A Review - Vitamin D and Calcium in Sarcoidosis

Trevor G Marshall, PhD, 5 July 2003

The active hormone of Vitamin D (1,25-dihydroxyvitamin-D)(1,25-D) performs a vital function in immune diseases, including Sarcoidosis. It causes hematopoetic-stem-cells to differentiate (grow) into monocytes, the basic White Blood Cell (leukocyte), and then it causes these to differentiate (grow) into the macrophages and giant cells characteristic of sarcoid granuloma[1,2]. Without this hormone there would be no formation of granuloma. The hormone is also responsible for maintaining proper operation of the ParaThyroid, Muscle, Pancreas, Bone, Intestine, Kidneys, Heart and the Brain [3]. (Image: Unversity of California, Riverside)

In the past it had been thought that this hormone was primarily responsible for maintaining the Calcium homeostasis (balance) in the body. But, now that the controlling Genes have been sequenced, Molecular Medicine has found that this is just not true. In fact, Hypercalciuria, the excess excretion of calcium in the urine, is actually a function of the PTH (ParaThyroid Hormone) and of the calcium-sensing receptor (CASR) in the kidney tubules[4,5]. The 1,25-D hormone affects these processes, but is not primarily responsible for hypercalciuria or hypercalcemia.

Sarcoidosis patients manufacture the 1,25-D hormone within the inflammatory granuloma, under the influence of Angiotensin II and Interferon-gamma [6]. While most Sarcoidosis patients possess high levels of 1,25-D in their blood[7,6], only a small fraction of them ever exhibit Hypercalcemia.

Physicians have been slow to assimilate the discoveries coming from Molecular Medicine.They often associate the 1,25-D hormone as solely related to calcium balance. Yet a search of the National Library of Medicine for 'VDR' (the Vitamin D Receptor molecule) yields 1410 studies, only half of which even mention the word "calcium".

High levels of the 1,25-D hormone affect muscle function, especially the cardiac muscle[8,9,10]. It is thus critical for a Clinician to measure this hormone and keep its level under control. One way of achieving control is to totally eliminate all sources of dietary Vitamin D intake from food, and all sources of exposure to bright light, until the Sarcodiosis patient is no longer producing the 1,25-D hormone beyond the Merck maximum (45pg/ml)[11].

At levels above about 42 pg/ml, the 1,25-D (generated by the sarcoid inflammation) begins to stimulate bone osteoclasts[12], causing bone to be resorbed (dissolved) back into the bloodstream. Not only does this lead to osteporosis, but also to calcium being deposited into soft tissue of the body, including the lungs, breasts, and the kidneys (where it forms kidney stones).

Some clinicians still administer Calcium and Vitamin D supplementation to their sarcoidosis patients in the vain hope that this supplementation will somehow prevent, or reverse, osteoporosis resulting from the sarcoid inflammation itself, or osteoporosis resulting from the use of corticosteroids. But the calcium metabolism of sarcodiosis patients is not the same as that of healthy individuals[13,16]. There is no clinical evidence that supplementation has any beneficial effect on sarcoid osteoporosis[14,15], indeed, since the Vitamin D supplement often causes the 1,25-D hormone to rise to extremely high levels, supplementation can actually increase bone resorption, increasing the rate of bone-weakening[17].

Corticosteroids reduce the formation of new bone by decreasing Cbfal, TGFbetaR1, BMP-2, IGF and the Bcl-2/BAX ratio, while increasing PPARgamma2[12]. None of these effects has anything to do with the Calcium metabolism. Calcium supplements will have no effect on any of the steroids' osteoporotic processes. Not only are there no conclusive studies to validate any supposed benefits of Vitamin D and Calcium supplementation in steroid-treated sarcoidosis[eg 14], the Molecular Medicine explains why such supplementation is futile, and will most probably make the osteoporosis worse.

Patients who have controlled their level of 1,25-D have discovered that the most annoying neural symptoms of Sarcoidosis have also disappeared: fatigue, irritability, panic, depression, and sleep disturbance[6]. Vitamin D supplements typically make these symptoms worse.

Clearly the gap between Molecular Medicine and Clinical Practice has to be narrowed if Clinicians are ever to understand the cause of Sarcoidosis, and be able to cure it. Knowledgable physicians and patients are routinely inducing remission[18]. But many sarcoid patients trust and rely upon Sarcoid Specialists for their care. It is encumbent upon those specialists to expend the energies needed to comprehend and apply the most up-to-date information about how the human body actually works... The cure for Sarcoidosis is within our reach. Carpe Diem!

References:
1. Ohta M, Okabe T, Ozawa K, Urabe A, Takaku F: In vitro formation of macrophage-epithelioid cells and multinucleated giant cells by 1 alpha,25-dihydroxyvitamin D from human circulating monocytes. Ann N Y Acad Sci. 1986; 465:211-20
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3460380&dopt=Abstract

2. 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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705327&dopt=Abstract

3. University of California, Riverside: Biochemistry and Physiology of Vitamin D.
http://vitamind.ucr.edu/biochem.html
http://vitamind.ucr.edu/Images/phy_vd3.gif

4. Watanabe T, Minagawa M: Familial hypoparathyroidism due to activating mutations in the calcium-sensing receptor gene. Nippon Rinsho. 2002 Feb;60(2):331-7
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11857922&dopt=Abstract

5. Thakker RV: Disorders of the calcium-sensing receptor. Biochim Biophys Acta. 1998 Dec 10;1448(2):166-70
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9920407&dopt=Abstract

6. Marshall TG, Marshall FE: New Treatments Emerge as Sarcoidosis Yields Up its Secrets. clinmed 2003 Jan 27; 2003010001
http://clinmed.netprints.org/cgi/content/full/2003010001#TheAngiotensinHypothesis

7. Marshall TG, Marshall FE: The Science Points to Angiotensin II and 1,25-Dihydroxyvitamin D. [Electronic Letter] CHEST 6 Feb 2003
http://www.chestjournal.org/cgi/eletters/123/1/18

8. Ashizawa N, Arakawa S, Koide Y, Toda G, Seto S, Yano K: Hypercalcemia due to vitamin D intoxication with clinical features mimicking acute myocardial infarction. Intern Med. 2003 Apr;42(4):340-4
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12729323&dopt=Abstract

9. Capiati D, Benassati S, Boland RL: 1,25(OH)2-vitamin D3 induces translocation of the vitamin D receptor (VDR) to the plasma membrane in skeletal muscle cells. J Cell Biochem. 2002;86(1):128-35
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12112023&dopt=Abstract

10. Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin HB, Dick W: In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J. 2001 Jan;33(1):19-24
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11352397&dopt=Abstract

11. The Merck Manual of Diagnosis and Therapy: Vitamin D Deficiency and Dependency. 17th Edition, Section 1, Chapter 3
http://www.merck.com/pubs/mmanual/section1/chapter3/3d.htm

12. Manolagas SC: Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis. Endocrine Reviews 21 (2): 115-137
http://edrv.endojournals.org/cgi/content/full/21/2/115

13. Basile JN, Liel Y, Shary J, Bell NH: Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis. J Clin Invest. 1993 Apr;91(4):1396-8
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8386185&dopt=Abstract

14. Adler RA, Funkhouser HL, Petkov VI, Berger MM: Glucocorticoid-induced osteoporosis in patients with sarcoidosis. Am J Med Sci. 2003 Jan;325(1):1-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12544077&dopt=Abstract

15. Conron M, Young C, Beynon HL: Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology (Oxford). 2000 Jul;39(7):707-13
http://rheumatology.oupjournals.org/cgi/content/full/39/7/707

16. Food and Drug Administration: Food Labeling: Nutrient Content Claims, General Principles; Health Claims, General Requirements and Other Specific Requirements for Individual Health Claims. 21 CFR part 101
http://www.cfsan.fda.gov/~lrd/nutrient.txt

17. Adams JS, Lee G: Gains in Bone Mineral Density with Resolution of Vitamin D Intoxication. Annals of Internal Medicine 1 August 1997. 127:203-206
http://www.acponline.org/journals/annals/01aug97/bmdgain.htm

18. Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2[Full Text]