CISRA’s Synergy Health Newsletter

Issue 7. Excess of Active Form of Vitamin D (1,25 D) Linked to Chronic Fatigue Syndrome, Lyme Disease, Fibromyalgia and Autoimmune Illnesses (2004)

by J. C. Waterhouse, Ph.D.

 
Abstract

Recent research shows that the active form of the vitamin D hormone (1,25 D) is present in excessive levels relative to the inactive 25 D form in patients diagnosed with a number of inflammatory illnesses, such as certain autoimmune illnesses, chronic fatigue syndrome, fibromyalgia and Lyme disease. Evidence suggests that this is due to unregulated production of 1,25 vitamin D by macrophages in the course of an excessive TH1 immune response. Research indicates that this occurs in response to cell wall deficient forms of bacteria parasitizing immune cells and other tissue. The relationship of this new information to past research on the role of vitamin D in autoimmune illnesses, like multiple sclerosis, is discussed. The potential benefits of additional research measuring both forms of vitamin D include improved diagnostic methods, testing of current theories and guidance for treatment in a variety of illnesses. The high rate of remissions using a new protocol developed by Marshall et al (2, 4, 5) for treating sarcoidosis provides additional evidence of the importance of 1,25 vitamin D hormone testing and the use of the D ratio (1,25 D:25 D). This protocol’s effectiveness in sarcoidosis suggests that a similar approach may be effective in other illnesses that are found to have similar vitamin D patterns. To ensure accurate results for 1,25 D in the serum, laboratories must freeze the sample for transport and not all labs currently do so.

Introduction

New insights into the role of the active vitamin D hormone (1,25 dihydroxycholecalciferol) in immune system modulation may be on the verge of requiring a new approach to vitamin D laboratory measurement and supplementation in clinical practice. It is now well known from molecular medicine and other research that besides its role in calcium and phosphorus metabolism, the active form of the vitamin D hormone (1,25 D) is closely tied to TH1 immune activity (1, 2). The active form of vitamin D is produced by activated macrophages and it, in turn, interacts with immune cells to aid in the development of monocytes into mature macrophages. Among its many other roles, it can also suppress inflammatory T cells and other aspects of immune function when present at higher levels (3). Research on the role of vitamin D in the TH1 autoimmune disease sarcoidosis has provided new insights into vitamin D’s possible role in TH1 diseases (2, 4, 5). These insights lead to the conclusion that measurement of the levels of both the inactive 25 D form of vitamin D and the active 1,25 D form of vitamin D may prove to be key to proper diagnosis and treatment of many inflammatory diseases (2).

Elevated Active Vitamin D Hormone (1,25 D) Linked to Inflammatory Diseases

In healthy people with a normally functioning immune system, the kidneys regulate the amount of conversion of the inactive form of vitamin D (25 D) into the active form (1,25 D), producing whatever amount of the active form the body needs. However, as has been shown in recent research ( 2, 5, 6), several chronic illnesses show evidence of excessive activity of TH1 immune function leading to an overabundance of 1,25 vitamin D produced by immune cells, such as macrophages. This occurs because, as part of the TH1 inflammatory response, activated macrophages convert 25 D to the 1,25 D form (2, 4). For example, in research on sarcoidosis, Marshall et al (4) have found an elevated ratio of 1,25 D to 25 D (D ratio), ranging from 1.7 to more than 4.5. In a large Danish study of smokers and nonsmokers, the data showed that a normal D ratio for healthy nonsmokers could be calculated to be 1.3 (7).

In addition, a recent study showed elevated 1,25 D levels (>60 pg/ml) in 40% of Crohn’s disease and 7% of ulcerative colitis patients tested (6). If the study had used the upper limit for elevated 1,25 D of 45 pg/ml from the Merck Manual (8), the percentages with elevated levels would have been much higher. It was found that this elevated 1,25 D was related to a negative effect on bone mineral density that was independent of glucocorticoid use. The authors concluded that the elevated levels of active 1,25 vitamin D might be due to inflamed tissue involved in the disease process.

The results of these peer-reviewed studies of TH1 autoimmune illnesses, sarcoidosis, Crohn’s disease and ulcerative colitis, suggest that similar results might be found in other TH1 inflammatory illnesses. Thus, it is important that more research be done that focuses on measuring 1,25 D levels and calculating D ratios. Although most research involving vitamin D is not designed for this purpose, Marshall et al (2) have described evidence of aberrant vitamin D regulation in lupus, fibromyalgia, rheumatoid arthritis and Parkinson’s disease in published studies. In addition, preliminary observations of more than 100 patients diagnosed with a variety of diseases, such as fibromyalgia, chronic Lyme disease, chronic fatigue syndrome and rheumatoid arthritis have shown elevated active vitamin D (9). Research on rheumatoid arthritis has shown a clear dysregulation of 1,25 D production (10). Marshall et al (2), also described how 1,25 D has been used as an indicator of the level of the TH1 response in AIDS (11) and breast cancer (12). In AIDS, an illness that is deficient in TH1 activity, there are often extremely low levels of 1,25 vitamin D (11).

The above patterns have been missed previously because there have been a number of problems with vitamin D testing. The most important problem is that most studies have only measured the inactive form of vitamin D (25 D). This tends to reflect the intake of vitamin D and thus largely misses the role of processes that cause dysregulation of the 1,25 vitamin D hormone levels, such as the conversion of 25 D to 1,25 D by macrophages. Also, since the active form of vitamin D (1,25 D) tends to degrade easily, it requires that the sample be frozen for transport, and not all labs do this. Another problem is that the normal reference ranges used by most labs are not accurate (9). This is because the population that they use to determine the reference range probably includes people with undiagnosed vitamin D dysregulation, since this appears to be much more common in the U.S. community than previously suspected (13). The Merck Manual’s reference range is more accurate (9) and gives an upper limit of 45 pg/ml for 1,25 D ( as opposed to many lab’s with upper limits in the range of 60-65 pg/ml). In addition, many of the estimates of serum levels of 25 D may be misleadingly low, since the inflammation from TH1 activity leads to conversion of the inactive 25 D form to the active 1,25 D form, often depleting serum levels of the measured inactive vitamin D (25 D) in order to increase active vitamin D (1,25 D).

Need for More Study of Active Vitamin D (1,25 D) Levels: Multiple Sclerosis and Other Diseases

There has been a growing movement to routinely recommend increased vitamin D supplementation and sun exposure based on the results of studies of levels of the inactive form of vitamin D (25 D). These studies, especially in higher latitudes, may truly reflect vitamin D deficiencies in many people (3). In most people, the kidneys regulate the conversion of 25 D to 1,25 D, so, in the past, many doctors and researchers have concluded that there is no need to measure the 1,25 D form. However, this view is contrary to the U.S. FDA’s recommendations for studies of osteoporotic therapies to include testing of the 1,25 D form (14). It would seem wise to also apply this more thorough level of testing to other diseases that may involve vitamin D, considering the recently widening understanding of its important immune system functions.

The relative lack of data on the active 1,25 D form of vitamin D and the D ratio in autoimmune illnesses suggests some new areas of research, especially in light of the recent research on sarcoidosis and Crohn’s disease discussed above. Multiple sclerosis (MS) provides a good example of how new data on levels of active vitamin D (1,25 D) might be helpful. Despite several lines of research, including epidemiological studies of MS incidence (3), studies on a rodent model of MS (e.g., 15), and studies in humans linking sunlight/vitamin D to MS severity (e.g., 3, 16), there are a number of unanswered questions remaining regarding the evidence. For instance, the initial establishment of MS may be linked to inadequate vitamin D, but supplementation of vitamin D after the disease is established may not be effective. The applicability of rodent models to human disease can be questioned, especially when the true cause of the disease is unknown. Most human studies relating MS progression to vitamin D have been short term and, in general, they have been methodologically inadequate to prove that increased vitamin D causes sustained improvement. It is also important to note that any short term benefit of vitamin D in autoimmune illness may be the result of a phenomenon observed in sarcoidosis patients, who sometimes seem to improve for a period of time when vitamin D is elevated, only to relapse later. This is thought to be due to immunosuppressive effects of higher levels of active vitamin D that lead, over time, to increased levels of CWD bacteria, which cause a worsening of the illness (see reference 17 and below). Also, an approach that has succeeded in achieving remission in more than 90% of sarcoidosis patients has included minimizing vitamin D exposure (2, 5).

Testing both forms of vitamin D and calculating the D ratio (1,25 D:25 D) might fill in the above-mentioned gaps in the knowledge on the relationship of vitamin D to MS, as well as serving a variety of other important roles. If the pattern of vitamin D levels in MS are found to differ significantly from sarcoidosis, they could be quite valuable in helping to distinguish the two diseases, since it can be nearly impossible at times to distinguish MS from neurosarcoidosis and some other demyelinating conditions (18, 19). Differences in D ratios might correlate with periods of exacerbation or remission or help distinguish progressive MS from relapsing and remitting MS. Testing levels of both types of vitamin D might even reveal previously unrecognized subgroups. At a more basic level, 1,25 D levels and the D ratio might be helpful in testing some of the theories regarding the cause of MS. Normal D ratios with low overall levels of both forms of vitamin D might support the theory of the importance of a vitamin D deficiency in progression of the disease. A high D ratio and/or 1,25 D might support the idea of a bacterial cause, as has been postulated in sarcoidosis. A low D ratio might support a viral cause, since certain chronic viral infections, like AIDS and Hepatitis B, have been shown to cause extremely low active 1,25 D levels (20, 21). Calculation of the D ratio might then be used to predict who might benefit from and who might potentially be harmed by increasing vitamin D. Similar sorts of benefits might be achieved in other diseases through testing of the 1,25 vitamin D hormone along with the inactive 25 D form and looking for patterns in the D ratio (1,25 D:25 D).

Interpretation of D Levels: An Example in Chronic Fatigue Syndrome

To illustrate the potential problems with supplementing vitamin D based on the levels of the inactive form of vitamin D (25 D) alone, I will present a brief example of a person disabled with chronic fatigue syndrome and fibromyalgia for 18 years and later diagnosed with chronic Lyme disease. Vitamin D testing revealed a borderline low level of the inactive 25 D form of vitamin D (11 mg/ml) despite moderate supplementation (500 IU/d), which might have prompted a recommendation to increase vitamin D intake. However, this patient was actually suffering from vitamin D intoxication, since the level of 1,25 D, the active form, was at 64 pg/ml, well above the Merck Manual upper limit of 45 pg/ml (8). This level was high enough to potentially decrease bone mineral density (6). Over a period of several weeks of minimizing vitamin D intake and avoiding sun exposure, many of the symptoms of hypervitaminosis D improved significantly (including fatigue, weakness and cognitive problems). Apparently, the 25 D form was low, not because of too low an intake, but because it was vigorously being converted by active macrophages into excessive levels of the active 1,25 D form. To clarify the interpretation of two other situations, it should be noted that a normal or even somewhat low 1,25 D level can yield a high D ratio when the 25 D is quite low. And for those with very high 25 D due to supplementation, the D ratio is not relied upon. Rather, an elevated 1,25 D is used, as it typically reflects the high macrophage activity. In either of these situations, D dysregulation due to excessive TH1 activity is thought to be occurring, just as in the simpler case where both 1,25 D and the D ratio are elevated, as in the above example (4, 9).

A Promising Treatment for the Proposed Bacterial Cause of TH1 Inflammatory Diseases

Research on sarcoidosis has revealed that the perpetuators of the TH1 inflammation are probably cell wall deficient forms of bacteria (also called L forms, cysts, pleomorphic), which are able to hide within immune cells (2, 22, 23). Marshall et al (2, 4, 5, 9) have developed a protocol to treat sarcoidosis that combats these bacteria through low doses of particular antibiotics and modulation of the immune system. Preliminary observations in chronic fatigue syndrome (24) and Lyme disease (25) showed elevated 1,25 D levels and/or D ratios, as well as showing promising initial results from treatment with this same protocol.

Conclusion

So far, the conclusions regarding elevated 1,25 D’s link to TH1 inflammatory diseases apply most clearly to sarcoidosis and Crohn’s disease. But the preliminary data from doctors and patients participating in Internet forums (9) show that many patients with a variety of inflammatory illnesses show a similar pattern of elevated active vitamin D and/or an elevated D ratio. It seems to this author, that it might be wise for anyone with a chronic inflammatory illness to keep their vitamin D from food, supplements and sun to a moderate level (e.g., 200-400 IU) until they can get both their 25 D and 1,25 vitamin D levels properly tested at a lab that freezes the sample for transport (e.g., Quest Labs). This might also apply to those who have symptoms of hypervitaminosis D, which include: fatigue, weakness, mood changes, insomnia, inability to concentrate, sleepiness, irritability, feeling of intoxication, metallic taste, difficulty swallowing, muscle and joint pains and a number of other symptoms (9). In assessing changes in vitamin D intake, it should be remembered that the inactive 25 D form of vitamin D is stored in fat tissue and has a half life of 1-2 months, thus any effects of vitamin D reduction may take weeks to appear. Experience has shown (4, 5) that the higher the 25 D level, the more it fuels the conversion to the active 1,25 D form by the unregulated macrophages in inflamed tissue. Finally, until much more research is done on both active and inactive forms of vitamin D and their role in inflammatory diseases, it seems advisable that any deviation from a moderate average vitamin D intake or, more precisely, a moderate level of active 1,25 D, should proceed only with great caution. And for those illnesses that are similar to sarcoidosis in patterns of vitamin D levels, it may be that one must temporarily minimize vitamin D ingestion and sun exposure in order to reduce an elevated 1,25 D level to a moderate level and thus achieve improvement in symptoms (4, 5 and above example of CFS/FM/Lyme patient).

Editorial Note (October 28, 2006): For my current views on the significance of vitamin D levels, and the best approach to fibromyalgia, chronic fatigue syndrome and a variety of chronic diseases involving inflammation, see the transcript of a talk I gave before a Support Group in 2005, published in Issue 9 of this newsletter. I give an overview of what has helped me most, with an emphasis on the Marshall Protocol (MP). Vitamin D levels are useful for diagnosis, but sometimes still appear normal in persons with Th1 disease. In these cases, a therapeutic probe with the Marshall Protocol is the “gold standard” test (see: “What is a Therapeutic Probe?” at http://www.marshallprotocol.com/forum32/1419.html . For further information on Vitamin D in relation to Th1 disease, see the upcoming DVDs from the 2006 Los Angeles Conference (LAX) presentation on Vitamin D (Autoimmunity Research Foundation at www.AutoimmunityResearch.org). Also, you may wish to consult the new textbook entitled Vitamin D: New Research. You will find a chapter written by Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G on High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor – Implications of dysregulated vitamin D for diagnosis and treatment of chronic disease. A copy of the chapter can be found at this Internet address: http://winmlm.neostrada.pl/vitamindbook/vitamindnewresearch.pdf.

Editorial Note (2008):  Some patients with low 1,25-D also appear to respond to the protocol.  See transcript of a presentation I made for Los Angeles Conference on Chronic Disease on Vitamin D.

References
(Note: The full text or abstracts of many of the references may be found at
www.marshallprotocol.com/forum2/2274.html or through the links within the articles found there.)

(1) Hewison M, Gacad MA, Lemire J, Adams JS: Vitamin D as a cytokine and hematopoetic factor. Rev Endocr Metab Disord 2001;2(2):217-27.
(2) Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics-implications for autoimmune disease. Autoimmun Rev 2004;3(4):295-300.
(3) Embry, AF, Vitamin D supplementation in the fight against multiple sclerosis. (www.direct-ms.org/food.html).
(4) Marshall TG, Marshall FE: Remission in Sarcoidosis. Clinmed 2002 Aug 22;2002080004v1.
(5) Marshall TG, Marshall FE: Antibiotics in Sarcoidosis – Reflections on the First Year. JOIMR 2003;1(3):2.
(6) Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, Chen S, Zehnder D, Lin Y-C, Yang H, Hewison M, Adams JS: Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut 2004;53:1129-1136.
(7) Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr Dec 1999; 53(12): 920-6.
(8) The Merck Manual of Diagnosis and Therapy – Vitamin D Deficiency and Dependency. 17th Edition, Section 1, Chapter 3.
(9) www.marshallprotocol.com and www.sarcinfo.com.
(10) Mawer EB, Hayes ME, Still PE, Davies M, Lumb GA, Palit J, Holt PJ: Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res 1991;6(7):733-9.
(11) Haug CJ, Aukrust P, Haug E, Morkrid L, Muller F, Froland SS: Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998;83(11):3832-8.
(12) Mawer EB, Walls J, Howell A, Davies M, Ratcliffe WA, Bundred NJ: Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases. J Clin Endocrinol Metab 1997;82(1):118-22;
(13) Marshall TG: 100,000 IU of vitamin D is a lethal dose for many in our community. Rapid response to: Trivedi DP, Doll R, Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial, BMJ 2003;326:469. (http://tinyurl.com/6gow4).
(14) Division of Metabolic and Endocrine Drug Products, Food and Drug Administration: Guidelines for Preclinical and Clinical Evaluation of Agents Used in the Prevention or Treatment of Postmenopausal Osteoporosis. 5600 Fishers Lane, HFD-510, Rockville, MD 20857-1706,
(15) Cantorna, MT, Hayes CE, DeLuca HF: 1,25-dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr 200;128:68-72.
(16) Freedman DM, Dosemeci M, Alavanja MC: Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates. Occup Environ Med 2000 57(6):418-21.
(17) Marshall TG: A dichotomy in the definition of Th1 and Th2 Processes. Rapid response to: Chris Clark Patient organizations in ME and CFS seek only understanding. BMJ 2004; 329: 112-b-113-b. (http://bmj.bmjjournals.com/cgi/eletters/329/7457/112-b#68914).
(18) Fauci, AS, and others, editors. 1997. Harrison’s Principles of Internal Medicine. McGraw Hill.
(19) Castellino G, Protti A, Canesi B: Multiple Sclerosis and autoimmune diseases: clinical cases and review of the literature, Reumatismo 2001 53 (3):196-203.
(20) Marshall TG: Rheumatic Disease is Th1, Viral Infections are (generally) Th2, 4 April 2004, Rapid Response to: Mudur G: Indian endocrinologists warn of vitamin D deficiency BMJ 2003; 326: 12b (http://bmj.bmjjournals.com/cgi/eletters/326/7379/12/b#28700).
(21) Vanlandschoot P, Van Houtte F, Roobrouck A, Farhoudi A, Leroux-Roels G: Hepatitis B virus surface antigen suppresses the activation of monocytes through interaction with a serum protein and a monocyte-specific receptor. J of General Virology 2002;83:1281-9.
(22) Almenoff PL, Johnson A, Lesser M, Mattman LH: Growth of acid fast L forms from the blood of patients with sarcoidosis. Thorax 1996;51(5):530-3.
(23) Cantwell AR Jr: Histologic observations of variably acid-fast pleomorphic bacteria in systemic sarcoidosis: a report of 3 cases. Growth 1982;46(2):113-25.
(24) Marshall TG, Marshall FE.:Poster Presentation. AACFS Seventh International Conference on Chronic Fatigue Syndrome, Fibromyalgia, and other Related Illnesses Conference, Oct. 8-10, 2004, Madison, WI.
(25) Marshall TG, Marshall FE: Poster Presentation. International Lyme and Associated Diseases Society (ILADS) Conference, Oct. 23-24, 2004, Rye, NY.

Disclaimer: All articles provided on the SynergyHN website are for information only and are not intended as medical advice. An effort is made to be accurate, however readers are advised to verify what is presented here and check with their own doctors. No guarantee of accuracy is expressed or implied. Neither CISRA nor the author receives any funding or income from any organization or manufacturer connected with the topics discussed.

Written by synergyhn

October 29, 2004 at 5:12 pm

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