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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 209-212
Copyright © 1997 by The Endocrine Society

Clinical Studies

Increased Catabolism of 25-Hydroxyvitamin D in Patients with Partial Gastrectomy and Elevated 1,25-Dihydroxyvitamin D Levels. Implications for Metabolic Bone Disease1

Michael Davies, Sara E. Heys, Peter L. Selby, Jacqueline L. Berry and E. Barbara Mawer

Bone Disease Research Centre, University Department of Medicine, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom

Address all correspondence and requests for reprints to: Dr. M. Davies, University Department of Medicine, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Serum vitamin D metabolites and PTH were measured in seven subjects with a history of previous partial gastrectomy (PGX) and metabolic bone disease. The elimination t1/2 of [3H]25-hydroxyvitamin D3 ([3H]25OHD3) in serum was assessed after an iv pulse dose of 5 µCi [26,27-3H]25OHD3. Median serum 25OHD3 was 37.5 (27.5–101.3) nmol/L, [normal range (NR) 10.8–58.5 nmol/L], mean serum 1,25-dihydroxyvitamin D [1, 25-(OH)2D3] was raised at 175 ± 72 pmol/L, (NR 48–120 pmol/L) and mean PTH was also high, 67 ± 27 ng/L, (NR 10–60 ng/L). Serum t1/2 [3H]25OHD3 ranged from 10.9–21.2 days. A strong negative correlation existed between t1/2 [3H]25OHD3 and serum 1,25-(OH)2D3 [Spearman’s rank correlation coefficient (r = -0.82, P = 0.002)] and PTH [Spearman’s rank correlation coefficient (r = -0.81, P = 0.001)]. Four subjects who had high initial PTH concentrations (60–115 ng/L) and elevated 1,25-(OH)2D levels (162–300 pmol/L) were reassessed after calcium supplementation to suppress secondary hyperparathyroidism (2°HPT). In this subgroup, after-treatment PTH fell from 82 ± 24 to 52 ± 24 ng/L (mean ± SD), not significant; 1,25-(OH)2D fell from 210 ± 61 to 116 ± 28 pmol/L, P = 0.015; and t1/2 [3H]25OHD3 increased from 13.2 ± 1.9 to 18.9 ± 3.1 days, P = 0.012.

Patients with PGX and evidence of 2°HPT with elevated 1,25-(OH)2D have a reduced t1/2 [3H]25OHD3, and this may explain the increased susceptibility of the subjects to osteomalacia. Calcium supplementation suppresses 2°HPT, increases t1/2 [3H]25OHD3 and may protect against PGX osteoporosis and osteomalacia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
VITAMIN D deficiency, osteomalacia, and osteoporosis are recognized complications in patients who have had previous partial gastrectomy (PGX) (1, 2, 3). Some patients have an associated postgastrectomy malabsorption syndrome with steatorrhea, but in others, intestinal absorption seems normal. We previously have documented normal intestinal absorption of vitamin D in five subjects with PGX (4), and vitamin D deficiency is reversed by physiological doses of vitamin D. It is therefore unclear why subjects with PGX should suffer from vitamin D deficiency, especially when the diet in the United Kingdom is not the major source of vitamin D. In the United Kingdom, the main source of vitamin D for an individual is cutaneous synthesis, and the principal cause of vitamin D deficiency is sunlight deprivation. A diet lacking in calcium produces secondary hyperparathyroidism (2°HPT) and elevated serum 1,25-dihydroxyvitamin D (1, 25-(OH)2D) (the active metabolite of vitamin D); in the rat this is associated with enhanced metabolic clearance of the precursor 25-hydroxyvitamin D (25OHD) (5). We have shown a similar mechanism in humans, and in a variety of clinical situations, the elimination t1/2 of a tracer dose of tritium-labeled 25OHD ([3H]25OHD3) is inversely related to the prevailing serum concentration of 1,25-(OH)2D (6, 7). Furthermore, an artificially induced abrupt increase in serum 1,25-(OH)2D is followed quickly by a reduction of t1/2 [3H]25OHD3 (7). Increased serum 1,25-(OH)2D and low serum 25OHD have been reported in subjects after gastrectomy (8, 9), suggesting that problems with calcium absorption may lead to 2°HPT in a way similar to the situation induced experimentally in the rat by Clements et al. (5).

We have studied a group of subjects with a history of PGX to examine the effect on the t1/2 [3H]25OHD3. In a subset with 2°HPT, we have repeated the investigation after suppression of the 2°HPT with large oral doses of calcium (1–2 g/day).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and protocol

Seven patients were studied (five female, two male) aged 53–73 yr. Clinical details are given in Table 1Go. The protocol was approved by the local ethical committee, and each patient gave informed consent. After an overnight fast, a rapid iv injection of 5 µCi (185 KBq) [26,27-3H]25OHD3 (762 GBq/mmol) Amersham International plc (Amersham Bucks, UK) in 5 mL of the patients’ own fasting plasma was given into one arm at 0900 h. Blood samples were taken immediately and at regular intervals for 14 days. The decline of [3H]25OHD3 in the patients’ plasma was followed by direct liquid scintillation counting of 400-µL samples with 4-mL Optiphase Safe Wallac (LKB) in an LKB 1217 Rackbeta scintillation spectrometer (LKB, South Croydon, UK). The decline of 3H in the plasma after an iv injection of [3H]25OHD3 is described by a biphasic exponential curve (10). Virtually all the plasma 3H is present as 25OHD3; even after 14 days, [3H]25OHD3 forms 97% of the plasma radioactivity (7).


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  		Table 1. Clinical details

 
Computation of t1/2 [3H]25OHD3

A [log plasma] concentration/time curve for the decay of plasma 3H was constructed for each subject, and the gradient of the slope from the fourth day after injection was determined by least-squares regression analysis. The long-phase t1/2 for [3H]25OHD3 in plasma was calculated using the formula: t1/2 = log2/gradient (7).

Assays

Serum vitamin D metabolites were extracted for assay as previously described (11). Metabolites were separated by automated high-performance liquid chromatography (Waters Associates). 25OHD was quantified by competitive protein-binding assay (12) using normal human serum as the source of vitamin D-binding protein at a dilution of 1:20,000. The reference range was 10.8–58.5 nmol/L (inter- and intraassay coefficients of variation 8.8% and 7.8%, respectively). 1,25-(OH)2D was measured by RIA using monoclonal antibody 5F2 (13) with a reference range of 48–120 pmol/L (inter- and intraassay coefficients of variation 10.7% and 7.8%, respectively).

Serum PTH was measured by immunoradiometric assay using a Nichols Institute Allegro Kit for intact PTH (Saffron Walden, UK, reference range 10–60 ng/L). Serum calcium, phosphate, albumin, creatinine, and alkaline phosphatase were analyzed on a multichannel autoanalyzer (American Monitor Corporation, Indianapolis, IN). Serum calcium was corrected for changes in serum albumin concentration according to the formula: corrected Ca = actual Ca + (40 - serum albumin) x 0.02 mmol/L (14).

Statistics

Statistical analysis was undertaken using Minitab (Minitab Inc., State College, PA). The distributions of all variables, apart from alkaline phosphatase and 25OHD, did not deviate from normality. Association between the variables was sought using Spearman’s rank correlation coefficient (rs) followed by stepwise linear regression to control for multiple interactions. The differences between group means were examined using Student’s two-tailed paired t tests; values are expressed as mean ± SD.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma biochemistry and values for the calculated t1/2 25OHD3 are detailed in Table 2Go. All patients except patient 4 had normal serum calcium, phosphate, and alkaline phosphatase and no biochemical evidence of osteomalacia. Patient 4 had an antecedent history of osteomalacia, and his biochemistry was consistent with the healing phase of that disease. All subjects were initially vitamin D-replete with serum 25OHD above 25 nmol/L, median 37.5 (27.5–101.3) nmol/L. Mean serum 1,25-(OH)2D was raised in the group, 175 ± 72 pmol/L, with elevated levels in five of the seven subjects. Mean serum PTH also was raised at 66.6 ± 27.2 ng/L with high levels in four patients, who also had raised 1,25-(OH)2D concentrations.


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  		Table 2. Biochemical data on patients with partial gastrectomy

 
Patients 2, 4, 6, and 7 (Table 2Go), who had high PTH and raised 1,25-(OH)2D levels, were restudied after attempts to suppress 2°HPT with oral calcium supplements; none became hypercalcemic with this treatment. In three of these patients, serum PTH fell to within the reference range; PTH remained elevated in patient 4, and the change in the group (from 82 ± 24 to 52 ± 24 ng/L) was not significant, P = 0.104. 1,25-(OH)2D levels became normal, the mean falling from 210 ± 61 to 116 ± 28 pmol/L, P = 0.015. Initial t1/2 25OHD3 ranged from 21.2–10.9 days (Table 2Go). After calcium supplementation, which lowered serum 1,25-(OH)2D, mean t1/2 25OHD3 increased by 35%, from 13.2 ± 1.9 to 18.9 ± 3.1 days, P = 0.016. A highly significant inverse relationship was demonstrated (Fig. 1Go) between t1/2 25OHD3 and the prevailing serum 1,25-(OH)2D (rs = -0.82, P = 0.002). A similar relationship also existed between t1/2 25OHD3 and serum PTH (rs = -0.81, P = 0.001). There was no association between t1/2 25OHD3 and serum calcium (rs = 0.31, P = 0.35), phosphate (rs = 0.08, P = 0.83), or 25OHD (rs = -0.07, P = 0.84). Because there is an association between the serum concentration of 1,25-(OH)2D and PTH (rs = 0.61, P = 0.05), stepwise multiple linear regression was used to determine whether the effects of 1,25-(OH)2D and PTH on t1/2 25OHD3 were independent. Both 1,25-(OH)2D and PTH remained as independent predictors within the regression equation, with t values of -5.32 (P < 0.001) and -3.53 (P = 0.008), respectively.



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  		Figure 1. The relationship between t1/2 25OHD3 and serum 1,25-(OH)2D concentration in seven patients with partial gastrectomy, untreated ({circ}) and after calcium treatment in four patients ({square}). There is a highly significant inverse correlation, rs = -0.82, P = 0.002.

 
When the present results are combined with those of our previously reported studies (6, 7), the strong relationship between t1/2 25OHD3 and 1,25-(OH)2D persists (Fig. 2Go, rs = -0.64, P = 0.0001). These aggregated results include data from patients with primary hyperparathyroidism (1°HPT) before and after surgery (6), and patients with disorders of bone and mineral metabolism before and after treatment with calcium or 1,25-(OH)2D (7).



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  		Figure 2. The relationship between t1/2 25OHD3 and serum 1,25-(OH)2D concentration in a group of 49 patients, shown as the regression line and 95% confidence limits; a strong inverse correlation persists, rs = -0.63, P = 0.0001. Data are included from the present study ({circ}), from patients with 1°HPT before and after surgery ({square}) (Ref. 6), and from patients with disorders of bone and mineral metabolism before and after treatment with calcium or 1,25-(OH)2D ({triangleup}) (Ref. 7).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study in PGX patients reaffirms the relationship between the prevailing serum concentration of 1,25-(OH)2D and the t1/2 for 25OHD3 in plasma. We have shown previously that the variation in observed t1/2 25OHD3 without change in vitamin D or parathyroid status is less than 2% when two consecutive measurements are made in individuals without change in vitamin D or parathyroid status (7). The present changes in t1/2 varied from 23–52% in the four patients in whom calcium supplements were given to suppress the high serum 1,25-(OH)2D values and are therefore significant and not explicable in terms of methodological error. In a previous study (7) of patients undergoing parathyroidectomy for 1°HPT, a reduced t1/2 25OHD3 was accompanied by increased fecal excretion of tritium as a result of enhanced metabolic inactivation of 25OHD3. Meyer et al. (15) have documented increased fecal loss of cholecalciferol after iv administration of radioactive cholecalciferol to gastrectomized rats; however, no data were available regarding serum 1,25-(OH)2D levels. Nilas et al. (8) found raised 1,25-(OH)2D levels in a group of patients with PGX in whom calcium absorption was low-normal, and PTH (using a C terminal assay) was not raised. Rao et al. (16) found evidence of 2°HPT in a subset of women with a past history of PGX. These collected observations suggest that after PGX, the intestinal absorption of calcium may be impaired and is only compensated for by the induction of 2°HPT and consequent increase in serum 1,25-(OH)2D.

The mechanisms whereby 1,25-(OH)2D enhances the catabolism of 25OHD are not fully understood but may involve reactions in both liver and kidney. 1,25-(OH)2D is known to suppress renal 1{alpha}-hydroxylase activity, thus down-regulating its own synthesis, and to stimulate 24-hydroxylase activity. Halloran et al. (17) have shown that 1,25-(OH)2D infusions increase the clearance of 24,25-(OH)2D and, in a study of men with Billroth II gastrectomy (18), 24,25-(OH)2D concentrations were lowered whereas 1,25-(OH)2D levels were increased, supporting Halloran’s data (18).

There is no evidence for hepatic 24-hydroxylation of 25OHD3, and in experiments investigating the effects of rearing rats on a low calcium diet to induce 2°HPT or sc infusing 1,25-(OH)2D3, Bolt et al. (19) could detect no metabolism of [3H]25OHD3 in hepatic homogenates and concluded that, in these circumstances, the increased metabolic clearance of [3H]25OHD3 was caused by urinary loss of catabolic products. However, increased biliary excretion of 3H also was observed, and the authors postulated that catabolic intermediates in the side-chain oxidation pathway for [3H]25OHD3 would enter the bloodstream and be eliminated via the liver. Clements et al. (5) also observed increased biliary excretion in rats of label from [3H]25OHD3 in response to 1,25-(OH)2D3 treatment and concluded that the time scale of the response favored a direct role for the liver. The reason for the failure of Bolt and co-workers (19) to observe hepatic metabolism of [3H]25OHD3 in homogenates may be that an intact biliary system is needed to drain the polar metabolites and stimulate secretion. We have clear evidence of rapid biliary excretion of polar metabolites of [3H]25OHD3 in isolated perfused pig livers (20). One way in which [3H]25OHD3 may be eliminated from the circulation is by biliary excretion of water soluble conjugates such as glucuronides. There is evidence to support this and other possible hepatic catabolic pathways (20, 21). Fox et al. (22) found a 48% increase in hepatic microsomal uridine diphosphate glucuronyl transferase activity in rats fed a low calcium diet (which elevated 1,25-(OH)2D3). The increased fecal 3H excretion we observed in our study of [3H]25OHD3 catabolism in 1°HPT (6) would support such an alternative pathway. The way in which low calcium and increased 1,25-(OH)2D3, which are often interrelated, may influence hepatic enzymes is not clear, but the liver is now known to express vitamin D receptor message and protein (23, 24) and thus can be regarded as a target organ for 1,25-(OH)2D3 activity.

In the present study, PTH seems to have an effect upon t1/2 25OHD3 that was independent of the effect of 1,25-(OH)2D. We have not observed this effect previously and have found the relationship between t1/2 25OHD3 and 1,25-(OH)2D in the absence of PTH (7). The mechanism(s) whereby PTH itself may be influencing the t1/2 25OHD3, other than via enhanced synthesis of 1,25-(OH)2D, is not clear, and our present observations may be similar to the experimental data obtained by Bolt et al. (19) and described above. Regardless of the mechanism responsible for the phenomenon we have observed, it is clear that the increased clearance of 25OHD in the presence of high 1,25-(OH)2D in subjects with PGX helps to explain the development of vitamin D deficiency when the supply of vitamin D is limited. Ultimately, when the amount of 25OHD substrate decreases to a critical point, synthesis of 1,25-(OH)2D will fall and calcium absorption will decrease. If the supply of vitamin D is adequate, the long-term effects of raised 1,25-(OH)2D and PTH (2°HPT) may be to enhance bone turnover, exacerbate any preexisting remodeling imbalance, and lead to osteopenia or osteoporosis, all well-known complications of PGX (18).


   Footnotes
 
1 This work was supported by Programme Grant 902-6370 from the Medical Research Council, United Kingdom. Back

Received May 20, 1996.

Revised August 16, 1996.

Accepted August 23, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Morgan DB, Paterson CR, Woods CG, Pulvertaft CN, Fourmau P. 1965 Osteomalacia after gastrectomy: a response to very small doses of vitamin D. Lancet. 2:1089–1091.[Medline]
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  7. Clements MR, Davies M, Hayes ME, et al. 1992 The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf). 37:17–27.[Medline]
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  9. Kozawa K, Imawari M, Shimazu H, Kobori O, Osuga T, Morioka Y. 1984 Vitamin D status after total gastrectomy. Dig Dis Sci. 29:411–416.[Medline]
  10. Gray RW, Weber HP, Dominguez JH, Lemann J. 1974 The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans. J Clin Endocrinol Metab. 39:1045–1056.[Medline]
  11. Mawer EB, Hann JT, Berry JL, Davies M. 1985 Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci. 68:135–141.[Medline]
  12. Aksnes L. 1980 Quantitation of the main metabolites of vitamin D in a single serum sample. II. Determination by uv-absorption and competitive protein binding assays. Clin Chim Acta. 104:147–159.[CrossRef][Medline]
  13. Mawer EB, Berry JL, Cundall JP, Still PE, White A. 1990 A sensitive radioimmunoassay that is equipotent for ercalcitriol and calcitriol (1, 25-dihydroxyvitamin D2 and D3). Clin Chim Acta. 190:199–200.[CrossRef][Medline]
  14. Varley H, Gowenlock AH, Bell M. 1980 Calcium, magnesium phosphorus and phosphates. In: Varley H, Gowenlock AH, Bell M, eds. Practical clinical biochemistry. 5th ed. London: Heinemann; 850–877.
  15. Meyer MS, Amerilo N, Lone R, Edelstein S, Shibolet S. 1984 Fecal loss of cholecalciferol in gastrectomized rats. Digestion. 30:200–203.[Medline]
  16. Rao SD, Kleerekoper M. Rogers M, Frame B, Parfitt AM. Is gastrectomy a risk factor for osteoporosis? In: Christiansen C, Armand CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL, eds. Osteoporosis. Proc of the Copenhagan International Symposium on Osteoporosis, Aalborg Stiftsbogtrykkeri, Copenhagan, 1984, pp 775–771.
  17. Halloran BP, Castro ME. 1989 Vitamin D kinetics in vivo: effect of 1,25-dihydroxyvitamin D administration. Am J Physiol. 256:E686–E691.
  18. Klein KB, Orwoll ES, Liebermann DA, Meier DE, McClung R, Parfitt AM. 1987 Metabolic bone disease in asymptomatic men after partial gastrectomy with Billroth II anastomosis. Gastroenterology. 92:608–616.[Medline]
  19. Bolt MJG, Jensen WE, Sitris MD. 1992 Metabolism of 25-hydroxyvitamin D in rats: low calcium diets vs calcitriol infusion. Am J Physiol. 262:E359–E367.
  20. Mawer EB. 1979 The role of the liver in the control of vitamin D metabolism. In: Norman AW, Schaefer K, Vherrath D, et al. eds. Vitamin D, basic research and its clinical application. Berlin: de Gruyter; 553–561.
  21. Avioli LV, Lee SW, McDonald JE, Lund J, DeLuca HF. 1967 Metabolism of vitamin D3-3H in human subjects: distribution in blood, bile, faeces and urine. J Cin Invest. 46:983–992.
  22. Fox J, Bunker JE, Kamimura M, Wong PF. 1990 Low calcium diets increase both production and clearance of 1,25-dihydroxyvitamin D3 in rats. Am J Physiol. 258:E828–E287.
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