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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-0045
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1489-1494
Copyright © 2005 by The Endocrine Society

Increased Gastrin and Calcitonin Secretion after Oral Calcium or Peptones Administration in Patients with Hypercalciuria: A Clue to an Alteration in Calcium-Sensing Receptor Activity

Maurizio Bevilacqua, Ligia J. Dominguez, Velella Righini, Valeria Valdes, Rosanna Toscano, Ornella Sangaletti, Tarcisio Vago, Gabriella Baldi, Massimo Barrella and Gabriele Bianchi-Porro

Endocrinology and Diabetes Unit (M.Be., V.R., V.V., T.V., G.B.) and Lorenz Research Center (R.T., M.Ba.), Department of Medicine (O.S., G.B.-P.), Luigi Sacco Hospital (Vialba), University of Milan, 21057 Milan, Italy; and Geriatric Unit (L.J.D.), Department of Internal Medicine and Geriatrics, University of Palermo, Italy

Address all correspondence and requests for reprints to: Maurizio Bevilacqua, Servizio di Endocrinologia e Diabetologia, Ospedale L. Sacco, Via GB Grassi 74, 20157 Milan, Italy. E-mail: mauriziobevilacqua{at}fastwebnet.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The calcium-sensing receptor (CaSR) has been detected in human antral gastrin-secreting cells, where, upon calcium and/or amino acid allosteric activation, it stimulates gastrin secretion. Patients with absorptive hypercalciuria (AH) display an enhanced gastric acid output; therefore, we evaluated the secretion of gastrin in subjects with AH (30 subjects vs. 30 healthy female controls, all postmenopausal) after oral calcium administration (1 g calcium gluconate) and, on a separate occasion, after peptone loading test (protein hydrolyzed, 10 g). Gastrin and monomeric calcitonin responses were higher in AH after both oral calcium administration (P < 0.01) and peptone loading (P < 0.01). Because the activation of CaSR by oral calcium and peptones directly induces gastrin release, the higher gastrin responses to these stimuli suggest an increased sensitivity of gastrin-secreting cells CaSR in patients with AH. A similar alteration in thyroid C cells might explain the enhanced calcitonin responses to both calcium and peptones. If the same alterations should in addition be present in the distal tubule (where CaSR is expressed as well), then a possible explanation for amino acid-induced hypercalciuria in AH would have been identified.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IDIOPATHIC HYPERCALCIURIA IS a relatively common finding in the general population (1, 2, 3, 4) and the principal cause of renal stones, and possibly of vertebral osteoporosis. The syndrome displays a large clinical variability with some patients, characterized by a prevalent renal calcium loss (fasting or renal type), and a prevalent increased intestinal absorption of calcium in other patients. The heritability of the absorptive syndrome is well documented (5), but the biochemical role of the gene identified is unknown. Linkage to genetic mutations in the genes coding for the epithelial calcium channel 1 (6), the vitamin D receptor (7, 8, 9, 10, 11, 12, 13), and the channels of phosphate metabolism (14, 15, 16, 17, 18, 19) has revealed that very few of these patients bear genetic mutations. The main consistent genetic finding so far identified is the presence of an abnormality in the CaMgATPase (20, 21).

Recently, the calcium-sensing receptor (CaSR) has been cloned and identified in a number of tissues, including gastrin-secreting antral cells and gastric parietal cells, parathyroid cells, thyroid C cells, and distal renal tubule (22, 23, 24). In all of these locations, CaSR acts as a sensor for calcium-mediated responses such as increases in gastrin and gastric acidity, decreases in PTH levels, increased calcitonin release, and increased calcium excretion. Vezzoli et al. (25) have proposed a link between hypercalciuria and a specific polymorphism in the CaSR protein (Arg990Gly); this variety is associated with a gain of function of CaSR resulting in increased calcium excretion. Investigations on other polymorphisms of CaSR have reported negative results, however (26).

Some years ago, we found that patients with absorptive hypercalciuria (AH) and renal stones are characterized by enhanced gastric acid output (27, 28). Indeed, there seems to be a strict correlation among acid-stimulating meals, acid output, and gastrin/calcitonin secretion (29), and secretin has been proposed as a mediator of acidity-induced PTH and calcitonin secretion (29).

As stated above, calcium plays an important role in the direct control of acid and gastrin secretion throughout biochemical mechanisms that have been elucidated (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40). Therefore, we evaluated the gastrin responses to oral calcium in patients with AH and observed a greater response of gastrin to calcium in these patients. Because recent findings suggest the existence of an allosteric regulatory pathway of the CaSR by amino acids (41, 42, 43), we also measured the gastrin responses to an oral peptone load (44), and again we observed an increased gastrin response in patients with AH. Finally, we evaluated the calcitonin responses to calcium and to peptones in the attempt to assess the effects on thyroid C cell CaSR, and we explored the PTH responses to calcium and peptones.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All subjects signed informed consents, and the Institutional Review Board approved the study. Patients were selected in the context of an ongoing program of evaluation of bone and nutritional status of postmenopausal women in northern Milan, Italy (45). Thirty postmenopausal women (45–75 yr old; mean ± SD, 60 ± 9 yr) with recurrent calcium oxalate and/or calcium phosphate stone formation were evaluated in comparison to 30 healthy postmenopausal women (46–74 yr old; mean ± SD, 60 ± 8 yr). Control subjects had no evidence of renal lithiasis, and there was no evidence of renal lithiasis in their first- and second-degree relatives. Controls and patients had normal renal function, as evaluated by normal creatinine clearance, and none of them had renal tubular acidosis. All had normal ionized calcium and intact PTH. Patients with AH recruited in the study had a calcium urinary excretion higher than 250 mg/d (6.25 mmol/d; normal values, 2.5–6.25 mmol/d) on a free diet, were not taking calcium-sparing diuretics, and were free of severe dyspepsia. Furthermore, after 1 month of dietitian-assisted calcium-free diet, they exhibited a reduction in daily calcium excretion (<100 mg/d or 2.5 mmol/d) and a decrease in calcium/creatinine ratio in fasting 2-h urine (<0.35 mmol Ca/mmol creatinine; normal values. 0.10–0.20 mmol Ca/mmol creatinine) (46, 47). Therefore, our patients fulfilled the conventional criteria for AH diagnosis. The study tests were performed while subjects were on an unrestricted calcium diet.

Oral calcium load and oral peptone administration

After an 8-h overnight fast, oral calcium test (1 g calcium gluconate, Calcium Sandoz fortissimo, administered with a slight breakfast) (46) and peptone-meal test (10 g Liebig meat extract diluted in 250 ml of 0.9% saline) were carried out as previously reported (44). Fasting 2-h urine samples (0700–0900 h) were collected in the morning of the days of the tests. At 0900 h, while still fasting, controls and patients were given calcium or peptones orally, and their urine was collected during the following 4 h. The tests were well tolerated, and we did not observe any side effects.

Analytical methods

Blood and urinary calcium, phosphate, and creatinine were measured with the Technicon Autoanalyzer SMA-12/60 (Technicon, Tarrytown, NY); plasma ionized calcium was measured by StatProfile M Nova; serum immunoreactive 1–84 PTH was evaluated by Nichols kit; gastrin, pepsinogen (44), and monomeric calcitonin were measured as previously described (48).

Statistical analysis was performed using GraphPad 4 package (GraphPad Software, Inc., San Diego, CA). The differences among values obtained during the tests vs. basal values were calculated with ANOVA. The comparisons between the two groups, patients and controls, were performed with Student t test for unpaired data. A P value lower than 0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean ± SEM responses to oral calcium load are depicted in Fig. 1Go. The ionized calcium increase after oral calcium loading was not significantly different between controls and AH patients (Fig. 1AGo). However, the increase in urine calcium was larger in subjects with AH. In controls, urinary calcium increased from 0.32 ± 0.06 to 0.45 ± 0.08 mmol Ca/mmol creatinine (P < 0.01), whereas in AH patients it increased from 0.45 ± 0.10 to 0.98 ± 0.11 mmol Ca/mmol creatinine (P < 0.01 vs. basal, and P < 0.01 vs. controls).



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  		FIG. 1. Effects of oral calcium load on plasma ionized calcium, gastrin, intact PTH, and monomeric calcitonin in controls and patients with AH. A, Calcium increase was statistically significant (P < 0.01) with respect to basal values in both groups at 3, 6, and 7 h and was not different between the groups. B, Gastrin increase was significant (P < 0.01) at 3 h in both groups compared with basal values, with a larger increase in AH (P < 0.01). C, PTH decrease was significant at 3, 6, and 7 h in both groups and was not different between the groups. D, Monomeric calcitonin increase was significant (P < 0.01) at 3 and 6 h in both groups, with respect to basal values; this increase was larger at 6 h in AH (P < 0.01). To change ionized calcium in millimoles per liter to milligrams per deciliter, multiply by 4. *, P < 0.01 vs. basal; **, P < 0.01 vs. controls.

 
The rise in gastrin (Fig. 1BGo) was almost double in subjects with AH as compared to controls (P < 0.01 at various time points). Basal PTH levels (Fig. 1CGo) and the decrease of PTH after oral calcium were similar in both groups. The increase in monomeric calcitonin was higher in AH patients at different time points (P < 0.01) (Fig. 1DGo). Pepsinogen levels were similar in both groups and did not change after oral calcium load (data not shown).

The mean and SE responses to oral peptone loading are shown in Fig. 2Go. The increases in gastrin (Fig. 2BGo) (P < 0.01 at different time points) and the decreases in ionized calcium were significantly larger (P < 0.01) in subjects with AH (Fig. 2AGo). Urinary calcium excretion did not change significantly after peptone administration in either group. In controls, it increased from 0.38 ± 0.09 to 0.45 ± 0.10 mmol Ca/mmol creatinine, and in AH patients it changed from 0.48 ± 0.010 to 0.52 ± 0.11 mmol Ca/mmol creatinine.



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  		FIG. 2. Effects of oral peptone meal on calcium, gastrin, intact PTH, and monomeric calcitonin in controls and patients with absorptive hypercalciuria. A, Calcium decrease was significant at 90 and 120 min (P < 0.01) with respect to basal levels and was larger in AH at the same time points (P < 0.01). B, Gastrin increase was significant at 15, 30, 45, and 60 min in both groups with respect to basal levels (P < 0.01) and was larger in AH at the same time point (P < 0.01). C, PTH did not change in controls, and there was a slight but significant decrease of PTH at 15 min in AH (P < 0.01 vs. basal levels). D, Calcitonin increase was significant at 15, 30, and 45 min (P < 0.01) with respect to basal values in both groups and was significantly larger at 15 and 30 min in AH (P < 0.01 vs. controls). To change ionized calcium in millimoles per liter to milligrams per deciliter, multiply by 4. *, P < 0.01 vs. basal; **, P < 0.01 vs. controls.

 
After peptone loading, monomeric calcitonin increased in both controls and AH patients with a greater elevation in subjects with AH when compared with controls at various time points (Fig. 2DGo) (P < 0.01). PTH decreased at 15 min in AH patients (P < 0.01 vs. basal levels), then returned to normal levels. PTH did not change in controls (Fig. 2CGo).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main new finding of the present study is the enhanced gastrin response to an oral calcium load and to a peptone-meal in patients with AH when compared with age- and gender-matched controls. Our results also confirm the previous finding of an increased calcitonin response to oral calcium loading in AH patients. An additional novel finding of our study is the increased response of calcitonin levels after oral peptone administration in subjects with AH. These findings bring about three possible areas of discussion: the appropriateness of the diagnosis formulation, the effect of calcium and amino acids on gastric physiology and calcitonin secretion, and the possibility of the existence of a generalized increase in calcium sensitivity of the CaSR in AH.

Patient selection

We examined patients with absorptive hypercalciuria who had been selected on the basis of urinary calcium/urinary creatinine ratio in a 2-h urine specimen collected in fasting conditions between 0600 and 0800 h after a 1-month calcium-free diet, as recommended previously by Pacifici et al. (46). In the clinical field of hypercalciuria, however, large fluctuations in metabolic parameters measured on different occasions during the same day or in different days may cause overlapping of hyperabsorptive and "fasting" type hypercalciuria, and it is possible that a relatively minor portion of the patients may have been misclassified. This would imply that the exaggerated response of gastrin to calcium and peptones is not the hallmark of "absorptive" hypercalciuria but it may be a characteristic of hypercalciuria per se.

Calcium and gastrin

Oral calcium is a well-known stimulus for gastrin secretion (31, 32, 33, 37), and the recent identification of CaSR on gastrin-secreting cells offers a possible new explanation of the secretagogue properties of calcium. Calcium is thought to directly activate antral gastrin-secreting cells and gastric parietal cells acting on CaSR on both the parietal and basolateral side (22, 23, 24). Furthermore, after oral calcium ingestion, other mechanisms may participate in the regulation of gastrin secretion. In particular oral calcium administration increases gastrin secretion by an action on duodenal cells (31), which express CaSR as well (22). Finally, the increase in acid secretion is thought to be partially independent of gastrin release, and it is possibly directly mediated by CaSR on parietal cells (on their apical side) (22, 23, 24). Then, the increased gastric acid secretion previously reported in patients with AH (27, 28) could indeed be related to an enhanced gastrin release induced by calcium and/or to an enhanced activity of the CaSR present on the parietal acid secreting cells; both mechanisms may possibly reflect a particular increased activity of the CaSR. The increase of gastrin after oral calcium load is low in our normal postmenopausal control women; the same was recently shown by others (38), and the response was normalized by estrogen treatment.

Calcium and calcitonin

Oral calcium load is also thought to give a larger increase of calcitonin in subjects with AH (49, 50, 51, 52, 53). Again, the existence of CaSR on C cells in thyroid and a possible generalized increased activity of CaSR in AH may help explain the small but significantly larger increase of calcitonin we observed in our study. The novel finding of a greater response of monomeric calcitonin to oral peptones loading suggests the existence of an allosteric mechanism of regulation of CaSR also in thyroid C cells.

Ionized calcium and peptone load

Interestingly, after food and amino acid administration, the ingestion-induced gastrin release is followed by a decrease in serum calcium which, in turn, seems to be related to the release of a hormone (gastrocalcin) that improves calcium utilization in osteoblasts (54, 55, 56, 57, 58). A larger increase in gastrin-mediated gastrocalcin release during peptone load may help to explain the larger decrease in ionized calcium observed in patients with AH after peptone loading. Alternatively, the hypocalcemic response to oral peptones might be related to the increase in calcitonin. However, we also observed a decrease in ionized calcium after oral peptone loading in two thyroidectomized patients in whom no increase in calcitonin was elicited by peptones, suggesting that calcitonin release is not the cause of hypocalcemia during peptone loading (data not shown). It is tempting to speculate that, on a long-term basis, the daily larger stimulation of gastrin secretion in these patients might be responsible for an enlargement of gastrin-secreting G cell population with the consequent appearance of antral G hyperplasia and expansion of enterochromafin like cells (59, 60, 61, 62, 63, 64, 65, 66, 67, 68). Indeed, we have found the presence of antral G cell hyperplasia and enterochromaffin expansion by esophagogastroduodenal endoscopy in 22 patients (data not shown).

Amino acids and hypercalciuria

The allosteric regulation of CaSR (41, 42, 43) by amino acid has clarified the finding by which diets with elevated protein content are hypercalciuric and diets with low protein content induce a secondary hyperparathyroidism and are protective in the patients with absorptive hypercalciuria (69). Elevated plasma levels of amino acids might allosterically regulate renal CaSR to induce hypercalciuria, and, by contrast, low levels of amino acids might affect the entry of calcium in parathyroid cells, therefore increasing PTH. Even if we observed an increased calcium urinary excretion in response to oral calcium loading in our patients with AH, we did not find evidence of hypercalciuria after oral administration of peptones; this contrasting result can probably be explained by the low dose we used, which perhaps did not permit a sufficient concentration at the distal tubule to stimulate CaSR at this location. Indeed, the finding of hypercalciuria after elevated protein content diets (69) confirms this possibility. The dose we used has been previously demonstrated as a good gastrin secretagogue; however, it is possible that this dose is not enough to reach an effect at the distal tubule. Another possible explanation of the lack of urinary calcium increase after peptone load may be related to the decreased ionized calcium observed during the test (Fig. 2AGo), probably mediated by gastrocalcin release; this may have induced a decreased calcium glomerular filtration with an insufficient calcium load arriving at the renal tubule to be excreted.

Conclusions

In conclusion, an elevated activity of the CaSR in gastrin-secreting cells and in gastric parietal cells could help to explain the increased gastrin secretion after oral calcium and after oral peptone administration and the greater acid output in patients with hypercalciuria (absorptive type). The same mechanism could help to explain the common finding of a slight increase in calcitonin by oral calcium administration (48, 49, 50, 51, 52) and by oral peptones. Our clinical observations on CaSR-regulated hormones may reflect an increased function of the CaSR that possibly mirrors a polymorphism of the receptor, such as the one described by Vezzoli et al. (25) (Arg990Gly) in patients with AH.


   Footnotes
 
First Published Online December 21, 2004

Abbreviations: AH, Absorptive hypercalciuria; CaSR, calcium-sensing receptor.

Received January 11, 2004.

Accepted December 1, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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