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Gastric Secretion in Duodenal Ulcer, with Particular Reference to the Diagnosis of Zollinger-Ellison Syndrome
Vol. 58, No.4 Printed in U.S.A..
GASTROENTEROLOGY
Copyright @ 1970 by The Williams & Wilkins Co.
GASTRIC SECRETION IN DUODENAL ULCER, WITH PARTICULAR REFERENCE TO THE DIAGNOSIS OF ZOLLINGER-ELLISON SYNDROME MICHAEL D. KAYE, B.M., JOHN RHODES, M.D., AND PETER BECK, M.B.
The Medical Unit, Royal Infirmary, Cardiff, Wales
Basal and maximal acid secretion were measured in 90 patients with duodenal ulcer. The results were analyzed in respect to three criteria now used in the diagnosis of Zollinger-Ellison syndrome. A basal acid output > 15 mEq per hr, a ratio of basal to stimulated acid output >0.6, and a ratio of basal to stimulated acid concentration >0.6 were found, respectively, in approximately 10, 2, and 12 % of the patients. Because of the overlap between subjects with duodenal ulcer and those with islet cell tumor, no one of these criteria is entirely reliable in the differentiation of these two disorders. The syndrome of peptic ulcer, gastric acid hypersecretion, and non-,B islet cell tumor of the pancreas, first was described by Zollinger and Ellison in 1955.1 Further facets of the syndrome which may assist in diagnosis since have become apparent. Watery diarrhea, frequently associated with hypokalemia and sometimes with steatorrhea, occurs in one-third of the patients and associated endocrine disease in about one-fifth. In 26% ulcers are found at unusual sites and in 10% they are multiple. 2 These features, separately or combined, may point to the diagnosis; in many patients, however, the differential diagnosis between duodenal ulcer and ZollingerEllison syndrome remains difficult. Various criteria, based upon measurement of gastric acid secretion, are said to be useful. Prominent among these are an hourly basal acid output greater than 15 mEq,3 a basal output more than 60% of maximal output,4 and a 12-hr nocturnal secretion exceeding 1000 ml or 100 mEq.1 These criteria may give false negative results in Zollinger-Ellison syndrome and ocReceived August 7, 1969. Accepted October 20, 1969. Address requests for reprints to: Dr. M. D. Kaye, Division of Gastroenterology, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220.
casional false positive results in uncomplicated duodenal ulcer. Recently it was reported that the ratio of basal acid concentration to maximal acid concentration (after stimulation with histamine) was greater than 0.6 in 5 patients with Zollinger-Ellison syndrome, but less than 0.6 in 300 patients with other diagnoses, including 48 with duodenal ulcer.5 It appeared from this report that this criterion might be of considerable value in the diagnosis of Zollinger-Ellison syndrome. We have analyzed the data on gastric acid secretion from 90 patients with duodenal ulcer with particular reference to this and other secretory criteria currently used to aid diagnosis of the ZollingerEllison syndrome. Methods Patients. Ninety male subjects, ranging in age from 20 to 65 years, were studied. For each, a barium meal had been interpreted independently by two radiologists as showing an ulcerated and/or deformed duodenal bulb, in the absence of gastric ulcer, hiatus hernia, or other upper gastrointestinal abnormality. They were consecutive patients selected for inclusion in a clinical trial designed to evaluate long term anticholinergic therapy. All had had symptoms compatible with peptic ulceration during the 6 months prior to the study. None had had gastric surgery, with the exception of 1 subject who
476
April 1970
GASTRIC SECRETION IN DUODENAL ULCER
had undergone simple suture of a perforated duodenal ulcer. There was no clinical or radiological evidence of gastric outlet obstruction in any patient. Measurement 0/ gastric acid secretion. Basal and maximal acid secretion were measured twice in each patient, at an interval of 1 year. Patients received no treatment for 7 days before each test. Patients fasted for at least 12 hr before tests. Gastric juice was collected by the method of Lawrie and co-workers." A nasogastric tube (Ryle-Levin, size 14, Fr, Bardic) was passed and the resting juice was aspirated. Throughout the test, gastric juice was collected by continuous suction with the patient recumbent on his left side. Patency of the tube was ensured by intermittent release of suction and injection of air. Basal secretion was collected for 30 min . A constant rate intravenous infusion of pentagastrin (6 j.tg per kg per hr) then was begun and was continued for 75 min, with aspiration of gastric juice in five 15-min samples. Collections were considered to be satisfactory, since in all tests there was an acceptably close correspondence between the volumes of successive samples. Acidity was measured by titration, with 0.1 N NaOH, to pH 7 in an automatic titrimeter (type TITI Radiometer, Copenhagen). The maximal rate of secretion was detem-,ined from the last three or four samples, depending upon when the plateau was reached . In 11 of 22 patients whose basal acid output exceeded 15 mEq per hr or whose ratio of basal to stimulated acid concentration was greater than 0.6, a third estimate of basal acid output was obtained by collection of basal secretion for 1 hr.
Results
This study provides information on three of the criteria used in the diagnosis of Zollinger-Ellison syndrome, namely, basal acid output (BAO), the ratio of basal to maximal acid output (BAO/ MAO), and the ratio of basal to stimulated acid concentration (BAC/MAC) . These values, together with maximal acid output, are shown in figures 1 and 2. Basal acid output, means 6.24 ± 6.54 and 7.75 ± 5.66 mEq per hr for first and second tests, respectively, exceeded 15 mEq per hr in 17 patients, but in only 2 on both occasions.
477
(BAO/ MAO), means 0.15 ± 0.13 and 0.20 ± 0.14 for first and second tests, respectively, was greater than 0.6 in 3 pa-
tients on one occasion. (BAC/ MAC), means, 0.37 ± 0.21 and 0.42 ± 0.19 for first and second tests, respectively, was greater than 0.6 in 16 patients. In 8 of these, values above this level were found in both tests. In some of the 16 patients whose concentration ratio exceeded 0.6, and of the 6 patients whose ratio was less than 0.6 but whose BAO was greater than 15 mEq per hr, a third collection of basal secretion was made. The results of these tests, together with relevant clinical data, are shown in table 1. The degree of overlap between the various criteria is indicated in table 2. BAO was greater than 15 mEq per hr in 50% of tests in which (BAC/ MAC) exceeded 0.6. Similarly, (BAC/MAC) exceeded 0.6 in 60% of tests in which BAO was greater than 15 mEq per hr. On the three occasions when (BAO/ MAO) exceeded 0 .6, criteria based upon BAO and the (BAC/ MAC) ratio also were positive. Discussion
The majority of peptic ulcers associated with Zollinger-Ellison syndrome are situated in the first part of the duodenum. It often is difficult to exclude the possibility that an ulcer in this site may be associated with a pancreatic non-f3 islet cell tumor. Patients with such a tumor may have an exceptionally high maximal acid output, but usually this measurement falls within the range of that associated with uncomplicated duodenal ulcer. The isolation of a gastrin-like substance from one of these tumors first was reported in 1960.7 Ellison and Wilson, reviewing the subject in 1964,2 reported that material with gastrin-like activity had been extracted in 17 out of 26 cases. It has been proposed that the continuous and autonomous production of this gastrin-like substance results in persistent basal hypersecretion. As a consequence of this, the increase in secretion which follows the administration of a maximal stimulus such as
478
Vol. 58, No . .4
KAYE ET AL .
Ratio TEST 1. o
ME.q./hr. <30
o
•
o
"3
••
•••
o
1
•
•
M.AA
.... 0
as -----wIi>cu - - - - - -
fa
LA.o.
, 1
.:q:
....J .1 I
iH:a: .::= -
FIG. 1. Individual measurements of maximal acid output (M.A.O.), basal acid output (B .AD.), r at io of basal to maximal output (B.A.O. I M.A.O.), and rati o of basal t o stimulated concentration (B.A .Cone.IM .A .Cone.). First test. e, patients in whom the ratio of basal t o stimulated concentration was less than 0. 6 in both tests. 0, patients in whom concentration ratio was greater than 0.6 in first test. 0 , patients in whom concentrat ion ratio was greater than 0.6 in second test .
histamine is ess l than normal. This proposal leads logically to the expectation that measurements of basal secretion or of the ratio of basal to stimulated acid output should differentiate between patients with Zollinger-Ellison syndrome and those with duodenal ulcer. Experience, however, has fallen short of expectation. Aoyagi and SummerskilP found that I-hI' basal secretion was less than 15 mEq in 10 of 31 patients with Zollinger-Ellison syndrome. This arbitrary level was exceeded in only 3% of patients with duodenal ulcer. Our own results, which are based upon 30-min collections of basal secretion in 90 patients, suggest that about 10% of patients with duodenal ulcer
have a basal secretion greater than 15 mEq per hr. However, in only 2 patients was the value greater than 15 mEq per hr on repeat testing. In the 15 patients with a basal output greater than 15 mEq per hI' on only one occasion, the basal output from the other test was usually high and, in 8 of the 15, more than 10 mEq per hrthat is to say, within the range considered by Aoy agi and Summerskill to be suggestive of Zollinger-Ellison syndrome. Although a persistently marked elevation of basal secretion is more strongly indicative of the latter diagnosis than intermittently high values, there is evidence that basal secretion is variable also in patients with islet cell tumor. s, 9
April 1970
479
GASTRIC SECRETION IN DUODENAL ULCER
Ratio .A)
TEST 2.
·8
MEq./hr.
.:
00 000
•
0
_____________ "8 _ ___
..,.
3~
i
••
•
:lao
J
J • • • 0
M.AD.
1
~ oc
••
----~----
t
LA.o.
•
..:;....
..-.. 1 .... if•
, t "
-alii"
M:A:a
-3
..
·2
I
·1
_..
...a.. LA.o.
·5
0:r
c8
"
-6
.Ie
• •
.II!ID
+
·7
0
0
0
I.A.Conc M.Aoconc
FIG. 2. Individual measurements 1 yr later.
The ratio of basal to stimulated acid output is likewise somewhat unreliable. Twenty per cent or more of patients with islet cell tumor have a ratio less than 0.6, while a ratio greater than 0.6 occasionally is found under other circumstances. 5 Our figures also show that this ratio is exceeded occasionally in patients with duodenal ulcer. It has been argued 3 that, since values for maximal acid output are similar in islet cell tumor and duodenal ulcer, the measurement of the ratio of basal to maximal acid output offers no advantage over basal output alone. However, the values quoted from the literature by Ruppert et aP suggest that false negative results in patients with islet cell tumor are no more likely to occur in respect of the ratio of basal to stimulated output than of absolute basal secretion. Our results indicate that more false positive results will be found in
duodenal ulcer if reliance is placed upon basal secretion alone. Ruppert et al. 5 reported a ratio of basal to stimulated acid concentration greater than 0.6 in all of 5 patients with islet cell tumor and in 4 others reported in the literature. This ratio was less than 0.6 in 300 patients with other diagnoses, including 48 with duodenal ulcer. They mention 3 patients with duodenal ulcer and gastric outlet obstruction in whom a ratio of >0.6 fell to <0.5 after a few days of antacid therapy. Such a diagnostic criterion, with no false negative results and occasional but transient false positive results, would appear to approach the ideal. However, a recent report by Winship 9 underlines the fallibility of this criterion. Basal and histamine-stimulated secretion were measured in 840 patients, of whom 89 were normal, 371 had a duodenal ulcer, 224 had a gastric
480
KAYE ET AL.
Vol . 58, No.4
1. Clinical features and values for acid secretion in patients whose ratio of basal La stimulated concentration exceeded 0.6 (patients 1 to 16) and in patients with a ratio of less than 0.6 whose basal secretion exceeded 15 mEq per hr (patients 17 to 22)
TABLE
Patient Age no.
---
:IT
Duration Severity of of symp- symptomsa toms
complications Test 1 ITest
--
"3
Basal acid output
Previous
21
Maximal acid output
Test 3 Test 1 ITest
mEg/ii,
mEg/ hr
2
(BAC/ MAC)
(BAO/MAO)
ratio
ratio
Test 1
Test
2
Test 1 Test 2
---- -- --
65 0.33 0.24 0.67 0 .62 + 23 10 37 47 0.62 0.22 0 .83 0.68 + 0 .77 13 62 44 28 58 0.70 0.48 0.8 3h +++ 31 0 . 14 0.20 0.42 0.61 36 6 5 4 ++ 48 0.28 0.15 0 .66 0.44 13 7 47 5 ++ 22 11 18 53 53 0.21 0.33 0 .74 0 .65 6 ++ Bleeding 10 48 43 0.31 0.24 0.72 0 .63 15 7 + 25 0.08 0.66 0.39 0.69 25 8b + Bleeding (twice) 2 16 5 29 0.35 0.32 0.74 0.58 10 9 29 9 + Bleeding lOb 42 12 11 0.28 0.45 0.57 0.83 5 +++ Bleeding 13 18 51 40 0.26 0.45 0.67 0.68 11 ++ 31 0.22 0.22 0 .53 0.67 37 7 12 8 7 + 12 51 61 0.36 0.20 0.54 0 .68 18 13 ++ 15 13 52 52 0.31 0.28 0.62 0 .69 16 14 + Bleeding 52 21 9 53 0.40 0.18 0.58 0 .63 15 + Perforation 12 52 8 18 37 0.35 0 .32 0.62 0 .61 16 + 19 17 11 15 56 55 0 . 19 0.27 0.45 0.57 ++ 13 22 47 49 0.06 0.44 0.33 0.47 3 18 + Bleeding 17 19 67 0.11 0.25 0.40 0 .57 8 68 19 +++ 24 52 2 22 20 38 0.03 0.58 0.15 0.58 + 16 25 28 0.28 0.57 0.52 0.58 21 7 + Bleeding 34 45 0.24 0.34 0.43 0 .56 22 15 8 ++ a +, ++, and +++ indicate respectively that symptoms were mild, moderate, or severe during the 1 2
39 44 35 57 28 36 59 37 49 44 55 41 23 41 58 56 45 53 52 30 32 21
Bleeding
18
15
17
54
2 10 20 8 7 40 1 6 21 7 13 4 2 1 3 5 20 12 2 11 1.5
year of observation. b Patient in whom vagotomy and pyloroplasty were carried out. No pancreatic abnormality was noted at. operation.
ulcer, 5 had Zollinger-Ellison syndrome, and 151 had other disorders. The (BAC/ MAC) ratio was greater than 0.6 in 6 norb Criterion No. of tests mal subjects (7%), in 4 patients with gastric ulcer (2%), and in 18 patients with (BAC/MAC) only ........... ... . 12 (7) duodenal ulcer (5% ). The criterion was BAO only ....... .......... .. . . . ... . . 8 (4) negative in 2 of 7 tests in patients with (BAO/MAO) only .......... . .... ... . o (0) Zollinger-Ellison syndrome. Our results in (BAC/ MAC) + BAO ......... ..... . 9 (5) 3 (2) (BAC/ MAC) + (BAO/ MAO) + BAO. patients with duodenal ulcer are similar. A 148 (82) All criteria negative. ratio greater than 0.6 was found in 9% on two occasions, and in a further 9% on one Total. . . . . . . . . . . . . . . . . . . .... . 180 . . . (100) . . . . of two occasions. More false positive results occurred with this than with either of a (BAC/MAC) > 0.6, (BAO/ MAO) > 0.6, and the other two criteria which we were able BAO > 15 mEq per hr. to examine. We conclude, therefore, that b Ninety patients with two tests in each patient. Figures in parentheses are percentages. while a ratio of <0.6 may render the diag2. The relationship between the three criteria for diagnosis of Zollinger-Ellison syndromea
TABLE
April 1970
GASTRIC SECRETION IN DUODENAL ULCER
nosis of islet cell tumor unlikely, a ratio >0.6 should be interpreted with considerable caution. Winship's results suggest that the diagnosis of Zollinger-Ellison syndrome is rendered more likely if two ' or more of the three criteria (BAO, (BAO/ MAO), and (BAC/MAC)) are positive. Again, however, our findings are discouraging, for two or more criteria were positive in 12 (7%) of the 180 tests. It may be argued that the diagnosis of islet cell tumor has not been excluded entirely in those of our patients whose ratio of basal to stimulated acid concentration exceeded 0.6. However, in none was there other suggestive evidence such as diarrhea, endocrine disease, recurrent complications, or a particularly fulminant course. In 3 patients whose symptoms were sufficiently severe and unresponsive to medical therapy to warrant surgery, laparotomy revealed no evidence of pancreatic tumor. Their uncomplicated progress after vagotomy and pyloroplasty makes the diagnosis of islet cell tumor improbable. REFERENCES 1. Zollinger, R. M., and E. H. Ellison. 1955. Primary peptic ulcerations of the jejunum, associated with islet cell tumor of the pancreas. Ann. Surg. 14~: 709-728. 2. Ellison, E. H., and S. D. Wilson. 1964. The
481
Zollinger-Ellison syndrome; reappraisal and evaluation of 2'60 registered cases. Ann. Surg. 160: 512-528. 3. Aoyagi, T., and W. H. J. Summerskill. 1966.
Gastric secretion with ulcerogenic islet cell tumor. Arch. Intern. Med. (Chicago) 117: 667-672.
4. Marks, 1. N., G. Selzer, J. H. Louw, and S. Bank. 1961. Zollinger-Ellison syndrome in a Bantu woman, with isolation of a gastrin-like substance from the primary and secondary tumors. 1. Case Report. Gastroenterology 41: 77-86. 5. Ruppert, R. D., N. J. Greenberger, F. M. Beman, and F. M . McCullough, 1967. Gastric secretion in ulcerogenic tumors of the pancreas . Ann. Intern. M ed. 67: 808--815. 6. Lawrie, J. H., G. M. R. Smith, and A. P . M. Forrest. 1964. The histamine-infusion test. Lancet 2: 270-273. 7. Gregory, R. A., H . J. Tracy, J. M. French and W. Sircus. 1960. Extraction of a gastrinlike substance from a pancreatic tumor in a case of Zollinger-Ellison syndrome. Lancet 1: 1045-1048.
8. Winship, D. H., and E. H. Ellison. 1967. Variability of gastric secretion in patients with and without the Zollinger-Ellison syndrome. Lancet 1: 1128--1130. 9. Winship, D. H. 1969. Problems in the diagnosis of Zollinger-Ellison syndrome by analysis of gastric secretion. In L. Demling and R. Ottenjann [eds.], Non-insulin-producing tumors of the pancreas. Georg Thieme Verlag, KG ., Stuttgart.
GASTROENTEROLOGY
Copyright @ 1970 by The Williams & Wilkins Co.
GASTRIC SECRETION IN DUODENAL ULCER, WITH PARTICULAR REFERENCE TO THE DIAGNOSIS OF ZOLLINGER-ELLISON SYNDROME MICHAEL D. KAYE, B.M., JOHN RHODES, M.D., AND PETER BECK, M.B.
The Medical Unit, Royal Infirmary, Cardiff, Wales
Basal and maximal acid secretion were measured in 90 patients with duodenal ulcer. The results were analyzed in respect to three criteria now used in the diagnosis of Zollinger-Ellison syndrome. A basal acid output > 15 mEq per hr, a ratio of basal to stimulated acid output >0.6, and a ratio of basal to stimulated acid concentration >0.6 were found, respectively, in approximately 10, 2, and 12 % of the patients. Because of the overlap between subjects with duodenal ulcer and those with islet cell tumor, no one of these criteria is entirely reliable in the differentiation of these two disorders. The syndrome of peptic ulcer, gastric acid hypersecretion, and non-,B islet cell tumor of the pancreas, first was described by Zollinger and Ellison in 1955.1 Further facets of the syndrome which may assist in diagnosis since have become apparent. Watery diarrhea, frequently associated with hypokalemia and sometimes with steatorrhea, occurs in one-third of the patients and associated endocrine disease in about one-fifth. In 26% ulcers are found at unusual sites and in 10% they are multiple. 2 These features, separately or combined, may point to the diagnosis; in many patients, however, the differential diagnosis between duodenal ulcer and ZollingerEllison syndrome remains difficult. Various criteria, based upon measurement of gastric acid secretion, are said to be useful. Prominent among these are an hourly basal acid output greater than 15 mEq,3 a basal output more than 60% of maximal output,4 and a 12-hr nocturnal secretion exceeding 1000 ml or 100 mEq.1 These criteria may give false negative results in Zollinger-Ellison syndrome and ocReceived August 7, 1969. Accepted October 20, 1969. Address requests for reprints to: Dr. M. D. Kaye, Division of Gastroenterology, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220.
casional false positive results in uncomplicated duodenal ulcer. Recently it was reported that the ratio of basal acid concentration to maximal acid concentration (after stimulation with histamine) was greater than 0.6 in 5 patients with Zollinger-Ellison syndrome, but less than 0.6 in 300 patients with other diagnoses, including 48 with duodenal ulcer.5 It appeared from this report that this criterion might be of considerable value in the diagnosis of Zollinger-Ellison syndrome. We have analyzed the data on gastric acid secretion from 90 patients with duodenal ulcer with particular reference to this and other secretory criteria currently used to aid diagnosis of the ZollingerEllison syndrome. Methods Patients. Ninety male subjects, ranging in age from 20 to 65 years, were studied. For each, a barium meal had been interpreted independently by two radiologists as showing an ulcerated and/or deformed duodenal bulb, in the absence of gastric ulcer, hiatus hernia, or other upper gastrointestinal abnormality. They were consecutive patients selected for inclusion in a clinical trial designed to evaluate long term anticholinergic therapy. All had had symptoms compatible with peptic ulceration during the 6 months prior to the study. None had had gastric surgery, with the exception of 1 subject who
476
April 1970
GASTRIC SECRETION IN DUODENAL ULCER
had undergone simple suture of a perforated duodenal ulcer. There was no clinical or radiological evidence of gastric outlet obstruction in any patient. Measurement 0/ gastric acid secretion. Basal and maximal acid secretion were measured twice in each patient, at an interval of 1 year. Patients received no treatment for 7 days before each test. Patients fasted for at least 12 hr before tests. Gastric juice was collected by the method of Lawrie and co-workers." A nasogastric tube (Ryle-Levin, size 14, Fr, Bardic) was passed and the resting juice was aspirated. Throughout the test, gastric juice was collected by continuous suction with the patient recumbent on his left side. Patency of the tube was ensured by intermittent release of suction and injection of air. Basal secretion was collected for 30 min . A constant rate intravenous infusion of pentagastrin (6 j.tg per kg per hr) then was begun and was continued for 75 min, with aspiration of gastric juice in five 15-min samples. Collections were considered to be satisfactory, since in all tests there was an acceptably close correspondence between the volumes of successive samples. Acidity was measured by titration, with 0.1 N NaOH, to pH 7 in an automatic titrimeter (type TITI Radiometer, Copenhagen). The maximal rate of secretion was detem-,ined from the last three or four samples, depending upon when the plateau was reached . In 11 of 22 patients whose basal acid output exceeded 15 mEq per hr or whose ratio of basal to stimulated acid concentration was greater than 0.6, a third estimate of basal acid output was obtained by collection of basal secretion for 1 hr.
Results
This study provides information on three of the criteria used in the diagnosis of Zollinger-Ellison syndrome, namely, basal acid output (BAO), the ratio of basal to maximal acid output (BAO/ MAO), and the ratio of basal to stimulated acid concentration (BAC/MAC) . These values, together with maximal acid output, are shown in figures 1 and 2. Basal acid output, means 6.24 ± 6.54 and 7.75 ± 5.66 mEq per hr for first and second tests, respectively, exceeded 15 mEq per hr in 17 patients, but in only 2 on both occasions.
477
(BAO/ MAO), means 0.15 ± 0.13 and 0.20 ± 0.14 for first and second tests, respectively, was greater than 0.6 in 3 pa-
tients on one occasion. (BAC/ MAC), means, 0.37 ± 0.21 and 0.42 ± 0.19 for first and second tests, respectively, was greater than 0.6 in 16 patients. In 8 of these, values above this level were found in both tests. In some of the 16 patients whose concentration ratio exceeded 0.6, and of the 6 patients whose ratio was less than 0.6 but whose BAO was greater than 15 mEq per hr, a third collection of basal secretion was made. The results of these tests, together with relevant clinical data, are shown in table 1. The degree of overlap between the various criteria is indicated in table 2. BAO was greater than 15 mEq per hr in 50% of tests in which (BAC/ MAC) exceeded 0.6. Similarly, (BAC/MAC) exceeded 0.6 in 60% of tests in which BAO was greater than 15 mEq per hr. On the three occasions when (BAO/ MAO) exceeded 0 .6, criteria based upon BAO and the (BAC/ MAC) ratio also were positive. Discussion
The majority of peptic ulcers associated with Zollinger-Ellison syndrome are situated in the first part of the duodenum. It often is difficult to exclude the possibility that an ulcer in this site may be associated with a pancreatic non-f3 islet cell tumor. Patients with such a tumor may have an exceptionally high maximal acid output, but usually this measurement falls within the range of that associated with uncomplicated duodenal ulcer. The isolation of a gastrin-like substance from one of these tumors first was reported in 1960.7 Ellison and Wilson, reviewing the subject in 1964,2 reported that material with gastrin-like activity had been extracted in 17 out of 26 cases. It has been proposed that the continuous and autonomous production of this gastrin-like substance results in persistent basal hypersecretion. As a consequence of this, the increase in secretion which follows the administration of a maximal stimulus such as
478
Vol. 58, No . .4
KAYE ET AL .
Ratio TEST 1. o
ME.q./hr. <30
o
•
o
"3
••
•••
o
1
•
•
M.AA
.... 0
as -----wIi>cu - - - - - -
fa
LA.o.
, 1
.:q:
....J .1 I
iH:a: .::= -
FIG. 1. Individual measurements of maximal acid output (M.A.O.), basal acid output (B .AD.), r at io of basal to maximal output (B.A.O. I M.A.O.), and rati o of basal t o stimulated concentration (B.A .Cone.IM .A .Cone.). First test. e, patients in whom the ratio of basal t o stimulated concentration was less than 0. 6 in both tests. 0, patients in whom concentration ratio was greater than 0.6 in first test. 0 , patients in whom concentrat ion ratio was greater than 0.6 in second test .
histamine is ess l than normal. This proposal leads logically to the expectation that measurements of basal secretion or of the ratio of basal to stimulated acid output should differentiate between patients with Zollinger-Ellison syndrome and those with duodenal ulcer. Experience, however, has fallen short of expectation. Aoyagi and SummerskilP found that I-hI' basal secretion was less than 15 mEq in 10 of 31 patients with Zollinger-Ellison syndrome. This arbitrary level was exceeded in only 3% of patients with duodenal ulcer. Our own results, which are based upon 30-min collections of basal secretion in 90 patients, suggest that about 10% of patients with duodenal ulcer
have a basal secretion greater than 15 mEq per hr. However, in only 2 patients was the value greater than 15 mEq per hr on repeat testing. In the 15 patients with a basal output greater than 15 mEq per hI' on only one occasion, the basal output from the other test was usually high and, in 8 of the 15, more than 10 mEq per hrthat is to say, within the range considered by Aoy agi and Summerskill to be suggestive of Zollinger-Ellison syndrome. Although a persistently marked elevation of basal secretion is more strongly indicative of the latter diagnosis than intermittently high values, there is evidence that basal secretion is variable also in patients with islet cell tumor. s, 9
April 1970
479
GASTRIC SECRETION IN DUODENAL ULCER
Ratio .A)
TEST 2.
·8
MEq./hr.
.:
00 000
•
0
_____________ "8 _ ___
..,.
3~
i
••
•
:lao
J
J • • • 0
M.AD.
1
~ oc
••
----~----
t
LA.o.
•
..:;....
..-.. 1 .... if•
, t "
-alii"
M:A:a
-3
..
·2
I
·1
_..
...a.. LA.o.
·5
0:r
c8
"
-6
.Ie
• •
.II!ID
+
·7
0
0
0
I.A.Conc M.Aoconc
FIG. 2. Individual measurements 1 yr later.
The ratio of basal to stimulated acid output is likewise somewhat unreliable. Twenty per cent or more of patients with islet cell tumor have a ratio less than 0.6, while a ratio greater than 0.6 occasionally is found under other circumstances. 5 Our figures also show that this ratio is exceeded occasionally in patients with duodenal ulcer. It has been argued 3 that, since values for maximal acid output are similar in islet cell tumor and duodenal ulcer, the measurement of the ratio of basal to maximal acid output offers no advantage over basal output alone. However, the values quoted from the literature by Ruppert et aP suggest that false negative results in patients with islet cell tumor are no more likely to occur in respect of the ratio of basal to stimulated output than of absolute basal secretion. Our results indicate that more false positive results will be found in
duodenal ulcer if reliance is placed upon basal secretion alone. Ruppert et al. 5 reported a ratio of basal to stimulated acid concentration greater than 0.6 in all of 5 patients with islet cell tumor and in 4 others reported in the literature. This ratio was less than 0.6 in 300 patients with other diagnoses, including 48 with duodenal ulcer. They mention 3 patients with duodenal ulcer and gastric outlet obstruction in whom a ratio of >0.6 fell to <0.5 after a few days of antacid therapy. Such a diagnostic criterion, with no false negative results and occasional but transient false positive results, would appear to approach the ideal. However, a recent report by Winship 9 underlines the fallibility of this criterion. Basal and histamine-stimulated secretion were measured in 840 patients, of whom 89 were normal, 371 had a duodenal ulcer, 224 had a gastric
480
KAYE ET AL.
Vol . 58, No.4
1. Clinical features and values for acid secretion in patients whose ratio of basal La stimulated concentration exceeded 0.6 (patients 1 to 16) and in patients with a ratio of less than 0.6 whose basal secretion exceeded 15 mEq per hr (patients 17 to 22)
TABLE
Patient Age no.
---
:IT
Duration Severity of of symp- symptomsa toms
complications Test 1 ITest
--
"3
Basal acid output
Previous
21
Maximal acid output
Test 3 Test 1 ITest
mEg/ii,
mEg/ hr
2
(BAC/ MAC)
(BAO/MAO)
ratio
ratio
Test 1
Test
2
Test 1 Test 2
---- -- --
65 0.33 0.24 0.67 0 .62 + 23 10 37 47 0.62 0.22 0 .83 0.68 + 0 .77 13 62 44 28 58 0.70 0.48 0.8 3h +++ 31 0 . 14 0.20 0.42 0.61 36 6 5 4 ++ 48 0.28 0.15 0 .66 0.44 13 7 47 5 ++ 22 11 18 53 53 0.21 0.33 0 .74 0 .65 6 ++ Bleeding 10 48 43 0.31 0.24 0.72 0 .63 15 7 + 25 0.08 0.66 0.39 0.69 25 8b + Bleeding (twice) 2 16 5 29 0.35 0.32 0.74 0.58 10 9 29 9 + Bleeding lOb 42 12 11 0.28 0.45 0.57 0.83 5 +++ Bleeding 13 18 51 40 0.26 0.45 0.67 0.68 11 ++ 31 0.22 0.22 0 .53 0.67 37 7 12 8 7 + 12 51 61 0.36 0.20 0.54 0 .68 18 13 ++ 15 13 52 52 0.31 0.28 0.62 0 .69 16 14 + Bleeding 52 21 9 53 0.40 0.18 0.58 0 .63 15 + Perforation 12 52 8 18 37 0.35 0 .32 0.62 0 .61 16 + 19 17 11 15 56 55 0 . 19 0.27 0.45 0.57 ++ 13 22 47 49 0.06 0.44 0.33 0.47 3 18 + Bleeding 17 19 67 0.11 0.25 0.40 0 .57 8 68 19 +++ 24 52 2 22 20 38 0.03 0.58 0.15 0.58 + 16 25 28 0.28 0.57 0.52 0.58 21 7 + Bleeding 34 45 0.24 0.34 0.43 0 .56 22 15 8 ++ a +, ++, and +++ indicate respectively that symptoms were mild, moderate, or severe during the 1 2
39 44 35 57 28 36 59 37 49 44 55 41 23 41 58 56 45 53 52 30 32 21
Bleeding
18
15
17
54
2 10 20 8 7 40 1 6 21 7 13 4 2 1 3 5 20 12 2 11 1.5
year of observation. b Patient in whom vagotomy and pyloroplasty were carried out. No pancreatic abnormality was noted at. operation.
ulcer, 5 had Zollinger-Ellison syndrome, and 151 had other disorders. The (BAC/ MAC) ratio was greater than 0.6 in 6 norb Criterion No. of tests mal subjects (7%), in 4 patients with gastric ulcer (2%), and in 18 patients with (BAC/MAC) only ........... ... . 12 (7) duodenal ulcer (5% ). The criterion was BAO only ....... .......... .. . . . ... . . 8 (4) negative in 2 of 7 tests in patients with (BAO/MAO) only .......... . .... ... . o (0) Zollinger-Ellison syndrome. Our results in (BAC/ MAC) + BAO ......... ..... . 9 (5) 3 (2) (BAC/ MAC) + (BAO/ MAO) + BAO. patients with duodenal ulcer are similar. A 148 (82) All criteria negative. ratio greater than 0.6 was found in 9% on two occasions, and in a further 9% on one Total. . . . . . . . . . . . . . . . . . . .... . 180 . . . (100) . . . . of two occasions. More false positive results occurred with this than with either of a (BAC/MAC) > 0.6, (BAO/ MAO) > 0.6, and the other two criteria which we were able BAO > 15 mEq per hr. to examine. We conclude, therefore, that b Ninety patients with two tests in each patient. Figures in parentheses are percentages. while a ratio of <0.6 may render the diag2. The relationship between the three criteria for diagnosis of Zollinger-Ellison syndromea
TABLE
April 1970
GASTRIC SECRETION IN DUODENAL ULCER
nosis of islet cell tumor unlikely, a ratio >0.6 should be interpreted with considerable caution. Winship's results suggest that the diagnosis of Zollinger-Ellison syndrome is rendered more likely if two ' or more of the three criteria (BAO, (BAO/ MAO), and (BAC/MAC)) are positive. Again, however, our findings are discouraging, for two or more criteria were positive in 12 (7%) of the 180 tests. It may be argued that the diagnosis of islet cell tumor has not been excluded entirely in those of our patients whose ratio of basal to stimulated acid concentration exceeded 0.6. However, in none was there other suggestive evidence such as diarrhea, endocrine disease, recurrent complications, or a particularly fulminant course. In 3 patients whose symptoms were sufficiently severe and unresponsive to medical therapy to warrant surgery, laparotomy revealed no evidence of pancreatic tumor. Their uncomplicated progress after vagotomy and pyloroplasty makes the diagnosis of islet cell tumor improbable. REFERENCES 1. Zollinger, R. M., and E. H. Ellison. 1955. Primary peptic ulcerations of the jejunum, associated with islet cell tumor of the pancreas. Ann. Surg. 14~: 709-728. 2. Ellison, E. H., and S. D. Wilson. 1964. The
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Zollinger-Ellison syndrome; reappraisal and evaluation of 2'60 registered cases. Ann. Surg. 160: 512-528. 3. Aoyagi, T., and W. H. J. Summerskill. 1966.
Gastric secretion with ulcerogenic islet cell tumor. Arch. Intern. Med. (Chicago) 117: 667-672.
4. Marks, 1. N., G. Selzer, J. H. Louw, and S. Bank. 1961. Zollinger-Ellison syndrome in a Bantu woman, with isolation of a gastrin-like substance from the primary and secondary tumors. 1. Case Report. Gastroenterology 41: 77-86. 5. Ruppert, R. D., N. J. Greenberger, F. M. Beman, and F. M . McCullough, 1967. Gastric secretion in ulcerogenic tumors of the pancreas . Ann. Intern. M ed. 67: 808--815. 6. Lawrie, J. H., G. M. R. Smith, and A. P . M. Forrest. 1964. The histamine-infusion test. Lancet 2: 270-273. 7. Gregory, R. A., H . J. Tracy, J. M. French and W. Sircus. 1960. Extraction of a gastrinlike substance from a pancreatic tumor in a case of Zollinger-Ellison syndrome. Lancet 1: 1045-1048.
8. Winship, D. H., and E. H. Ellison. 1967. Variability of gastric secretion in patients with and without the Zollinger-Ellison syndrome. Lancet 1: 1128--1130. 9. Winship, D. H. 1969. Problems in the diagnosis of Zollinger-Ellison syndrome by analysis of gastric secretion. In L. Demling and R. Ottenjann [eds.], Non-insulin-producing tumors of the pancreas. Georg Thieme Verlag, KG ., Stuttgart.