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
with sarcoidosis; hypercalciuria is about three times
more frequent. These abnormalities of calcium me¬
tabolism are due to dysregulated production of 1,25-
(OH)2-D3 (calcitriol) by activated macrophages
trapped in pulmonary alveoli and granulomatous in¬
flammation. Undetected hyperealcemia and hypercal¬
ciuria can cause nephrocalcinosis, renal stones, and
renal failure. Corticosteroids cause prompt reversal of
^7itamin D, a prohormone, is produced in human
* skin from 7
dehydrocholesterol
under the influ¬
ence of ultraviolet B rays from the sun. Provitamin D,
concentrated in the basal layer of epidermis and upper
layer of theto dermis, energizeda by ultraviolet B photons,
changes previtamin D, photically thermally and
unstable intermediate metabolite, that at body tem¬
perature isomerizes to vitamin D3. Vitamin D3, in or¬
der become biologically active, must first be hy-
to
droxylated. The process of hydroxylation has two steps.
The first step occurs in the liver resulting in 25-
hydroxyvitamin-D3 (25-OH-D3) a biologically inert
intermediary; the second step, conversion of 25-OH-
D3 to l,25-(OH)2-D3, occurs in the proximal convo¬
luted tubules of the kidney under the influence of the
25-OH-D3-l-hydroxylase, a mitochondrial cytochrome
P 450-linked mixed function oxidase.13 The renal hy¬
droxylation, unlike the hepatic hydroxylation, is en¬
hanced by parathyroid hormone and a low serum
phosphate concentration.45 l,25-(OH)2-D3, like other
steroidal hormones (thyronine and retinoid acid), acts
through a specific intracellular receptor on the target
cell.6 The important targets of l,25-(OH)2-D3 are the
intestinal epithelium and bone where the hormone7 (1)
increases intestinal calcium and phosphate absorption,
(2) increases osteoclastic recruitment and bone resorp-
tion,8 and (3) modulates an increase in osteoblastic
bone formation.910
Vitamin D and Sarcoidosis
The relationship between vitamin D and sarcoido¬
sis was first recognized by Harrell and Fisher11 in 1939.
They described the occurrence of hyperealcemia in 6
of 11 patients with sarcoidosis. In one oftheir patients,
the serum calcium level rose from a value of 9.6 to 14.2
mg/dL after the consumption of cod-liver oil. Almost
6 decades ago, these authors made three pertinent
*From the Department of Pulmonary and Critical Care Medicine,
USC School of Medicine, Los Angeles.
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
the metabolic defect. Chloroquine, hydroxychloro-
qune, and ketoconazole are the drugs that should be
used if the patient fails to respond or develops dan¬
gerous side effects to corticosteroid therapy.
(CHEST 1996; 109:535-39)
Key words: alveolar macrophage; calcitriol; chloroquine;
hyperealcemia; hypercalciuria; ketoconazole; sarcoidosis;
vitamin D
clinical observations: (1) hyperealcemia is a feature of
sarcoidosis; (2) hyperealcemia can be aggravated by
consuming a vitamin D-rich diet; and (3) vitamin D
may be related to the calcium abnormality in the dis¬
ease. Soon after, Henneman et al12 postulated that
disordered calcium homeostasis in patients with sar¬
coidosis was similar to the one seen with vitamin D
intoxication. In 1963, Taylor et al13 found that in 345
patients with sarcoidosis in North Carolina, the mean
serum calcium level during the winter months was 9.89
mg, but it rose to 10.26 mg/dL during the summer
months; whereas, among 12,027 control subjects, the
levels in winter and summer remained unchanged. In
two hypercalcemic patients of Dent,14 further rise in
serum calcium level occurred after whole-body ultra¬
violet light irradiation. Hendrix15 gave two sarcoidosis
patients with hyperealcemia and hypercalciuria vita¬
min D-deficient diets and shielded them from sunlight;
in 8 weeks, serum calcium levels became normal, hy¬
percalciuria subsided, and fecal excretion of calcium
increased.
These seemingly unrelated observations led clini¬
cians to believe that the development of hypercalce-
mia/hypercalciuria in patients with sarcoidosis was due
to enhanced target organ responsiveness to vitamin D
in the intestine, increasing calcium absorption; in the
bones, increasing resorption; and in the kidneys,
increasing excretion. The theory that vitamin D may be
a factor in hypercalcemia-hypercalciuria syndrome of
sarcoidosis became a topic of intense investigation. In
the beginning, the results were conflicting, but the
discovery of potent metabolites of vitamin D, includ¬
ing l,25-(OH)2-D3 provided the solution to the puzzle
of hyperealcemia in sarcoidosis.16"19
Synthesis and Source of l,25-(OH)2-D3 in
Sarcoidosis
The most active metabolite of vitamin D, 1,25-
(OH)2-D3 is produced in the kidney from 25-hydrox-
ycholecalciferol (25-[OH]-D3) which is produced in
CHEST /109 / 2 / FEBRUARY, 1996 535
the liver.20 Bell et al21 reported that in three sarcoido¬
sis patients with hyperealcemia, the plasma levels of
l,25-(OH)2~D3 were high when calcium levels were
raised and fell when calcium levels returned to normal
either spontaneously or after prednisone treatment.
Further evidence that abnormal levels of 1,25-
(OH)2-D3 occur in hyperealcemia sarcoidosis patients
was provided by Mitchell et al22 who described a 28-
year-oldDwoman with hypoparathyroidism requiring
vitamin since the age of 19 years. When she devel¬
oped sarcoidosis, she became hypercalcemic. On ces¬
sation of vitamin D therapy, calcium levels returned to
normal, but the administration of hydrocortisone
caused hypocalcemia. The plasma l,25-(OH)2-D3 level
was three times the highest recorded in patients with
hypoparathyroidism under treatment with vitamin
D. Another patient studied by Zimerman et al23 had
hypoparathyroidism, but was able to discontinue vita¬
min D treatment with maintenance of normal serum
calcium level when she developed sarcoidosis. An el¬
evated serum concentration of l,25-(OH)-D, a me¬
tabolite solely synthesized in the kidney in normal
nonpregnant human subjects, occurred in a hypercal¬
cemic, anephric male patient with sarcoidosis. These
observations not only support the original contention
of Henneman et al12 that the hyperealcemia of sarcoi¬
dosis is a form of vitamin D intoxication, but also es¬
tablish that the hormone is produced at an extrarenal
site. Adams et al19 demonstrated that l,25-(OH)2-D3
is the hypercalcemia-causing factor in sarcoidosis and
that the macrophage from patients with sarcoidosis is
the synthetic source of hormone in the disease. Mason
et al25 identified a similar metabolite in preparations of
sarcoid granulomas incubated with 25-OH-D. Al¬
though the identity of the hormone and its origin are
clearly known, the question remains, why does nature
elaborate this hormone?25 Is the production of 1,25-
(OH)2-D3 solely for the purpose of causing damage to
the tissue or is it a protective phenomenon to check the
uncontested immunologic cascade? Of course, there is
a third possibility of the hormone being a harmless
byproduct.
Role of l,25-(OH)2-D3
Recent studies have pointed the way toward an im¬
mune regulator role for l,25-(OH)2-D3.26,27 Evidence
supporting its immunologic role consists of the follow¬
ing: (1) the presence of specific high-affinity intracel¬
lular Vitamin D receptors (VDR) for calcitriol in acti¬
vated lymphocytes, macrophages, and dendritic
cells;2830 (2) l,25-(OH)2-D3inhibits mitogen-induced
lymphocyte proliferation and immunoglobulin pro¬
duction;^1-33; (3) l,25-(OH)2-D3 reduces in lympho¬
cyte interleukin-2 (IL-2) production; and (4) 1,25-
(OH)2-D3 enhances the ability of macrophages to
inhibit proliferation of Mycobacterium tuberculosis in
536
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
vitro.34,35 Thus, the hormonal form of vitamin D seems
to possess a role similar to that of other cytokines. The
precise lesion that controls the abnormal regulation of
l,25-(OH)2-D3 synthesis is obscure, but it may be due
to a defective feedback control of calcitriol production
at the site of synthesis in macrophages or in target cells
for calcitriol such as lymphocytes.36 Production of the
hormone may thus be a part of the normal immune
response in retaliation to an infection and may induce
secretion of other mediators, including IL-1. Calcitriol
modulates cytotoxic and antibody producing functions
of lymphocytes.37 The action depends on the thresh¬
old of VDR expression and is mediated through inhi¬
bition of T-cell secretion of lymphokine IL-2.38 Cal¬
citriol retards the gamma-interferon synthesis by T
cells and this may act as part of the control of calcitriol
synthesis by macrophages that produce the hormone
when stimulated by gamma-interferon.39'40 The inhi¬
bition of the immunoglobulin production is due to di¬
rect suppression of helper T cells or macrophages.41
VDRs are also present in T cell-mediated natural
killer cells indicating that calcitriol may modulate the
immune response to viral and neoplastic processes.
Hypercalcemia
The reported incidence of hypercalcemia in sarcoi¬
dosis varies from 2 to 63%. The frequency, with a few
exceptions, tends to be higher in the North American
series. The highest incidence of 63% was reported by
McCort et al.42 Cummings43 found calcium levels
above 11 mg (100 mL)"1 (2.7 mmol. -1) in 35% ofhis
patients. Mayock et al,44 in their review of 509 patients,
recorded a frequency of 17%. Similar results were
obtained by Taylor et al13 in their study of 345 patients
with sarcoidosis. Only six of the 62 patients of Scad-
ding45 in London had serum calcium levels of more
than 11.0 mg. Mather46 reported a still lower preva¬
lence: only 4 of his 86 untreated patients with sarcoi¬
dosis exhibited hypercalcemia. In Finland, Putkonen
et al4/ could find only two patients with hypercalcemia
in a series of 60.
There is no conclusive evidence that race, age, sex,
occupation, or geographic distribution influences the
development of hypercalcemia. Although hypercalce¬
mia appears to be a consistent feature, the studies
showing excessively high (10 to 63%) frequency need
to be revised. Goldstein et al,48 in their positive stud¬
ies with a controlled intake of calcium, found that only
2% of their patients had hypercalcemia. I believe this
figure is excessively low and that further studies are
needed to establish the frequency of hypercalcemia.
Meanwhile, it seems reasonable to accept the inci¬
dence of 11% noted by James et al49 in their world¬
wide review of 3,676 patients with sarcoidosis.
Hypercalcemia is usually transient in subacute sar¬
coidosis and may fluctuate in chronic sarcoidosis, de-
Reviews
 the disease. Furthermore,
pending on the activity ofoccur
hypercalcemia may only at a certain phase dur¬
ing the long course of chronic sarcoidosis. Conse¬
quently, one is not likely to get a true picture of the
calcium abnormality if serum calcium levels are not
measured regularly and consistently over a long period
of time.
It has been suggested that hypercalcemia is more
frequent during the summer months when exposure to
sun is at its maximum.1316'50'51 If this were an impor¬
tant factor, then the incidence of hypercalcemia would
be highest in southern California, the land of sun
worshippers. But it is not so! Hypercalcemia occurs
more frequently in sarcoidosis patients in London,
Reading (UK), New York, and Lisbon.49 Besides,
Putkonen et al47 found lower values in summer months
and slightly higher mean levels in late autumn.
Hypercalciuria
Although hypercalcemia has long been recognized
as a complication of sarcoidosis, the importance of hy¬
percalciuria has been less isthoroughly appreciated.
Nevertheless, hypercalciuria three times more com¬
mon than hypercalcemia 52 In some studies, its fre¬
quency seems to have reached 60% of the cases.53
Hypercalciuria is slighdy more common in men than
women and, in London, in whites than in West Indian
patients. In patients with renal function, hypercalciuria
is always present when the patient has sareoidosis-re-
lated hypercalcemia. The mechanism of hypercalciuria
appears to be threefold:54 (1) absorptive, associated
with elevated serum l,25-(OH)2-D3 levels and abnor¬
urinary calcium/creatinine ratio;55 (2) re-
mally highassociated
sorptive, with an extensive dissemination of
sarcoidosis, including bones and high serum angio-
tensin-converting enzyme; osteopenia may occur; hy¬
percalciuria persists on a calcium-poor diet;56"58 and (3)
associated with osteoclast-activating factor, a bone-re-
absorbing substance, produced by activated lympho¬
cytes and mononuclear cells, and sarcoid granulomas
that may be responsible for inducing bone resorp-
tion.59 According to Broulik and coworkers,60 urinary
excretion rate of calcium is based primarily on the fil¬
tered load of calcium when corrected for urinary cal¬
cium excretion; the tubular maximum reabsorptive
rate for calcium is not increased. These results suggest
that 1, 25-(OH)2-D3 has no direct effect on renal cal¬
cium handling and hypercalciuria is due to the flow of
calcium from the bone and gut.60
Serum Phosphate
Much less attention has been paid to serum phos¬
phate levels in sarcoidosis. Longcope and Frieman61
found levels ranging from 2.4 to 4.8 mg (100 mL)-1
(0.78 to 1.55 mmol-L-1). Putkonen et ar7 found sig¬
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1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
nificantlythe
low serum phosphate levels in 8 of their 57
patients; abnormality was more marked in patients
with chronic disease. Twelve of 53 patients investigated
by Selroos62 had phosphate levels under 2.8 mg (100
mL)-1 (0.9 mmol-L"1; 6 of the 12 had
patients stage I
disease, four had stage II disease, and the disease was
far advanced in two patients. Renal functions were
normal in all the patients.62
Who Needs Treatment
The magnitude and persistence of the hypercalce¬
mia are key indications for therapy.63 Severe hyper¬
calcemia, defined as serum calcium concentration
greater than 14 mg/dL, is unusual in sarcoidosis, hence
aggressive treatment israrely indicated; whereas,
chronically high urinary calcium excretion always
needs correcting.64"66 The goals of therapy include the
following: (1) to reduce oral and IV intake of vitamin
D, calcium supplement, and diet rich in calcium; (2) to
maintain an expanded intravascular volume; (3) to re¬
duce inappropriate production of l,25-(OH)2-D3 by
sarcoid macrophages and granulomata; and (4) to re¬
duce l,25-(OH)2-D3-induced intestinal calcium ab¬
sorption and bone resorption.
Drugs
Prednisone, 20 to 40 mg/d, is the drug of choice to
reduce the endogenous production of l,25-(OH)2-
q3 10,67,68 institution of corticosteroid therapy causes a
relatively swift decrease in circulating l,25-(OH)2-D3
and serum calcium level within 3 to 5 days. A decrease
in urinary calcium excretion rate soon follows, within
7 to 10 days. Failure to normalize the serum calcium
level after 2 weeks should lead the clinician to exclude
the possibility of a coexisting disorder, including
hyperparathyroidism, carcinoma, lymphoma, and my¬
eloma. Once the calcium abnormality is brought under
control, prednisone dosage can be reduced over a pe¬
riod of 4 to 6 weeks. Serum calcium and cal¬
urinary
cium excretion rate will need to be monitored fre¬
quently.
If the patient develops unbearable side effects of
corticosteroid therapy or fails to respond, chloroquine
or hydrochloroquine should be given. The latter two
drugs are known to reduce serum l,25-(OH)2-D3 and
calcium concentrations.69"71
The antifungal drug ketoconazole, a known inhibi¬
tor of cytochrome P450andsteroid oxidases, lowers circu¬
lating l,25-(OH)2-D3 serum calcium levels; how¬
ever, its efficacy is not widely recognized.72,73
Drugs Not Recommended
Calcitonin, indomethacin, biphosphonates, gallium
nitrate, plicamycin, phosphate (oral or intravenous),
and thiazide diuretics are not indicated.
CHEST /109 / 2 / FEBRUARY, 1996 537
 Role of Surgery
Urinary stones due to untreated, persistent hyper¬
calciuria can be pulverized by extracorporeal litho-
tripsy before resorting to surgery.7475
Dietary Restriction
Since sarcoidosis patients exhibit abnormal regula¬
tion of vitamin D metabolism, it is desirable to mon¬
itor serum calcium levels frequently. The patient
should be instructed to avoid high-calcium diet, cal¬
cium supplement, and exposure to sunlight. These
precautions should be strictly adhered because even
normocalcemic patients with sarcoidosis may develop
hypercalcemia, renal stones, and renal failure.7475
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CHEST /109 / 2 / FEBRUARY, 1996 539
 Vitamin D, Calcium, and Sarcoidosis
Om P. Sharma
Chest 1996;109; 535-539
DOI 10.1378/chest.109.2.535
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