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Vitamin D, Calcium, and Sarcoidosis

Om P. Sharma

Chest 1996;109;535-539
DOI 10.1378/chest.109.2.535
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
Vitamin D, Calcium, and Sarcoidosis"
Om P. Sharma, MD, FCCP

Hyperealcemia occurs in about 10% of the patients the metabolic defect. Chloroquine, hydroxychloro-
with sarcoidosis; hypercalciuria is about three times qune, and ketoconazole are the drugs that should be
more frequent. These abnormalities of calcium me¬ used if the patient fails to respond or develops dan¬
tabolism are due to dysregulated production of 1,25- gerous side effects to corticosteroid therapy.
(OH)2-D3 (calcitriol) by activated macrophages (CHEST 1996; 109:535-39)
trapped in pulmonary alveoli and granulomatous in¬
flammation. Undetected hyperealcemia and hypercal¬ Key words: alveolar macrophage; calcitriol; chloroquine;
ciuria can cause nephrocalcinosis, renal stones, and hyperealcemia; hypercalciuria; ketoconazole; sarcoidosis;
renal failure. Corticosteroids cause prompt reversal of vitamin D

^7itamin D, a prohormone, is produced in human clinical observations: (1) hyperealcemia is a feature of


* skin from 7
dehydrocholesterol
under the influ¬ sarcoidosis; (2) hyperealcemia can be aggravated by
ence of ultraviolet B rays from the sun. Provitamin D, consuming a vitamin D-rich diet; and (3) vitamin D
concentrated in the basal layer of epidermis and upper may be related to the calcium abnormality in the dis¬
layer of theto dermis, energizeda by ultraviolet B photons, ease. Soon after, Henneman et al12 postulated that
changes previtamin D, photically thermally and disordered calcium homeostasis in patients with sar¬
unstable intermediate metabolite, that at body tem¬ coidosis was similar to the one seen with vitamin D
perature isomerizes to vitamin D3. Vitamin D3, in or¬ intoxication. In 1963, Taylor et al13 found that in 345
der become biologically active, must first be hy-
to patients with sarcoidosis in North Carolina, the mean
droxylated. The process of hydroxylation has two steps. serum calcium level during the winter months was 9.89
The first step occurs in the liver resulting in 25- mg, but it rose to 10.26 mg/dL during the summer
hydroxyvitamin-D3 (25-OH-D3) a biologically inert months; whereas, among 12,027 control subjects, the
intermediary; the second step, conversion of 25-OH- levels in winter and summer remained unchanged. In
D3 to l,25-(OH)2-D3, occurs in the proximal convo¬ two hypercalcemic patients of Dent,14 further rise in
luted tubules of the kidney under the influence of the serum calcium level occurred after whole-body ultra¬
25-OH-D3-l-hydroxylase, a mitochondrial cytochrome violet light irradiation. Hendrix15 gave two sarcoidosis
P 450-linked mixed function oxidase.13 The renal hy¬ patients with hyperealcemia and hypercalciuria vita¬
droxylation, unlike the hepatic hydroxylation, is en¬ min D-deficient diets and shielded them from sunlight;
hanced by parathyroid hormone and a low serum in 8 weeks, serum calcium levels became normal, hy¬
phosphate concentration.45 l,25-(OH)2-D3, like other percalciuria subsided, and fecal excretion of calcium
steroidal hormones (thyronine and retinoid acid), acts increased.
through a specific intracellular receptor on the target These seemingly unrelated observations led clini¬
cell.6 The important targets of l,25-(OH)2-D3 are the cians to believe that the development of hypercalce-
intestinal epithelium and bone where the hormone7 (1) mia/hypercalciuria in patients with sarcoidosis was due
increases intestinal calcium and phosphate absorption, to enhanced target organ responsiveness to vitamin D
(2) increases osteoclastic recruitment and bone resorp- in the intestine, increasing calcium absorption; in the
tion,8 and (3) modulates an increase in osteoblastic bones, increasing resorption; and in the kidneys,
bone formation.910 increasing excretion. The theory that vitamin D may be
a factor in hypercalcemia-hypercalciuria syndrome of
Vitamin D and Sarcoidosis sarcoidosis became a topic of intense investigation. In
The relationship between vitamin D and sarcoido¬ the beginning, the results were conflicting, but the
sis was first recognized by Harrell and Fisher11 in 1939. discovery of potent metabolites of vitamin D, includ¬
They described the occurrence of hyperealcemia in 6 ing l,25-(OH)2-D3 provided the solution to the puzzle
of 11 patients with sarcoidosis. In one oftheir patients, of hyperealcemia in sarcoidosis.16"19
the serum calcium level rose from a value of 9.6 to 14.2
Synthesis and Source of l,25-(OH)2-D3 in
mg/dL after the consumption of cod-liver oil. Almost
6 decades ago, these authors made three pertinent Sarcoidosis
The most active metabolite of vitamin D, 1,25-
*From the Department of Pulmonary and Critical Care Medicine, (OH)2-D3 is produced in the kidney from 25-hydrox-
USC School of Medicine, Los Angeles. ycholecalciferol (25-[OH]-D3) which is produced in
CHEST /109 / 2 / FEBRUARY, 1996 535
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
the liver.20 Bell et al21 reported that in three sarcoido¬ vitro.34,35 Thus, the hormonal form of vitamin D seems
sis patients with hyperealcemia, the plasma levels of to possess a role similar to that of other cytokines. The
l,25-(OH)2~D3 were high when calcium levels were precise lesion that controls the abnormal regulation of
raised and fell when calcium levels returned to normal l,25-(OH)2-D3 synthesis is obscure, but it may be due
either spontaneously or after prednisone treatment. to a defective feedback control of calcitriol production
Further evidence that abnormal levels of 1,25- at the site of synthesis in macrophages or in target cells
(OH)2-D3 occur in hyperealcemia sarcoidosis patients for calcitriol such as lymphocytes.36 Production of the
was provided by Mitchell et al22 who described a 28- hormone may thus be a part of the normal immune
year-oldDwoman with hypoparathyroidism requiring response in retaliation to an infection and may induce
vitamin since the age of 19 years. When she devel¬ secretion of other mediators, including IL-1. Calcitriol
oped sarcoidosis, she became hypercalcemic. On ces¬ modulates cytotoxic and antibody producing functions
sation of vitamin D therapy, calcium levels returned to of lymphocytes.37 The action depends on the thresh¬
normal, but the administration of hydrocortisone old of VDR expression and is mediated through inhi¬
caused hypocalcemia. The plasma l,25-(OH)2-D3 level bition of T-cell secretion of lymphokine IL-2.38 Cal¬
was three times the highest recorded in patients with citriol retards the gamma-interferon synthesis by T
hypoparathyroidism under treatment with vitamin
D. Another patient studied by Zimerman et al23 had
cells and this may act as part of the control of calcitriol
synthesis by macrophages that produce the hormone
hypoparathyroidism, but was able to discontinue vita¬
min D treatment with maintenance of normal serum
when stimulated by gamma-interferon.39'40 The inhi¬
bition of the immunoglobulin production is due to di¬
calcium level when she developed sarcoidosis. An el¬ rect suppression of helper T cells or macrophages.41
evated serum concentration of l,25-(OH)-D, a me¬ VDRs are also present in T cell-mediated natural
tabolite solely synthesized in the kidney in normal killer cells indicating that calcitriol may modulate the
nonpregnant human subjects, occurred in a hypercal¬ immune response to viral and neoplastic processes.
cemic, anephric male patient with sarcoidosis. These
observations not only support the original contention Hypercalcemia
of Henneman et al12 that the hyperealcemia of sarcoi¬ The reported incidence of hypercalcemia in sarcoi¬
dosis is a form of vitamin D intoxication, but also es¬ dosis varies from 2 to 63%. The frequency, with a few
tablish that the hormone is produced at an extrarenal exceptions, tends to be higher in the North American
site. Adams et al19 demonstrated that l,25-(OH)2-D3 series. The highest incidence of 63% was reported by
is the hypercalcemia-causing factor in sarcoidosis and McCort et al.42 Cummings43 found calcium levels
that the macrophage from patients with sarcoidosis is above 11 mg (100 mL)"1 (2.7 mmol. -1) in 35% ofhis
the synthetic source of hormone in the disease. Mason patients. Mayock et al,44 in their review of 509 patients,
et al25 identified a similar metabolite in preparations of recorded a frequency of 17%. Similar results were
sarcoid granulomas incubated with 25-OH-D. Al¬ obtained by Taylor et al13 in their study of 345 patients
though the identity of the hormone and its origin are with sarcoidosis. Only six of the 62 patients of Scad-
clearly known, the question remains, why does nature
elaborate this hormone?25 Is the production of 1,25-
ding45 in London had serum calcium levels of more
than 11.0 mg. Mather46 reported a still lower preva¬
(OH)2-D3 solely for the purpose of causing damage to lence: only 4 of his 86 untreated patients with sarcoi¬
the tissue or is it a protective phenomenon to check the dosis exhibited hypercalcemia. In Finland, Putkonen
uncontested immunologic cascade? Of course, there is et al4/ could find only two patients with hypercalcemia
a third possibility of the hormone being a harmless in a series of 60.
byproduct. There is no conclusive evidence that race, age, sex,
Role of l,25-(OH)2-D3 occupation, or geographic distribution influences the
Recent studies have pointed the way toward an im¬
development of hypercalcemia. Although hypercalce¬
mia appears to be a consistent feature, the studies
mune regulator role for l,25-(OH)2-D3.26,27 Evidence showing excessively high (10 to 63%) frequency need
supporting its immunologic role consists of the follow¬ to be revised. Goldstein et al,48 in their positive stud¬
ing: (1) the presence of specific high-affinity intracel¬ ies with a controlled intake of calcium, found that only
lular Vitamin D receptors (VDR) for calcitriol in acti¬ 2% of their patients had hypercalcemia. I believe this
vated lymphocytes, macrophages, and dendritic figure is excessively low and that further studies are
cells;2830 (2) l,25-(OH)2-D3inhibits mitogen-induced needed to establish the frequency of hypercalcemia.
lymphocyte proliferation and immunoglobulin pro¬ Meanwhile, it seems reasonable to accept the inci¬
duction;^1-33; (3) l,25-(OH)2-D3 reduces in lympho¬ dence of 11% noted by James et al49 in their world¬
cyte interleukin-2 (IL-2) production; and (4) 1,25- wide review of 3,676 patients with sarcoidosis.
(OH)2-D3 enhances the ability of macrophages to Hypercalcemia is usually transient in subacute sar¬
inhibit proliferation of Mycobacterium tuberculosis in coidosis and may fluctuate in chronic sarcoidosis, de-
536 Reviews
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
the disease. Furthermore,
pending on the activity ofoccur nificantlythe
low serum phosphate levels in 8 of their 57
hypercalcemia may only at a certain phase dur¬ patients; abnormality was more marked in patients
ing the long course of chronic sarcoidosis. Conse¬ with chronic disease. Twelve of 53 patients investigated
quently, one is not likely to get a true picture of the by Selroos62 had phosphate levels under 2.8 mg (100
calcium abnormality if serum calcium levels are not mL)-1 (0.9 mmol-L"1; 6 of the 12 had
patients stage I
measured regularly and consistently over a long period disease, four had stage II disease, and the disease was
of time. far advanced in two patients. Renal functions were
It has been suggested that hypercalcemia is more normal in all the patients.62
frequent during the summer months when exposure to
sun is at its maximum.1316'50'51 If this were an impor¬ Who Needs Treatment
tant factor, then the incidence of hypercalcemia would The magnitude and persistence of the hypercalce¬
be highest in southern California, the land of sun mia are key indications for therapy.63 Severe hyper¬
worshippers. But it is not so! Hypercalcemia occurs
more frequently in sarcoidosis patients in London,
calcemia, defined as serum calcium concentration
Reading (UK), New York, and Lisbon.49 Besides, greater than 14 mg/dL, is unusual in sarcoidosis, hence
Putkonen et al47 found lower values in summer months aggressive treatment israrely indicated; whereas,
and slightly higher mean levels in late autumn. chronically high urinary calcium excretion always
needs correcting.64"66 The goals of therapy include the
Hypercalciuria
following: (1) to reduce oral and IV intake of vitamin
D, calcium supplement, and diet rich in calcium; (2) to
Although hypercalcemia has long been recognized maintain an expanded intravascular volume; (3) to re¬
as a complication of sarcoidosis, the importance of hy¬ duce inappropriate production of l,25-(OH)2-D3 by
percalciuria has been less isthoroughly appreciated. sarcoid macrophages and granulomata; and (4) to re¬
Nevertheless, hypercalciuria three times more com¬ duce l,25-(OH)2-D3-induced intestinal calcium ab¬
mon than hypercalcemia 52 In some studies, its fre¬ sorption and bone resorption.
quency seems to have reached 60% of the cases.53
Hypercalciuria is slighdy more common in men than Drugs
women and, in London, in whites than in West Indian Prednisone, 20 to 40 mg/d, is the drug of choice to
patients. In patients with renal function, hypercalciuria reduce the endogenous production of l,25-(OH)2-
is always present when the patient has sareoidosis-re- q3 10,67,68 institution of corticosteroid therapy causes a
lated hypercalcemia. The mechanism of hypercalciuria relatively swift decrease in circulating l,25-(OH)2-D3
appears to be threefold:54 (1) absorptive, associated and serum calcium level within 3 to 5 days. A decrease
with elevated serum l,25-(OH)2-D3 levels and abnor¬ in urinary calcium excretion rate soon follows, within
urinary calcium/creatinine ratio;55 (2) re-
mally highassociated 7 to 10 days. Failure to normalize the serum calcium
sorptive, with an extensive dissemination of level after 2 weeks should lead the clinician to exclude
sarcoidosis, including bones and high serum angio- the possibility of a coexisting disorder, including
tensin-converting enzyme; osteopenia may occur; hy¬ hyperparathyroidism, carcinoma, lymphoma, and my¬
percalciuria persists on a calcium-poor diet;56"58 and (3) eloma. Once the calcium abnormality is brought under
associated with osteoclast-activating factor, a bone-re- control, prednisone dosage can be reduced over a pe¬
absorbing substance, produced by activated lympho¬ riod of 4 to 6 weeks. Serum calcium and cal¬
urinary
cytes and mononuclear cells, and sarcoid granulomas cium excretion rate will need to be monitored fre¬
that may be responsible for inducing bone resorp- quently.
tion.59 According to Broulik and coworkers,60 urinary If the patient develops unbearable side effects of
excretion rate of calcium is based primarily on the fil¬ corticosteroid therapy or fails to respond, chloroquine
tered load of calcium when corrected for urinary cal¬ or hydrochloroquine should be given. The latter two
cium excretion; the tubular maximum reabsorptive drugs are known to reduce serum l,25-(OH)2-D3 and
rate for calcium is not increased. These results suggest calcium concentrations.69"71
that 1, 25-(OH)2-D3 has no direct effect on renal cal¬ The antifungal drug ketoconazole, a known inhibi¬
cium handling and hypercalciuria is due to the flow of tor of cytochrome P450andsteroid oxidases, lowers circu¬
calcium from the bone and gut.60 lating l,25-(OH)2-D3 serum calcium levels; how¬
ever, its efficacy is not widely recognized.72,73
Serum Phosphate
Much less attention has been paid to serum phos¬ Drugs Not Recommended
phate levels in sarcoidosis. Longcope and Frieman61 Calcitonin, indomethacin, biphosphonates, gallium
found levels ranging from 2.4 to 4.8 mg (100 mL)-1 nitrate, plicamycin, phosphate (oral or intravenous),
(0.78 to 1.55 mmol-L-1). Putkonen et ar7 found sig¬ and thiazide diuretics are not indicated.
CHEST /109 / 2 / FEBRUARY, 1996 537
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
Role of Surgery dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria:
different responseto therapy. J Clin Endocrinol Metab 1980;
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tripsy before resorting to surgery.7475 vitamin D3 by cultured pulmonary alveolar macrophages in sar¬
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21 Bell NH, Stern PH, Pantzer E, et al. Evidence that increase cir¬
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itor serum calcium levels frequently. The patient abnormal calcium metabolism in sarcoidosis. J Clin Invest 1979;
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22 Mitchell TH, Stamp TCB, Jenkins JL. Hypercalcemic sarcoido¬
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precautions should be strictly adhered because even 23 Zimerman J, Holick MF, Silver J. Normocalcemia in a hypothy-
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24 Barbour GL, Cobwin JW, Slatopolsky E, et al. Hypercalcemia in
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CHEST /109 / 2 / FEBRUARY, 1996 539


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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
Vitamin D, Calcium, and Sarcoidosis
Om P. Sharma
Chest 1996;109; 535-539
DOI 10.1378/chest.109.2.535
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS