Evidence for abnormal regulation of circulating 1 alpha,25-dihydroxyvitamin D in patients with sarcoidosis and normal calcium metabolism.

Abstract

A B S T R A C T The effects of vitamin D, 2.5 mg (100,000 U)/d for 4 d, on serum calcium, serum 25-hydroxyvitamin D (25-OHD), and serum 1a,25-dihydroxyvitamin D [la,25(OH)2D] were compared in 17 normal subjects and 6 patients with sarcoidosis who had normocalcemia and no history of hypercalcemia. The diagnosis was confirmed histologically in each of them. Vitamin D increased mean serum 25-OHD from 30±4 to 99±15 nglml (P < 0.001) and did not change mean serum 1a,25(OH)2D (32±3 vs. 29±3 pg/ml) or mean serum calcium (9.5±0.1 vs. 9.6±0.1 mg/dl) in the normal subjects. In contrast, vitamin D increased mean serum 25-OHD from 19±3 to 65±19 ng/ml (p < 0.05), increased mean serum la,25(OH)2D threefold from 40±7 to 120±24 pg/ml, and increased mean serum calcium from 9.4±0.2 to 9.8±0.2 mg/dl (P < 0.01). There was a significant positive correlation between the serum la,25(OH)2D and serum calcium in these individuals (r = 0.663, P < 0.01) but not in the normal subjects. The results (a) provide further evidence for abnormal regulation of circulating la,25(OH)2D in sarcoidosis and (b) indicate that the abnormality may exist in patients with normal calcium metabolism. Thus, the defect in vitamin D metabolism in sarcoid apparently is more common than was previously recognized.

Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials

“…For example, in patients with granulomatous diseases (for example, sarcoidosis), in which there is substantial extra-renal expression of 1a-OHase, serum concentrations of 1,25(OH)2D rise dramatically in response to oral vitamin D administration. 57 Decidualplacental expression of 1a-OHase throughout pregnancy raises the possibility of heightened sensitivity to increases in circulating [25(OH)D] during pregnancy. 58 The regulation of placentaldecidual vitamin D metabolism is only beginning to be described, 59 but in direct contrast to the feedback mechanism in the kidney, the 1a-OHase may in fact be downregulated by PTH.…”

Ionized calcium and 1,25-dihydroxyvitamin D concentration in serum of patients with sarcoidosis

“…This extrarenal production of 1,25(OH) 2 D 3 , although not as tightly regulated as in the kidneys, occurs in a substrate-dependent manner [2,5]. A portion of extrarenally produced 1,25(OH) 2 D 3 , taken into systemic blood circulation, probably causes an excess of calcium transport at the small intestine and, at the same time, an excess of bone resorption, which is thought to bring on an imbalance of calcium, hypercalcaemia or hypercalciuria, in patients with sarcoidosis [6][7][8][9][10][11].Since HARRELL and FISHER [12] suggested a positive correlation between vitamin D and hypercalcaemia in sarcoidosis for the first time in 1939 [12], a number of studies has been reported about the abnormal metabolism of calcium and vitamin D in patients with sarcoidosis. However, the significance of the correlation between sCa and s1,25 (OH) 2 D 3 is thus far controversial.…”

“…This extrarenal production of 1,25(OH) 2 D 3 , although not as tightly regulated as in the kidneys, occurs in a substrate-dependent manner [2,5]. A portion of extrarenally produced 1,25(OH) 2 D 3 , taken into systemic blood circulation, probably causes an excess of calcium transport at the small intestine and, at the same time, an excess of bone resorption, which is thought to bring on an imbalance of calcium, hypercalcaemia or hypercalciuria, in patients with sarcoidosis [6][7][8][9][10][11].…”

Hormones and immune function: implications of aging

“…In particular, the immune modulatory actions of 1,25(OH) 2 D 3 appear to be mediated at an autocrine or paracrine level with antigen presenting cells (APCs) such as dendritic cells (DCs) (Hewison et al ., 2003) and macrophages (Kreutz et al ., 1993) showing a high capacity for generating 1,25(OH) 2 D 3 from inactive 25-hydroxyvitamin D 3 (25OHD 3 ). This pathway can become dysregulated during inflammatory diseases such as sarcoidosis and may lead to hypercalcaemic complications (Stern et al, 1980;Hewison et al, 2001). However, the ability of APCs to metabolize 25OHD 3 −1,25(OH) 2 D 3 may also play an important role in normal physiology by providing a conduit through which vitamin D can influence APC function and, ultimately, T-cell responses.…”

“…Dysregulated synthesis of 1,25(OH) 2 D 3 is a feature of inflammatory disease (Stern et al, 1980;Hewison et al, 2001), but there may also be altered immune function associated with vitamin D insufficiency that is an increasingly prevalent problem, particularly in more northerly latitudes and within elderly populations. Circulating levels of vitamin D have been linked to autoimmune diseases such as type 1 diabetes and multiple sclerosis and other related disorders such as Crohn's disease (Muller et al, 1995;Cantorna, 2000;Hayes, 2000;Hypponen et al, 2001;Zella & DeLuca, 2003).…”