PROGRESS IN GASTROENTEROLOGY

Transcription

1 GASTROENTEROLOGY 64: , 1973 Copyright 1973 by The Williams & Wilkins Co. Vol. 64, No. 6 Printed in U.S.A. PROGRESS IN GASTROENTEROLOGY CALCIUM AND GASTRIC SECRETION ROBERT F. BARRERAS, M.D. Department of Medicine, University of Wisconsin Medical Center, Madison, Wisconsin The induction of hypercalcemia in man by the intravenous administration of various calcium salts is usually associated with an increase in the volume, acidity, and pepsin content of gastric secretion. An increase in circulating gastrin accompanies these changes and may be the chief mediator of the increased secretory response. The oral ingestion of calcium carbonate by man is also associated with increased serum gastrin levels and increased gastric secretion. It does not appear that the occurrence of hypercalcemia is essential to this phenomenon. Although the subject of continuing controversy, there appears to be a substantially greater prevalence of peptic ulcer disease in patients with primary hyperparathyroidism. The coexistence of gastrin-producing tumors accounts for part of this increase. Hypercalcemia appears to increase the release of gastrin from such tumors and may thereby lead to or enhance an increase in gastric secretion. The dog and the rat, the classical models for gastric secretory studies, do not respond to hypercalcemia with an increase in gastric secretion, and so are not suitable models for the study of this phenomenon. The observation that hypercalcemia actually inhibits gastric secretion in the dog and the rat poses interesting questions for students of gastric secretion. Preliminary studies in the monkey, the ferret, and the cat suggest that these animals, like man, show an increase in gastric secretion during Received October 30, Address requests for reprints to: Dr. Robert F. Barreras, Department of Medicine, 1300 University Avenue, Madison, Wisconsin induced hypercalcemia, and they may prove to be suitable models of the human response. Hypocalcemia appears to inhibit gastric secretion in all species so far studied. Intravenous Calcium Infusion and Human Gastric Secretion The first description of the effects of induced hypercalcemia on human gastric secretion appeared in 1927 when Sereghy and von Gyurkovich 1 reported that the acidity of gastric juice increased in 8 of 10 normal subjects to whom they gave an intravenous injection of 1 g of calcium chlorate. The method for evaluating the gastric juice involved the introduction of 400 ml of tap water via a tube into the fasting stomach with periodic sampling for 2 V2 hr. The free and total acidity of the gastric aspirates after intravenous calcium were about double the values observed when calcium was not injected. The authors also noted increased gastric motor activity after calcium and concluded that the effect of calcium on the human stomach corresponds to vagal stimulation. In the ensuing 33 years no additional studies on the effects of calcium administration on human gastric secretion appeared, although the original observations were occasionally supported and more frequently denounced on the basis of studies in dogs (see below). It was not until 1960 that additional studies in man were reported when Donegan and Spir02 described the effects of a constant intravenous infusion of calcium gluconate in 5 normal subjects. They administered the calcium in a dose of 15 mg per kg in 4 hr, and

2 June 1973 PROGRESS IN GASTROENTEROLOGY 1169 compared gastric secretory rates with those observed during control saline infusions. In all 5 subjects the volume and titratable acid increased. Pepsin activity increased in the 4 subjects in whom it was measured. Mean acid output, calculated from their graphs, increased from 1.3 meq of H+ per hr to 3.5. Serum calcium in all subjects rose above 12.7 mg per 100 ml. The authors postulated that the hypercalcemic enhancement of human gastric secretion might be the result of increased blood flow. Interest in the effects of hypercalcemia accelerated, and in 1963, Ottenjahn et al. 3 published the first of a series of papers dealing with various aspects of the calciumgastric secretion relationship. In this study they administered calcium gluconate in a dose providing 630 or 720 mg of calcium in a period of 30 to 60 min. Serum calcium levels rose to a mean value above 14 mg per 100 ml. Of 32 patients studied, serum calcium levels rose above 12 mg per 100 ml in 30 subjects, all of whom had an increase in the titratable acidity of the gastric juice and a fall in gastric ph. On the basis of gastric biopsies, the patients were divided into two groups-15 with gastritis and 15 with an intact mucosa. The authors noted a greater rise in acidity in the patients who did not have histologic evidence of gastritis. At about the same time a study by Fillastr6 et al. 4 described the effects of a rapid (12 min) injection of calcium gluconate providing 450 mg of calcium to patients convalescing from various benign afflictions. Gastric responses to calcium injection were compared, in 15 patients, to spontaneous gastric secretion or to responses to saline injection. Mean gastric juice volume and acidity were greater after calcium in each of the 2 hr after injection. The authors noted that 4 patients did not demonstrate an increase in gastric juice acidity in the 1st hr after calcium injection, and 3 did not in the 2nd hr. It appeared at this point that the usual human gastric response to induced hypercalcemia was an increase in gastric juice volume, acid, and pepsin, with a small number of subjects apparently failing to respond. There then appeared a study from Egypt by Fikry and Dorry 5 which suggested that rapid intravenous calcium injections in 23 normal subjects did not stimulate human gastric secretion, and, in fact, were inhibitory. They found that mean values for gastric juice volume, titratable acidity, and peptic acidity decreased after calcium. However, if one applies Student's t-test to the data, the differences in titratable acidity and peptic activity are not significant at the 0.05 level, and only the volume decrease appears significant. Furthermore, a calculation of the acid and pepsin outputs after calcium yields figures which do not differ significantly from the control values. Perhaps a more accurate interpretation of their data is that in the 23 normal subjects studied, intravenous calcium did not significantly alter the concentration or output of acid or pepsin but did appear to decrease the volume of gastric juice. It has been suggested that differences in technique may account for the unusual results. An alternative interpretation is that there may simply have been a predominance of calcium "non-responders" in their study group. Rather than dismiss their data, it would appear useful to examine a similar population by more standardized methods in order to determine whether there may be a hereditary or ethnic determinant of the frequency of calcium nonresponders. Subsequent studies, conducted in European or European descendant populations, confirmed the earlier observations of induced hypercalcemia as a stimulant of human gastric secretion and served to define more precisely the magnitude of the gastric responses as well as the interaction of other agents with the effects of hypercalcemia. In 1966, Murphy et al. 6 observed the effects of intravenous calcium glue onate (15 mg of calcium per kg in 4 hr) in 8 subjects. The hydrogen ion concentration, the volume, and the acid output increased in all subjects. Whereas mean basal acid output in this group was 1.6 meq per hr, the peak calcium-stimulated secretion was 10 meq per hr. Further comparison with peak Histalog responses indicated that the

3 1170 PROGRESS IN GASTROENTEROLOGY Vol. 64, No. 6 peak calcium responses represented 19 to 43% of the peak acid output with an average value of 30% of peak acid output. The mean rise in serum calcium in this group was 3.8 mg per 100 m1. The authors noted also that the stimulation of gastric acid output persisted for 2 hr after cessation of calcium infusion in 6 of 8 subjects. One subject had a repeat infusion with calcium chloride and the responses were similar to those observed with calcium gluconate. A study of the effects of intravenous calcium on gastric secretion in 24 duodenal ulcer patients was reported by Barreras and Donaldson. 7 Calcium glucono-galactono-gluconate was given to deliver 12 mg of calcium per kg in 3 hr. Serum calcium rose from a mean of 9.5 to 12.3 mg per 100 ml. Basal acid output was 2.6 meq per hr and mean peak acid output (betazole) was 30.9 meq per hr. In the 3rd hr of hypercalcemia, mean acid output was 12.2 meq per hr, a value 4Y2 times basal acid output and 29% of peak acid output. In 12 subjects, pepsin was measured and pepsin output was found to increase during hypercalcemia to a rate that was 2.8 times the basal rate and 45% of that after betazole. Control saline infusions in 12 subjects did not alter the acid or pepsin secretory rates. Smallwood,8 in Australia, administered calcium gluconate to 19 subjects of whom 14 had duodenal ulcer disease. He used a variety of doses and schedules of calcium administration and found an increase in acid secretion in all subjects after calcium, and in pepsin secretion in those in whom it was measured. Vagotomy inhibited the gastric hypersecretory effect of calcium administration. Kocian and Hlavackova 9 in Prague, administered 2.7 mg of calcium per kg in 7 min (as calcium gluconate) and found that 20 patients with a variety of diseases had an increase in gastric acid secretion after the administration of calcium. Baranska-Pawlowska)O in Poland, demonstrated increases in mean volume and acidity of gastric juice in 46 subjects given calcium (15 mg per kg) as the gluconate. She found no difference in the increases among three groups tested (24 duodenal ulcer patients, 11 gastric ulcer patients, and 11 normal subjects). Basso and Passaro ll studied 5 ulcer patients who did not have the Zollinger-Ellison syndrome but who had had vagotomy and distal gastrectomy. The induction of hypercalcemia by the 4-hr infusion test described above 2. 6 produced a gradual rise in acid secretion, peaking at 2 hr, and falling thereafter. That calcium infusion stimulated gastric secretion in patients who had had vagotomy and antrectomy suggests that calcium may act through nonantral gastrin-releasing cells or may have some direct neural, parietal cell, or other effect on gastric secretion. This observation contrasts with that of Smallwood 8 who did not observe a rise in gastric secretion in vagotomized patients after a briefer calcium infusion. Interference with Calcium-stimulated Gastric Secretion The stimulating effect of induced hypercalcemia on human gastric secretion was completely abolished by the administration of an anticholinergic (atropine), as well as of a ganglionic blocker (pentolinium).7 The complete abolition of the calcium-stimulating effect on human gastric secretion by simultaneous intravenous magnesium infusion demonstrated by the same authors 7 in 4 patients was confirmed by Ottenjann et a1. 12 in 20 subjects who received calcium infusions leading to stimulation of secretion, which was then abolished by the simultaneous administration of magnesium sulfate. The same group13 had previously shown that magnesium administration alone inhibited human gastric secretion. In a variant of these experiments, Dehyle et a1. 14 demonstrated that the inhibition of gastric secretion by initial magnesium infusion is abolished by subsequent calcium infusion, with a return of gastric secretion to basal rates. Glucagon infusion was also found to inhibit the increased gastric secretion associated with induced hypercalcemia. IS This touches on a series of hormonal inter-

4 June 1973 PROGRESS IN GASTROENTEROLOGY 1171 relationships which are just coming to Hypercalcemia and Serum Gastrin light, including such things as calcium- Levels induced glucagon release,16 glucagon- The development of a radioimmunoasinduced calcitonin release, 17 and calcitonin say for gastrin has led to additional insight inhibition of gastric secretion. 18 Ottenjann into the interaction of calcium with the et al. 15 postulated that glucagon inhibition gastric secretory process. Trudeau and of calcium-stimulated gastric secretion was McGuigan 19 studied a patient with a total not related to the slight lowering of calcium gastrectomy and high blood levels of gaslevels. This was based on separate work in trin associated with the Zollinger-Ellison which a phosphate infusion which pro- syndrome. The patient developed hyperduced a slight drop in serum calcium did, parathyroidism, and after parathroidecnot inhibit gastric secretion, whereas a tomy, during episodes of hypocalcemia, the glucagon infusion leading to even less of a serum gastrin levels fell some 20-fold. After drop in serum calcium did inhibit gastric restoration of normal serum calcium levels secretion. The possibility that calcitonin is with vitamin D and calcium administrathe mediator of glucagon-induced inhibi- tion there was a return of the marked tion of gastric secretion is to be considered. elevation in the serum gastrin. Further The work of Hesch et al. 18 indicates that more, when serum calcium levels were calcitonin inhibits gastric secretion in the normal and intravenous calcium was given absence of any measurable change in to induce hypercalcemia, there was a subserum calcium levels. stantial rise in the serum gastrin. It seems clear from this work that the release of How Does Calcium Stimulate Human gastrin from Zollinger-Ellison tumor tissue Gastric Secretion? is very sensitive to alterations in the serum Recent evidence has implicated gastrin calcium level. as the important mediator of calciuminduced human gastric hypersecretion. Beported on the serum gastrin and gastric Reeder and colleagues 20 subsequently refore examining the gastrin story, however, secretory responses of 7 normal subjects it should be kept in mind that calcium is and 7 duodenal ulcer patients. 2o In both capable of acting at a large number of sites groups, the induction of hypercalcemia by which affect gastric secretory responses, intravenous infusion of calcium gluconate and that the final observed gastric secretory pattern is the net result of a set of levels as well as in the rate of gastric acid led to significant rises in the serum gastrin inhibitory and stimulatory events. Some of secretion. Calcium (as the gluconate) was the ways in which hypercalcemia may given in a loading dose of 6 mg per kg in the induce gastric hypersecretion other than by first 1/2 hr followed by a dose of 4 mg per kg gastrin release have been mentioned above per hr for the remaining 41/2 hr for a total of and include vagal stimulation,1 increased 24 mg per kg in 5 hr. Mean serum calcium blood flow, 2 a local cholinergic effect, 6 levels rose to 14.7 in normal subjects and to increased sensitivity of the parietal cell to 16.0 in duodenal ulcer patients. Mean acetylcholine,9 calcium-dependent acetylcholine release,6 either at the preganglionic ml to 175 ± 69 in the normal subjects and serum gastrin levels rose from 93 ± 7 pg per or postganglionic neurone,7 and enhancement of the intracellular spread of excita...i.uodenal ulcer patients. Mean acid secre from 125 ± 8 to 229 ± 23 pg per ml in the tion, promoting the coupling between exterior excitation and the functional reaction normal subjects and from 8.2 to 22.2 meq tion rose from 3.6 meq per hr to 7.5 in the of the cell interior.12 Some of these mechanisms may be operative on the gastrin would appear from these studies that the per hr in the duodenal ulcer patients. It releasing cells as well as on the parietal cell gastric secretory increases seen in man and other cells which affect gastric secretiondiated by rises in serum during induced hypercalcemia may be me gastrin.

5 un PROGRESS IN GASTROENTEROLOGY Vol. 64, No.6 It is of interest that the mean serum calcium, serum gastrin, and gastric secretory responses in the 7 duodenal ulcer patients were greater than those seen in the 7 normal subjects. Also of note was the observation that whereas the administration of atropine abolished the increase in gastric secretion, there was no associated drop in serum gastrin levels. In fact, the serum gastrin levels rose even more during atropinization, while gastric secretion fell below base line levels. It would appear that whereas the increase in gastric secretion during hypercalcemia may be mediated via the hormone gastrin, the inhibition of gastric secretion by atropine in this situation is mediated by some other mechanism, perhaps a direct effect on the parietal cell. An additional observation made by Reeder and colleagues 20 was that in dogs with Heidenhain pouches, no increase in serum gastrin was observed during induced hypercalcemia. This lack of gastrin responsiveness may account for the lack of gastric secretory increases in the dog during induced hypercalcemia, and may in part explain the species difference described below. Basso and Passar0 11 studied the effects of induced hypercalcemia on 4 patients who had had partial gastrectomy and vagotomy for the Zollinger-Ellison (ZE) syndrome and found that gastric secretion in these patients increased markedly during induced hypercalcemia to levels that equalled or exceeded the levels after maximal betazole stimulation. In an extension of this work, Passaro et a1. 21 measured serum gastrin responses as well as gastric secretory responses during intravenous calcium administration. They found marked increases in gastric secretion and serum gastrin levels in unoperated ZE patients, and, in addition, found that the responses were in excess of those seen in hypersecreting duodenal ulcer patients without the ZE syndrome (i.e., patients with normal fasting gastrin levels). They suggested that the calcium infusion test may provide additional diagnostic information in evaluating patients for the ZE syndrome. If we combine the observations of Reeder et a1. 20 and Passaro et a1. 21 it appears that both serum gastrin and gastric secretion increase during hypercalcemia in normal subjects, but do so to a greater extent in duodenal ulcer patients, and to an even greater extent in patients with the ZE syndrome. The individual variations in this responsiveness to calcium have yet to be explored, as do the precise limits of the expected responses for these three groups of patients. The manner in which hypercalcemia leads to increased serum gastrin levels remains to be demonstrated. The mechanisms discussed above for the actions of calcium on the gastric secretory apparatus all deserve exploration. Perhaps of greater interest, however, is the observation that in a number of endocrine as well as exocrine glands, as well as in neuromuscular nerve endings, calcium appears to serve the role of coupling factor between excitation and secretion or excitation and contraction. This phenomenon has been extensively reviewed recently by Rasmussen 22 and will not be explored further in this review, for the data are applicable only by analogy, and the definitive studies on the gastrinsecreting mechanism have not yet been done. Hyperparathyroidism and Peptic Ulcer Disease Gastrointestinal symptoms, including epigastric pain and vomiting, are prominent in the earliest case reports of clinical hyperparathyroidism which appeared in the 1920's It was not until 1946, however, that the coexistence of primary hyperparathyroidism and peptic ulcer disease was described by Rogers,26 who reported 2 patients with duodenal ulcers. Reports of an increased frequency of peptic ulcer disease in hyperparathyroidism appeared in the early 1950's,27-29 and since then there have been many such reports describing the coincidence of these diseases. The larger series (also J. E. Howard, T. B. Connor, L. Haddock, personal communication to Ostrow et a1. 35) are summarized in table 1. There is some difference of opinion as to whether peptic ulcer disease occurs more frequently in hyperparathyroidism

6 June 1973 PROGRESS IN GASTROENTEROLOGY 1173 TABLE 1. Frequency of radiologically or anatomically proved peptic ulcer disease in patients with primary hyperparathyroidism Place Author Year No. of patients Proved ulcer disease Percentage Boston St. GOar" New York St. Goar" New York Moses" Stockholm Hellstrom Baltimore Howard et al." (also personal communication to Ostrow et al. 35) Boston Ostrow et al Rochester Keating Detroit Wilder et al Prague Pacovsky et al Minneapolis Ellis and Nicoloff'" Over-all a Excluding a case of secondary hyperparathyroidism noted by Ostrow et al. 35 than in control populations. This controversy cannot be settled with certainty, for no one has attempted to establish peptic ulcer incidence or prevalence by using the same methods in control and hyperparathyroid populations. The case against an increased frequency of peptic ulcer disease in hyperparathyroidism was made quite forcefully by Ostrow et al. 35 On examining the available data, however, I think that a good case can be made for an increased prevalence of peptic ulcer disease in hyperparathyroidism. To begin with, the over-all 14% prevalence figure derived in table 1 is at best a minimal figure. Only patients with objective evidence (radiographic or surgical) or ulcer disease are included. The studies are retrospective and include patients evaluated before there was general recognition of the association of the two diseases. Consequently, in at least half of the patients, including many with gastrointestinal symptoms, no attempt was made to obtain objective evidence of peptic ulcer disease. For example, in the series with the lowest reported coincidence of peptic ulcer disease and hyperparathyroidism (Ostrow et al. 35), we find that of 39 patients with surgically proved or clinically probable hyperparathyroidism, only 3 had ulcers demonstrated at the hospital in which the series was collected, an incidence of 7.7%. However, if we adjust these figures to include patients with typical ulcer symptoms and prior demonstration of ulcer plus patients with typical peptic ulcer symptoms in whom X-rays were negative or not obtained, the prevalence rises to 25.7%. One worries also about an additional 6 patients in this series with atypical upper abdominal symptoms in whom no gastrointestinal X-rays were obtained. Similar problems are found with the other early series and the 14% incidence of objectively demonstrated peptic ulcer disease in hyperparathyroidism is quite probably a major underestimation. Because most of the prevalence figures for peptic ulcer disease in control populations are based not only on objective evidence, but also include clinical diagnoses, it becomes important to estimate the over-all (radiologic plus clinical) prevalence of peptic ulcer disease in hyperparathyroidism. If we recognize the limitations of the earlier studies of hyperparathyroid patients and consider the higher figures in the series reported since 1960, the likelihood of objectively demonstrating peptic ulcer disease in hyperparathyroidism would appear to exceed 20%, and the figure for the over-all prevalence of peptic ulcer disease in hyperparathyroidism based on radiologic as well

7 1174 PROGRESS IN GASTROENTEROLOGY Vol. 64, No. 6 as clinical or historical evidence is probably in excess of 30%. The next problem is to determine just what the prevalence of peptic ulcer disease is in the absence of hyperparathyroidism. This is not easily done, and the problems have been dealt with at length elsewhere The large United States National Health Survey43 indicates that in the United States there is an over-all peptic ulcer prevalence of 1.4%, which rises to a peak lifetime prevalence of 2.9% (4.3% for men, 1.8% for women). This figure agrees with several other surveys cited by Susser 40 and in the United States Public Health Service monograph,43 as well as with the Survey of Metropolitan Life Insurance employees conducted by Jennison,44 who cites a prevalence in the over-30 population of 2.5% (3.8% in men, 1.0% in women). The prevalence data in these surveys include clinical diagnoses as well as anatomically proved peptic ulcer disease. The prevalence of anatomically proved peptic ulcer disease in hyperparathyroidism (at least 14%) exceeds these estimates for the general population by a factor of 5. If we include clinically as well as anatomically diagnosed peptic ulcer disease, as was done in the estimates in normal populations, then the excess of peptic ulcer disease in hyperparathyroidism may be as much as 10-fold. In an interesting study on the effects of occupations and other factors on peptic ulcer prevalence, Doll and his co-workers 45 arrived at a peak lifetime prevalence rate of 9.6% for men and 6.1% for women (7.8% over-all). Whether these higher figures reflect the thoroughness of English investigators or the weakness of English gastrointestinal tracts is not known, but the figures are certainly higher than those obtained in the studies conducted in the United States. 43, 44 Yet even the higher figures from Great Britain provide a basis for concluding that there is an excess of peptic ulcer disease in hyperparathyroidism, The peak lifetime prevalence figures of Doll and associates 45 (7,8%) is based on clinical plus radiologic diagnoses, The minimal figure for anatomically proved peptic ulcer disease (table 1) is double this, and if one includes clinical as well as anatomically proved peptic ulcer disease, it would appear that patients around the world with hyperparathyroidism have about four times the prevalence of peptic ulcer disease found in Doll's Londoners during their peak decade of susceptibility to ulcer disease. Some of the drawbacks of the various retrospective hospital and clinic series are overcome in the report of 121 cases of hyperparathyroidism in Stockholm, all evaluated by one investigator, John Hellstrom. 33 His report, in addition to providing a strong argument for the increased prevalence of peptic ulcer disease in hyperparathyroidism, provides an interesting breakdown according to sex. In the hyperparathyroid men, the incidence of radiologically proved ulcer disease was 28.6%, a figure which exceeds by 3-fold that of Doll et al. 45 and by 7 -fold the data from the United States. 43, 44 The women in Hellstrom's series had a peptic ulcer prevalence of 4.6% (radiologically proved) which is higher by 2- to 4-fold than the reported peak prevalences in American women,43, 44 but not higher than the peak prevalence for London women determined by Doll et al. 45 on the basis of radiologic and clinical criteria. Data from Stockholm, with which Hellstroms' series might better be compared, indicate, in a survey conducted by Tomenius,46 that in the population of patients who visited outpatient clinics in Stockholm, peptic ulcer disease was diagnosed in 3.2%, including 5% of the men and 2% of the women. Why is there an increased prevalence of peptic ulcer disease in patients with hyper "l'3rathyroidism? Gastric secretory studies indicate that basal hypersecretion occurs in about one-third of patients with hyperparathyroidism, and it is possible that this is an important pathogenetic mechanism (see discussion below). Mechanisms other than gastric hypersecretion have been proposed. It has been suggested that depressed or altered mucus production in hyperparathyroidism might account for the peptic ulceration,35 but there is no evi-

8 June 1973 PROGRESS IN GASTROENTEROLOGY 1175 dence to substantiate this in man, and in the rat, the effect of parathormone administration is to increase gastric mucus and protect against peptic ulceration. 47 Calcinosis of the gastrointestinal wall has been suggested but not demonstrated in man,48 although in some experimental animals calcium deposition may occur (see below). A study of the gastric juice of 10 patients with hyperparathyroidism by Christiansen and Aagaard 49 demonstrated an increase in the basal gastric juice content of calcium and phosphorus, as compared with 20 controls, but no difference in the content in stimulated gastric secretions. Whether the increase in the basal calcium has some pathogenetic importance is not clear, but in view of the possible local effects of calcium on gastrin release (see below) the increased gastric juice calcium may have some significance. Gastric Secretion in Hyperparathyroidism The data on gastric secretion in hyperparathyroidism are not abundant. Ward et al. 50 studied gastric secretion in 9 patients with hyperparathyroidism. In 5 of the 9, basal acid output was greater than the upper limit of normal for their laboratory (mean ± 3 so). After parathyroidectomy the basal secretion fell in 8 of the 9 patients. The average reduction was 38% and all but 1 of the patients had a basal acid output within the normal range after parathyroidectomy. In 5 patients with hyperparathyroidism studied by Barreras and Donaldson,51 2 were basal hypersecretors (7.5 and 19.6 meq per hr). After parathyroidectomy, normal basal secretion was observed in these patients (1.2 and 2.1 meq per hr). The induction of hypercalcemia in both patients, after parathyroidectomy, led to a rise in gastric secretion to the levels seen before parathyroidectomy. In the patient with the higher secretory rate, who also had severe peptic ulcer disease, a 5-year follow-up has failed to demonstrate recurrence of basal hypersecretion, abnormal serum gastrin levels, or recurrence of peptic ulcer disease, and in this patient the induction of hypercalcemia has repeatedly led to gastric hypersecretion and elevated serum gastrin levels (unpublished observations). In a study of 13 patients with hyperparathyroidism, Patterson et al. 52 found 4 to be basal hypersecretors. Parathyroidectomy in 8 of the patients led to a reduction of basal secretion in all but 1. An additional 13 patients with hyperparathyroidism were studied by Christiansen and Aagaard, S8 and of these, 4 had basal acid outputs of greater than 6 meq per hr. Parathyroidectomy decreased gastric secretion in 2 of the 4, but in 1 of these the level, although reduced to one-third of the preoperative value, was still abnormally high (20 meq per hr). Combining the four series, we thus have 40 patients with hyperparathyroidism of whom 15 were basal hypersecretors and in whom parathyroidectomy was followed by normal basal gastric secretory levels in 10 of the 15 previous hypersecretors. How are we to account for the occurrence of basal gastric hypersecretion in 37.5% of patients with hyperparathyroidism? Some of these can probably be accounted for by the coexistence of gastrinomas. The incidence of islet cell tumors in 442 patients with parathyroid adenomas was 4% in a series reported by Huizenga et al. 54 There may well be additional patients with occult gastrinomas. It has been suggested by Grossman 55 that such coexistent tumors may explain the increased incidence of peptic ulcer disease and gastric hypersecretion in hyperparathyroidism. This hypothesis is neither supported nor refuted by the available data, for systematic studies of gastrin levels in hyperparathyroid patients are not available. It is of course possible that gastric hypersecretion may occur as a result of hypercalcemia-induced gastrin release and gastric hypersecretion in the absence of a gastrinoma. Whether the persistent hypercalcemia of parathyroid disease or the fluctuations in calcium levels in such patients are associated with rises in gastrin levels remains to be studied. Of interest are some preliminary observations made by Creutzfeldt et al. 56 which indicate a significant increase in the num-

9 1176 PROGRESS IN GASTROENTEROLOGY Vol. 64,No. 6 ber of antral G-cells in 3 patients with parathyroid adenomas and hypercalcemia. Two of the patients had an increased gastrin content in the antral mucosa as well. None of these patients had increased gastrin levels or gastric secretion. The authors suggest a trophic role for hypercalcemia, leading to proliferation of gastrinproducing cells. Multiple Endocrine Adenomatosis The occurrence of peptic ulcer disease in patients with hyperparathyroidism and coexisting gastrin-producing tumors with gastric hypersecretion presents little difficulty in understanding the basis for the peptic ulcer disease. As noted above, it has been suggested that any excessive prevalence of peptic ulcer disease in hyperparathyroidism and the abnormally high gastric secretion sometimes seen in such patients may simply be a manifestation of the coexistence of overt or occult gastrin-producing tumors. 54, 55 The coexistence of the three entities-hyperparathyroidism, pancreatic islet cell tumor, and peptic ulcer disease-has been described by several workers The reviews of Ballard et al. 60 and of Ptak and Kirsner 63 provide a good discussion of the complexities involved. It is apparent that the hypercalcemia of hyperparathyroidism may aggravate the effects of pancreatic islet cell tumors by increasing the output of gastrin and thereby increasing gastric secretion. Surgical correction of the hyperparathyroidism in such patients has sometimes diminished the gastrin levels, 19, 62 decreased gastric secretion,62 and ameliorated the peptic ulcer disease,62 In several instances, parathyroidectomy, although leading to decreased gastric secretion, has not decreased it sufficiently to alter the peptic ulcer diathesis significantly, 61 An additional hormone interaction related to calcium and gastric secretion is the recent finding that the hormone gastrin is capable of inducing the release of calcitonin from the thyroid gland in vitro and in experimental animals. 64, 65 Although pentagastrin administration to normal subjects has not led to increased calcitonin levels,66 it has been demonstrated recently that 6 of 8 patients with the ZE syndrome had elevated serum levels of immunoreactive calcitonin. 67 A discussion of the interrelationships of these various hormones and their relation to gastric secretion is to be found above. Oral Calcium and Gastric Secretion The oral ingestion of calcium carbonate leads to gastric hypersecretion in duodenal ulcer patients. Although a gastric rebound to orally ingested alkali has long been suggested and looked for in man, no convincing evidence of this phenomenon has been forthcoming. However, after ingestion of the antacid calcium carbonate, there is evidence of gastric hypersecretion and of increased serum gastrin levels as well. The first clear demonstration of calcium carbonate-induced gastric hypersecretion was made by Breuhaus et al. 68 who studied nocturnal gastric secretion in 6 patients after a day of food and various antacids. They found that gastric secretory volume and acidity during the night was greater after a day of calcium carbonate ingestion than after a day of aluminum hydroxide ingestion, or a day on which food but no antacid was ingested. Fordtran 69 observed, in 24 patients with duodenal ulcer disease, that calcium carbonate ingestion (4 or 8 g in a single dose) after a standard meal, was followed by a significantly greater output of acid in the period 3 to 5 1 /2 hr after calcium carbonate intake. On days in which 4 or 8 g of sodium bicarbonate or 30 or 60 ml of a magnesiumaluminum preparation were ingested, there was no increase in gastric acid output compared with control days on which food but no antacid was ingested. In repeated studies of calcium carbonate effects on gastric secretion in 1 subject, measurements of serum calcium and serum calcium ion activity suggested that a rise in serum calcium was not necessary for r;astric hypersecretion to occur. In another study in this patient, the introduction into the duodenum of calcium carbonate that had been mixed with hydrochloric acid led to a rise in gastric secretion, suggesting

10 June 1973 PROGRESS IN GASTROENTEROLOGY 1177 that calcium need not come into contact with the stomach for hypersecretion to occur. A study of the effects of calcium carbonate, sodium bicarbonate, and magnesium hydroxide, given in four equivalent neutralizing doses at hourly intervals to 20 duodenal ulcer patients in the fasting state, also implicated calcium carbonate as a stimulant of gastric secretion (Barreras 70 ). In this study, the mean gastric acid output in the 60-min period beginning 2 hr after the last dose of antacid and 30 min after the insertion of a nasogastric tube was twice as great after calcium carbonate as it was in the basal state or after the sodium and magnesium antacids. The acid output after the sodium and magnesium antacids did not differ from each other nor from the basal acid output. The serum calcium was found, in this study, to rise an average of 0.7 mg per 100 ml. The correlation of rise in serum calcium and rise in acid output was poor, and 4 of the 20 subjects failed to demonstrate gastric hypersecretion after calcium carbonate. Reeder et ai., 7 1 using a similar protocol to that in the previous study (four doses of antacid hourly in the fasting state), examined the effects of calcium carbonate and sodium bicarbonate on gastric secretion in 12 duodenal ulcer patients and found changes quite similar to those in the previous study. Serum gastrin levels during the study were also measured, and it was found that whereas with sodium bicarbonate ingestion there was no rise in serum gastrin, there was a 44% increase in serum gastrin levels during the days of calcium carbonate ingestion. Serum calcium concentrations 90 min after the last dose of calcium carbonate were not higher than basal levels (in contrast to the prior study70) suggesting that a rise in serum calcium may not be essential to the rise in serum gastrin or gastric secretion, a conclusion also drawn by Fordtran. 69 In view of Fordtran's demonstration that intraduodenal calcium may produce gastric hypersecretion, it appears reasonable to hypothesize that a local effect of calcium on the gastrin-releasing cells of the duodenum may be one operative mechanism as may of course a local effect of calcium on antral gastrin -prod ucing cells. In view of the antagonistic effect of intravenous magnesium on calciuminduced gastric hypersecretion, the possibility that the simultaneous ingestion of calcium and magnesium compounds may abolish the gastric stimulation observed after calcium alone deserves consideration. This hypothesis, without apparent verification, appears to have led to the introduction of a number of antacid preparations in which calcium and magnesium are mixed. Paul et al. 72 attempted to examine this hypothesis by studying the gastric secretion of 28 male subjects after the ingestion of a dose of 3 g of calcium carbonate, plus 1 g of magnesium oxide. The difference in the sample group (previous studies were confined to duodenal ulcer patients) and the absence of control observations (e.g., calcium carbonate without magnesium, a non calcium antacid or no antacid at all) make the obervation that there was not a significant rise over basal acid output after the calcium and magnesium mixture somewhat tenuous. Apparently, the authors assumed that calcium carbonate alone would have induced hypersecretion in their subjects, but in their failure to test this, the usefulness of a calcium-magnesium antacid mixture remains unproved. Calcium Effects on Gastric Secretion in Experimental Animals Attempts to understand the effects of calcium on gastric secretion have been hindered by the unfortunate fact that the dog and the rat, so long the models for human gastric secretion, demonstrate an inhibition of gastric secretion during hypercalcemia. The mechanisms for this inhibition are of interest, and the experimental results in the dog, the rat, as well as in the pigeon and in the isolated frog gastric mucosa which also demonstrate inhibition, are reviewed below. Recent work suggests that the ferret, the monkey, and the cat may be more suitable

11 1178 PROGRESS IN GASTROENTEROLOGY Vol. 64, No.6 models for studies which are applicable to man, for in these species, as in man, induced hypercalcemia leads to an increase in gastric secretion, and, at least in the monkey and cat, to increased gastrin levels. Basso and Passaro 73 administered calcium and other agents intra peritoneally to the gastric fistula ferret and found that calcium instillation led to increased spontaneous gastric secretion as well as to augmented responses to pentagastrin, bethanecol, and insulin, but not to histamine. The gastric secretory response to calcium was dose-dependent and was abolished by atropine. In studies on 4 macaque monkeys, Rosato et al. 74 found that during constant intravenous infusions of calcium gluconate, the plasma gastrin concentration rose in all 4 animals, and that the gastric acid secretion rose in 2 of the 4. The constancy of the gastrin increase and the variability of the gastric secretory response is one possible problem with this model. The cat has been recently used as a model for the study of responses to induce hypercalcemia by S. Konturek, D. D. Reeder, Becker, et al. (personal communication), who found that gastrin levels and gastric acid secretion are consistently elevated by the induction of hypercalcemia, and that both gastrin release and gastric secretory responses are blocked by atropine. Canine studies of hypercalcemia. Gastric secretion has been studied in the dog during hypercalcemia induced by the intravenous administration of calcium salts, vitamin D administration, and parathyroid hormone administration. There is complete agreement that the intravenous administration of calcium salts fails to stimulate spontaneous gastric secretion in the dog. Further, it is agreed that intravenous calcium salts markedly inhibit gastric secretion which has been induced by hormonal stimulation as well as by neural stimulation. When we turn to the case of histamine-stimulated secretion in the dog, it is agreed that intravenous calcium salts fail to increase the gastric responses, but whether there is inhibition of histamine-stimulated secretion is in dispute. The first apparent attempt to alter canine gastric secretion by intravenous calcium salts was recorded in 1930 by Cowgill and Rakieten. 75 They gave a single intravenous injection of calcium lactate (0.1 mg per kg) to each of 5 dogs (1 Pavlov pouch, 4 Heidenhain pouch) on two occasions. They failed to observe any increase in gastric secretory volume and mentioned that the data might indicate that hypercalcemia exerts a transient inhibitory influence on gastric secretion. They noted that their observations in dogs were contrary to those observed by Sereghy and von Gyrukovich in man. 1 Babkin et al. 76 confirmed this finding in a dog with a Pavlov pouch. The inhibition of canine gastric secretion by intravenous calcium salts was also described by Grant 77 who studied the effect on stimulated gastric secretion in anesthetized dogs. She employed electrical stimulation of the vagus as well as histamine injections. In all cases, she observed a decrease in the volume of gastric secretion when calcium salts were given, a decrease which ranged from 22 to 99% and averaged 75%. She used repeated bolus injections of calcium lactate and calcium chloride to induce hypercalcemia. Control injections of sodium lactate and sodium chloride failed to decrease gastric secretion. Thus, Grant demonstrated that both histaminestimulated and vagus-stimulated canine gastric secretion are profoundly inhibited by acute injections of calcium salts. Ward et al. 50 examined these phenomena further, with single intravenous injections of calcium lactate in dogs with Heidenhain pouches. The mean basal secretion in the 6 dogs studied decreased in volume by 42%, but there was no consistent change in the acidity of the juice. During continuous submaximal intravenous histamine infusion, 4 Heidenhain pouch dogs all manifested a decrease, not only in the volume of gastric juice but in the acidity of the juice as well. Lick et al. 78 went on to examine gastric secretion which was induced by gastrin, by feeding, and by prostigmine, as well as

12 June 1973 PROGRESS IN GASTROENTEROLOGY 1179 basal and histamine-stimulated secretion in the Heidenhain pouch dog. In addition to observations of acid and volume output they also measured pepsin output. In no case did intravenous calcium salts augment the secretory state studied. Volume, acid output, and pepsin output were markedly depressed after intravenous calcium against a background of (1) unstimulated secretion, (2) exogenous gastrin administration (whole partly purified porcine gastrin, as well as tetrapeptide), (3) "endogenous" gastrin (after a test meal), and (4) cholinergic stimulation (administration of the cholinesterase inhibitor, prostigmine). However, they found no depression of histamine-stimulated gastric secretion after calcium injection. Mignon et al. 79 in studies of the Heidenhain pouch dog, found, as had Lick et ai., 78 that hypercalcemia inhibited canine gastric secretion which was induced by gastrin (endogenous and exogenous) but not that induced by histamine. Lick et al. 80 extended their previous observations to include vagal stimulation by insulin and 2-deoxyglucose, and to smaller gastrin peptides and other stimulants. In addition, observations were made on the innervated main stomach as well as from the denervated (Heidenhain) pouch. Calcium given intravenously severely inhibited basal secretion, prostigmineinduced secretion, insulin-hypoglycemiainduced secretion, 2-deoxyglucose-induced secretion, and gastrin-induced secretion (whole gastrin as well as pentapeptide and tetrapeptide). The inhibition was observed in volume, acidity, acid output, and pepsin output from both denervated pouch and innervated main stomach. Reeder et al. 20 measured serum gastrin responses in the dog in response to induced hypercalcemia, and, in addition to finding no rise in spontaneous gastric secretion, found that serum gastrin levels did not rise, whereas in man, induced hypercalcemia did lead to increased gastrin levels. Canine studies with vitamin D and parathormone. Vitamin D administration in the dog has been associated with increases as well as decreases in gastric secretion. It appears that during vitamin D administration, gastric secretion falls, but after cessation of vitamin D, at a time of still raised but falling serum calcium levels, gastric secretion tends to increase. Babkin et al. 76 observed the gastric secretory responses in 2 dogs with innervated (Pavlov) gastric pouches during prolonged ergosterol administration (43 and 22 days). During vitamin D administration the average 24-hr gastric volume was 57% of control levels, the acidity of gastric juice was decreased, and the pepsin output was about 50% of control levels. During vitamin D study periods the response to bread and milk ingestion was diminished. Serum calcium rose from 14.7 to 15.1 mg per 100 ml during vitamin D administration. Schiffrin 81 administered ergosterol to 1 Heidenhain pouch dog for 12 days, and in contrast to Babkin, found that gastric secretory volume doubled and remained elevated for 2 weeks. Neely and Goldman 82 induced hypercalcemia by vitamin D administration to 1 Heidenhain pouch dog over a 22-day period. During the 3 weeks of vitamin D administration there was no change in volume or pepsin output, but free HCI output diminished. During the initial 3 weeks after cessation of vitamin D administration the volume and acidity rose and pepsin output diminished. In the next 4 weeks serum calcium fell towards normal, and, as this occurred, there was a marked increase in gastric voh!me and acid output. The authors interpret these data as demonstrating an increase in gastric volume and acid output during hypercalcemia. However, the increase did not begin until vitamin D injections had ceased and the major increase in secretion was observed later, when the animal's blood levels of calcium, although still elevated, were falling toward normal. It should be noted that the work in this dog has frequently been cited to demonstrate that hypercalcemia increases gastric secretion in the dog. Ward et al. 50 observed the effects of vitamin D administration in 4 Heidenhain pouch dogs. During the period of vitamin D

13 l180 PROGRESS IN GASTROENTEROLOGY Vol. 64, No.6 administration, and in the week thereafter, there was no increase in acidity. However, later, after cessation of vitamin D administration, the mean basal secretion increased 29%, and the juice became more acid (mean ph drop of 2.3). The most marked changes in basal acidity were observed after cessation of vitamin D administration, during which time the gastric juice became more acid as the hypercalcemia diminished, as was the case in the dog of Neely and Goldman. 82 Thus, in spite of variant conclusions drawn by the authors above about the effects of vitamin D on gastric secretion in the dog, there is some agreement in the actual observations. During the period of vitamin D administration 50, 75, 82 gastric secretion was inhibited, whereas after the cessation of vitamin D administration,50, 82 at a time when serum calcium was elevated but not rising, gastric secretion was augmented. Further, the most marked increase in gastric secretion occurred during the time in which the serum calcium was falling. The inhibition during the rise in calcium due to vitamin D is in accord with the inhibition observed during the acute induction of hypercalcemia by calcium salts. Whether the augmentation of gastric secretion observed in dogs during the period of decreasing hypercalcemia after cessation of vitamin D administration occurs during the return to normal after the intravenous administration of calcium, has not been examined. The administration of parathyroid hormone to dogs has led to varying gastric secretory responses. The first report of the effects of parathyroid hormone on gastric secretion was made by Rogers et al. 83 in They injected the residue of an aqueous extract of porcine parathyroid glands into dogs with Pavlov pouches and observed an increase in the volume and acidity of the gastric juice. However, even greater changes occurred after injections of extracts of thyroid, thymus, spleen, liver, and pancreas, and it is difficult to conclude that they described a specific parathormone effect. Austin and Matthews 84 examined the influence of an extract of parathyroid glands (CoUip's extract) with a demonstrable hypercalcemic effect. They studied 4 dogs with Pavlov pouches and found that gastric volume and acid responses to histamine were unchanged in 3 dogs and decreased in 1. Variable results have been reported by others.76, 81 Parathyroid extract given to 7 dogs with Heidenhain pouches by Allen and Elliott 85 led, in all 7, to a 60 to 75% reduction in the 24-hr gastric secretion. No consistent change was seen in pepsin content, but in view of the volume drop the pepsin output appears to have decreased. Other nonresponses. The rat has also been found to be an unsuitable model of human gastric responses to hypercalcemia, for as in the case of the dog, a variety of techniques for inducing hypercalcemia serve to inhibit rather than stimulate gastric secretion. Intravenous calcium infusions inhibit gastric secretion in the rat, 86, 87 as do parathormone injections, sufficient to induce hypercalcemia. 87 The production of hypercalcemia in rats by means of implanted parathyroid glands is also accompanied by inhibition of gastric secretion in the rat. 88 Gastric secretion in the pigeon 89 is inhibited by calcium administration, and in studies of isolated gastric mucosa of the frog, very high (as well as very low) concentrations of calcium inhibit gastric secretion.90, 91 Hypocalcemia and Gastric Secretion In addition to the various effects of hypercalcemia on gastric secretion, it appears that there are levels of hypocalcemia at which gastric secretion is inhibited or abolished. Babbott et al. 92 described l1 cases of infantile tetany in which there was gastric hyposecretion and in which correction of hypocalcemia was accompanied by a return of normal gastric secretion. Donegan and Spiro,2 in a study of an adult with hypoparathyroidism, demonstrated an absence of acid secretion and diminished pepsin secretion when serum calcium was below 7.0 mg per 100 ml. Correction of hypocalcemia by calcium infusion as well