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CAN PSYCHIC STIMULATION CAUSE GASTRIC ACID SECRETION IN MAN ?
66
in one of these high levels were detected in the plasma. CAN PSYCHIC STIMULATION CAUSE Melvin and Tashjian (1968) described a patient with GASTRIC ACID SECRETION IN MAN ? medullary carcinoma, hypocalcaemia, and raised levels of H. M. CRAWSHAW D. M. PHASER In a hypocalcaemic factor in both tumour and blood. this case thyroidectomy had been done previously, and T. S. WARRENDER analysis was made difficult by the presence of severe PRECLINICAL MEDICAL STUDENTS, UNIVERSITY OF EDINBURGH diarrhoea, widespread metastases, and bilateral phseoGastric acid secretion in response to chromocytomas. Meyer and Abdel-Bari (1968) found Sum ary in tumour carcinoma activity hypocalcæmic medullary psychic stimulation of appetite was meatissue, but did not investigate the plasma. In all these sured on sixteen normal medical students. After a latent cases the hypocalcaemic factor was not shown to have the period of 10-20 minutes, secretion increased, reaching a properties of calcitonin in gel filtration, countercurrent mean value of 3·8 meq. per hour. The maximum reached distribution, or tissue-culture. Our observations with in any one subject was 3-6 meq. in 20 minutes. these techniques provide strong evidence that the hypoIntroduction calcaemic activity is calcitonin. The observations of IN 1852 Bidder and Schmidt observed that the mere Milhaud et al. (1968), Melvin and Tashjian (1968), and Meyer and Abdel-Bari (1968) together with our findings in sight of food provokes secretion of gastric juice in dogs, and the acid content of this juice has been repeatedly this case, and unpublished observations of other cases, measured in subsequent studies on animals (Jemerin et al. make it likely that medullary carcinoma usually produces calcitonin. 1943, Burstall and Schofield 1953, Sircus et al. 1963). In man Bulavinzev in 1903 demonstrated similar secretion of The normal plasma-calcium levels found in this case require some explanation since calcitonin is active in juice, but Bennett and Venables (1920) failed, even with In the two man (Foster, Joplin, MacIntyre, et al. 1966). light hypnosis. We have "not found any measurement of its acid content, except in Tom " (Wolf and Wolff 1947), cases reported by Milhaud et al. (1968) plasma-calcium who had a gastric fistula. We present evidence of gastric levels were not discussed, but Melvin and Tashjian (1968) acid production in normal man, before tasting or eating found hypocalcaemia in their case. One possibility is that an increased secretion of parastarts, during psychic stimulation of appetite. thyroid hormone, together with the continued responsiveSubjects and Methods ness of the tumour to normal stimuli, maintained normoThe work was done over one academic term as a practical calcsemia. Studies of the level of parathyroid hormone in teaching experiment. The subjects were sixteen healthy thirdthis patient are incomplete but the parathyroid glands year male medical students. They had had a liquid breakfast showed no evidence of hyperplasia. (i.e., tea or coffee, with milk and sugar as desired) 2 or more hours previously. They passed a Levine nasogastric tube, size Another explanation for the absence of hypocalcaemia 14FG, into their stomachs. The position of the tube tip at the that a normal be It is considered. usually thought may lowest Rart of the greater curvature was verified by radiological plasma-calcium depends on active resorption of bone in the erect screening Preliminary measurements (McLean and Urist 1961). But if resorption normally made it possible to ensureposition. that the skin dose received was never plays little part, its inhibition by calcitonin would not more than 400 mr, and one subject was rejected because in his produce hypocalcaemia. If this explanation is correct, it case the tube had bent on itself so that the tip lay high in the means that the action of parathyroid hormone on bone is fundus; it proved impossible to achieve a satisfactory location not important in plasma calcium regulation in healthy within the brief screening time permissible, and his aspirates contained less acid than those of any other subject. adults. This conflicts with accepted theories of calcium Subjects then lay horizontal on their left side. For the 1st homoeostasis (McLean and Urist 1961). The evidence is hour they aspirated gastric contents continuously, either by a insufficient to choose between these hypotheses to explain mechanical pump producing a negative pressure not exceeding the absence of hypocalcæmia in this patient, and further 30 mm. Hg, or by gentle syringe suction. During this period studies are necessary. they selected the meal to be cooked for them by their colleagues The demonstration that medullary carcinoma of the in the second half of the experiment. This consisted of such thyroid may contain and secrete high levels of calcitonin items as soup, fried sausage, bacon, egg, chips, and rice. Gastric is of great interest. It shows that medullary carcinoma contents were collected in 15-minute instalments. The subjects then walked to the room where their meal was originates from the C cells. There is also a practical being cooked, and again lay on their left side for an hour. consequence. It may be possible to diagnose medullary carcinoma preoperatively by measuring plasma-calcitonin Aspiration continued as before. During this period subjects levels, and recurrence might also be detected at an early did not swallow their saliva, and dental packs were employed to absorb it. Subjects removed their nasogastric n1bes at the stage. Finally, the investigation of further cases offers a unique DR. CUNLIFFE AND OTHERS: REFERENCES—continued opportunity to study the role of calcitonin in human
physiology. This work was supported in part by grants from the Medical Research Council, Ciba Limited, and the Wellcome Trust. We thank Dr. J. A. Parsons and the statistical staff of the division of biological standards, National Institute for Medical Research, Mill Hill, for assistance with the computer analysis of the bioassay results. REFERENCES
Bussolati, G., Pearse, A. G. E. (1967) J. Endocr. 37, 205. Foster, G. V., Joplin, G. F., MacIntyre, I., Melvin, K. E. W., Slack, E. (1966) Lancet, i, 107. MacIntyre, I., Pearse, A. G. E. (1964) Nature, Lond. 203, 1029. Kumar, M. A., (1967). Personal communication. —
— Slack, E., Edwards, A., Soliman, H. A., Baghdiantz, A., Foster, G. V., MacIntyre, I. (1965) J. Endocr. 33, 469. Laljee, H. C. K., Smith, R. N., Dorrington, K. J. (1967) ibid. 39, 507. McLean, F. C., Urist, M. R. (1961) in Bone, 2nd. ed; p. 124. Chicago Melvin, K. E. W., Tashjian, A. H., Jr. (1968) Proc. natn. Acad. Sci. U.S.A. 59, 1216. Meyer, J. S., Abdel-Bari, W. (1968) New Engl. J. Med. 278, 523. Milhaud, G., Tubiana, M., Parmentier, C., Coutris, G. (1968) C. r. hebd. Séanc., Acad. Sci. Paris, Sér. D. 266, 608. Moseley, J. M., Matthews, E. W., Breed, R. H., Galante, L., Tse, A., MacIntyre, I. (1968) Lancet, i, 108. Pearse, A. G. E., Carvalheira, A. F. (1967) Nature, Lond. 214, 929. Reynolds, J. J. (1968) Personal communication. Williams, E. D. (1966) J. clin. Path. 19, 114. (1967) ibid. 20, 395. — Pollock, D. J. (1966) J. Path. Bact. 91, 71. —
67
Fig. 1-Human gastric acid secretion before and during psychic stimulation of appetite (mean±S.E.M.).
end of the experiment and began their meal. The quarter-hour aspirates were titrated against 0-1 N sodium hydroxide, with phenol-red as indicator. Sodium-hydroxide solutions were standardised on each occasion by titration against a master solution of 0.1 N HC1. Similar techniques were used
to measure
the response
to
kg. subcutaneously in twenty-two other similar male subjects, but no meal was prepared nor expected.
pentagastrin
6 µg. per
Results
Four subjects did not complete the experiment, and those providing three or four 15-minute measurements after stimulation were accepted. Fig. 1 shows the mean acid production of these subjects. In three cases no final reading was available, because the tube became too uncomfortable to retain for the final 15 minutes. In response to intubation, an increased output was observed; the output then fell to a minimum in the first 15-minute period of psychic stimulation. This was followed by a steady increase in acid output during the stimulation, reaching a maximum of 3-8 meq. per hour in the third 15-minute period. The outputs during the first and third 15-minute periods of stimulation differ signifi-
only
cantly (student’s
t test:
0005 >p>0.001).
Fig. 2-Human gastric acid secretion before and during psychic stimulation of appetite in four subjects. The start of teasing with food is indicated by an arrow.
In the above procedure food was discussed with many subjects before the end of the first hour, when they chose their menu. It could be argued that this was the start of psychic stimulation, and that the results obtained show that psychic stimulation inhibits acid secretion by the stomach. Consequently an additional experiment was undertaken with four subjects, taking great care to ensure that they knew nothing of the forthcoming meal until after the basal secretion period. Also in this experiment the subjects had fasted for 12 hours previously; basal secretion was collected for 2 hours instead of 1 hour; all secretion was pooled in 20-minute instead of 15-minute instalments; and after the first 20-minute period of psychic stimulation the subjects were repeatedly " teased " with food being cooked. The results in these four subjects are shown in fig. 2. Increase in output was again observed during the first hour in all four subjects, but in three of the four subjects output fell thereafter to a minimum in the last 20-minute period before the stimulus was applied. Thus a progressive fall or a flattening out of secretion occurred in the 2nd hour in the absence of psychic stimulation. When the stimulus was applied there was a rise in acid output, especially marked when " teasing " was introduced. These results do not suggest that psychic stimulation inhibits acid secretion, nor that choosing food has any effect on acid secretion. In the experiment using pentagastrin as the stimulus to gastric secretion, the maximal output over a 15-minute period was found for each subject. The mean value for twenty-two subjects was 36-0 (±S.E.M. 2-0) meq. per hour. Discussion The results indicate that, after a latent interval of the order of 10-20 minutes, a definite increase in gastric acid secretion is obtained when the thought, sight, and smell of food are encountered, and an even greater increase when teasing is introduced. However, the values we describe may not represent the normal amount of hydrochloric acid secreted before a meal. Irritation or distaste produced by the nasogastric tube might stimulate or inhibit gastric acid secretion. We find an anticipatory response reaching about 11% of the maximal response produced by pentagastrin. Preshaw and Webster (1967) found in dogs that teasing with food evokes about 27% of the maximal response produced by gastrin extract. It is therefore possible that our value is an underestimate. However, Wolf and Wolff (1947) evidently found that " Tom ", who had a gastric fistula, produced a total of 2-1 meq. of acid during half an hour’s discussion of appetising food, which was followed by the tasting of food (apparently Tom’s basal secretory rate was about half as much); this value is of the same order as those we obtained. But maximum production by one of the subjects was 3-6 meq. per 20 minutes, which is equivalent to 10-8 meq. per hour, and is 30% of the average maximal response obtained using pentagastrin-a proportion similar to that obtained by Preshaw and Webster in dogs. Failure to collect all the gastric juice would cause our values to be too low. However, the acid response to pentagastrin injection, measured by an identical technique, is the same as that reported by Johnson and Jepson (1967), is comparable to the personal responses of McManus and Makhlouf (Makhlouf et al. 1966), and appears larger than that of normal subjects in other studies (Konturek 1966, Wormsley et al. 1966, Multicentre Pilot Study 1967). The true physiological response may be smaller than our measurement. This is because, in the erect posture,
68
rapidly reach the antrum, and its inhibits there gastrin production (Woodward presence et al. 1954). Burstall and Schofield (1953, 1954) have shown that, in dogs, gastrin is responsible for a significant part of gastric acid secretion, even before food has entered the stomach. The ancient Greeks and Romans habitually ate their meals in the left lateral position (Plutarch C.A.D. 90); if they did so in the interests of comfort (Fowler 1909) it is strange that we no longer follow their example. We surmise that, in this posture, more anticipatory secretion will be produced, since the pool in the stomach may become larger before acid reaches the antrum. Thus digestion of a substantial meal might commence more promptly. We should like to thank Dr. J. M. Forrester, of the Physiology Department, University of Edinburgh, and Dr. W. Sircus, Gastrointestinal Unit, Western General Hospital, Edinburgh, for invaluable help and criticism; Dr. J. B. King, of the Anatomy Department, University of Edinburgh, for carrying out the radiological screening; Imperial Chemical Industries Ltd. for the supply of pentagastrin; Mr. V. G. Cattrell, of the Medical Physics Department, University of Edinburgh, for providing measurements of X-ray dosage and advice on precautions; and our fellow medical students for acting as subjects and as their own technicians. Requests for reprints should be addressed to H. M. C., c/o Dr. J. M. Forrester, Department of Physiology, University Medical School, Edinburgh 8.
mechanism causing malnutrition in cœliac syndrome. Exfoliative enteropathy seems an appropriate term for describing this mechanism. Introduction IN coeliac syndrome the small-intestinal mucosa loses villi and becomes flat or convoluted. There is thus a substantial loss of absorptive area, which probably accounts for much of the alteration in absorptive function. However, it is difficult to account for some of the clinical features of coeliac syndrome by the loss of absorptive capacity alone. We have been interested in the possibility that endogenous substances may be lost into the smallbowel lumen, and that this may be a mechanism causing malnutrition in patients with coeliac syndrome. In the small intestine there is a rapid turnover of epithelial cells and at the end of their life-span these cells are shed into the lumen of the gut. This cell-loss has been measured by estimating the rate of accumulation of deoxyribonucleic acid (D.N.A.) , in the lumen (Croft, Loehry, Taylor, and Cole 1968b), and there is evidence that the method reflects intestinal epithelial turnover (Loehry, Croft, Singh, and Creamer 1968). In the cceliac syndrome the turnover of epithelial cells is abnormal (Creamer 1962), but the rate of loss of cells from the REFERENCES mucosa has not been measured. In this study we have Bennett, T. I., Venables, J. F. (1920) Br. med. J. ii, 662. measured small-bowel D.N.A.-loss rates in patients with Bidder, F. H., Schmidt, C. E. H. (1852) Die Verdauungsäfte und der coeliac syndrome in remission and relapse. Stoffwechsel. Leipzig. Bulavinzev (1903) Cited by Pavlov, I .P. (1910) The Work of the Digestive Patients and Methods Glands; p. 90. London. Small-bowel D.N.A.-loss rates were measured on sixteen Burstall, P. A., Schofield, B. (1953) J. Physiol., Lond. 120, 383.
any acid secreted may
,
(1954) ibid. 123, 168. Fowler, W. W. (1909) Social Life in the Age of Cicero; p. 280. London. E. E., Hollander, F., Weinstein, V. A. (1943) Gastroenterology, 1, Jemerin, —
occasions in eleven patients with coeliac syndrome. There were seven women and four men, and their average age was 47 years (see table). The clinical presentation andfeatures of malnutrition varied, and included steatorrhoea with weight-loss, iron and folic-acid deficient anaemia, hypoproteinaemia, and neuropathy. Six of these subjects (nos. 1, 3, 5, 7, 10, and 11) had not had the usual dramatic response to gluten withdrawal. The patients had been under observation from 4 months to 5 years, and at the time of the tests their clinical states and therapeutic regimens varied. Patients 1-7 were in clinical remission, for their recorded weights had been steady (±L5 kg.) for 6-40 weeks. Patient 3 was studied on two occasions when in this clinical state. Patients 8, 9, and 11 were studied when in relapse, with weight loss ( > 5 kg.), at a time when they were on no treatment. Small-bowel D.N.A.-loss rates were measured on patients 10 and 11 during relapses which had not responded to a gluten-free diet. Patients 8, 10, and 11 were studied again when a remission had been induced by a gluten-free diet, or prednisone, and they
—
500.
Johnson, D., Jepson, K. (1967) Lancet ii, 585. Konturek, S. J. (1966) Am. J. dig. Dis. 12, 285. Makhlouf, G. M., McManus, J. P. A., Card, W. I. (1966) Gastroenterology, 51, 455. Multicentre Pilot Study (1967) Lancet, i, 291. Plutarch (C.A.D. 90) Quæstionum Convivialium, vol. v, p. 6. Preshaw, R. M., Webster, D. R. (1967) Q. Jl exp. Physiol. 52, 37. Sircus, W., Huston, C. J. W., Preshaw, R. M., Barshaw, H., Harkness, R. A. (1963) Gut, 4, 42. Wolf, S., Wolff, H. G. (1947) Human Gastric Function; p. 131. New York. Woodward, E. R., Lyon, E. S., Lander, J., Dragstedt, L. R. (1954) Gastroenterology, 27, 766. Wormsley, K. G., Mahoney, M. P., Ng, M. (1966) Lancet, i, 993.
SMALL-BOWEL CELL-LOSS AND WEIGHT-LOSS IN THE CŒLIAC SYNDROME D. N. CROFT D.M. Oxon., M.R.C.P.
C. A. LOEHRY M.D. Cantab., M.R.C.P.
SENIOR MEDICAL REGISTRAR
SENIOR MEDICAL REGISTRAR
were
B. CREAMER M.D. Lond., F.R.C.P. PHYSICIAN
ST.
THOMAS’S HOSPITAL,
LONDON
gaining weight.
The method of measuring the small-bowel D.N.A.-loss rate has been described (Croft et al. 1968b). Bilirubin was used as a marker of contamination of the distal specimens, and was 0-5 mg. per 100 ml. or less in all studies. The recovery of polyethylene glycol (P.E.G.) in these studies did not differ significantly from that in seven control patients, in whom the range of small-bowel D.N.A.-loss rates was 84-173 (mean 120) mll-g. atoms D.N.A.-P per minute.
S.E.1
Results
Small-bowel D.N.A.-loss rates were Summary Summary measured on sixteen occasions in eleven patients with cœliac syndrome. During clinical relapse associated with weight-loss, the mean D.N.A.-loss rate was 39·8 (S.D. 19·0) mµg. atoms D.N.A.-P per minute, which was significantly higher than that of patients with cœliac syndrome in remission (mean 9·5, S.D. 3·8). In three patients, high small-bowel D.N.A.-loss rates fell to normal after a remission had been induced. It is suggested that: high epithelial turnover may cause excessive loss of: endogenous substances, and that this may be an important: .
Small-bowel D.N.A.-loss rates were measured on four patients who at the time were not on a gluten-free diet. One of these patients (no. 2) was symptom free, having had oral iron and folic-acid treatment for anaemia. Her weight was steady and her small-bowel D.N.A.-loss rate was within the normal range, being 8-1 m!1-g. atoms D.N.A.-PP per minute. The other three patients (nos. 8, 9, and 11) were ill, having lost 57-73 kg. body-weight, and their small-bowel D.N.A.-loss rates were 20-6, 36-9, and 71-8, respectively; these were all above our normal range (fig. 1). Nine patients were studied when on a gluten-free diet.
in one of these high levels were detected in the plasma. CAN PSYCHIC STIMULATION CAUSE Melvin and Tashjian (1968) described a patient with GASTRIC ACID SECRETION IN MAN ? medullary carcinoma, hypocalcaemia, and raised levels of H. M. CRAWSHAW D. M. PHASER In a hypocalcaemic factor in both tumour and blood. this case thyroidectomy had been done previously, and T. S. WARRENDER analysis was made difficult by the presence of severe PRECLINICAL MEDICAL STUDENTS, UNIVERSITY OF EDINBURGH diarrhoea, widespread metastases, and bilateral phseoGastric acid secretion in response to chromocytomas. Meyer and Abdel-Bari (1968) found Sum ary in tumour carcinoma activity hypocalcæmic medullary psychic stimulation of appetite was meatissue, but did not investigate the plasma. In all these sured on sixteen normal medical students. After a latent cases the hypocalcaemic factor was not shown to have the period of 10-20 minutes, secretion increased, reaching a properties of calcitonin in gel filtration, countercurrent mean value of 3·8 meq. per hour. The maximum reached distribution, or tissue-culture. Our observations with in any one subject was 3-6 meq. in 20 minutes. these techniques provide strong evidence that the hypoIntroduction calcaemic activity is calcitonin. The observations of IN 1852 Bidder and Schmidt observed that the mere Milhaud et al. (1968), Melvin and Tashjian (1968), and Meyer and Abdel-Bari (1968) together with our findings in sight of food provokes secretion of gastric juice in dogs, and the acid content of this juice has been repeatedly this case, and unpublished observations of other cases, measured in subsequent studies on animals (Jemerin et al. make it likely that medullary carcinoma usually produces calcitonin. 1943, Burstall and Schofield 1953, Sircus et al. 1963). In man Bulavinzev in 1903 demonstrated similar secretion of The normal plasma-calcium levels found in this case require some explanation since calcitonin is active in juice, but Bennett and Venables (1920) failed, even with In the two man (Foster, Joplin, MacIntyre, et al. 1966). light hypnosis. We have "not found any measurement of its acid content, except in Tom " (Wolf and Wolff 1947), cases reported by Milhaud et al. (1968) plasma-calcium who had a gastric fistula. We present evidence of gastric levels were not discussed, but Melvin and Tashjian (1968) acid production in normal man, before tasting or eating found hypocalcaemia in their case. One possibility is that an increased secretion of parastarts, during psychic stimulation of appetite. thyroid hormone, together with the continued responsiveSubjects and Methods ness of the tumour to normal stimuli, maintained normoThe work was done over one academic term as a practical calcsemia. Studies of the level of parathyroid hormone in teaching experiment. The subjects were sixteen healthy thirdthis patient are incomplete but the parathyroid glands year male medical students. They had had a liquid breakfast showed no evidence of hyperplasia. (i.e., tea or coffee, with milk and sugar as desired) 2 or more hours previously. They passed a Levine nasogastric tube, size Another explanation for the absence of hypocalcaemia 14FG, into their stomachs. The position of the tube tip at the that a normal be It is considered. usually thought may lowest Rart of the greater curvature was verified by radiological plasma-calcium depends on active resorption of bone in the erect screening Preliminary measurements (McLean and Urist 1961). But if resorption normally made it possible to ensureposition. that the skin dose received was never plays little part, its inhibition by calcitonin would not more than 400 mr, and one subject was rejected because in his produce hypocalcaemia. If this explanation is correct, it case the tube had bent on itself so that the tip lay high in the means that the action of parathyroid hormone on bone is fundus; it proved impossible to achieve a satisfactory location not important in plasma calcium regulation in healthy within the brief screening time permissible, and his aspirates contained less acid than those of any other subject. adults. This conflicts with accepted theories of calcium Subjects then lay horizontal on their left side. For the 1st homoeostasis (McLean and Urist 1961). The evidence is hour they aspirated gastric contents continuously, either by a insufficient to choose between these hypotheses to explain mechanical pump producing a negative pressure not exceeding the absence of hypocalcæmia in this patient, and further 30 mm. Hg, or by gentle syringe suction. During this period studies are necessary. they selected the meal to be cooked for them by their colleagues The demonstration that medullary carcinoma of the in the second half of the experiment. This consisted of such thyroid may contain and secrete high levels of calcitonin items as soup, fried sausage, bacon, egg, chips, and rice. Gastric is of great interest. It shows that medullary carcinoma contents were collected in 15-minute instalments. The subjects then walked to the room where their meal was originates from the C cells. There is also a practical being cooked, and again lay on their left side for an hour. consequence. It may be possible to diagnose medullary carcinoma preoperatively by measuring plasma-calcitonin Aspiration continued as before. During this period subjects levels, and recurrence might also be detected at an early did not swallow their saliva, and dental packs were employed to absorb it. Subjects removed their nasogastric n1bes at the stage. Finally, the investigation of further cases offers a unique DR. CUNLIFFE AND OTHERS: REFERENCES—continued opportunity to study the role of calcitonin in human
physiology. This work was supported in part by grants from the Medical Research Council, Ciba Limited, and the Wellcome Trust. We thank Dr. J. A. Parsons and the statistical staff of the division of biological standards, National Institute for Medical Research, Mill Hill, for assistance with the computer analysis of the bioassay results. REFERENCES
Bussolati, G., Pearse, A. G. E. (1967) J. Endocr. 37, 205. Foster, G. V., Joplin, G. F., MacIntyre, I., Melvin, K. E. W., Slack, E. (1966) Lancet, i, 107. MacIntyre, I., Pearse, A. G. E. (1964) Nature, Lond. 203, 1029. Kumar, M. A., (1967). Personal communication. —
— Slack, E., Edwards, A., Soliman, H. A., Baghdiantz, A., Foster, G. V., MacIntyre, I. (1965) J. Endocr. 33, 469. Laljee, H. C. K., Smith, R. N., Dorrington, K. J. (1967) ibid. 39, 507. McLean, F. C., Urist, M. R. (1961) in Bone, 2nd. ed; p. 124. Chicago Melvin, K. E. W., Tashjian, A. H., Jr. (1968) Proc. natn. Acad. Sci. U.S.A. 59, 1216. Meyer, J. S., Abdel-Bari, W. (1968) New Engl. J. Med. 278, 523. Milhaud, G., Tubiana, M., Parmentier, C., Coutris, G. (1968) C. r. hebd. Séanc., Acad. Sci. Paris, Sér. D. 266, 608. Moseley, J. M., Matthews, E. W., Breed, R. H., Galante, L., Tse, A., MacIntyre, I. (1968) Lancet, i, 108. Pearse, A. G. E., Carvalheira, A. F. (1967) Nature, Lond. 214, 929. Reynolds, J. J. (1968) Personal communication. Williams, E. D. (1966) J. clin. Path. 19, 114. (1967) ibid. 20, 395. — Pollock, D. J. (1966) J. Path. Bact. 91, 71. —
67
Fig. 1-Human gastric acid secretion before and during psychic stimulation of appetite (mean±S.E.M.).
end of the experiment and began their meal. The quarter-hour aspirates were titrated against 0-1 N sodium hydroxide, with phenol-red as indicator. Sodium-hydroxide solutions were standardised on each occasion by titration against a master solution of 0.1 N HC1. Similar techniques were used
to measure
the response
to
kg. subcutaneously in twenty-two other similar male subjects, but no meal was prepared nor expected.
pentagastrin
6 µg. per
Results
Four subjects did not complete the experiment, and those providing three or four 15-minute measurements after stimulation were accepted. Fig. 1 shows the mean acid production of these subjects. In three cases no final reading was available, because the tube became too uncomfortable to retain for the final 15 minutes. In response to intubation, an increased output was observed; the output then fell to a minimum in the first 15-minute period of psychic stimulation. This was followed by a steady increase in acid output during the stimulation, reaching a maximum of 3-8 meq. per hour in the third 15-minute period. The outputs during the first and third 15-minute periods of stimulation differ signifi-
only
cantly (student’s
t test:
0005 >p>0.001).
Fig. 2-Human gastric acid secretion before and during psychic stimulation of appetite in four subjects. The start of teasing with food is indicated by an arrow.
In the above procedure food was discussed with many subjects before the end of the first hour, when they chose their menu. It could be argued that this was the start of psychic stimulation, and that the results obtained show that psychic stimulation inhibits acid secretion by the stomach. Consequently an additional experiment was undertaken with four subjects, taking great care to ensure that they knew nothing of the forthcoming meal until after the basal secretion period. Also in this experiment the subjects had fasted for 12 hours previously; basal secretion was collected for 2 hours instead of 1 hour; all secretion was pooled in 20-minute instead of 15-minute instalments; and after the first 20-minute period of psychic stimulation the subjects were repeatedly " teased " with food being cooked. The results in these four subjects are shown in fig. 2. Increase in output was again observed during the first hour in all four subjects, but in three of the four subjects output fell thereafter to a minimum in the last 20-minute period before the stimulus was applied. Thus a progressive fall or a flattening out of secretion occurred in the 2nd hour in the absence of psychic stimulation. When the stimulus was applied there was a rise in acid output, especially marked when " teasing " was introduced. These results do not suggest that psychic stimulation inhibits acid secretion, nor that choosing food has any effect on acid secretion. In the experiment using pentagastrin as the stimulus to gastric secretion, the maximal output over a 15-minute period was found for each subject. The mean value for twenty-two subjects was 36-0 (±S.E.M. 2-0) meq. per hour. Discussion The results indicate that, after a latent interval of the order of 10-20 minutes, a definite increase in gastric acid secretion is obtained when the thought, sight, and smell of food are encountered, and an even greater increase when teasing is introduced. However, the values we describe may not represent the normal amount of hydrochloric acid secreted before a meal. Irritation or distaste produced by the nasogastric tube might stimulate or inhibit gastric acid secretion. We find an anticipatory response reaching about 11% of the maximal response produced by pentagastrin. Preshaw and Webster (1967) found in dogs that teasing with food evokes about 27% of the maximal response produced by gastrin extract. It is therefore possible that our value is an underestimate. However, Wolf and Wolff (1947) evidently found that " Tom ", who had a gastric fistula, produced a total of 2-1 meq. of acid during half an hour’s discussion of appetising food, which was followed by the tasting of food (apparently Tom’s basal secretory rate was about half as much); this value is of the same order as those we obtained. But maximum production by one of the subjects was 3-6 meq. per 20 minutes, which is equivalent to 10-8 meq. per hour, and is 30% of the average maximal response obtained using pentagastrin-a proportion similar to that obtained by Preshaw and Webster in dogs. Failure to collect all the gastric juice would cause our values to be too low. However, the acid response to pentagastrin injection, measured by an identical technique, is the same as that reported by Johnson and Jepson (1967), is comparable to the personal responses of McManus and Makhlouf (Makhlouf et al. 1966), and appears larger than that of normal subjects in other studies (Konturek 1966, Wormsley et al. 1966, Multicentre Pilot Study 1967). The true physiological response may be smaller than our measurement. This is because, in the erect posture,
68
rapidly reach the antrum, and its inhibits there gastrin production (Woodward presence et al. 1954). Burstall and Schofield (1953, 1954) have shown that, in dogs, gastrin is responsible for a significant part of gastric acid secretion, even before food has entered the stomach. The ancient Greeks and Romans habitually ate their meals in the left lateral position (Plutarch C.A.D. 90); if they did so in the interests of comfort (Fowler 1909) it is strange that we no longer follow their example. We surmise that, in this posture, more anticipatory secretion will be produced, since the pool in the stomach may become larger before acid reaches the antrum. Thus digestion of a substantial meal might commence more promptly. We should like to thank Dr. J. M. Forrester, of the Physiology Department, University of Edinburgh, and Dr. W. Sircus, Gastrointestinal Unit, Western General Hospital, Edinburgh, for invaluable help and criticism; Dr. J. B. King, of the Anatomy Department, University of Edinburgh, for carrying out the radiological screening; Imperial Chemical Industries Ltd. for the supply of pentagastrin; Mr. V. G. Cattrell, of the Medical Physics Department, University of Edinburgh, for providing measurements of X-ray dosage and advice on precautions; and our fellow medical students for acting as subjects and as their own technicians. Requests for reprints should be addressed to H. M. C., c/o Dr. J. M. Forrester, Department of Physiology, University Medical School, Edinburgh 8.
mechanism causing malnutrition in cœliac syndrome. Exfoliative enteropathy seems an appropriate term for describing this mechanism. Introduction IN coeliac syndrome the small-intestinal mucosa loses villi and becomes flat or convoluted. There is thus a substantial loss of absorptive area, which probably accounts for much of the alteration in absorptive function. However, it is difficult to account for some of the clinical features of coeliac syndrome by the loss of absorptive capacity alone. We have been interested in the possibility that endogenous substances may be lost into the smallbowel lumen, and that this may be a mechanism causing malnutrition in patients with coeliac syndrome. In the small intestine there is a rapid turnover of epithelial cells and at the end of their life-span these cells are shed into the lumen of the gut. This cell-loss has been measured by estimating the rate of accumulation of deoxyribonucleic acid (D.N.A.) , in the lumen (Croft, Loehry, Taylor, and Cole 1968b), and there is evidence that the method reflects intestinal epithelial turnover (Loehry, Croft, Singh, and Creamer 1968). In the cceliac syndrome the turnover of epithelial cells is abnormal (Creamer 1962), but the rate of loss of cells from the REFERENCES mucosa has not been measured. In this study we have Bennett, T. I., Venables, J. F. (1920) Br. med. J. ii, 662. measured small-bowel D.N.A.-loss rates in patients with Bidder, F. H., Schmidt, C. E. H. (1852) Die Verdauungsäfte und der coeliac syndrome in remission and relapse. Stoffwechsel. Leipzig. Bulavinzev (1903) Cited by Pavlov, I .P. (1910) The Work of the Digestive Patients and Methods Glands; p. 90. London. Small-bowel D.N.A.-loss rates were measured on sixteen Burstall, P. A., Schofield, B. (1953) J. Physiol., Lond. 120, 383.
any acid secreted may
,
(1954) ibid. 123, 168. Fowler, W. W. (1909) Social Life in the Age of Cicero; p. 280. London. E. E., Hollander, F., Weinstein, V. A. (1943) Gastroenterology, 1, Jemerin, —
occasions in eleven patients with coeliac syndrome. There were seven women and four men, and their average age was 47 years (see table). The clinical presentation andfeatures of malnutrition varied, and included steatorrhoea with weight-loss, iron and folic-acid deficient anaemia, hypoproteinaemia, and neuropathy. Six of these subjects (nos. 1, 3, 5, 7, 10, and 11) had not had the usual dramatic response to gluten withdrawal. The patients had been under observation from 4 months to 5 years, and at the time of the tests their clinical states and therapeutic regimens varied. Patients 1-7 were in clinical remission, for their recorded weights had been steady (±L5 kg.) for 6-40 weeks. Patient 3 was studied on two occasions when in this clinical state. Patients 8, 9, and 11 were studied when in relapse, with weight loss ( > 5 kg.), at a time when they were on no treatment. Small-bowel D.N.A.-loss rates were measured on patients 10 and 11 during relapses which had not responded to a gluten-free diet. Patients 8, 10, and 11 were studied again when a remission had been induced by a gluten-free diet, or prednisone, and they
—
500.
Johnson, D., Jepson, K. (1967) Lancet ii, 585. Konturek, S. J. (1966) Am. J. dig. Dis. 12, 285. Makhlouf, G. M., McManus, J. P. A., Card, W. I. (1966) Gastroenterology, 51, 455. Multicentre Pilot Study (1967) Lancet, i, 291. Plutarch (C.A.D. 90) Quæstionum Convivialium, vol. v, p. 6. Preshaw, R. M., Webster, D. R. (1967) Q. Jl exp. Physiol. 52, 37. Sircus, W., Huston, C. J. W., Preshaw, R. M., Barshaw, H., Harkness, R. A. (1963) Gut, 4, 42. Wolf, S., Wolff, H. G. (1947) Human Gastric Function; p. 131. New York. Woodward, E. R., Lyon, E. S., Lander, J., Dragstedt, L. R. (1954) Gastroenterology, 27, 766. Wormsley, K. G., Mahoney, M. P., Ng, M. (1966) Lancet, i, 993.
SMALL-BOWEL CELL-LOSS AND WEIGHT-LOSS IN THE CŒLIAC SYNDROME D. N. CROFT D.M. Oxon., M.R.C.P.
C. A. LOEHRY M.D. Cantab., M.R.C.P.
SENIOR MEDICAL REGISTRAR
SENIOR MEDICAL REGISTRAR
were
B. CREAMER M.D. Lond., F.R.C.P. PHYSICIAN
ST.
THOMAS’S HOSPITAL,
LONDON
gaining weight.
The method of measuring the small-bowel D.N.A.-loss rate has been described (Croft et al. 1968b). Bilirubin was used as a marker of contamination of the distal specimens, and was 0-5 mg. per 100 ml. or less in all studies. The recovery of polyethylene glycol (P.E.G.) in these studies did not differ significantly from that in seven control patients, in whom the range of small-bowel D.N.A.-loss rates was 84-173 (mean 120) mll-g. atoms D.N.A.-P per minute.
S.E.1
Results
Small-bowel D.N.A.-loss rates were Summary Summary measured on sixteen occasions in eleven patients with cœliac syndrome. During clinical relapse associated with weight-loss, the mean D.N.A.-loss rate was 39·8 (S.D. 19·0) mµg. atoms D.N.A.-P per minute, which was significantly higher than that of patients with cœliac syndrome in remission (mean 9·5, S.D. 3·8). In three patients, high small-bowel D.N.A.-loss rates fell to normal after a remission had been induced. It is suggested that: high epithelial turnover may cause excessive loss of: endogenous substances, and that this may be an important: .
Small-bowel D.N.A.-loss rates were measured on four patients who at the time were not on a gluten-free diet. One of these patients (no. 2) was symptom free, having had oral iron and folic-acid treatment for anaemia. Her weight was steady and her small-bowel D.N.A.-loss rate was within the normal range, being 8-1 m!1-g. atoms D.N.A.-PP per minute. The other three patients (nos. 8, 9, and 11) were ill, having lost 57-73 kg. body-weight, and their small-bowel D.N.A.-loss rates were 20-6, 36-9, and 71-8, respectively; these were all above our normal range (fig. 1). Nine patients were studied when on a gluten-free diet.