Antral Gastrin Concentration in Gastric Ulcer Disease

The Finding of High Concentrations in a Few Patients

WILLIAM H U G H E S , GARY VAN D E V E N T E R , MARC SHABOT, and STEVEN B E C K E R

Antral gastrin concentration (AGC) was measured in forceps biopsy specimens of pre- pyloric mucosa obtained at endoscopy in 65 patients with various kinds of gastric ulcer and in 31 nonulcer control patients. AGC in 32 patients with a lesser curvature gastric ulcer, 10.0 +- 2.0 (mean +- 1 SE) ng gastrin/mg tissue was significantly less (P < 0.01) than AGC in 31 nonulcer control patients, 14.4 +_ 1.4. AGC was similar to the control values in 23 patients with a pyloric channel ulcer, 15.2 + 1.7; 5 patients with a greater curvature ulcer, 15.0 +- 4.8; and 3 patients with both duodenal and gastric ulcers, 15.8 +_ 0.7. AGC was significantly greater (P < 0.01) than the control values in 3 patients with a vagotomy and pyloroplasty and a gastric ulcer, 29.8 +_ 5.0. In contrast with most lesser curvature gastric utcer patients who had tow AGC, 3 gastric ulcer patients had antral gastrin values which were about three times the mean AGC of the controls. Two of these patients had fasting serum gastrin values which were more than twice the mean control fasting serum gastrin. Meal-stimulated integrated gastrin responses in these 3 patients ranged from three to nine times the mean control response. These findings suggest that a high AGC may account for a few instances of increased serum gastrin concentrations in gastric ulcer patients.

A few reports have shown that antral gastrin con- centration (AGC) in patients with gastric ulcer is significantly less than AGC in nonulcer control pa- tients (1-3); however , only small numbers of pa- tients with gastric ulcer have been studied. The pur- pose of this study was to measure AGC in a larger number of gastric ulcer patients, to determine AGC in patients with different types of gastric ulcer, to

study the relation between serum and AGC in gas- tric ulcer patients, and to look for a possible relation between AGC and antral mucosa histology iv, gas- tric ulcer patients. In the course of conducting this study, 3 of 32 gastric ulcer patients were discovered who, in contrast with most patients with gastJ ic ul- cer, had markedly elevated antral gastrin concen- trations.

Manuscript received February 19, 1979; revisedmanuscript received January 18, 1980; accepted February 15, 1980.

From the Division of Gastroenterology, Department of Medi- cine and Department of Pathology, University of Texas Medical Branch, Galveston, Texas.

This study was supported in part by Clinical Research Center Grant RR-00093 from the United States Public Health Service, Washington, D.C.

The authors thank Norris Green for technical assistance, Billie Roach for secretarial assistance, and the clinical research center staff for help in the care of the patients. �9

Address requests for reprints to Dr. William S. Hughes, 2550 M St. N.W., Washington, D.C. 20037.

MATERIALS AND METHODS

This investigation was approved by the Human Re- search Committee of the University of Texas M~dical Branch. Informed written consent was obtained from each patient for this study. The technique used t~ mea- sure antral gastrin concentration has been described pre- viously in detail (1). Biopsies were taken during endosco- py (Olympus, New Hyde Park, New York, model GIF- D2) by forceps (Olympus, type FB-2K) biopsy. Or~ each patient three biopsies were obtained from within a 1 esti- mated distance of 5 cm proximal to the pyloric channel

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AGC IN GASTRIC ULCER DISEASE

approximately equidistant from each other around the cir- cumference of the pylorus.

The specimens for gastric assay were weighed wet. Gastrin was extracted by hot saline (100~ for 30 rain). The saline-extracted gastrin was frozen at - 2 0 ~ C until as- say, Gastrin was measured by a double-antibody radioim- munoassay (1). The gastrin antibody in this assay had similar affinity for human big (G-34) and little (G-17) gas- trins. The mean of the three values obtained for antral gastrin concentration in each patient was used for com- parison of the patients. The mean coefficient of variation of the three values in all the patients was 43%.

Antral gastrin concentration was determined in 32 pa- tients with an active gastric ulcer on the lesser curve of the stomach at or near the gastric incisura (referred to in this paper as gastric ulcer patients), 23 patients with an active pyloric channel ulcer, 5 patients with an active gas- tric ulcer on the greater curve, 3 patients with an active gastric ulcer and an active duodenal ulcer, 3 patients with an active gastric ulcer which developed after a vagotomy and pyloroplasty for a duodenal ulcer and 31 control pa- tients who had no abnormal findings on panendoscopy. The sex and age of the gastric ulcer, pyloric channel ul- cer, and control patients were: gastric ulcer-- 17 males, 15 females, mean age 45 years (range 23-70); pyloric channel ulcer--14 males, 9 females, mean age 57 years (range 38- 74); controls--17 males, 14 females, mean age 45 years (range 23-70). The control group had at least one of three complaints which led to endoscopy: (1) abdominal pain, (2) persistent nausea and vomiting, (3) suspicion of upper gastrointestinal bleeding. A history of excessive alcohol intake was obtained in 8 gastric ulcer patients and 6 con- trois. A history of salicylate ingestion was obtained in 5 gastric Ulcer patients and 1 control patient. The gastric ulcer size and position was estimated from the upper gas- rointestinal roentgenogram. The ulcers varied from 0.7 to 3.2 cm in diameter: The ulcer was located in the incisura in 20 patients. The ulcer was located on the lesser curva- ture from 1 to 4 cm proximal to the incisura in 4 patients and from I to 3 cm distal to the incisura in 8 patients.

A standard meat meal and a gastric analysis were given to unselected subgroups of 19 gastric ulcer patients, 9 py- loric channel ulcer patients, 2 patients with a vagotomy and pyloroplasty and a gastric ulcer, and 10 control pa- tients. The subgroups of patients had sex and age distri- butions similar to the whole groups. The meat meal con- sisted of a six-ounce steak, lettuce salad with dressing, two pieces of bread and butter, and 8 ounces of iced tea. Serum gastrin levels were measured on venous blood samples obtained from an indwelling needle in the antecu- bital vein during fasting and 15, 30, 45, 60, 90, and 120 rain after starting the meal. Meal-stimulated gastrin release was calculated as the 2-hr integrated gastrin response ex- pressed in nanograms per minute per milliliter (4). Gastric analysis was done using betazole hydrochioride (Hista- log) 1.5 mg/kg for maximal stimulation.

The two-tailed Student ' s t test and the Pearson's prod- uct-moment correlation test were used routinely in the statistical treatment of the data. The Wilcoxin rank sum test and the Spearman rank correlation test were used in evaluating some of the data on the gastric ulcer patients, as noted in the paper.

Histology of the antral mucosa was studied in l0 gastric ulcer patients and in one patient with a vagotom5 and py- loroplasty and a gastric ulcer. One to three prepyloric for- ceps biopsy specimens obtained at endoscopy w~ re stud- ied in 7 patients. Prepyloric mucosa obtained at surgery for gastric ulcer was available for study in 4 patie ~ts. The endoscopic forceps biopsy specimens were takea at the same time and from the same region as specimens taken for measurement of gastrin concentration. The surgical specimens were taken 6-12 weeks after specimens were taken for measurement of gastrin concentratk,n. The biopsies were fixed in formalin, embedded in paraffin, and serially sectioned. The specimens were stained with he- matoxylin and eosin and Alcian blue at pH 2.5. The slides were examined by a pathologist (S.B.) who had n~, knowl- edge of either the endoscopic appearance of the antral mucosa or the concentration of the anti'al gast)in. The biopsies were graded according to the following criteria: (1) the presence of polymorphonuclear cells: 0 : poty- morphonuclear cells in blood vessels only, I+ : poly- morphonuclear cells in the lamina propria, 2+ = epithe- lial transmigration of polymorphonuclear cells, 3+ = crypt abcesses: (2) the number of mononuclear cells in the mucosa: 1+ = occasional to a moderate number of mononuclear cells, 2+ = an increased number of mono- nuclear cells, 3+ = a markedly increased number of mononuclear cells: (3) pyloric gland atrophy: 0 --: none. 1+ = minimal. 2+ = moderate, 3+ = marked: and (4) intestinal metaplasia: 0 = none, 1 + = minimal or focal. 2+ = moderate or multifocal, 3+ =marked or diffuse.

R E S U L T S

A G C in pa t i en t s with a l e s se r cu rve gastric: u lce r va r i ed w ide ly f rom 0.5 to 44.4 ng gas t r in /mg t i ssue (F igure 1). The mean A G C in gas t r i c u lcer pa t i en t s , 10.0 + 2.0 (mean -+ I sE) ng gas t r in /mg tisst~e was s ignif icant ly less (P < 0.01, by the Wi lcox in r ank sum test) t han the mean A G C in con t ro l pa t i en t s , 14.4 --+ 1.4 ng gas t r in /mg t i ssue . A G C was s i r r i la r to con t ro l va lues in pa t i en t s wi th a py lo r i c chan ~el ul- cer , 15.2 + 1.7 ng gas t r in /mg t i s sue : in pa t i en t s with an u l ce r on the g r e a t e r cu rve , 15.0 + 4.8 ng gas t r in / mg t i ssue ; and in pa t i en t s wi th bo th a gas t r ic and duodena l ulcer , 15.8 - 0.7 ng gas t r i rdmg t i s s u e A G C in pa t ien ts who d e v e l o p e d a gastr ic u lcer af ter a vagot- o m y and p y l o r o p l a s t y for d u o d e n a l u l ce r d i s ea se , 29.8 - 5.0 ng gas t r in /mg t i s sue , was s ignif icant ly g rea t e r (P < 0.01) than the c on t ro l va lues .

The resu l t s o f all s tud ies in the s u b g r o u p s ) f pa- t ients who r e c e i v e d a mea t meal and a gas t r ic ~tnaly- sis a re g iven in Tab le 1. Fa s t i ng s e r u m gastr i~ con- cen t r a t i on and m e a l - s t i m u l a t e d i n t eg ra t ed gas t r in r e s p o n s e were bo th s igni f icant ly g r e a t e r (P < 0.05) in the gas t r ic u lce r pa t i en t s than in the con t ro l pa- t ien ts . M a x i m u m ac id ou tpu t was s ignif icant ly g r e a t e r (P < 0.05) in the py lor ic channe l u lce r pa-

Digestive Diseases and Sciences, Vol. 25, No. 8 (August 1980) 569

50

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(31) C H A N N E L CURVE CURVE ULCER ULCER ULCER (23) (32) (5)

--4:

Q

L f GASTRIC GASTRIC ULCER ULCER AND POST

DUODENAL VAGOTOMY ULCER AND

(3) PYLOROPLASTY (3)

Fig 1. A G C in patients with various types of gastric ulcer and in controls. The vertical bars give the mean --- 1 SEM, A G C in patients with a lesser curve gastric ulcer was significantly less (P <

0.01) than A G C in controls. AGC in patients with vagotomy and pyloroplasty and a gastric ulcer was significntly greater (P < 0.01) than A G C in controls.

HUGHES ET AL

tients than in the controls. In two patients with va- gotomy and pyloroplasty and a gastric ulcer, fasting serum gastrin concentrations were more than twice the mean control value and meal-stimulated in- tegrated gastrin responses were more than eight times the mean control value. Gastric analysis in both patients with vagotomy and pyloroplasty showed retention of food after a 12-hr fast and a low-normal maximum acid output.

The individual gastrin and acid secretion values in the three patients with gastric ulcer and high AGC are given in Table 2. In two patients fasting serum gastrin concentrations were more than twice

the mean control value and in all three patients the meal-stimulated integrated gastrin responses i anged from three to nine times the mean control value. Gastric analysis showed a low basal acid output and a normal maximum acid output in each patient.

Examination of the relation of serum gastrm val- ues to antral gastrin values and acid secretion rates within the patient groups (Table 3) showed t[,at the meal-stimulated integrated gastrin response in gas- tric ulcer patients was significantly related, r = 0.68 (P < 0.01), to AGC (Figure 2). The relation between fasting serum gastrin concentration and AGC in gastric ulcer patients approached but did not reach

TABLE 1. GASI-RIN AND ACID SECRETION VALUES IN GASTRIC ULCER, PYLORIC CHANNEL ULCER, VAGOTOMY AND PYLOROf LASTY AND GASTRIC ULCER, AND CONTROL PATIENTS*

IRG (ng.min/ml

FG (pg/ml) per 120 min) A G C (ng/mg) BAO (rnEq/hr) M A O (mEq/hr)

Gastric ulcer (19) 79 _ l i t 10.1 ~ 0 .6 t 12.7 • 0.7 2.5 • 0.9 19.4 _- 2.6 Pyloric channel ulcer (9) 67 _+ 9 5.9 - 1.5 12.2 • 2.5 3.0 • 1.2 31.9 : 4.6+ Vagotomy and pyloroplasty (2) 127 52.4 30.7 ~ 13,72

and gastric ulcer 207 49.5 38.0 $ I0,75 Nonulcer control (10) 52 --- 9 4,5 • 0.7 14.8 ~ 3.1 1.4 • 0.5 19.3 _-: 3.4

*FG, fasting serum gastrin concentration; IGR, meal-stimulated integrated gastrin response; AGC, antral gastrin concentration; BAO, basal acid output; MAO, maximum acid output.

t V a l u e significantly different from the control value, P < 0.05. CBAO values invalid due to presence of food particles after a 12-hr fast ,

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AGC IN GASTRIC ULCER DISEASE

TABLE 2. GASTRIN AND ACID SECRETION VALUES IN PATIENTS WITH GASTRIC ULCER AND HIGH ANTRAL GASTRIN

CONCENTRATION

IGR FG (ng.min/ml AGC BAO MAO

Patient (pghnl) pet" 120 min) (ng/mg) (mEq/hr) (mEq/hr)

1 74 16.9 42.6 0.78 19,43 2 168 23.8 43.3 0.03 12.53 3 114 44.4 38.4 0.45 16.86

statistical significance, r = 0.41 (P < 0.10). Serum gastrin values were not significantly related to AGC in the smaller groups of pyloric channel ulcer pa- tients and controls. Serum gastrin values were not significantly related to either basal or maximum acid output in any of the patient groups.

Findings on the histology of the antral mucosa in the gastric ulcer patients ranged from moderate in- filtration of the lamina propria With chro~ic inflam- matory cells (Figure 3a) to marked antral mucosal atrophy and intestinal metaplasia (Figure 3b). When the findings on the histology of the antral mucosa in the gastric ulcer patients were stratified on the basis of AGC (Table 4), low concentrations in the gastric ulcer patients appeared to be closely associated with atrophy of the antral mucosa and intestinal metaplasia. On the other hand, the 5 gastric ulcer patients with the highest antral gastrin concentra- tions, ranging from 7.0 to 38.4 ng/mg (patients 6-I0, Table 4), had only minimal to moderate atrophy and intestinal metaplasia of the antral mucosa. The one patient (patient 11) with a vagotomy and pyloro- plasty and a gastric ulcer who had a high AGC had only minimal atrophy of the antral mucosa.

DISCUSSION

This study showed that mean AGC in gastric ul- cer patients is significantly less than mean AGC in nonulcer controls. This observation is in agreement with findings in three previous studies (1-3). How-

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ANTRAL GASTRIN CONCENTRATION ng/m 9

Fig 2. The relation of 2-hr meal-s t imulated integrated gastrin re- sponse in gastric ulcer patients to AGC. The Pearson ' s correla- tion coefficient for this relation was 0.68 (P < 0.01) and the Spearman ' s rank correlat ion coefficient was 0.54 (P < 0.02).

ever, in contrast with earlier observations a few gastric ulcer patients were found to have a high AGC. Mean antral gastrin values in patients with pyloric channel ulcers, greater curvature ulcers, and both gastric and duodenal ulcers were similar to the mean control value. The similarity among antral gastrin values associated with these ulcers and con- trol AGC supports the concept that these ulcers have a different pathogenesis than the lesser curva- ture gastric ulcer. The finding of high AGC i ~ three patients with a vagotomy and pyloroplasty and a gastric ulcer is similar to our previously reported finding of high AGC in patients with a vagotomy and pyloroplasty and no gastric ulcer (5).

In a previous study we reported that fasting serum gastrin concentration and meal-stimulated in-

TABLE 3. CORRELATION COEFFICIENTS FOR RELATION OF SERUM GASTRIN VALUES TO ANTRAL GASTRIN CONCENTRATION A'.D ACID SECRETION RATES IN GASTRIC ULCER, PYLORIC CHANNEL ULCER. AND CONTROL PATIENTS

Antral gastrin concentration* Basal acid output Maximum acid ou put

GU PU C GU PU C GU PU C

Fast ing serum gastrin concent ra t ion 0.41b? - 0 . 2 8 -0 .07 - 0 . 0 8 - 0 . I 1 - 0 . 4 0 - 0 . 0 7 - 0 . 1 8 0.46

Integrated gastrin response 0.68a 0.55b 0.26 - 0 . 2 0 - 0 . 2 7 - 0 . 0 7 -0 .02 -0 .62b 0.06

*GU, gastric ulcer pat ients (19); PU, pyloric channel ulcer patients (9): C, nonulcer control pat ients (10). t a = P < 0 . 0 1 ; b = P < 0 . 1 0 .

Digestive Diseases and Sciences, Vol: 25, No. 8 (August 1980) 5 7 1

H U G H E S ET A L

Fig 3a. Antral mucosal biopsy from a gastric ulcer patient with an AGC of 38.4 ng/mg showing a moderate number of mononuclear cells in the lamina propria. There is no epithelial transmigration of polymorphonuclear cells and the pyloric glands appear normal.

tegrated gastrin response were directly related to AGC in a large heterogeneous group of patients (1), Even though patients with gastric ulcer have high fasting (6-10) and postprandial serum ga~trin values (7) and low antral gastrin values (1-3), this study shows that within a group of gastric ulcer patients meal-stimulated integrated gastrin response and, possibly, fasting serum gastrin concentration as well are directly related to AGC. This relation does not explain why fasting and postprandial serum gas- trin values are higher than normal in most gastric ulcer patients who have low or normal antral gastrin values; however, a high AGC may account for high fasting and postprandial serum gastrin concentra- tions in a few patients with gastric ulcer.

The findings on serum gastrin values and acid se- cretion rates suggest that fasting and meal-stimulat, ed serum gastrin concentrations are not related to

acid secretion rates in gastric ulcer patients. The lack of a relation between fasting serum gastrJn val- ues and acid secretion rates in this study is in agree- ment with findings in two previous studies (9, 10), but it differs from the observation by McGuigan that the fasting serum gastrin value in gastric ulcer pa- tients is inversely related to the maximum acid se- cretion rate (6).

The histologic findings in this study indicat ~ that low AGC in gastric ulcer patients is associatec with atrophy of the antral mucosa, although it is net cor- related with inflammatory cell infiltration. Fhese observations complement findings by Stave and coworkers of low numbers of antral gastrin-cells (G cells) in gastric ulcer patients with antral mucosal atrophy (11). Stave also found no correlation be- tween G cell numbers and inflammatory cell infil- tration. Consideration of the findings in beth of

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A G C I N G A S T R I C U L C E R D I S E A S E

Fig 3b. Antral mucosal biopsy from a gastric ulcer patient with an AGC of 0.5 ng/mg, showing diffuse a t rophy and intestinal metaplasia (H&E, x 125).

TABLE 4. ANTRAL GASTRIN CONCENTRATION AND GRADING OF ANTRAL HISTOLOGY IN GASTRIC ULCER PATIENTS

Patient

Antral gastrin Acute inflammation Chronic inflammation concentration polymorphonuclear cells mononuclear cells Atrophy

Age Sex (ng/mg) (Oto3+) (I to3+) (Oto3+) §

In testinal m~ taplasia (0 to 3 +)

1", * 61 M 0.5 + + § 2* 47 M 4.3 0 + + + + + 3* 73 M 4.4 + + + + 4* 44 M 4.8 0 + + + + + + 5* 51 F 6.0 + + + + + 6* 73 M 7.0 + + + + + + + 7* 54 F 7,5 + + + + 8* 22 F 11.1 + + * 9* 54 F 13.7 0 + + +

10", w 51 F 38.4 + + 0 1 t*, '~ 59 F 38.0 + + +

+ + + + + +

O + + + + + + + + + + + + + + :)

*Tissue for histology obtained by endoscopic forceps biopsy. * T issue for histology obtained by surgical partial gastric resection. * Antral histology given in Figure 3b. w Antral histology given in Figure 3a. ~1Postvagotomy and pyloroplasty patient.

Digestive Diseases and Sciences, Vol. 25, No. 8 (August 1980) 573

HUGHESEFAL

these studies suggests that low AGC in patients with gastric ulcer is due at least in part to a de- creased number of antral G cells resulting from at- rophy of the antral mucosa.

High AGC was found in only 9% of the gastric ulcer patients, therefore it is not surprising that ear- lier studies of AGC in small numbers of gastric ulcer patients have not revealed this condition. In this study the association of high AGC with only mini- mal antral mucosal atrophy suggests that an ab- sence of severe chronic antral gastritis may be a prerequisite tot the presence of high AGC. In an extensive histologic study of stomachs in patients with gastric ulcer, Duplessis found only 4 of 61 pa- tients who did not have severe chronic antral gastri- tis (12).

The cause of the high AGC found in three gastric ulcer patients is unknown. In previous studies we have found high antral gastrin concentrations in two clinical situations: (1) in patients who had hypo- or achlorhydria on maximum histalog stimulation (13) and (2) in patients who had a vagotomy and pyloro- plasty (5). Since the three gastric ulcer patients who had high antral gastrin concentrations in this study had normal acid secretion rates on maximum hista- log stimulation, decreased maximum acid secretion rates do not appear to account for the increased AGC. On the other hand, it is tempting to speculate that decreased vagal activity may account for in- creased AGC in some patients with gastric ulcer. All three patients with high AGC had low basal acid secretion rates consistent with decreased vagal ac- tivity. Furthermore, the findings in the gastric ulcer patients with a high AGC were similar in several ways to the findings in patients who developed a gastric ulcer after having had a vagotomy and py- loroplasty. Both groups of patients showed high an- tral and post-prandial serum gastrin concentrations, two patients in each group had fasting serum gastrin levels more than twice the mean control value, and histology on the antral mucosa of one patient in each group showed an absence of severe chronic antral gastritis. The similarity between the two groups was not complete as the two post-vagotomy gastric ulcer patients who were studied with gastric

analysis had retained gastric contents af:er a twelve-hour fast, whereas the three gastric ulcer pa- tients with high AGC did not. However, gastric re- tention probably does not account for the high an- tral and serum gastrin values in patients with ~ agot- omy and pyloroplas ty and gastric ulcer since patients with vagotomy and pyloroplasty who show no retention of food after a 12-hr fast also have high values for antral and serum gastrin concentrations (5).

REFERENCES

1. Hughes WS, Snyder N, Hernandez A: Antral gastriq con- centration in upper gastrointestinal disease. Am J Dig Dis 22:201-208, 1977

2. Malmstrom J, Stadil F: Measurement of immunort active gastrin in gastric mucosa. Scand J Gastroenterol 10:433-439, 1975

3. Emas S, Borg I, Fyro B: Antral and duodenal gastrin activity in non-ulcer and ulcer patients. Scand J Gastroentero 6:39- 43, 1971

4. Richardson CT, Walsh JH, Hicks MI, Fordtran JS: Studies on the mechanisms of food-stimulated gastric acid set retion in normal human subjects. J Clin Invest 58:623-631, 976

5. Hughes WS, Hernandez A J: Antral gastrin concentra:ion in patients with vagotomy and pyloroplasty. Gastroenterology 71:720-722, 1976

6. Trudeau WL, McGuigan JE: Relations between serum gas- trin levels and rates of gastric hydrochloric acid secretion. N Engl J Med 28~,(8):408-4t2, 1971

7. Korman MG, Soveny C, Hansky J: Gastrin studies in gastric ulcer. Gut 13:166-169. 1972

8. Ganguli PC, Hunter WM: Radioimmunoassay of gastrin in human plasma. J Physiol (London) 220:499-510, 1972

9. Gedde-Dahl D: Radioimmunoassay ofgastrin. Fasting serum levels in humans with normal and high gastric acid sec~ etion. Scand J Gastroenterol 9:41-47, 1974

10. Wesdorp RIC, Fischer JE: Plasma gastrin and acid set retion in patients with peptic ulceration. Lancet 2:857-860, 1974

11. Stave R, Elgjo K, Brandtzaeg P: Quantification of g tstrin- producing cells (G cells) and parietal cells in relation to his- topathological alterations in resected stomachs from p itients with peptic ulcer disease. Scand J Gastroenterol 13:747-757, 1978

12. Duplessis DJ: Pathogenesis of gastric ulceration. Lancet 1:974-978, 1965

13. Hughes WS, Wharton E: The interrelations of gast:in re- lease, antral gastrin concentration, and acid secretio~ rate. Digestion 17:151-158, 1978

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