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CLINICAL CASE SEMINAR |
Divisions of Endocrinology (Y.K., M.T., A.T., Y.T.) and Endocrine Surgery (D.M., S.T.), Toranomon Hospital Endocrine Center, Tokyo 105-8470, Japan; and Okinaka Memorial Institute for Medical Research (M.T., A.T., D.M., S.T., Y.T.), 105-8470 Tokyo, Japan
Address all correspondence and requests for reprints to: Yasuhiro Takeuchi, M.D., Ph.D., Toranomon Hospital Endocrine Center, 2-2-2 Toranomon Minato-ku, Tokyo 105-8470, Japan. E-mail: takeuchi-tky{at}umin.ac.jp.
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Abstract |
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Objective: The objective of the study was to clarify whether 1,25(OH)2D indeed inhibits circulating levels of PTH and influences bone turnover, even in a patient with primary hyperparathyroidism.
Design, Setting, and Patient: We evaluated PTH levels in a patient with primary hyperparathyroidism and coexistent sarcoidosis whose serum 1,25(OH)2D levels were independent of PTH.
Interventions and Main Outcome Measures: The present case was treated with prednisolone before and after surgical resection of parathyroid adenoma, and Ca-regulating hormones and bone markers were measured.
Results: Serum Ca and PTH levels significantly decreased after parathyroid surgery, whereas serum 1,25(OH)2D levels remained high. Prednisolone administration promptly decreased serum 1,25(OH)2D levels and reciprocally increased PTH levels despite consistent serum Ca levels either before or after surgery. PTH levels were negatively correlated with serum 1,25(OH)2D levels before and after surgery. Urine N-telopeptides, serum osteocalcin, and bone-type alkaline phosphatase all decreased to physiological ranges after parathyroid surgery.
Conclusions: These results suggest that 1,25(OH)2D indeed inhibits the production of PTH not to exacerbate hypercalcemia in a patient with primary hyperparathyroidism. Furthermore, PTH but not 1,25(OH)2D may primarily be involved in the stimulation of bone turnover.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-hydroxylase activity in renal proximal tubular cells to generate 1,25-dihydroxyvitamin D [1,25(OH)2D], which mediates a part of PTH actions. 1,25(OH)2D in turn inhibits the synthesis of PTH in parathyroid cells and thus creates a negative feedback loop, although an increase in circulating Ca ion levels most critically decreases plasma PTH levels (1). The inhibitory effect of 1,25(OH)2D is clinically established in patients with end-stage renal failure presenting secondary hyperparathyroidism (2). Administration of sufficient amounts of 1,25(OH)2D3 or its analogs could suppress plasma PTH levels to avoid some features of renal osteodystrophy (2). Inappropriately high levels of serum 1,25(OH)2D were shown to suppress plasma PTH levels possibly via hypercalcemia in tuberculous patients with end-stage renal disease (3). However, it is yet uncertain whether circulating PTH levels are in fact negatively regulated by 1,25(OH)2D in primary hyperparathyroidism and how 1,25(OH)2D affects bone metabolism in concert with PTH. In patients with primary hyperparathyroidism, excessive secretion of PTH increases both serum Ca and 1,25(OH)2D levels. Because either parameter could positively correlate with plasma PTH level, one cannot evaluate whether 1,25(OH)2D actually suppresses the synthesis of PTH in primary hyperparathyroidism. Then it is unclear whether 1,25(OH)2D exacerbates hypercalcemia concomitantly with excess PTH in primary hyperparathyroidism. To answer these questions, it is necessary to evaluate PTH levels in the patient whose serum 1,25(OH)2D levels are independent of PTH. Patients with hypercalcemia due to sarcoidosis show inappropriately high serum levels of 1,25(OH)2D, and they are independent of PTH (4). We here describe a patient presenting with hypercalcemia with sarcoidosis and coexistent primary hyperparathyroidism. Clinical investigation of this case before and after parathyroid surgery would provide useful lessons for the regulation by 1,25(OH)2D of circulating levels of PTH, Ca, and bone metabolism in human, in particular with primary hyperparathyroidism.
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Patients and Methods |
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A 70-yr-old woman was evaluated at Toranomon Hospital Endocrine Center in June 2004 for persistent hypercalcemia. She had been diagnosed as sarcoidosis and was treated with oral prednisolone from 1983 to 1992. Thereafter she had been well in the absence of treatment with glucocorticoids. Hypercalcemia became obvious sometime after withdrawal of prednisolone and persisted with no specific clinical symptoms. The physical examination was unremarkable, although her chest x-ray indicated bilateral hilar lymphadenopathy typical to sarcoidosis. She had no history of urolithiasis. There was no family history of endocrine disorders or hypercalcemia.
Laboratory data on her admission showed hypercalcemia (adjusted serum Ca, 10.9 mg/dl; reference range 8.7–10.1) with intact PTH 35.4 pg/ml (reference range 15–65) that was inappropriately high in the presence of hypercalcemia. The serum level of 1,25(OH)2D concentration (108.0 pg/ml; reference range 20–60) was also high. Serum angiotensin-converting enzyme activity was elevated (44.2 IU/liter; reference range 7.0–25.0) as being observed in patients with active sarcoidosis. Treatment with 20 mg/d prednisolone for 10 d had no effect on serum Ca levels and urinary Ca excretion (Fig. 1
, A and B). Her renal function was not impaired and no signs of urolithiasis were observed in ultrasonogram.
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Measurements
All measurements were performed on blood samples collected after overnight fasting and on 24-h urinary collection. Total serum Ca, phosphate, albumin, and creatinine were measured using an autoanalyzer routinely used for daily practice. An albumin-adjusted serum Ca was calculated using the formula adjusted Ca (milligrams per deciliter) = total Ca (milligrams per deciliter) + 0.8 x [4 – albumin (grams per deciliter)]. Urinary measurements were adjusted by creatinine excretion. Serum 1,25(OH)2D was measured by RIA kit (TFB Co., Tokyo, Japan), intact PTH by a two-site immunoradiometric assay (Nichols Institute Diagnostics, San Clemente, CA). Urine N-telopeptides of type I collagen (NTX) were measured by an enzyme-linked immunoassay using Osteomark NTx (Mochida Pharmaceutical Co., Tokyo, Japan), serum osteocalcin by an immunoradiometric assay using a BGP-IRMA kit (Mitsubishi Kagaku BCL, Tokyo, Japan), and serum bone-type alkaline phosphatase (BAP) by an immunoassay using Alkphase-B kit (Quidel, San Diego, CA).
All measurements during 30 months before surgery and 10 months after surgery were included for analyses.
Patients with primary hyperparathyroidism. Clinical data [serum Ca, 1,25(OH)2D, intact PTH, and urine N-telopeptides] were evaluated in 15 consecutive patients with primary hyperparathyroidism who were treated with parathyroid surgery in our institute.
Statistical analysis
All statistical analyses were performed using Stat View software (version 4.51.1; Abacus Concepts, Berkeley, CA). Values were expressed as means ± SD, and the differences between those before and after parathyroid surgery were analyzed by Student’s t test. The coefficients of correlation were calculated by Pearson’s method. Probability values less than 0.05 were defined as significant.
The patient consented to the treatment and investigations described as a part of her ordinary medical care.
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Results |
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Before parathyroid surgery, adjusted serum Ca levels were consistently and stably elevated to 11.0 ± 0.3 mg/dl (mean ± SD, n = 19) over 30 months (Table 1). Plasma PTH levels (37.5 ± 5.7 pg/ml) were not suppressed, even in the presence of significant hypercalcemia, indicating an autonomous secretion of PTH. Serum 1,25(OH)2D levels were constantly higher (79.3 ± 17.5 pg/ml) than a upper limit of reference range (Table 1). Data during treatment with prednisolone are not included in Table 1. There was no correlation between serum Ca and either PTH or 1,25(OH)2D levels (Table 2). In contrast, among patients with ordinary primary hyperparathyroidism, serum Ca levels were positively correlated with either PTH (P < 0.001) or 1,25(OH)2D (P < 0.03) (Table 3).
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, A and B). Urinary Ca excretion did not change significantly during the treatment with prednisolone (Fig. 1B). Serum levels of angiotensin-converting enzyme simultaneously decreased with those of 1,25(OH)2D during the treatment with prednisolone (data not shown), as usually observed in patients with sarcoidosis.
After resection of parathyroid adenoma, serum Ca levels significantly decreased to 9.6 ± 0.4 mg/dl and were normalized with a significant fall of plasma PTH level from 37.5 ± 5.7 to 21.9 ± 8.3 pg/ml (P < 0.001), whereas serum 1,25(OH)2D levels (68.9 ± 21.9 pg/ml) did not decrease and yet remained to be over the reference range (Table 1). Serum Ca levels were negatively correlated with plasma PTH but had no correlation with 1,25(OH)2D after surgery (Table 2). Urinary Ca excretion rate remarkably decreased after parathyroid surgery (Table 1 and Fig. 1B).
Relationship between PTH and 1,25(OH)2D levels
Plasma PTH levels were negatively correlated with serum 1,25(OH)2D before parathyroid surgery (Table 2 and Fig. 2A), whereas serum Ca levels were constant (Table 1 and Fig. 1A). In a multivariate analysis, no other parameters than serum 1,25(OH)2D determined in the present study had correlation with PTH levels (data not shown). In contrast, among patients with ordinary primary hyperparathyroidism, serum 1,25(OH)2D and PTH levels demonstrated a positive correlation (P < 0.04) (Table 3 and Fig. 2B).
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). Negative correlation between 1,25(OH)2D and PTH still remained in the present case when all measurements were incorporated into analyses (P < 0.03), and their relationship did not change after surgery (Fig. 2A), although statistical power was not significant enough if data during treatment with prednisolone were not included (Table 2). These results suggest that 1,25(OH)2D negatively regulates PTH levels in a patient with or without primary hyperparathyroidism and that serum Ca levels are strictly regulated to be stable, even in a patient with sarcoidosis and coexistent primary hyperparathyroidism. Bone metabolic markers and calcitropic hormones
Bone formation markers, serum osteocalcin, and BAP, and bone resorption marker, urine N-telopeptides, were all decreased into a reference range with time after a resection of parathyroid adenoma (Table 1 and Fig. 1C). Because serum 1,25(OH)2D levels did not significantly decrease after surgery, it is suggested that inappropriately high circulating PTH levels are primarily involved in the stimulation of bone turnover.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The activation of 25 hydroxyvitamin D to 1,25(OH)2D autonomously progresses in macrophages from patients with sarcoidosis (6, 7). Because this activation is not regulated by Ca or PTH (7, 8), serum levels of 1,25(OH)2D are independent of Ca and PTH in these patients. Because the present case showed high serum levels of 1,25(OH)2D after parathyroid surgery, the activation of vitamin D is suggested to be autonomous in sarcoidosis granulomas. The activation of 25 hydroxyvitamin D to 1,25(OH)2D is dependent on an aberrant expression of 1-hydroxylase in macrophages in sarcoidosis granulomas (4). Because the expression of this enzyme is pharmacologically suppressed by the treatment with glucocorticoid (7, 9), taking prednisolone effectively decreases serum 1,25(OH)2D levels within a week (10). After parathyroid surgery, treatment of the present case with 20 mg/d prednisolone remarkably decreased serum 1,25(OH)2D level as expected, whereas serum Ca levels were constant and PTH levels reciprocally increased, suggesting that 1,25(OH)2D suppressed PTH synthesis by parathyroid glands. Before parathyroid surgery, treatment with 20 mg/d prednisolone also reduced the serum 1,25(OH)2D level and serum Ca levels were constant, but plasma PTH levels increased twice as much.
Because either serum Ca level or urinary Ca excretion was constant and was still over a physiological range during taking prednisolone before surgery, PTH levels could increase in response to the fall of serum 1,25(OH)2D or to that of serum Ca concentration secondary to the putative decrease in intestinal Ca absorption. If there was a small but substantial decrease in serum Ca levels that triggered the increase in PTH levels, urinary Ca excretion was to be reduced. Then the latter possibility might not account for the 2-fold increase in PTH levels. The increase in PTH levels that maintained hypercalcemia could account for constant hypercalciuria. A slight decrease in fractional excretion of Ca (urine Ca/serum Ca x serum creatinine/urine creatinine) form 0.026 to 0.020 after treatment with prednisolone might reflect augmentation of PTH actions. There is another possibility that Ca balance might be negative during the treatment with prednisolone enough to stimulate the secretion of PTH: because prednisolone suppresses intestinal Ca absorption and enhances urinary Ca excretion. This is, however, not the case in humans. Short-term (11) or chronic administration (12) of glucocorticoid has been reported not to increase plasma PTH levels. Thus, it is suggested that the decrease in serum 1,25(OH)2D is directly involved in the increase in PTH levels in the present case. Accordingly, it is suggested that 1,25(OH)2D inhibits PTH synthesis by parathyroid glands, even in a patient with primary hyperparathyroidism.
Based on clinical observations of this case, one might speculate that an administration of 1,25(OH)2D3 or its analogs to patients with primary hyperparathyroidism suppresses PTH levels but does not exacerbate hypercalcemia. Although this possibility has not been generally elucidated yet in humans, in the patient with primary hyperparathyroidism with severe osteitis fibrosa cystica, iv administration of 1,25(OH)2D3 that doubled the level of circulating 1,25(OH)2D has been shown to be associated with a marked decline in PTH levels without a change in serum Ca concentrations (13). Treatment with 1,25(OH)2D3 may increase urinary Ca excretion and thus requires careful attention to renal function.
A recent report by Grey et al. (14) demonstrated vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency decreased circulating PTH levels without significant changes in serum Ca, although there was no significant correlation between changes in serum 1,25(OH)2D and that in PTH. This report showed no evidence that an elevation of 1,25(OH)2D was involved in the suppression of PTH levels but presented data that bone turnover was concomitantly decreased with fall in PTH levels after vitamin D repletion (14).
Among patients with primary hyperparathyroidism, bone turnover represented by an increase in urine N-telopeptides was positively correlated with either PTH or 1,25(OH)2D (Table 3). In the present case, a significant but slight decrease in PTH levels after parathyroid surgery was associated with a remarkable reduction of metabolic bone markers, urine N-telopeptides, and serum osteocalcin and BAP, whereas there was not a significant change in serum 1,25(OH)2D levels. This observation suggests that PTH but not 1,25(OH)2D is mainly involved in the stimulation of bone turnover in primary hyperparathyroidism. Urinary Ca excretion in the present case significantly decreased after parathyroid surgery, further supporting the notion that bone resorption was depressed as indicated by the decrease in urine N-telopeptides. Taken together with clinical observations that vitamin D repletion resulted in a decrease in PTH and bone turnover with no significant changes in 1,25(OH)2D (14), PTH seems to primarily stimulate bone turnover, at least in patients with primary hyperparathyroidism, although the involvement of 1,25(OH)2D in the maintenance of bone turnover cannot be neglected.
In conclusion, 1,25(OH)2D could indeed decrease the circulating levels of PTH not to exacerbate hypercalcemia in a patient with primary hyperparathyroidism. Furthermore, PTH but not 1,25(OH)2D may primarily be involved in the stimulation of bone turnover. This notion implicates therapeutic relevance and should be verified by further clinical investigations.
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Acknowledgments |
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Footnotes |
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First Published Online September 13, 2005
Abbreviations: BAP, Bone-type alkaline phosphatase; NTX, N-telopeptides of type I collagen; 1,25(OH)2D, 1,25-dihydroxyvitamin D.
Received June 21, 2005.
Accepted September 6, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-hydroxylation of vitamin D sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 161:755–765This article has been cited by other articles:
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  F. W. Lafferty, C. R. Hamlin, K. R. Corrado, A. Arnold, and J. M. Shuck Primary Hyperparathyroidism with a Low-Normal, Atypical Serum Parathyroid Hormone as Shown by Discordant Immunoassay Curves J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3826 - 3829. [Abstract] [Full Text] [PDF]
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 B Moosgaard, P Vestergaard, L Heickendorff, F Melsen, P Christiansen, and L Mosekilde Plasma 25-hydroxyvitamin D and not 1,25-dihydroxyvitamin D is associated with parathyroid adenoma secretion in primary hyperparathyroidism: a cross-sectional study. Eur. J. Endocrinol., August 1, 2006; 155(2): 237 - 244. [Abstract] [Full Text] [PDF]
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), and closed triangles (
) indicate plasma PTH, serum 1,25(OH)2D, and serum Ca levels, respectively. Bars indicate urinary Ca excretion of 24-h urinary collection. The reference range of serum Ca is indicated by the dotted area. Open circles, open triangles, and open squares indicate serum osteocalcin, BAP, and urine NTX, respectively. The hatched areas indicate the treatment with prednisolone. To convert values for Ca to millimoles per liter, multiply by 0.25. To convert values for creatinine to micromoles per liter, multiply by 88.4. To convert values for PTH to picomoles per liter, multiply by 0.106. To convert values for 1,25(OH)2D to picomoles per liter, multiply by 2.6. BCE, Bone collagen equivalent; U-Ca, urinary Ca excretion; Cr, creatinine.