University of Melbourne.)

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1 6I THE AUTOMATIC REGULATION OF GASTRIC ACIDITY. BY FRANK L. APPERLY, M.A., M.D. (OXON.), D.Sc. (MELB.), AND JOAN H. NORRIS, M.Sc. (MELB.). (From the William MacLeod Laboratory, Department of Pathology, University of Melbourne.) IT is well known that during the course of a fractional test-meal, on a normal subject, the curve representing the acidity of the gastric content rises during the first hour or hour and a quarter, and thereafter falls. For long it was assumed that this fall resulted from the regurgitation of alkaline duodenal contents into the stomach (Boldyreff (i)) with neutralization of the acid therein. In 1926 Apperly(2) investigated this fall in acidity by placing foreign acids in the empty stomachs of normal people, and showed that the fall in acid concentration was due mainly to dilution of the acid by neutral fluid, and only to a small extent to neutralization. In 1928 MacLean and Griffiths(3), using the same and other methods, confirmed these results. Apperly had, however, assumed that, though the acidity fell principally by dilution, the diluting fluid came wholly from the duodenum by regurgitation through the pylorus. MacLean and Griffiths showed conclusively that this was not so, and that the stomach under these conditions can and does secrete a neutral fluid containing sodium chloride, which dilutes and gradually replaces the gastric acid. They state that "the presence of a certain concentration of acid in the stomach inhibits secretion of acid, with the result that a neutral fluid containing chloride is secreted, which, by dilution, reduces the acidity of the gastric contents(3)," and that "slight regurgitation of alkaline fluid into the stomach occasionally takes place, but this plays little or no part in the regulation of gastric acidity (4)." They believe, in fact, that the dilution of acid placed in the stomach takes place wholly or almost wholly by this neutral gastric secretion. In discussing the possible sources of the neutral chloride that appears in the stomach, they point out that "it may come from the mouth (saliva), the duodenum, or the stomach itself." "The saliva contains very

2 REGULATION OF GASTRIC ACIDITY 159 little chloride; its entry into the stomach may be prevented by abstention from swallowing. With regard to duodenal chloride, regurgitation would certainly cause an influx of chloride into the stomach as the Cl' concentration in the duodenal fluids is approximately equal to that of the stomach... but regurgitation is only occasionally responsible. We are therefore left with the only possibility, namely, that the stomach secretes sodium chloride, as we have shown already(3)." Their remarks about the first and third of these possible sources have been proved conclusively, as already stated, but in none of their experiments do they show that regurgitation does not occur. It is true they showed, as Apperly had earlier shown, that neutralization by duodenal alkali accounted for only a small part of the reduction of acid, but reflux of neutral or nearly neutral duodenal fluids was not, so far as we could see from their papers, excluded. We believe that the experiments here recorded cannot be satisfactorily explained by either Apperly's original hypothesis or by the later one of MacLean and his colleagues, but that both phenomena occur, namely, that in the stomach into which acid has been introduced (or secreted) the reduction in acidity takes place mostly by dilution, the diluting fluid being partly secreted by the gastric mucosa, and partly regurgitated from the duodenum, and that, in the majority of cases, the reduction in acidity is partly affected by duodenal alkali in addition. (See Table I.) TABLE I. After placing acid-glucose mixture in stomach Bile Fasting contents appearance Average Aver- Aver- Aver- within volume age age No. Bile Aver- age first left acidity value of Inter- of appear- age total half at 1J at glucose pretation cases ance volume acidity hour hours 1 hour 1 hour Group I. Acid Duodenal 24 9/14* curve lower than regurgitation dilution curve Group II. Acid Dilution by 11 4/7* and dilution curves neutral fluids coincide Group III. Acid Secretion of 8 5/7* curve higher than gastric acid dilution curve in presence of foreign acid Other cases in 3 2/2* 3 which dilution curve was omitted Total 46 * The second figure indicates the number of cases in which observation was made: the first the number in which bile appeared. 11-2

3 160 F. L. APPERLY AND J. H. NORRIS. We were first led to suspect that the explanation of Ma cl e an and his colleagues was incomplete by an inspection of their charts in their third paper(3). Figs. 3, 7 and 8 in their paper, for instance, show the succession of events when acid is placed in the fasting stomach, or the stomach has been stimulated to secrete acid by the administration of alcohol. At quarter-hour intervals the concentration of acid, of neutral chloride and the dilution of an indifferent substance is estimated and curves constructed to show the alterations in these values over a period of time (as in our experiments about to be described). They found that the dilution and acid curves coincided in their fall, while the neutral chloride curve rose. They concluded, as stated above, that the fall in acid concentration was due entirely to dilution by a neutral chloride solution, but assumed that this solution was derived wholly from the gastric wall, and that none entered the stomach by duodenal regurgitation. Beforethis MacLean, Griffiths and Williams(4) had shown that the total chloride concentration in gastric juice is a constant, whether made up of varying amounts of hydrochloric acid and neutral chloride, or of the latter alone. This total chloride has an average value of about 0.11 N. Now in the charts referred to above, the fact that the acid and the dilution curves coincided showed that the stomach was not secreting acid, but neutral chloride only. If this neutral chloride came wholly from the gastric wall it must be of the same concentration throughout. When, however, we calculate the chloride concentration of this diluting fluid, from the dilutioncurve and concentration of neutralchlorides in themied gastric contents, we find that the curve so calculated is not a straight level line but a rapidly rising one. This suggested to us that the neutral chloride secreted by the gastric wall, known to have a fixed concentration, was being mixed in varying proportions with a neutral chloride solution derived from another situation, possibly the duodenum. We, therefore, decided to repeat these experiments in a large series of individuals, in order to investigate the problem still further. EXPERIMENTAL. The experiments were carried out exactly as one of us has described elsewhere (2). 250 c.c. of dilute hydrochloric acid mixed with some indifferent substance which could easily be estimated, were placed in the empty stomach. The strength of acid employed varied from N to 0*128 N and the indifferent substance varied also in different cases, the

4 REGULATION OF GASTRIC ACIDITY 161 substances being glucose, phenol-sulphone-phthalein dye, urea, or ferric chloride. Each experiment was carried out on the fasting subject. The Rehfuss tube was first swallowed, the fasting contents withdrawn by a syringe attached to the tube, the stomach washed out with water till clear, and the acid mixture then run in from a large pipette attached to the R ehf us s tube. At this moment the subject was instructed to expectorate all saliva into a beaker until the end of the experiment. This saliva contained no titratable alkali when phenolphthalein was used as indicator. At 15-minute intervals 10 c.c. samples were withdrawn from the stomach, after mixing the contents thoroughly by moving the piston of the syringe back and forth seven or eight times. In each sample were estimated the concentrations of both acid and glucose (or urea, dye, or iron). The acid was estimated by titration with fresh 0 01 N sodium hydroxide, using phenolphthalein as indicator. When glucose was used MacLean's method was employed: for urea MacLean's urease method; for ferric chloride the method of San Yin Wong(5): and for phenol-sulphonephthalein a Klett colorimeter. In none of the subjects examined did the fasting contents contain glucose, urea, or iron. In all, 57 people were examined by this method, 22 healthy students, 24 hospital patients with no gastric symptoms, and 11 dyspeptics. In the normal group, the results varied, but the majority were similar to that shown in Fig. 1. A study of this shows that the concentration of the acid falls more rapidly than does that of the glucose (or urea, etc.). This indicates that at, say, 1 hour after the administration of the acid mixture the acidity has been reduced from its original strength, mostly by dilution (represented by the distance A, B) but partly by destruction of acid (represented by the distance B, C). As this destruction could occur only by neutralization, and there was no obvious mucus (which may be alkaline) in the specimens, it would appear that duodenal alkali must have been responsible. In other words, duodenal contents had regurgitated into the stomach. Now it has been shown by Baird, Campbell and Hern(6) and other writers that the duodenal fluids may be only slightly alkaline, so that the neutralization of only a small part of the gastric acid might indicate the regurgitation of a fair volume of duodenal fluids. We therefore believe that a part of the dilution of acid in the stomach takes place by duodenal regurgitation as well as by gastric secretion of a neutral fluid. In a number of other cases the acidity curve coincided with the dilution curve (Fig. 2), indicating that the fall of acidity was due entirely to

5 162 F. L. APPERLY AND J. H. NORRIS. dilution by neutral fluids derived from either stomach or duodenum or both. The early presence of bile in many of these cases shows that duodenal fluids were at least partly responsible GROUP I 12 GROUP II 10 -A 24 cases 11 cases 1.00 ' *1*00 leoo (N11@ \ B 0.80 \ B 0* '40 C " 0.40 Dilution Acid 83 Dilution 0-20 _ Acid 0.20 Curves coincide hours hours 1/ Y2 1 1 Y2 Fig. 1. Fig. 2. Fig. 1. Showing curves representing averages of concentration of acid, and dilution of glucose in Group I (alkaline regurgitation group). Fig. 2. Showing curves representing averages of acid concentration and dilution of glucose in Group II (in which both curves coincide). In a third group the dilution curve fell more rapidly than the acidity curve. On occasion the latter even rose to 0103 N, the concentration of the original acid introduced into the stomach being 0O085 N. Obviously in these cases secretion of gastric acid took place in spite of the presence of a foreign acid in the stomach, though Pavlov (7) states that "acid prevents the further secretion of gastric juice when it has accumulated in any considerable quantity in the cavity of the organ." Fig. 3 shows the average acid and dilution curves from this group. In addition, in almost all of these cases, the fasting juice showed a higher acidity and a larger volume than that usually found. It is incidentally interesting that not one of the students in this group was a smoker, though smoking has

6 REGULATION OF GASTRIC ACIDITY been blamed for producing increased gastric secretion estimations in most of this group were made in duplicate. 163 of acid. The 1 * *00 GROUP III 8 cases 0O801 Fig \ \ '.4 \\ Acid hours Showing curves representing averages of acid concentration and dilution of glucose in Group III ("hypersecretion" group). Our reason for examining such a large number of individuals was that we were aware of the very wide range of variation among normal human stomachs, and we wished to avoid the error of generalizing from a small series. Our results are set out in Table I. The results in the dyspeptic group were similar to those detailed above. An examination of this table shows evidence of duodenal regurgitation in 24 cases in Group I (as indicated by divergence of acid and dilution curves), and in three other cases in which the dilution curve figures had been accidentally mislaid; in 6 cases of Group II as shown by the appearance of bile within one-half hour of the commencement of the test, and in none of Group III. This gives a total of 33 cases out of 46 (72 p.c.) in which duodenal regurgitation occurs within the first half hour. We have chosen the first half hour arbitrarily since Mac Lea n and Griffiths state that regurgitation occurs, if at all, only at the very end of the experiment or test-meal, i.e. about 2 hours after the commencement of the test. '4 '4 I, 1 V2 ~~~~~~1/2 '4 Dilution

7 164 F. L. APPERLY AND J. H. NORRIS. When we come to compare the three sets of average curves in Figs. 1 to 3, we find that the acid curve in the " hypersecretion " group (Fig. 3) is highest, and in the regurgitation group (Fig. 1) it is lowest. This is what we might expect. When we compare the average dilution curves, however, this order is reversed, i.e. the acid has been more rapidly diluted in Group III than in the other groups. Possibly this was due to an increased secretion of acid, though there may be other explanations. FURTHER OBSERVATIONS. In 1923 Apperly(s) showed that those individuals who normally had hyperchlorhydria also had high acid curves when 250 c.c. of 0.11 N acid was placed in the stomach, i.e. they were able to reduce their acid only slowly. Conversely, those who normally were hypochlorhydric were able to reduce rapidly a foreign acid placed in the stomach. Later, in 1928, Apperly and Se mmens (9, lo) showed that the height of the acid curve in the fractional test-meal varied, in different individuals, with the value of the ratio Vital capacity of lungs Body weight (i.e. with the oxygenating surface per unit of body weight), and with the tonus and activity of the gastric musculature. We therefore arranged our students in three equal groups according to their values of the ratio vital capacity to weight, and averaged the acidity and dilution curves in each of these groups (Figs. 4 and 5). These figures show that those with a high ratio of vital capacity to weight (people who also have stomachs of good or high tone and activity (9, 10)) also have high acidity and dilution curves. The emptying rates of each group were about the same. If, as is often stated, the hypertonic stomach secretes more gastric juice, we should expect this group to have the lowest dilution and acidity curves when a foreign acid is placed in the stomach. But, if these curves are governed partly by duodenal regurgitation, we should expect less regurgitation to take place into the hypertonic active stomach than into the less active stomach, since the retropulsive forces in the duodenum are antagonized by the propulsive forces of the stomach. In this latter case, a diminished regurgitation would mean higher acidity and dilution curves, which is the state of affairs found. These observations therefore support the theory that early duodenal regurgitation is at least partly responsible for the regulation of gastric acidity.

8 REGULATION OF GASTRIC ACIDITY 165 DISCUSSION. We believe that the fractional test-meal is an important means of determining what the stomach is doing under the conditions of the test. _ _ \\ ~ N * \. x hours II V2 1 11/2 V2 1 11/2 Fig. 4. Fig. 5. Fig. 4. Showing curves representing the averages of acid concentration in individuals grouped according to the value of the ratio of pulmonary vital capacity (in c.c.) to body weight (in kg.). (Ordinates represent concentration 0.1 N.) Fig. 5. Showing curves representing averages of glucose concentration in individuals grouped according to the value of the ratio of pulmonary vital capacity (in c.c.) to body weight (in kg.). (The curves have been reduced to the same scale as the acidity curves in Fig. 4.) Until lately, however, our interpretation of the acidity and other curves has always rested on the assumption that duodenal regurgitation takes place, and is partly responsible for the fall of the acid curve. Obviously it is important to determine if, in fact, regurgitation does normally occur. Bolton( 1) has published a mass of evidence supporting the theory of duodenal regurgitation, but we will content ourselves here by stating that interpretations of the fractional test-meal curves based on the assumption that regurgitation normally occurs, fit the clinical I

9 166 F. L. APPERLY AND J. H. NORRIS. facts. If the fall in the acidity curve during the second hour of a fractional test-meal is really due in part to regurgitation of duodenal fluids, then we should expect any interference with this mechanism to result in a steadily rising acid curve instead of that normally found. Such interference might follow: (a) Failure of pancreatic secretion due to disease of the pancreas or its ducts. Apperly and Cameron(12), in 1923, showed that in pancreatic disease a steadily rising curve characterized the test-meal, while a foreign acid in the stomach was reduced very slowly. On this latter fact they based their test for pancreatic efficiency, and in practice it has proved its value. (b) Failure of the retropulsive forces in the duodenum to overcome / I I 1 hours J/ I I 0 V2 1 1V2 Q 1/2 1 11/2 Mrs M. S., aet. 40. Hour-glass stomach. Fig. 6. Hour-glass stomach. Curves of acidity, chlorides, and dilution in each pouch after placing a mixture of hydrochloric acid and dye in each.

10 REGULATION OF GASTRIC ACIDITY 167 the propulsive forces of the stomach at certain moments during the period of the experiment or test. This might be due to marked atonicity of the gastro-intestine, to a powerful rapidly emptying stomach, to any form of pyloric obstruction, tonic or organic, or to any influence which interferes with the ability of the stomach to relax during the period of regurgitation, such as hypertonicity or organic fibroses. In all the above types of interference with normal gastric function, the acidity curve rises steadily without any fall, as is well known to all those familiar with fractional test-meal work. Fig. 6 illustrates interestingly the failure of duodenal regurgitation in a female patient aged 40, with an "hour-glass" stomach, as shown by X-ray examination. She had a syphilitic history and a strongly positive Wassermann reaction. A Rehfuss tube was passed into each pouch under an X-ray screen, and into each pouch was passed, by the method explained above, about 140 c.c. of 0*118 N hydrochloric acid mixed with some phenol-sulphone-phthalein dye. The graphs show that in neither pouch was there any acid secretion, or alkaline or bile regurgitation. In the first half hour the fall in the lower pouch was more rapid than in the upper pouch, suggesting some regurgitation. On the whole, however, both curves are nearly the same, the fall in both being undoubtedly due almost entirely to gastric secretion of a neutral fluid. In a similar experiment recorded by Bolton(11) in which, however, gruel was placed in the stomach instead of acid, alkaline regurgitation undoubtedly took place into the lower pouch. CONCLUSIONS. 1. When acid above a certain concentration enters the normal stomach, whether it is secreted or artificially placed there, in the majority of cases the concentration is reduced mainly by dilution, but partly by neutralization. The diluting fluid is derived partly from the gastric wall and partly from the duodenal fluids. 2. In a few cases no alkali appears in the duodenal fluids, and in a few others gastric acid is secreted even in the presence of a foreign acid. 3. There was evidence of early duodenal regurgitation in 72 p.c. of 46 cases examined. ACKNOWLEDGMENTS. Our thanks are due to Prof. P. MacCallum for his help and suggestions, and to the Edward Wilson (The Argus) Trust for their kind gift of funds to cover the expenses of this work.

11 168 F. L. APPERLY AND J. H. NORRIS. REFERENCES. 1. Boldyreff. Quart. J. Exp. Physiol. 8. p Apperly. Brit. J. Exp. Path. 7. p MacLean and Griffiths. This Journ. 66. p MacLeanandGriffiths. Ibid. 65. p MacLean, Griffiths and Williams. Ibid. 65. p San Yin Wong. J. Biol. Chem. 77. p Baird, Campbell and Hern. Guy's Hosp. Rep. 74. p Pavlov. The Work of the Digestive Glands. (Thompson's translation.) Griffin: London, Apperly. Med. J. Australia, 1. p Apperly and Semmens. Ibid. 2. p Apperly and Semmens. Ibid. 2. p Bolton. Lancet, i. p Apperly and Cameron. Med. J. Australia, 1. p