The information of the following article is very important in order for an intelligent discussion with physicians and people with Sarcoidosis. As always, each patient has an individual presentation, as we point out with the symbol of the snowflake, and it is to that end that we pass on information as it comes to light. It is vital to each of us that our own physician evaluates all diagnostic data as it applies to treatment programs.
Please read Dr. Soskel's article below. It gives more information on the function of Vitamin D in the body.
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The Significance of Calcium and Vitamin D in Sarcoidosis
Norman T. Soskel,
MD, FACP, FCCP
Sarcoidosis Center
Memphis,
Tennessee
February 4, 2003
Calcium metabolism in patients with sarcoidosis has been studied since the first intriguing reports by Harrell, et al in 1939 demonstrated elevated serum levels of calcium (hypercalcemia) in those patients. Even more common is hypercalciuria (elevated calcium in the urine).
Exposure to sunlight is believed to contribute to this by way of vitamin D metabolism and is counteracted with therapy by avoiding sunlight as
well as corticosteroid ingestion. Newer data suggests immunological functions of vitamin D with respect to granuloma formation. The exact significance of these will be discussed in this communication.
A detailed scientific discussion is beyond the scope and intent of this
article. The major purpose is to discuss in terms most people can
appreciate, the way in which calcium is handled by the body in normal
individuals and in people with sarcoidosis, what health concerns result and how and when they are treated.
A certain amount of scientific/medical jargon is required but this will be kept to a minimum.
Calcium and Vitamin D Metabolism Calcium is taken in orally and is absorbed in the gastrointestinal tract. It is excreted through the kidneys into the urine. Additional calcium can be reclaimed from the bones. This process is regulated by vitamin D and parathyroid hormone, among other factors. Vitamin D enhances absorption in the GI tract but not excretion in the kidneys. The latter is determined by calcium fluxes from the gut and bone. Vitamin D is produced in the skin as a result of exposure to ultraviolet B rays from sunlight in the form of a
precursor that is inactive. It spontaneously converts to vitamin D3 which is initially inert. In order to become biologically active it must undergo
addition of two chemicals called hydroxyl groups.
The first is attached in the liver forming 25 hydroxyvitamin D3. The second is added in the kidney to form 1,25 dihydroxy-vitamin D3 or
1,25(OH)2-D3 which is the active form of the hormone, sometimes referred to as calcitriol.
A major finding was thatthe macrophages (cells) can convert the inactive to the active form of vitamin D in the granulomas of sarcoidosis.
Hypercalcemia and Hypercalciuria in Sarcoidosis
While it is true that hypercalciuria is three times more common than
hypercalcemia in sarcoidosis, several important discoveries aid our
understanding of the uniqueness of the findings in that disease.
The site of overproduction of calcitriol is extrarenal. Alveolar macrophages (cells in the lungs) make calcitriol in sarcoidosis, specifically the macrophages in the granulomas themselves.
Another important observation is the fact that hypercalcemia can
occur in other granulomatous diseases. Hypercalciuria may
occur without hypercalcemia, but the reverse is not true; that is,
hypercalcemia is always associated with hypercalciuria. Hypercalcemia, if extreme, can cause severe health problems, however, this rarely occurs even in the worst cases of sarcoidosis. Development of kidney stones can occur,especially with hypercalciuria, and, if left unchecked, could lead to kidney damage and even kidney failure.
But, again, this is very uncommon and can be avoided by monitoring very simple parameters such as serum and urine calcium levels and
paying attention to flank pain and other symptoms of kidney stones.
Additional Effects of Vitamin D in Sarcoidosis
Recently it has been demonstrated that calcitriol affects the immune system in a manner that favors granuloma formation. Various immune
cells have receptors for vitamin D. When vitamin D binds to these
receptors,lymphocytes (a type of white blood cell) proliferate,
immunoglobulin (antibody) production increases andmonocytes/macrophages differentiate into the types of cells that form granulomas.
One reference demonstrates that calcitriol stimulates macrophages in the granulomas to make angiotensin converting enzyme (ACE) which has been used as a marker for sarcoidosis for many years. In turn, ACE may stimulate macrophages to perform many of their protective functions. Overall this suggests that calcitriol may favor mechanisms that protect against invasion by foreign bodies. However, the data could also be interpreted as being detrimental or even just neutral to
the whole process. Clear-cut ramifications of these findings awaits
further study as it is too premature to formulate conclusions at this time. Clinical trials involving patients (not only cells in culture) need to be performed.
Therapy and Other Recommendations
Not everyone with Sarcoidosis needs therapy Furthermore, not everyone with hypercalcemia or hypercalciuria needs therapy. The magnitude of elevations of calcium levels as well as the duration of elevation will determine the need for therapy. Frequently, elevations are transient and require no therapy. Chronic elevations might need to be treated.
Prednisone (a corticosteroid) is usually the drug of choice since it can reduce production of calcitriol fairly quickly. Usually the effect on lowering serum calcium is noticeable within 3-5 days. The effect on urinary calcium occurs shortly thereafter, about 7-10 days. This short duration of therapy usually minimizes the side effects, but, if the side effects are unbearable,chloroquine or hydroxychloroquine can be
used.
Ketoconazole has been used but with variable results, and most physicians do not use it for this purpose. Dietary restriction of calcium is needed but not total elimination of calcium from the diet. The same can be said for sunlight; it is not necessary to totally avoid sunlight, just to
minimize excessive exposure.
Summary
Hypercalcemia and hypercalciuria occur in a minority of patients with
sarcoidosis. Usually the consequences are minimal, but, if left unchecked,
could lead to kidney stones and even kidney failure. Mechanisms suggest a broader role for vitamin D than just hormonal, and may include various
immunologic regulatory functions. While these functions are intermediary and not causal, suppression of some of them by corticosteroids or other immunosuppressive medications could play a role in controlling some of the manifestations of sarcoidosis. More accurate and more clinically oriented studies are required before further implications can be made at this time. In addition to medication, simple measures may be of benefit in a subgroup of patients. These include refraining from overindulgence in exposure to sunlight and ingestion of calcium and vitamin D. However, total abstinence from these substances is not usually required or recommended.
References
1. Harrell GT and Fisher S. Blood chemical
changes in Boeck's sarcoid, with
particular reference to protein, calcium and
phosphatase values. J. Clin
Invest 18:687-693, 1939.
2. Scadding G.
Sarcoidosis. Eyre and Spottiswoode, London., 1967, pp. 193,
338, 340, 341,
346, 347, 348, 349, 352, 353, 354, 509.
3. Barbour GL, Coburn JW,
Slatopolosky E. Hypercalcemia in an anephric
patient with
sarcoidosis.
Evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N
Engl J Med
305:440-443, 1981.
4. Adams JS, Sharma OP, Gacad MA, et al:
Metabolism of 25-hydroxyvitamin D3
by cultured pulmonary macrophages in
sarcoidosis. J Clin Invest
72:1856-1860, 1983.
5. Selroos OBN:
Biochemical markers in sarcoidosis. Crit Rev Clin Lab Sci
24:185-216,
1986.
6. Nishimua M, Hara A, Nojima H, Mashimo M, Hori Y. Possible role
of the
hormonal form of vitamin D3 in the
granuloma-associated
angiotensin-converting enzyme activity. Sarcoidosis 1991
8:101-4.
7. Basile JN, Liel Y, Shary J, et al: Increased calcium intake
does not
suppress circulating 1,25-dihydroxyvitamin D in normocalcemic
patients with
sarcoidosis. J Clin Invest 91:1396-1398, 1993.
8. Sharma
OP. Vitamin D, Calcium, and Sarcoidosis. Chest 109:535-539, 1996.
9.
Costabel U, Teschler H. Biochemical Changes in Sarcoidosis. Clinics in
Chest
Medicine 18:827-842, 1997.
Reprinted by permission. Norman T.
Soskel, MD http://www.sarcoidcenter.com
The above questions are taken from Dr. Soskel's site linking the online book entitled "Sarcoidosis" by Dr. Sharma.Ed.
NOTE: A patient should consult with his or her personal physician before changing or considering any medical treatments or health related
changes.
