Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin d in patients with inflammatory arthritis

Abstract

The extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25-(OH)2D] is a characteristic of activated macrophages and has been demonstrated to occur in vitro in synovial fluid macrophages from patients with inflammatory arthritis. To examine whether such synthesis occurs in vivo, 19 patients with rheumatoid arthritis, 5 patient controls, and 5 healthy controls received a challenge oral dose of 250 micrograms 25-hydroxyvitamin D3 (25-OHD3) and the serum 1,25-(OH)2D3 response was measured. The median rise in serum 1,25-(OH)2D3 was significantly greater (22 pg/ml) in the rheumatoid patients compared to either of the control groups (8 pg/ml), although the increase in precursor 25-OHD3 was similar in all groups. The serum 1,25-(OH)2D concentration did not rise above the normal upper limit in any of the control subjects but exceeded the normal range in 8 of the rheumatoid patients. Extrarenal 1,25-(OH)2D synthesis is substrate dependent, unlike renal 1 alpha-hydroxylation, which is homeostatically controlled. Excessive 1,25-(OH)2D3 synthesis in the rheumatoid group on raising the 25-OHD3 concentration is indicative of nonrenal production of the hormonal metabolite. Further evidence for substrate-dependent extrarenal synthesis came from measurements of 25-OHD and 1,25-(OH)2D in paired serum and synovial fluid samples from 19 patients with inflammatory arthritis, including 15 with rheumatoid arthritis. Synovial fluid 1,25-(OH)2D was usually present at a lower concentration than serum 1,25(OH)2D, with which it was strongly correlated (Kendall's R = 0.46, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D Deficiency in Patients with Pancreatitis: Is Vitamin D Replacement Required?

“…Instead, the 1,25(OH)2D3 molecules produced in these tissues act through intracrine and paracrine mechanisms to regulate VDRdependent activities of the local cells. However, excessive production of 1,25(OH)2D3 in extrarenal tissues can result in spilling over of 1,25(OH)2D3 to the blood circulation, thus raising blood levels of 1,25(OH)2D3, which in turn can cause hypercalcemia [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Therefore, extrarenal production of 1,25(OH)2D3 can have deleterious consequences, such as the development of acute pancreatitis as discussed below.…”

“…Given that inflammation in various tissues is a major cause of extrarenal synthesis of 1,25(OH)2D3 [16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], it is not surprising that epidemiological studies have found high incidence of acute pancreatitis in patients with rheumatoid arthritis or systemic lupus erythematous disease [49][50][51][52].…”

“…It is important to note that there is accelerated CYP27B1-catalyzed conversion of 25(OH)D3 to 1,25(OH)2D3 by activated macrophages in the extrarenal tissues undergoing inflammation [16]. This explains why patients with different inflammatory diseases, such as sarcoidosis [17][18][19][20][21], rheumatoid arthritis [22][23][24][25], pulmonary tuberculosis [26][27][28][29], inflammatory bowel disease [30][31][32] and leprosy [33], have elevated blood levels of 1,25(OH)2D3 and develop hypercalcemia.It should be noted that the synthesis of 1,25(OH)2D3 in extrarenal tissues is not intended to raise the systemic level of 1,25(OH)2D3. Instead, the 1,25(OH)2D3 molecules produced in these tissues act through intracrine and paracrine mechanisms to regulate VDRdependent activities of the local cells.…”

“…In addition, individuals who use excessive amounts of vitamin D or biologically active synthetic analogs of vitamin D may not only develop hypercalcemia, but also acute pancreatitis ( Table 1). Given that inflammation in various tissues is a major cause of extrarenal synthesis of 1,25(OH)2D3 [16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], it is not surprising that epidemiological studies have found high incidence of acute pancreatitis in patients with rheumatoid arthritis or systemic lupus erythematous disease [49][50][51][52].Sarcoidosis is another inflammatory disorder that is characterized by the presence of granulomas, mainly in lymph nodes and pulmonary tissues, that serve to "quarantine" infectious microorganisms and/or other foreign particles when the immune system fails to eliminate them [53]. The granulomas contain large numbers of activated macrophages that use CYP27B1 to actively convert 25(OH)D3 to 1,25(OH)2D3 [18][19][20][21].…”

Immunostimulation in the era of the metagenome

“…45 Confirmation of this observation has been demonstrated in Crohn's disease 46 and rheumatoid arthritis, 44 with Kavathia et al tying higher levels of 1,25-D to greater disease severity in sarcoidosis patients, 47 and Mawer et al finding that 1,25-D levels were particularly elevated in the synovial fluid surrounding the joints of subjects with rheumatoid arthritis. 48 We have previously predicted, based on molecular in silico emulation, that at higher concentrations, 1,25-D interferes with expression of several of the body's other key nuclear receptors, including the glucocorticoid receptor, the androgen receptor and the thyroid receptor. 49 These receptors also express various families of AmPs-20, 17 and 15 families, respectively, out of the 22 analyzed by Brahmachary.…”