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The role of circulating vitamin D metabolites in hypercalcemia of malignancy: A reappraisal
Abstracts From the Bone & Tooth Society
increased from 28 + 5 to 68 rt 18 pglml (P < 0.05) when the NCaLP diet was fed, and from 23 f 4 to 82 f 22 pg/ml (P < 0.05) during the LCaNP diet. The PR of calcitriol increased frcm 26 + 6 to 58 f 10 pg/min per kg MBS (P < 0.01) during the NCaLP diet and from 22f 5 to 88 f 23 pglmin per kg MBS (P < 0.05) when the LCaNP diet was fed. We conclude that the increase in plasma calcitriol levels during P depletion in pigs is not caused by a decrease in its MCR. Thus in P deficiency, plasmacalcitriol levels are a good index of PR. In contrast, Ca depletion is associated with a higher PR than indicated by measurement of plasmacalcitriol because of the increased MCR.
THE ROLE OF CHXlH.ATlNG VlTAMlN II METABOUTES IN HYPERCALCEMIA OF MALIGNANCY: A REAPPRAISAL S. Ralston,’ R.A. Cowan,’ AS. Jenkins,’ A.G. Robertson,* M.D. Gardner,’ and I.T. Boyle.’ ‘Departments of Medicine and Pathological Biochemistry, Royal Infirmary and *Department of Radiotherapeutics and Oncology, Western Infirmary, Glasgow It is generally considered that 1,25 dihydroxyvitamin D [1 ,25(OH),D3] synthesis is suppressed in malignancy associated hypercatcemia. Accordingly, circulating 1 ,25(OH),D3 is thought not to play a major role in the pathogenesis of hypercalcemia in malignancy. Further, measurement of plasma 1,25(OH),D, has been proposed as a means by which the hypercalcemia of malignancy may be differentiated from primary hyperparathyroidism. In the present study, plasma concentrations of 1 ,25(OH),D3 were measured in 44 patients with malignancy-associated hypercalcemia and related to other hormonal regulators of calcium metabolism. lmmunoreactive PTH concentrations were suppressed in all but two patients, and, as a group, patients with hypercalcemia of malignancy had lower 1,25-dihydroxycholecalciferol concentrations than normocalcemic cancer patients. Nonetheless, 1,25-dihydroxycholecalciferol concentrations were clearly detectable in a significant proportion (43%) of hypercalcemic patients, a response that may be considered inappropriate to a hypercalcemic of nonparathyroid origin. While the mechanism of continued 1,25(OH),D, production in this situation is unclear, it is evident that measurement of plasma 1,2ddihydroxycholecalciferol concentration does not provide a reliable method for distinguishing the hypercalcemia of malignancy from primary hyperparathyroidism. Further, the active vitamin D metabolites may pqssibly contribute to the pathogenesis and maintenance of the hypercalcemia by stimulating bone resorption and by increasing absorption of calcium from the intestine.
VITAMIN D NUTRITION IN INSTITUTIONALIZED ELDERLY PEOPLE J.T. Harm,’ E.B. Mawer,’ M. Davies,’ and J .L. Taylor* ‘Department of Medicine, Medical School, Stopford Building, University of Manchester and *Birch Hill Hospital, Rochdale, Lanes, UK The elderly housebound and institutionalized population is known to be at risk of developing the clinical manifestations of vitamin D deficiency. Although only a minority develop overt disease, there is a high prevalence of biochemical vitamin D deficiency, and recently an association between vitamin D deficiency and femoral neck fractures has been established. The
55
vitamin D status of elderly people in Rochdale, both institutionalized and attending a geriatric day-hospital, was assessed by measuring their serum 25(OH)D2 and 25(OH)D, levels in the spring and autumn of 1982 using a quantitative HPLC method. The vitamin D, and D3 content of their food was determined so that the relative contributions of isolation and diet could be established. Analysis of serum 25(OH)D, and 25(OH)D, showed the following results: Group ng/ml *50-w, *WW, n
7. Long-stay wards
2. CommwMy
homes
3. Geriatric day hospital
spnns
Autumn
spnng
Autumn
sprvlg
0.8 4.8
0.8 4.8
2.9 57
2.4 89
4.2 12.2
36
78
Autumn 27 13.7 10
Results show that vitamin D status is poor in inmates of longstay wards (group 1) and in many residents in homes (group 2) but was satisfactory in attenders of the geriatric day hospital (group 3). Seasonal variation in 25(OH)D, was significant in group 2 only, as assessed by paired t-test (P < 0.001). Serum 25(OH)D, levels in groups 1 and 2 combined were positively correlated with dietary vitamin D, intake (n = 0.79, P = 0.05). The poor state of vitamin D nutrition in the institutionalized people studied here shows that, in the absence of sufficient exposure to sunlight, vitamin D requirement was not met by an otherwise satisfactory diet. Investigations into the efficacy of high-dose vitamin D treatment given once or twice yearly to the same institutionalized people are in progress. We are grateful to the Rochdale Area Health Authority for supporting this project.
VITAMIN D-DEPENDENT RICKETS TYPE II: STUDIES OF THE MOLECULAR BASIS OF THE DISEASE USING CULTURED SKIN FIBROBLASTS L.J. Fraher,’ G.N. Hendy,’ H. Jani,’ L. Nicholson,’ F.R.J. Hinde,* D. Grant,* and J.L.H. O’Riordan* ’ The Middlesex Hospital, London and *The Hospital for Sick Children, Great Ormond Street, London, UK Cultured skin fibroblasts have proved to be a useful source of human tissue to study interactions of 1,25(OH),D, with its specific intracellular binding protein. We have recently used such a system to investigate a patient with severe rickets due to vitamin D dependency type II. This patient was a 3-year-old boy who failed to respond to massive doses of calcitriol and eventually died of pneumonia. Fibroblasts, obtained from collagenase digests of punch skin biopsies, were cultured in Ham’s F 12 supplemented with 10% fetal calf serum, antibiotics, and insulin. Using these cells, studies were conducted to (1) detect the presence of both cytosolic and nuclear association of tritiated 1,25(OH),D, within the cells, (2) investigate the influence of unlabeled 1,25(OH),D, on the metabolism of tritiated 25(OH) D, and (3) study the metabolism of tritiated 1 ,25(OH),D3 itself. In fibroblasts from two normal infants both binding cytosolic by a 3.7 S protein and nuclear association of 1,25(OH),D, could be demonstrated. However, both were absent in cells from the patient. When normal cells were preincubated with increasing concentrations of 1,25(OH),D,, the metabolism of 3H 250H D, could be influenced in a biphasic manner. Through the physiologic range of 1,25(OH),D, concentrations increasing amounts of 3H 24,25(OH),D, were formed. However, at supraphysiologic concentrations 1,25(OH),D,, production of 3H 24,25(OH)*D, ceased, presumably due to substratecompetition by 1,25(OH),D, itself. This phenomenon was also absent in fibroblasts from the patient. Tritiated
increased from 28 + 5 to 68 rt 18 pglml (P < 0.05) when the NCaLP diet was fed, and from 23 f 4 to 82 f 22 pg/ml (P < 0.05) during the LCaNP diet. The PR of calcitriol increased frcm 26 + 6 to 58 f 10 pg/min per kg MBS (P < 0.01) during the NCaLP diet and from 22f 5 to 88 f 23 pglmin per kg MBS (P < 0.05) when the LCaNP diet was fed. We conclude that the increase in plasma calcitriol levels during P depletion in pigs is not caused by a decrease in its MCR. Thus in P deficiency, plasmacalcitriol levels are a good index of PR. In contrast, Ca depletion is associated with a higher PR than indicated by measurement of plasmacalcitriol because of the increased MCR.
THE ROLE OF CHXlH.ATlNG VlTAMlN II METABOUTES IN HYPERCALCEMIA OF MALIGNANCY: A REAPPRAISAL S. Ralston,’ R.A. Cowan,’ AS. Jenkins,’ A.G. Robertson,* M.D. Gardner,’ and I.T. Boyle.’ ‘Departments of Medicine and Pathological Biochemistry, Royal Infirmary and *Department of Radiotherapeutics and Oncology, Western Infirmary, Glasgow It is generally considered that 1,25 dihydroxyvitamin D [1 ,25(OH),D3] synthesis is suppressed in malignancy associated hypercatcemia. Accordingly, circulating 1 ,25(OH),D3 is thought not to play a major role in the pathogenesis of hypercalcemia in malignancy. Further, measurement of plasma 1,25(OH),D, has been proposed as a means by which the hypercalcemia of malignancy may be differentiated from primary hyperparathyroidism. In the present study, plasma concentrations of 1 ,25(OH),D3 were measured in 44 patients with malignancy-associated hypercalcemia and related to other hormonal regulators of calcium metabolism. lmmunoreactive PTH concentrations were suppressed in all but two patients, and, as a group, patients with hypercalcemia of malignancy had lower 1,25-dihydroxycholecalciferol concentrations than normocalcemic cancer patients. Nonetheless, 1,25-dihydroxycholecalciferol concentrations were clearly detectable in a significant proportion (43%) of hypercalcemic patients, a response that may be considered inappropriate to a hypercalcemic of nonparathyroid origin. While the mechanism of continued 1,25(OH),D, production in this situation is unclear, it is evident that measurement of plasma 1,2ddihydroxycholecalciferol concentration does not provide a reliable method for distinguishing the hypercalcemia of malignancy from primary hyperparathyroidism. Further, the active vitamin D metabolites may pqssibly contribute to the pathogenesis and maintenance of the hypercalcemia by stimulating bone resorption and by increasing absorption of calcium from the intestine.
VITAMIN D NUTRITION IN INSTITUTIONALIZED ELDERLY PEOPLE J.T. Harm,’ E.B. Mawer,’ M. Davies,’ and J .L. Taylor* ‘Department of Medicine, Medical School, Stopford Building, University of Manchester and *Birch Hill Hospital, Rochdale, Lanes, UK The elderly housebound and institutionalized population is known to be at risk of developing the clinical manifestations of vitamin D deficiency. Although only a minority develop overt disease, there is a high prevalence of biochemical vitamin D deficiency, and recently an association between vitamin D deficiency and femoral neck fractures has been established. The
55
vitamin D status of elderly people in Rochdale, both institutionalized and attending a geriatric day-hospital, was assessed by measuring their serum 25(OH)D2 and 25(OH)D, levels in the spring and autumn of 1982 using a quantitative HPLC method. The vitamin D, and D3 content of their food was determined so that the relative contributions of isolation and diet could be established. Analysis of serum 25(OH)D, and 25(OH)D, showed the following results: Group ng/ml *50-w, *WW, n
7. Long-stay wards
2. CommwMy
homes
3. Geriatric day hospital
spnns
Autumn
spnng
Autumn
sprvlg
0.8 4.8
0.8 4.8
2.9 57
2.4 89
4.2 12.2
36
78
Autumn 27 13.7 10
Results show that vitamin D status is poor in inmates of longstay wards (group 1) and in many residents in homes (group 2) but was satisfactory in attenders of the geriatric day hospital (group 3). Seasonal variation in 25(OH)D, was significant in group 2 only, as assessed by paired t-test (P < 0.001). Serum 25(OH)D, levels in groups 1 and 2 combined were positively correlated with dietary vitamin D, intake (n = 0.79, P = 0.05). The poor state of vitamin D nutrition in the institutionalized people studied here shows that, in the absence of sufficient exposure to sunlight, vitamin D requirement was not met by an otherwise satisfactory diet. Investigations into the efficacy of high-dose vitamin D treatment given once or twice yearly to the same institutionalized people are in progress. We are grateful to the Rochdale Area Health Authority for supporting this project.
VITAMIN D-DEPENDENT RICKETS TYPE II: STUDIES OF THE MOLECULAR BASIS OF THE DISEASE USING CULTURED SKIN FIBROBLASTS L.J. Fraher,’ G.N. Hendy,’ H. Jani,’ L. Nicholson,’ F.R.J. Hinde,* D. Grant,* and J.L.H. O’Riordan* ’ The Middlesex Hospital, London and *The Hospital for Sick Children, Great Ormond Street, London, UK Cultured skin fibroblasts have proved to be a useful source of human tissue to study interactions of 1,25(OH),D, with its specific intracellular binding protein. We have recently used such a system to investigate a patient with severe rickets due to vitamin D dependency type II. This patient was a 3-year-old boy who failed to respond to massive doses of calcitriol and eventually died of pneumonia. Fibroblasts, obtained from collagenase digests of punch skin biopsies, were cultured in Ham’s F 12 supplemented with 10% fetal calf serum, antibiotics, and insulin. Using these cells, studies were conducted to (1) detect the presence of both cytosolic and nuclear association of tritiated 1,25(OH),D, within the cells, (2) investigate the influence of unlabeled 1,25(OH),D, on the metabolism of tritiated 25(OH) D, and (3) study the metabolism of tritiated 1 ,25(OH),D3 itself. In fibroblasts from two normal infants both binding cytosolic by a 3.7 S protein and nuclear association of 1,25(OH),D, could be demonstrated. However, both were absent in cells from the patient. When normal cells were preincubated with increasing concentrations of 1,25(OH),D,, the metabolism of 3H 250H D, could be influenced in a biphasic manner. Through the physiologic range of 1,25(OH),D, concentrations increasing amounts of 3H 24,25(OH),D, were formed. However, at supraphysiologic concentrations 1,25(OH),D,, production of 3H 24,25(OH)*D, ceased, presumably due to substratecompetition by 1,25(OH),D, itself. This phenomenon was also absent in fibroblasts from the patient. Tritiated