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ReviewsVitamin D, Calcium, and Sarcoidosis
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VITAMIN D AND SARCOIDOSIS
The relationship between vitamin D and sarcoidosis was first recognized by Harrell and Fisher11 in 1939. They described the occurrence of hypercalcemia in 6 of 11 patients with sarcoidosis. In one of their 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 clinical observations: (1) hypercalcemia is a feature of sarcoidosis; (2) hypercalcemia can be aggravated by consuming a
SYNTHESIS AND SOURCE OF 1,25-(OH)2-D3 IN SARCOIDOSIS
The most active metabolite of vitamin D, 1,25-(OH)2-D3 is produced in the kidney from 25-hydroxycholecalciferol (25-[OH]-D3) which is produced in the liver.20 Bell et al21 reported that in three sarcoidosis patients with hypercalcemia, 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 hypercalcemia
ROLE OF 1,25-(OH)2-D3
Recent studies have pointed the way toward an immune regulator role for l,25-(OH)2-D3.26, 27 Evidence supporting its immunologic role consists of the following: (1) the presence of specific high-affinity intracellular Vitamin D receptors (VDR) for calcitriol in activated lymphocytes, macrophages, and dendritic cells;28, 29, 30 (2) l,25-(OH)2-D3 inhibits mitogen-induced lymphocyte proliferation and immunoglobulin production;31, 32, 33; (3) l,25-(OH)2-D3 reduces in lymphocyte interleukin-2 (IL-2)
HYPERCALCEMIA
The reported incidence of hypercalcemia in sarcoidosis 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% of his 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
HYPERCALCIURIA
Although hypercalcemia has long been recognized as a complication of sarcoidosis, the importance of hypercalciuria has been less thoroughly appreciated. Nevertheless, hypercalciuria is three times more common than hypercalcemia.52 In some studies, its frequency seems to have reached 60% of the cases.53 Hypercalciuria is slightly 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
SERUM PHOSPHATE
Much less attention has been paid to serum phosphate 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 al47 found significantly low serum phosphate levels in 8 of their 57 patients; the 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 patients had stage I disease, four had stage II
WHO NEEDS TREATMENT
The magnitude and persistence of the hypercalcemia are key indications for therapy.63 Severe hypercalcemia, defined as serum calcium concentration greater than 14 mg/dL, is unusual in sarcoidosis, hence aggressive treatment is rarely indicated; whereas, chronically high urinary calcium excretion always needs correcting.64, 65, 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
DRUGS
Prednisone, 20 to 40 mg/d, is the drug of choice to reduce the endogenous production of l,25-(OH)2-D3.10, 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
DRUGS NOT RECOMMENDED
Calcitonin, indomethacin, biphosphonates, gallium nitrate, plicamycin, phosphate (oral or intravenous), and thiazide diuretics are not indicated.
ROLE OF SURGERY
Urinary stones due to untreated, persistent hypercalciuria can be pulverized by extracorporeal lithotripsy before resorting to surgery.74, 75
DIETARY RESTRICTION
Since sarcoidosis patients exhibit abnormal regulation of vitamin D metabolism, it is desirable to monitor serum calcium levels frequently. The patient should be instructed to avoid high-calcium diet, calcium 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.74, 75
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