | investigation? | ||
+ | unknown cause. | ||
+ | |||
+ | But especially diseases where some link to vitamin D has been | ||
+ | found — either a positive or negative effect, since this might be a | ||
+ | sign of increased synthesis of 1,25D by macrophages. | ||
+ | |||
+ | |||
+ | Examples of some of the diseases that might have Vitamin D | ||
+ | dysregulation include: heart disease and stroke; psychiatric | ||
+ | illnesses, like bipolar, depression and schizophrenia; | ||
+ | Disease; Alzheimer’s; | ||
+ | |||
+ | Listed on the slide are studies that find evidence suggesting a role | ||
+ | for bacterial pathogens or a beneficial effect of antibiotics or | ||
+ | suggestions of vitamin D having a positive or negative effect. | ||
+ | I should mention that there has been research, mostly | ||
+ | observational studies, that support a positive role for Vitamin D in | ||
+ | cancer prevention. We think many of the problems with these types | ||
+ | of studies in cancer are similar to the problems we discussed in the | ||
+ | section on MS. And one must also be careful to distinguish the | ||
+ | effects of calcium from that of vitamin D and oftentimes it’s not | ||
+ | clear whether it’s the calcium. | ||
+ | |||
+ | |||
+ | Cancer Treatment and Progression in Relation to Vitamin D | ||
+ | With regard to cancer treatment, there are many studies | ||
+ | supporting 1,25D’s anti-tumor effects. But for this effect to be | ||
+ | useful in treatment, the 1,25D must be at high levels that produce | ||
+ | a high risk of side effects. Neither 1,25D, nor any of the synthetic | ||
+ | analogs created to mimic it, has yet been approved to treat | ||
+ | cancer. The Mayo clinic, on their web site, concludes the data on | ||
+ | vitamin D’s role in cancer is still unclear. | ||
+ | |||
+ | We have seen no evidence for an increase in cancer rates in | ||
+ | patients on the MP who have lowered their vitamin D levels. | ||
+ | Research discussed above, shows high 1,25D may be reducing the | ||
+ | killing of intracellular bacteria. If bacteria, and the inflammation | ||
+ | that accompanies the bacterial infection, are the underlying cause | ||
+ | of a cancer, then we think effectively treating the bacteria may | ||
+ | outweigh any anti-tumor effect of increasing 1,25D. | ||
+ | |||
+ | And as was mentioned, H. pylori has been linked to ulcers, but it’s | ||
+ | also been linked to stomach cancer. So there is a clear example | ||
+ | where the bacteria is the carcinogen. | ||
+ | |||
+ | |||
+ | There is some interesting work on breast cancer and Vitamin D | ||
+ | that may suggest bacterial involvement. There was a study that | ||
+ | found a tendency for 1,25D to become very low in late stage | ||
+ | breast cancer. In a possibly parallel situation, in some of the very | ||
+ | sickest patients with a very high bacterial load, 1,25D has become | ||
+ | quite low through an unknown mechanism. | ||
+ | In tuberculosis, | ||
+ | Blaney has found this also — this very low 1,25D also. But then, | ||
+ | remarkably, the 1,25D increased with appropriate antibacterial | ||
+ | treatment. | ||
+ | This may suggest that the progression of a bacterial infection to a | ||
+ | very severe level could account for the very low 1,25D in late | ||
+ | stage breast cancer and thus bacteria could be the underlying | ||
+ | cause of the cancer. Perhaps effective antibiotic treatment for CWD | ||
+ | bacteria could reverse the process in breast cancer and restore the | ||
+ | 1,25D levels as it did in the tuberculosis and the very sick Th1 | ||
+ | patients I just mentioned. | ||
+ | |||
+ | |||
+ | As you know from what I have said before, the 1,25D is usually | ||
+ | elevated in Th1 disease. So it is interesting that some of the early | ||
+ | breast cancer patients had an unexplained elevation in 1,25D, | ||
+ | which may reflect the more typical situation of a Th1 disease | ||
+ | before bacterial loads become too extreme and 1,25D drops. | ||
+ | |||
+ | |||
+ | A recent article showed breast cancer rates correlate with more | ||
+ | frequent antibiotic use. We think this may suggest a bacterial | ||
+ | cause for breast cancer. | ||
+ | |||
+ | In our view, antibiotic use can be thought of as reflecting the | ||
+ | susceptibility to and frequency of bacterial infections. Many species | ||
+ | of bacteria have been shown to be able to transform into cell wall | ||
+ | deficient forms when under attack in order to escape destruction. | ||
+ | CWD bacteria are resistant to antibiotics in the usual ways they are | ||
+ | used, so taking antibiotics will not generally eliminate them. And | ||
+ | treatment with the most commonly used antibiotics even promotes | ||
+ | the transformation of bacteria into their CWD forms, which can | ||
+ | then persist inside the body inside macrophages and other cells | ||
+ | and increase over time. | ||
+ | |||
+ | Thus, in our interpretation, | ||
+ | indicated by the greater antibiotic use in the study, the more | ||
+ | opportunities for the creation of CWD bacterial forms, which may | ||
+ | then lead to Th1 disease and possibly to cancer. | ||
+ | |||
+ | A particularly interesting, | ||
+ | prostate cancer went beyond the geographical correlational | ||
+ | studies and actually measured the 25D levels. They found that the | ||
+ | highest rates of cancer occurred when serum 25D was low (<8 | ||
+ | ng/ml) and when it was high (>33 ng/ml), giving a U shaped | ||
+ | curve. | ||
+ | |||
+ | We think these patterns may indicate Th1 disease due to bacteria. | ||
+ | Here is our hypothesis to explain this pattern. The low 25D link to | ||
+ | cancer, rather than indicating a deficiency, could be a sign of | ||
+ | depletion of 25D through conversion to 1,25D. Thus, it may be | ||
+ | simply a marker for a Th1 process. As we have discussed, the | ||
+ | resulting high 1,25D in Th1 disease suppresses the immune | ||
+ | system’s ability to fight bacteria and thus may help lead to cancer. | ||
+ | |||
+ | On the other hand, a very high level of 25D could help cause a | ||
+ | higher rate of cancer due to the high 25D suppressing the immune | ||
+ | system, as previously discussed. The result would then be that | ||
+ | innate immunity is less functional and less able to combat | ||
+ | bacteria, which may then lead to cancer. | ||
+ | |||
+ | The lowest cancer rate was in the middle region, 16-24 ng/ml, | ||
+ | where the above two factors are least prominent. But it should be | ||
+ | emphasized, that we do not think this data shows that the optimal | ||
+ | level of 25D is in the middle region. In our view, the low 25D is | ||
+ | linked to cancer merely because it is a marker of Th1 disease, not | ||
+ | a causal factor. | ||
+ | |||
+ | The authors of the prostate cancer study concluded that too high a | ||
+ | level of 25D might increase the risk of prostate cancer. As you saw from our patients slide, it isn’t that hard to exceed 30 ng/ml of | ||
+ | 25D, especially with vitamin D supplements — 3 of the 4 patients | ||
+ | had levels above 30. | ||
+ | |||
+ | In conclusion, we have shown that Vitamin D dysregulation may | ||
+ | produce patterns of elevated 1,25D, depleted 25D or an elevated | ||
+ | D-ratio, as we show for a variety of chronic Th1 diseases. | ||
+ | Elevated 25D or 1,25D might make the patient feel better or | ||
+ | worse in the short run, but in either case, make them worse in the | ||
+ | long run. This worsening occurs through immunosuppression | ||
+ | promoting bacterial increase. | ||
+ | |||
+ | We think the evidence for this new view of vitamin D | ||
+ | requires re-evaluation of many previous studies and calls for | ||
+ | new types of studies in many chronic diseases. | ||
+ | |||
+ | Although usually quite helpful, Vitamin D blood tests do not always | ||
+ | accurately reveal Th1 disease. Thus, if the clinical picture suggests | ||
+ | Th1 disease, we find a therapeutic probe using the Marshall | ||
+ | Protocol as the “gold standard” test for Th1 disease and bacterial | ||
+ | involvement. | ||
+ | |||
+ | If you think about it, it seems little wonder that vitamin D has | ||
+ | become so popular. It’s basically an over-the-counter steroid — | ||
+ | but its effects are more subtle and insidious than something like | ||
+ | prednisone since it blocks only innate immunity, leaving adaptive | ||
+ | immunity intact. | ||
+ | |||
+ | We think that further study of vitamin D dysregulation appears | ||
+ | likely to provide a window onto the immune system, improving | ||
+ | diagnosis and treatment for many chronic diseases. | ||
+ | Thank you for your attention. | ||
+ | |||
+ | {{tag> | ||