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The pathologic physiology of peptic ulcer
The Pathologic
Physiology MORTON
of Peptic Ulcer*
I. GROSSMAN, M.D.
Los Angeles, California
T
HIS paper summarizes information on the ways in which patients with peptic ulcer differ physiologically from persons without ulcer. Particular attention is given to recent contributions to knowledge in this area. Such information is of the first importance for evaluating hypotheses about the etiology and pathogenesis of the disease and for developing a physiologically rational therapy. These topics are, however, beyond the scope of this presentation. GASTRIC
SECRETION
response which these patients give to this stimulus [3]. The matter is worthy of further study for it may shed light on the mechanism of hypersecretion. The mechanism of hypersecretion of acid in patients with duodenal ulcer is not fully established. The hypotheses which have been advanced include (1) impaired inhibition of secretion, (2) excessive stimuli for secretion, especially vagal, and (3) increased reactivity of the glands to stimulation. Hunt [8,9] studied the inhibition of acid secretion which occurs when glucose or acid enters the duodenum. With glucose there was no difference between normal subjects and patients with duodenal ulcer, but with acid about a third of the patients with duodenal ulcer failed to show a normal degree of inhibition. However, since some patients with marked hypersecretion had normal inhibition by acid, it was concluded that a defect in the inhibitory mechanism is not a major cause of hypersecretion. Because vagotomy usually abolishes the hypersecretion of patients with duodenal ulcer, it has been argued that the hypersecretion is caused by an excess of vagal stimuli [ 701. There is a flaw in this reasoning [77]. Vagotomy not only abolishes secretion caused by vagal stimuli but also greatly decreases the response to other stimuli such as histamine [72]. Therefare, the reduction in secretion seen after vagotomy cannot be ascribed categorically to removal of excessive vagal stimuli for secretion. On the other hand, it is not possible, on the basis of the evidence available, to say that excessive vagal stimuli are not present in patients with duodenal ulcer. New methods are required to solve the problem. That salivary hypersecretion is correlated with gastric hypersecretion [73] is suggestive but far from conclusive evidence that parasympathetic overactivity may be present. The most appealing hypothesis that has been offered to account for the hypersecretion of acid in patients with ulcer of the duodenum is that it
Acid. The mean concentration of acid in the gastric and proximal duodenal contents under basal conditions and after food is higher in patients with duodenal ulcer than in persons without ulcer [ 71. That this is caused primarily by increased rate of secretion of acid, rather than by failure of acid to be neutralized, is supported by many observations showing that the mean rate of acid secretion under basal conditions, after food or after stimulation by drugs (histamine, caffeine, insulin) is higher in patients with duodenal ulcer than in those without this disease. (Table I.) From such data on mean values the inference is frequently drawn that most patients with duodenal ulcer secrete an abnormally large amount of acid. Table I summarizes the incidence of abnormally high rates of secretion in patients with duodenal ulcer studied with various kinds of secretory tests. It is apparent that, although the mean rate of acid secretion is substantially higher in patients with duodenal ulcer, the percentage of such patients who secrete more than the upper limit of normal is, except in the instance of the caffeine test, 50 or less. It follows that only a minority of patients with duodenal ulcer will be distinguishable from persons without the disease on the basis of most of the standard secretory tests. The reason for the superiority of caffeine as a stimulus in segregating secretory responses of patients with duodenal ulcer is not known. It would appear to depend upon the prolonged * From the V. A. Hospital and University of California Medical Center at Los Angeles, LOS Angeles, California. 748
AMERICAN
JOURNAL
OF
MEDICINE
Pathologic Physiology of Peptic Ulcer-Grossman TABLE INCIDENCE OF HYPERSECRETION
I
OF ACID AS MEASURED BY VARIOUS TESTS IN PATIENTS DUODENAL
T Stimulus
Upper
Mean
-Basal Caffeine Caffeine Caffeine Histamine Insulin Ewald meal Maximal histamine
Free acid, mEq./hr. Free acid at 90 min., mEq./L. Free acid, mEq./90 min. Free acid at 90 min., mEq./L. Free acid, mEq./hr. Free acid, mEq./hr. Free acid at 90 min., mEq./L. Free acid, mEq./0.5 hr.
i
Patients with Duodenal Ulcer
____
T Subjects (no.)
WITH
ULCER
Control Subjects
Units
/
749
Limit of Normal *
Subjects (no.)
Mean
Subjects Exceeding Upper Limit of Normal (%)
Reference
I-
137 100
1.4 25
2.8 58
100
NAt
8.8
82
14.7
43
24 24 100
11.8 16.5 31
25
11.3
238 100
2.8 79
42 86
NAt 48
55.1
18.7 23.4 55
20 20 100
15.2 17.1 41
21
105
22.3
-
* Upper limit of normal was calculated by the method of Herrera [7] using 0.975 probability that more than 5 per cent of the control population was excluded. t NA: not available.
results from the increased number of parietal cells which the gastric mucosa of these patients is known to have. Cox [ 74] found that both the area of the fundic gastric mucosa and its thickness were greater, on the average, in patients with duodenal ulcer than in persons without the disease. Corresponding to the increased volume of fundic mucosa was an increased number of parietal cells, with a mean of 1.8 billion in patients with duodenal ulcer and 1.0 billion in the control group. In patients undergoing gastric resection, Card and Marks [75] correlated the decrease in acid secreted in response to maximal histamine stimulation with the number of parietal cells removed. They found a nearly linear relation between these two variables, with a slope of about 23 mEq./hour per billion parietal cells. This makes it possible to estimate the parietal cell mass from the secretory response to maximal stimulation with histamine in intact subjects. Such indirect studies [6,76] support the direct observations of Cox showing, in patients with duodenal ulcer, an increased mean secretory response to maximal stimulation with histamine and thus, by inference, an increased parietal cell population. NOVEMBER
1960
Hunt [ 771 and Hunt and Kay [ 781 found that the rate of acid secretion of control subjects and of patients with duodenal ulcer under basal conditions or in response to stimulation by test meals or drugs was proportional to their response to histamine. This held both for small and maximally stimulating doses of histamine. The fraction of maximal secretory response elicited by small doses of histamine was found to be the same in control subjects and patients with duodenal ulcer. These findings led to the conclusion that the hypersecretion of acid in patients with duodenal ulcer could be fully accounted for by the increased peripheral reactivity resulting from the increased parietal cell mass, making it unnecessary to postulate any abnormal secretory drive. Hunt and Kay [78] used the mean rates of secretion of the group to calculate the ratio of basal secretion to maximal secretion. Recently, Sircus [79] studied the basal and maximal secretion in 176 male patients with duodenal ulcer. He found that the percentage of maxima1 capacity to secrete represented by basal output increased as the basal rate of secretion increased. This suggests that high rates of basal secretion are associated with increased stimuli for secretion as well as with increased
750
Pathologic Physiology of Peptic Ulcer-Gros.man TABLE
INCIDENCE
OF HYPERSECRETION
OF PEPSIN
II
AS MEASURED
DUODENAL
BY
Control Subjects
Test
Units Subjects (no.1
Mean
VARIOUS
TESTS
IN
PATIENTS
WITH
ULCER
Patients with Duodenal Ulcer
UPPer Limit of Normal *
Subjects (No.)
11,000 2.84
20 203
Mean
Subjects Exceeding Upper Limit of Normal
Reference
(%I
~Insulin Serum pepsino-
Units/hr. Log units/ml.
gen Urinary pepsinogen
UXlitS/hr.
*Upper
24 4,150 38
7,639 2.64 54
77
51
12,599 2.88 80
45 55
5 25
45
26
limit of normal was calculated by the method of Herrera [A using 0.975 probability that more than 5 per
cent of the control population was excluded.
capacity to secrete. The subject invites further study, with attention to ratios of basal to maximal secretion in individual subjects rather than ratios of means of groups. Why do patients with duodenal ulcer have larger than normal numbers of parietal cells? One possibility is that it is a genetically determined trait but there is no evidence for or against this supposition. Another possibility is that prolonged increased stimulation of secretion leads to hyperplasia of parietal cells. There is some evidence from studies in animals for the occurrence of such hyperplasia in response to prolonged increases in stimulation [20]. Sircus [ 191found that both basal and maximal secretory rates increased with increasing length of history of symptoms in patients with duodenal ulcer. Hunt and Kay [78], however, found that such an increase occurred only in patients with pyloric stenosis. The high secretory rates seen in patients with duodenal ulcer probably are present for years before the ulcer and its symptoms appear [.27]. The rate of basal secretion does not change when the duodenal ulcer heals [22]. These findings indicate that the hypersecretion is not caused by the ulcer itself; they also suggest that the cyclic appearance and disappearance of the ulcer is related to factors other than variations in acid secretion. In sharp contrast to patients with duodenal ulcer, those with gastric ulcer do not, in general, have abnormally elevated rates of acid secretion. There are, however, two categories of gastric ul-
cer to which this generalization does not apply, namely, prepyloric gastric ulcers and gastric ulcers occurring concurrently with duodenal ulcers. In both of these situations the mean rate of acid secretion is about the same as in patients with duodenal ulcer alone [ 79,23,24]. The remainder of patients with gastric ulcer secrete, on the average, less acid than persons without ulcer. Perhaps the same factor which causes depressed acid secretion also renders the mucosa more susceptible to ulceration. Pepsin. In normal subjects and in patients with gastric or duodenal ulcer the rate of pepsin secretion is correlated with the rate of acid secretion, both under basal conditions and after stimulation by test meals or drugs [77]. Thus, just as with acid secretion, patients with duodenal ulcer show increased rates of pepsin secretion. (Table II.) The concentration of pepsinogen in blood serum and its rate of excretion in the urine are also increased in patients with duodenal ulcer. (Table II.) Serum and urinary pepsinogen do not fluctuate with short term changes in rate of gastric pepsin secretion produced by stimulation with food or drugs [271. It is reasonable to assume that variations in pepsinogen levels in blood and urine reflect mainly variations in the gastric secretory capacity for pepsin secretion rather than changes in the extent to which this capacity is active. Mucus. That mucus serves to protect the mucosa against digestion by acid and pepsin is an ancient and plausible notion which it is difficult either to prove or refute. The methods AMERlCAN JOURNAL
OF
MEDICINE
Pathologic Physiology of Peptic Ulcer-Gkxman available for measurement of the various kinds of mutinous substances in aspirated gastric juice have failed to reveal differences between persons with and without ulcer [28,29], except to show that increase in acid secretion is correlated with an increase in one class of mucoprotein. Presumably the layer of mucus which separates the mucosal cells from the contents in the lumen is of greatest importance in providing the alleged protection [30]. Study of the aspirated juices may not reflect changes at this critical site. Resolution of the matter awaits the development of suitable methods for study. The same may be said for other factors which are put under the necessarily vague, but probably crucially important, heading of tissue resistance to digestion. Until these factors are identified and means for measuring them are developed little can be said about them. GASTRODUODENAL
MOTILITY
The mean rate of gastric emptying of test meals of saline solution, glucose or acid is normal in patients with duodenal ulcer [a$]. The frequency and amplitude of pressure waves during fasting in the stomach and duodenum of patients with gastric or duodenal ulcer do not differ from those of normal subjects [31]. There is some indication that pressure waves in the stomach and duodenum may be increased in frequency and amplitude during the occurrence of pain from peptic ulcer [31,32]. There is no evidence for the existence of a derangement of gastroduodenal motor activity which might act as a causative factor in peptic ulceration. BLOOD
GROUP
Observations in many countries have established that persons who possess blood group 0 have a higher incidence of peptic ulcer than those with other blood groups. Although some of the individual series which have been reported fail to show a higher than expected incidence of blood group 0 in patients with peptic ulcer, when all reported series are combined and examined by suitable statistical methods the association between blood group 0 and peptic ulcer, both gastric and duodenal, is fully supported [33]. The combined results from all centers show that the risk of having a duodenal ulcer among persons with blood group 0 is approximately 1.4 times the risk among persons with groups A, B or AB. Similarly, the risk of 0 NOVEMBER
1960
751
subjects having gastric ulcer is 1.2 times that of persons having the other three blood groups. Some have claimed that the association between blood group and gastric ulcer is valid only for ulcers in certain locations in the stomach. Several large recent studies [34,3fl have, however, shown that there is no evidence of an association between blood groups and the site of the ulcer. Several groups [35,36] have noted that the association with blood group 0 is more marked for stoma1 ulcer than for duodenal ulcer. In patients with duodenal ulcer no significant correlation was found between blood group and acid output in response to maximal stimulation with histamine [36]. Another genetic factor which may be involved in the etiology of peptic ulcer is the secretor status. This trait is determined by a single pair of allelic genes independent of those for ABO groups. About 75 per cent of persons secrete ABH substances in saliva and gastric juice (A and H secreted in group A secretors, B and H in group B secretors, A, B and H in group AB secretors, and H in group 0 secretors). Clarke and co-workers [37] found a clear association between ABH non-secretion and duodenal ulcers. The excess incidence of non-secretors was found with equal frequency in patients with all four ABO blood groups. The liability to duodenal ulceration from being simultaneously 0 and non-secretor is at least additive. Thus Clarke and co-workers [37] calculated that 0 non-secretors were 2.49 times more liable; A, B and AB non-secretors 1.60 times more liable; and 0 secretors 1.35 times more liable to develop duodenal ulcer than are A, B and AB secretors. Using fluorescent antibodies, Glynn and coworkers [38] demonstrated that A substance is present in the surface epithelial cells of the stomach and duodenum in A secretors but not in non-secretors. All of these observations invite the speculation that the presence of certain blood group substances in the secretions and cells of the stomach and duodenum in some way protect against duodenal ulceration. Non-secretors of ABH usually secrete much more of another blood group substance, Lewis, than do ABH secretors. The total amount of all blood group substances, as estimated from the fucose content of saliva, has been shown to be the same in secretors and nonsecretors and in subjects with and without
752
Pathologic Physiology of Peptic Ulcer-Gros.man
duodenal ulcer [39]. This suggests that the association between blood groups and secretor status and duodenal ulcer may be related to differences in the properties of A, B, H and Lewis group-specific substances. MISCELLANEOUS OBSERVATIONS
The secretory response of the pancreas to intravenously administered secretin is normal in patients with duodenal ulcer [do]. Certain rare forms of peptic ulcer disease are clearly associated with endocrinopathies [47]. This has led to an interest in endocrine function, particularly adrenocortical, in the usual patient with ulcer. There is no evidence for increased adrenocortical activity in patients with active or inactive peptic ulcers [&I. CONCLUDING REMARKS
Although some patients with duodenal ulcer secrete abnormally large amounts of acid and pepsin, many secrete normal amounts. Patients with prepyloric gastric ulcer have secretory patterns similar to those with duodenal ulcer. Ulcer of the body of the stomach is associated with decreased acid secretion. The secretory levels of these various groups are to a large extent determined by the amount of glandular tissue in the stomach; alterations in the amount of stimulation playing upon the glands may contribute but have not as yet been clearly established. Because many instances of gastroduodenal ulceration cannot be ascribed to hypersecretion of acid-pepsin, a decrease in resistance of the mucosa to ulceration is postulated but means of measuring this factor are, as yet, lacking. No characteristic alterations in gastroduodenal motor activity exist in patients with peptic ulcer, except perhaps during periods of pain. The demonstration that persons with blood group 0 and persons who are non-secretors of ABH substances are more likely to have duodenal ulcer has established the existence of a genetic factor in this disease and has opened new avenues for research on its pathogenesis. REFERENCES 1. ATKINSON,M. and HENLEY, K. S. Levels of intragastric and intraduodenal acidity. Clin. SC., 14: 1, 1955. 2. GROSSMAN, M. I. Unpublished data. 3. ROTH,J. L. A. Clinical evaluation of the caffeine gastric analysis in duodenal ulcer patients. Gostroenterology,19: 199, 1951.
4. LITTMAN, A., Fox, B. W., KAMMERLING,E. M. and FOX, N. I. A single aspiration caffeine gastric analysis in duodenal ulcer and control patients. Gastsoenterology,28: 953, 1955. 5. IHRE, B. J. E. Human Gastric Secretion. London, 1939. Oxford University Press. 6. KAY, A. W. Effect of large doses of histamine on gastric secretion of HCI. Brit. M. J.. 2: 77. 1953. 7. H~RRERA, L. The precision of percentiles in establishing normal limits in medicine. J. Lab. &? Clin. Med., 52: 34, 1958. 8. HUNT, J. N. Influence of hydrochloric acid on secretion and emptying in patients with duodenal ulcer. Brit. M. J., 1: 681, 1957. 9. HUNT, J. N. Inhibition of gastric emptying and secretion in patients with duodenal ulcer. Lance& 1: 132, 1957. 10. DRAGSTEDT,L. R. A concept of the etiology of gastric and duodenal ulcers. Gastroenterology,30: 208,1956. Il. GROSSMAN,M. I. Is the hypersecretion observed in duodenal ulcer patients due to excessive vagal stimuli to the stomach? Gustroenterology, 13: 91, 1948. 12. OBERHELMAN,J. A., JR. and DRAGSTEDT,L. R. Effect of vagotomy on gastric secretory response to histamine. Proc. Sot. Exper. Biol. & Med., 67: 336, 1948. 13. GROSSMAN,M. I. Inhibition of gastric and salivary secretion by Darbid. Gastroenterology, 35: 312, 1958. 14. COX, A. J. Stomach size and its relation to chronic peptic ulcer. Arch. Path., 54: 407, 1952. 15. CARD, W. I. and MARKS, I. N. The relationship between the acid output of the stomach following “maximal” histamine stimuIation and the parietal cell mass. Clin. SC., 19: 147, 1960. 16. BRUCE,J., CARD, W. I., MARKS, I. N. and SIRCUS, W. The rationale of selective surgery in the treatment of duodenal ulcer. J. Roy. Coil. Surgeons, 4: 85, 1959. 17. HUNT, J. N. Some notes on the pathogenesis of duodenal ulcer. Am. J. Digest. Dis.: 2: 445, 1957. 18. HUNT. J. N. and KAY. A. W. The nature of pastric hypkrsecretion of adid in patients with dugdenal ulcer. Brit. M. J., 2: 1444, 1954. 19. Sr~cus, W. The aetiology of peptic ulcer. In: Peptic Ulceration, a Symposium for Surgeons. Edited by Wells, C. and Kyle, J. Edinburgh, 1960. E. & S. Livingstone, Ltd. 20. MARKS, I. N. The effect of prolonged histamine stimulation on the parietal cell population and the secretory function of the guinea-pig stomach. Quart. J. Exper. Physiol., 42: 180, 1957. 21. DOLL, R., JONES,F. A. and MCLAGAN, N. F. Gastric secretion and subsequent dyspepsia. Lancet, 2: 984, 1949. 22. LEVIN, E., KIRSNER,J. 3. and PALMER,W. L. Twelve hour nocturnal gastric secretion in uncomplicated duodenz%l ulcer patients; before and after healing. Proc. Sot. Exper. Biol. &. Med., 69: 1.53, 1948. 23. BORO, I. Gastric flow and acidity before and after Billroth I and Billroth II for gastro-duodenal ulcer. Acta chir. scandinav.,supp. 253, p. I, 1959. 24. MARKS. I. N. and SHAY, H. Observations on the pathogenesis of gastric ulcer. Lancet, 1: 1107, 1959. 25. MIRSKY, A. I. Physiologic, psychologic, and social AMERICAN
JOURNAL
OP MEDICINE
Pathologic Physiology of Peptic Ulcer-Gromnan
26.
27. 28.
29.
30. 31.
32.
33.
determinants in the etiology of duodenal ulcer. Am. J. Digest. Dis., 3: 285, 1958. SEOAL, H. L., MILLER, L. L., REICHMAN,F., PLUMB, E. J. and GLASER, G. L. Proteolytic enzyme activity. I. Urinary proteofytic activity at pH 1.5 in adults. Gastro&terology, 33: 557, 1957. HIRSCHOWITZ,B. I. Pepsinogen: its origins, secretion and excretion. Physiol. Rev., 37: 475, 1957. GLASS, G. B. J. and BOYD, L. J. Patterns of response of gastric mucoprotein and acid to insulin: correlation with underlying disease in the nonoperated stomach of man. Gastroenterology, 15: 439, 1950. GLASS, G. B. J., STEPHANSON, L. and RICH, M. Paper electrophoretic analysis of gastric juice in health and disease and its physiological and clinical significance. Gastroenterologia, 86: 384, 1956. HEATLEY, N. G. Mucosubstance as a barrier to diffusion. Gastroenterology, 37: 313, 1959. SMITH, H. W., TEXTER, E. C., JR., STICKLEY,J. H. and BARBORKA,C. J. Intraluminai pressures from the upper gastrointestinal tract. II. Correlations with gastroduodenal motor activity in normal subjects and patients with ulcer distress. Gastroenterology, 32: 1025, 1957. HIGHTOWER, N. C., JR. and GAMBILL, E. E. The effects of Banthine on pain and antral gastric motility in patients with duodenal ulcer. Gastroenterology, 23: 244, 1953. ROBERTS,J. A. F. Blood groups and susceptibility to disease: a review. Brit. J. Preu. @ Social Med., 11: 107,1957.
NOVEMBER
19 60
753
34. BEASLEY, W. H. Blood groups of gastric ulcer and carcinoma. Brit. M. J., 1: 1167, 1960. 35. DOLL, R., SWYNNERTON,B. F. and NEWELL, A. C. Observations on blood group distribution in peptic ulcer and gastric can&. G&t, 1: 31, 1960. 36. BROWN. D. A. P.. MELROSE, A. G. and WALLACE. J. The blood grobps in peptic ulceration. Brit. M. ‘J., 2: 135, 1956. 37. CLARKE, C. A., EVANS,D. A. P., MCCONNELL, R. B. and SHEPPARD, P. M. Secretion of blood group antigens and peptic ulcer. Brit. M. J., 1: 603, 1959. 38. GLYNN, L. E., HOLBOROW,E. J. and JOHNSON,G. D. The distribution of blood-group substances in human gastric and duodenal mucosa. Luncet, 2: 1083, 1957. 39. EVANS, D. A. P. The fucose and agglutinogen contents of saliva in subjects with duodenal ulcer. J. Lab. & Clin. Med., 55: 386, 1960. 40. DREILING, D. A. Studies in pancreatic function. v. The use of the secretin test in the diagnosis of pancreatitis and in the demonstration of pancreatic insufficiencies in gastrointestinal disorders. Gastroenterology, 24: 540, 1953. 41. FISHER, E. R. and FLANDREAU, R. H. Multiple endocrine tumors and peptic ulcer. Gastroenterology, 32: 1075, 1957. 42. SLEISENGER,M. H., LEWIS, C. M., LIPKIN, M. and WIERUM, C. Uropepsin and 17-hydroxycorticoid excretion in normal subjects and patients with peptic ulcer during both states of activity and quiescence. Am. J. Med., 25: 395, 1958.
Physiology MORTON
of Peptic Ulcer*
I. GROSSMAN, M.D.
Los Angeles, California
T
HIS paper summarizes information on the ways in which patients with peptic ulcer differ physiologically from persons without ulcer. Particular attention is given to recent contributions to knowledge in this area. Such information is of the first importance for evaluating hypotheses about the etiology and pathogenesis of the disease and for developing a physiologically rational therapy. These topics are, however, beyond the scope of this presentation. GASTRIC
SECRETION
response which these patients give to this stimulus [3]. The matter is worthy of further study for it may shed light on the mechanism of hypersecretion. The mechanism of hypersecretion of acid in patients with duodenal ulcer is not fully established. The hypotheses which have been advanced include (1) impaired inhibition of secretion, (2) excessive stimuli for secretion, especially vagal, and (3) increased reactivity of the glands to stimulation. Hunt [8,9] studied the inhibition of acid secretion which occurs when glucose or acid enters the duodenum. With glucose there was no difference between normal subjects and patients with duodenal ulcer, but with acid about a third of the patients with duodenal ulcer failed to show a normal degree of inhibition. However, since some patients with marked hypersecretion had normal inhibition by acid, it was concluded that a defect in the inhibitory mechanism is not a major cause of hypersecretion. Because vagotomy usually abolishes the hypersecretion of patients with duodenal ulcer, it has been argued that the hypersecretion is caused by an excess of vagal stimuli [ 701. There is a flaw in this reasoning [77]. Vagotomy not only abolishes secretion caused by vagal stimuli but also greatly decreases the response to other stimuli such as histamine [72]. Therefare, the reduction in secretion seen after vagotomy cannot be ascribed categorically to removal of excessive vagal stimuli for secretion. On the other hand, it is not possible, on the basis of the evidence available, to say that excessive vagal stimuli are not present in patients with duodenal ulcer. New methods are required to solve the problem. That salivary hypersecretion is correlated with gastric hypersecretion [73] is suggestive but far from conclusive evidence that parasympathetic overactivity may be present. The most appealing hypothesis that has been offered to account for the hypersecretion of acid in patients with ulcer of the duodenum is that it
Acid. The mean concentration of acid in the gastric and proximal duodenal contents under basal conditions and after food is higher in patients with duodenal ulcer than in persons without ulcer [ 71. That this is caused primarily by increased rate of secretion of acid, rather than by failure of acid to be neutralized, is supported by many observations showing that the mean rate of acid secretion under basal conditions, after food or after stimulation by drugs (histamine, caffeine, insulin) is higher in patients with duodenal ulcer than in those without this disease. (Table I.) From such data on mean values the inference is frequently drawn that most patients with duodenal ulcer secrete an abnormally large amount of acid. Table I summarizes the incidence of abnormally high rates of secretion in patients with duodenal ulcer studied with various kinds of secretory tests. It is apparent that, although the mean rate of acid secretion is substantially higher in patients with duodenal ulcer, the percentage of such patients who secrete more than the upper limit of normal is, except in the instance of the caffeine test, 50 or less. It follows that only a minority of patients with duodenal ulcer will be distinguishable from persons without the disease on the basis of most of the standard secretory tests. The reason for the superiority of caffeine as a stimulus in segregating secretory responses of patients with duodenal ulcer is not known. It would appear to depend upon the prolonged * From the V. A. Hospital and University of California Medical Center at Los Angeles, LOS Angeles, California. 748
AMERICAN
JOURNAL
OF
MEDICINE
Pathologic Physiology of Peptic Ulcer-Grossman TABLE INCIDENCE OF HYPERSECRETION
I
OF ACID AS MEASURED BY VARIOUS TESTS IN PATIENTS DUODENAL
T Stimulus
Upper
Mean
-Basal Caffeine Caffeine Caffeine Histamine Insulin Ewald meal Maximal histamine
Free acid, mEq./hr. Free acid at 90 min., mEq./L. Free acid, mEq./90 min. Free acid at 90 min., mEq./L. Free acid, mEq./hr. Free acid, mEq./hr. Free acid at 90 min., mEq./L. Free acid, mEq./0.5 hr.
i
Patients with Duodenal Ulcer
____
T Subjects (no.)
WITH
ULCER
Control Subjects
Units
/
749
Limit of Normal *
Subjects (no.)
Mean
Subjects Exceeding Upper Limit of Normal (%)
Reference
I-
137 100
1.4 25
2.8 58
100
NAt
8.8
82
14.7
43
24 24 100
11.8 16.5 31
25
11.3
238 100
2.8 79
42 86
NAt 48
55.1
18.7 23.4 55
20 20 100
15.2 17.1 41
21
105
22.3
-
* Upper limit of normal was calculated by the method of Herrera [7] using 0.975 probability that more than 5 per cent of the control population was excluded. t NA: not available.
results from the increased number of parietal cells which the gastric mucosa of these patients is known to have. Cox [ 74] found that both the area of the fundic gastric mucosa and its thickness were greater, on the average, in patients with duodenal ulcer than in persons without the disease. Corresponding to the increased volume of fundic mucosa was an increased number of parietal cells, with a mean of 1.8 billion in patients with duodenal ulcer and 1.0 billion in the control group. In patients undergoing gastric resection, Card and Marks [75] correlated the decrease in acid secreted in response to maximal histamine stimulation with the number of parietal cells removed. They found a nearly linear relation between these two variables, with a slope of about 23 mEq./hour per billion parietal cells. This makes it possible to estimate the parietal cell mass from the secretory response to maximal stimulation with histamine in intact subjects. Such indirect studies [6,76] support the direct observations of Cox showing, in patients with duodenal ulcer, an increased mean secretory response to maximal stimulation with histamine and thus, by inference, an increased parietal cell population. NOVEMBER
1960
Hunt [ 771 and Hunt and Kay [ 781 found that the rate of acid secretion of control subjects and of patients with duodenal ulcer under basal conditions or in response to stimulation by test meals or drugs was proportional to their response to histamine. This held both for small and maximally stimulating doses of histamine. The fraction of maximal secretory response elicited by small doses of histamine was found to be the same in control subjects and patients with duodenal ulcer. These findings led to the conclusion that the hypersecretion of acid in patients with duodenal ulcer could be fully accounted for by the increased peripheral reactivity resulting from the increased parietal cell mass, making it unnecessary to postulate any abnormal secretory drive. Hunt and Kay [78] used the mean rates of secretion of the group to calculate the ratio of basal secretion to maximal secretion. Recently, Sircus [79] studied the basal and maximal secretion in 176 male patients with duodenal ulcer. He found that the percentage of maxima1 capacity to secrete represented by basal output increased as the basal rate of secretion increased. This suggests that high rates of basal secretion are associated with increased stimuli for secretion as well as with increased
750
Pathologic Physiology of Peptic Ulcer-Gros.man TABLE
INCIDENCE
OF HYPERSECRETION
OF PEPSIN
II
AS MEASURED
DUODENAL
BY
Control Subjects
Test
Units Subjects (no.1
Mean
VARIOUS
TESTS
IN
PATIENTS
WITH
ULCER
Patients with Duodenal Ulcer
UPPer Limit of Normal *
Subjects (No.)
11,000 2.84
20 203
Mean
Subjects Exceeding Upper Limit of Normal
Reference
(%I
~Insulin Serum pepsino-
Units/hr. Log units/ml.
gen Urinary pepsinogen
UXlitS/hr.
*Upper
24 4,150 38
7,639 2.64 54
77
51
12,599 2.88 80
45 55
5 25
45
26
limit of normal was calculated by the method of Herrera [A using 0.975 probability that more than 5 per
cent of the control population was excluded.
capacity to secrete. The subject invites further study, with attention to ratios of basal to maximal secretion in individual subjects rather than ratios of means of groups. Why do patients with duodenal ulcer have larger than normal numbers of parietal cells? One possibility is that it is a genetically determined trait but there is no evidence for or against this supposition. Another possibility is that prolonged increased stimulation of secretion leads to hyperplasia of parietal cells. There is some evidence from studies in animals for the occurrence of such hyperplasia in response to prolonged increases in stimulation [20]. Sircus [ 191found that both basal and maximal secretory rates increased with increasing length of history of symptoms in patients with duodenal ulcer. Hunt and Kay [78], however, found that such an increase occurred only in patients with pyloric stenosis. The high secretory rates seen in patients with duodenal ulcer probably are present for years before the ulcer and its symptoms appear [.27]. The rate of basal secretion does not change when the duodenal ulcer heals [22]. These findings indicate that the hypersecretion is not caused by the ulcer itself; they also suggest that the cyclic appearance and disappearance of the ulcer is related to factors other than variations in acid secretion. In sharp contrast to patients with duodenal ulcer, those with gastric ulcer do not, in general, have abnormally elevated rates of acid secretion. There are, however, two categories of gastric ul-
cer to which this generalization does not apply, namely, prepyloric gastric ulcers and gastric ulcers occurring concurrently with duodenal ulcers. In both of these situations the mean rate of acid secretion is about the same as in patients with duodenal ulcer alone [ 79,23,24]. The remainder of patients with gastric ulcer secrete, on the average, less acid than persons without ulcer. Perhaps the same factor which causes depressed acid secretion also renders the mucosa more susceptible to ulceration. Pepsin. In normal subjects and in patients with gastric or duodenal ulcer the rate of pepsin secretion is correlated with the rate of acid secretion, both under basal conditions and after stimulation by test meals or drugs [77]. Thus, just as with acid secretion, patients with duodenal ulcer show increased rates of pepsin secretion. (Table II.) The concentration of pepsinogen in blood serum and its rate of excretion in the urine are also increased in patients with duodenal ulcer. (Table II.) Serum and urinary pepsinogen do not fluctuate with short term changes in rate of gastric pepsin secretion produced by stimulation with food or drugs [271. It is reasonable to assume that variations in pepsinogen levels in blood and urine reflect mainly variations in the gastric secretory capacity for pepsin secretion rather than changes in the extent to which this capacity is active. Mucus. That mucus serves to protect the mucosa against digestion by acid and pepsin is an ancient and plausible notion which it is difficult either to prove or refute. The methods AMERlCAN JOURNAL
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Pathologic Physiology of Peptic Ulcer-Gkxman available for measurement of the various kinds of mutinous substances in aspirated gastric juice have failed to reveal differences between persons with and without ulcer [28,29], except to show that increase in acid secretion is correlated with an increase in one class of mucoprotein. Presumably the layer of mucus which separates the mucosal cells from the contents in the lumen is of greatest importance in providing the alleged protection [30]. Study of the aspirated juices may not reflect changes at this critical site. Resolution of the matter awaits the development of suitable methods for study. The same may be said for other factors which are put under the necessarily vague, but probably crucially important, heading of tissue resistance to digestion. Until these factors are identified and means for measuring them are developed little can be said about them. GASTRODUODENAL
MOTILITY
The mean rate of gastric emptying of test meals of saline solution, glucose or acid is normal in patients with duodenal ulcer [a$]. The frequency and amplitude of pressure waves during fasting in the stomach and duodenum of patients with gastric or duodenal ulcer do not differ from those of normal subjects [31]. There is some indication that pressure waves in the stomach and duodenum may be increased in frequency and amplitude during the occurrence of pain from peptic ulcer [31,32]. There is no evidence for the existence of a derangement of gastroduodenal motor activity which might act as a causative factor in peptic ulceration. BLOOD
GROUP
Observations in many countries have established that persons who possess blood group 0 have a higher incidence of peptic ulcer than those with other blood groups. Although some of the individual series which have been reported fail to show a higher than expected incidence of blood group 0 in patients with peptic ulcer, when all reported series are combined and examined by suitable statistical methods the association between blood group 0 and peptic ulcer, both gastric and duodenal, is fully supported [33]. The combined results from all centers show that the risk of having a duodenal ulcer among persons with blood group 0 is approximately 1.4 times the risk among persons with groups A, B or AB. Similarly, the risk of 0 NOVEMBER
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751
subjects having gastric ulcer is 1.2 times that of persons having the other three blood groups. Some have claimed that the association between blood group and gastric ulcer is valid only for ulcers in certain locations in the stomach. Several large recent studies [34,3fl have, however, shown that there is no evidence of an association between blood groups and the site of the ulcer. Several groups [35,36] have noted that the association with blood group 0 is more marked for stoma1 ulcer than for duodenal ulcer. In patients with duodenal ulcer no significant correlation was found between blood group and acid output in response to maximal stimulation with histamine [36]. Another genetic factor which may be involved in the etiology of peptic ulcer is the secretor status. This trait is determined by a single pair of allelic genes independent of those for ABO groups. About 75 per cent of persons secrete ABH substances in saliva and gastric juice (A and H secreted in group A secretors, B and H in group B secretors, A, B and H in group AB secretors, and H in group 0 secretors). Clarke and co-workers [37] found a clear association between ABH non-secretion and duodenal ulcers. The excess incidence of non-secretors was found with equal frequency in patients with all four ABO blood groups. The liability to duodenal ulceration from being simultaneously 0 and non-secretor is at least additive. Thus Clarke and co-workers [37] calculated that 0 non-secretors were 2.49 times more liable; A, B and AB non-secretors 1.60 times more liable; and 0 secretors 1.35 times more liable to develop duodenal ulcer than are A, B and AB secretors. Using fluorescent antibodies, Glynn and coworkers [38] demonstrated that A substance is present in the surface epithelial cells of the stomach and duodenum in A secretors but not in non-secretors. All of these observations invite the speculation that the presence of certain blood group substances in the secretions and cells of the stomach and duodenum in some way protect against duodenal ulceration. Non-secretors of ABH usually secrete much more of another blood group substance, Lewis, than do ABH secretors. The total amount of all blood group substances, as estimated from the fucose content of saliva, has been shown to be the same in secretors and nonsecretors and in subjects with and without
752
Pathologic Physiology of Peptic Ulcer-Gros.man
duodenal ulcer [39]. This suggests that the association between blood groups and secretor status and duodenal ulcer may be related to differences in the properties of A, B, H and Lewis group-specific substances. MISCELLANEOUS OBSERVATIONS
The secretory response of the pancreas to intravenously administered secretin is normal in patients with duodenal ulcer [do]. Certain rare forms of peptic ulcer disease are clearly associated with endocrinopathies [47]. This has led to an interest in endocrine function, particularly adrenocortical, in the usual patient with ulcer. There is no evidence for increased adrenocortical activity in patients with active or inactive peptic ulcers [&I. CONCLUDING REMARKS
Although some patients with duodenal ulcer secrete abnormally large amounts of acid and pepsin, many secrete normal amounts. Patients with prepyloric gastric ulcer have secretory patterns similar to those with duodenal ulcer. Ulcer of the body of the stomach is associated with decreased acid secretion. The secretory levels of these various groups are to a large extent determined by the amount of glandular tissue in the stomach; alterations in the amount of stimulation playing upon the glands may contribute but have not as yet been clearly established. Because many instances of gastroduodenal ulceration cannot be ascribed to hypersecretion of acid-pepsin, a decrease in resistance of the mucosa to ulceration is postulated but means of measuring this factor are, as yet, lacking. No characteristic alterations in gastroduodenal motor activity exist in patients with peptic ulcer, except perhaps during periods of pain. The demonstration that persons with blood group 0 and persons who are non-secretors of ABH substances are more likely to have duodenal ulcer has established the existence of a genetic factor in this disease and has opened new avenues for research on its pathogenesis. REFERENCES 1. ATKINSON,M. and HENLEY, K. S. Levels of intragastric and intraduodenal acidity. Clin. SC., 14: 1, 1955. 2. GROSSMAN, M. I. Unpublished data. 3. ROTH,J. L. A. Clinical evaluation of the caffeine gastric analysis in duodenal ulcer patients. Gostroenterology,19: 199, 1951.
4. LITTMAN, A., Fox, B. W., KAMMERLING,E. M. and FOX, N. I. A single aspiration caffeine gastric analysis in duodenal ulcer and control patients. Gastsoenterology,28: 953, 1955. 5. IHRE, B. J. E. Human Gastric Secretion. London, 1939. Oxford University Press. 6. KAY, A. W. Effect of large doses of histamine on gastric secretion of HCI. Brit. M. J.. 2: 77. 1953. 7. H~RRERA, L. The precision of percentiles in establishing normal limits in medicine. J. Lab. &? Clin. Med., 52: 34, 1958. 8. HUNT, J. N. Influence of hydrochloric acid on secretion and emptying in patients with duodenal ulcer. Brit. M. J., 1: 681, 1957. 9. HUNT, J. N. Inhibition of gastric emptying and secretion in patients with duodenal ulcer. Lance& 1: 132, 1957. 10. DRAGSTEDT,L. R. A concept of the etiology of gastric and duodenal ulcers. Gastroenterology,30: 208,1956. Il. GROSSMAN,M. I. Is the hypersecretion observed in duodenal ulcer patients due to excessive vagal stimuli to the stomach? Gustroenterology, 13: 91, 1948. 12. OBERHELMAN,J. A., JR. and DRAGSTEDT,L. R. Effect of vagotomy on gastric secretory response to histamine. Proc. Sot. Exper. Biol. & Med., 67: 336, 1948. 13. GROSSMAN,M. I. Inhibition of gastric and salivary secretion by Darbid. Gastroenterology, 35: 312, 1958. 14. COX, A. J. Stomach size and its relation to chronic peptic ulcer. Arch. Path., 54: 407, 1952. 15. CARD, W. I. and MARKS, I. N. The relationship between the acid output of the stomach following “maximal” histamine stimuIation and the parietal cell mass. Clin. SC., 19: 147, 1960. 16. BRUCE,J., CARD, W. I., MARKS, I. N. and SIRCUS, W. The rationale of selective surgery in the treatment of duodenal ulcer. J. Roy. Coil. Surgeons, 4: 85, 1959. 17. HUNT, J. N. Some notes on the pathogenesis of duodenal ulcer. Am. J. Digest. Dis.: 2: 445, 1957. 18. HUNT. J. N. and KAY. A. W. The nature of pastric hypkrsecretion of adid in patients with dugdenal ulcer. Brit. M. J., 2: 1444, 1954. 19. Sr~cus, W. The aetiology of peptic ulcer. In: Peptic Ulceration, a Symposium for Surgeons. Edited by Wells, C. and Kyle, J. Edinburgh, 1960. E. & S. Livingstone, Ltd. 20. MARKS, I. N. The effect of prolonged histamine stimulation on the parietal cell population and the secretory function of the guinea-pig stomach. Quart. J. Exper. Physiol., 42: 180, 1957. 21. DOLL, R., JONES,F. A. and MCLAGAN, N. F. Gastric secretion and subsequent dyspepsia. Lancet, 2: 984, 1949. 22. LEVIN, E., KIRSNER,J. 3. and PALMER,W. L. Twelve hour nocturnal gastric secretion in uncomplicated duodenz%l ulcer patients; before and after healing. Proc. Sot. Exper. Biol. &. Med., 69: 1.53, 1948. 23. BORO, I. Gastric flow and acidity before and after Billroth I and Billroth II for gastro-duodenal ulcer. Acta chir. scandinav.,supp. 253, p. I, 1959. 24. MARKS. I. N. and SHAY, H. Observations on the pathogenesis of gastric ulcer. Lancet, 1: 1107, 1959. 25. MIRSKY, A. I. Physiologic, psychologic, and social AMERICAN
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determinants in the etiology of duodenal ulcer. Am. J. Digest. Dis., 3: 285, 1958. SEOAL, H. L., MILLER, L. L., REICHMAN,F., PLUMB, E. J. and GLASER, G. L. Proteolytic enzyme activity. I. Urinary proteofytic activity at pH 1.5 in adults. Gastro&terology, 33: 557, 1957. HIRSCHOWITZ,B. I. Pepsinogen: its origins, secretion and excretion. Physiol. Rev., 37: 475, 1957. GLASS, G. B. J. and BOYD, L. J. Patterns of response of gastric mucoprotein and acid to insulin: correlation with underlying disease in the nonoperated stomach of man. Gastroenterology, 15: 439, 1950. GLASS, G. B. J., STEPHANSON, L. and RICH, M. Paper electrophoretic analysis of gastric juice in health and disease and its physiological and clinical significance. Gastroenterologia, 86: 384, 1956. HEATLEY, N. G. Mucosubstance as a barrier to diffusion. Gastroenterology, 37: 313, 1959. SMITH, H. W., TEXTER, E. C., JR., STICKLEY,J. H. and BARBORKA,C. J. Intraluminai pressures from the upper gastrointestinal tract. II. Correlations with gastroduodenal motor activity in normal subjects and patients with ulcer distress. Gastroenterology, 32: 1025, 1957. HIGHTOWER, N. C., JR. and GAMBILL, E. E. The effects of Banthine on pain and antral gastric motility in patients with duodenal ulcer. Gastroenterology, 23: 244, 1953. ROBERTS,J. A. F. Blood groups and susceptibility to disease: a review. Brit. J. Preu. @ Social Med., 11: 107,1957.
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34. BEASLEY, W. H. Blood groups of gastric ulcer and carcinoma. Brit. M. J., 1: 1167, 1960. 35. DOLL, R., SWYNNERTON,B. F. and NEWELL, A. C. Observations on blood group distribution in peptic ulcer and gastric can&. G&t, 1: 31, 1960. 36. BROWN. D. A. P.. MELROSE, A. G. and WALLACE. J. The blood grobps in peptic ulceration. Brit. M. ‘J., 2: 135, 1956. 37. CLARKE, C. A., EVANS,D. A. P., MCCONNELL, R. B. and SHEPPARD, P. M. Secretion of blood group antigens and peptic ulcer. Brit. M. J., 1: 603, 1959. 38. GLYNN, L. E., HOLBOROW,E. J. and JOHNSON,G. D. The distribution of blood-group substances in human gastric and duodenal mucosa. Luncet, 2: 1083, 1957. 39. EVANS, D. A. P. The fucose and agglutinogen contents of saliva in subjects with duodenal ulcer. J. Lab. & Clin. Med., 55: 386, 1960. 40. DREILING, D. A. Studies in pancreatic function. v. The use of the secretin test in the diagnosis of pancreatitis and in the demonstration of pancreatic insufficiencies in gastrointestinal disorders. Gastroenterology, 24: 540, 1953. 41. FISHER, E. R. and FLANDREAU, R. H. Multiple endocrine tumors and peptic ulcer. Gastroenterology, 32: 1075, 1957. 42. SLEISENGER,M. H., LEWIS, C. M., LIPKIN, M. and WIERUM, C. Uropepsin and 17-hydroxycorticoid excretion in normal subjects and patients with peptic ulcer during both states of activity and quiescence. Am. J. Med., 25: 395, 1958.