EDITORIAL

New Dimensions in Digestive Physiology

Elsewhere in this issue, Malagelada et al (1) have attempted to quantitate secretory responses and gastric emptying patterns after the ingestion of an ordinary meal of solids plus liquids vs a meal composed of a homogenate of the same foods. This work is the latest of a series of descriptive studies from the Mayo group and an example of a variety of new methods published in the last five years examining these aspects of digestive physiology. The question asked in the present work (are there major differences between solid and liquid meals of the same chemical composition?) is an important one. The methods needed to answer such a question have become more and more complex and probably less and less precise as the complexity of the test meals used in such studies has increased. The basic design of the present study is similar to that used in previous works: a double-lumen tube and dilution indicator technique was utilized in the duodenum to quantitate (1) the rate of passage of a meal indicator out of the stomach, and (2) outputs of pancreatic and biliary secretions. Since the amount of meal indicator remaining in the stomach at any time can be determined by subtracting the amount emptied from the amount ingested, intragastric volume (ml) can be calculated by dividing this amount (g) of remaining intragastric marker, by its intragastric (g/ml) concentration at the sampling time (2.3); the product of this volume, and the concentration of acid or pepsin in the stomach computed sequentially every sampling period, is the basis from which secretory output of the stomach is determined. The fundamental measurement, duodenal flow, is itself an approximation, which assumes both a relatively steady state and uniform mixing This work was supported by research funds from the Veterans A d m i n i s t r a t i o n and t h e N a t i o n a l I n s t i t u t e s of H e a l t h (AM 19182). Address for reprint requests: Dr. James H. Meyer, VA Hospital Sepulveda, 16111 Plummer Street, Sepulveda, California 91343.

and sampling of meal and indicators within the stomach and duodenum. Since the stomach varies its rate of emptying over the test period, a steady state is not achieved; and some error in estimating flow would be expected (4, 5). The magnitude of error would vary with vicissitudes in gastric emptying but is likely to be small during tests with liquid meals of concentrated sugar, which are emptied fairly uniformly. Estimates of the magnitude of imprecision (6) indicate the error in any one sampling period may be as high as 40% but over the period of complete emptying of the meal averages _+15%, a figure in close agreement with the range of calculated recovery of meal markers during duodenal sampling in several studies of this nature (1, 3, 7, 8). To overcome the problem of sampling under non-steady-state conditions, Johansson and Lagert6f (4) have developed a system of analyzing time-concentration profiles of sequentially perfused duodenal indicators. Their results with in vitro model systems indicate much greater accuracy and precision than is obtainable with single indicators, but the price of greater accuracy is a considerably more laborious experiment. Studies of the less-precise, single-indicator methods have failed to demonstrate a systematic error in estimating intragastric volumes (3, 7), so long as perfusion indicator does not reflux into the stomach. Moreover, duplicate tests show good reproducibility within subjects (3). Despite the inherent imprecision and inaccuracy in sampling from the nonsteady state, such simple methods have disclosed hitherto unappreciated interrelations between the time course of gastric emptying and the time courses of biliary or pancratic secretion (9); have shown a 60% reduction in pancreatic response to a meal stimulus after truncal vagotomy (8) (confirming more precise experiments in animals); and have shown us that less than 10% of orally ingested lipase enzymes escapes destruction in the stomach to arrive in the duodenum (10). This type of qualita-

Digestive Disease and Sciences, Vol. 24, No. 2 (February 1979)

0163-2116/79/0200-0097503.00/19 1979DigestiveDiseaseSystems,Inc.

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MEYER TABLE 1. RELATIVE EFFICIENCES IN SAMPLING LIVER PARTICLES OF VARIOUS SIZES THROUGH 1.12 MM ORIFICES

Mean particle sizes (ram) 99"~Tc'-liver

l~3"In-liver

0.125 0.25 0.5 - 0.001 as compared to the % of ideal in experiments with particles of equal (0.5 mm) sizes.

tive information is not likely to suffer much from random errors of ___15%, or even +30%. Uniform sampling and mixing of gastric and duodenal contents is also crucial for accuracy and precision. In the present work, a fundamental assumption is a uniform distribution of meal marker throughout the total intragastric volume (solid plus liquid). Even with purely liquid meals containing fat, protein, and carbohydrate, the distribution of PEG within the stomach has been shown to vary from fundus to antrum because of separation of fat (and protein curd) from the bulk aqueous phase (4). With liquid meals, this problem has been ignored because (1) the magnitude is small and (2) substances of interest (H § pepsin, trypsin) are distributed in the aqueous phase in which the PEG is also distributed. The addition of a solid phase greatly increases the complexities. Malagelada et al (1) have approached the problem by assuming solid particles could be aspirated with the liquid phase in a ratio close to that in the lumen. Even in an ideally wellstirred situation (Table 1), this assumption is inaccurate: 0.5-mm particles of liver tagged with 113mln were used as indicator particles aspirated from a rapidly stirred beaker containing liver particles in saline which, in various experiments, also contained particles of 99mTc-labeled liver of 0.125 mm, 0.25 mm, 0.5 mm, or particles approaching (but less than) 1.0 ram. The mixtures of particles were aspirated through a metal bubble trap (11) with orifices of 1.12 mm. Particles nearly 1.0 mm were poorly sampled as compared to the indicator particles of 0.5 mm, a result not unexpected because of the 1.12-ram size of aspirating orifices.

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Nevertheless, even with particles in a range of much smaller sizes, sampling was biased toward the smaller particles; for example, significantly more particles with a mean size of 0.125 mm were aspirated than particles of 0.5 mm. In feeding experiments, there are two orifices which may bias the sample: those on the sampling tube and those on the analytical pipettes. Furthermore, it is unlikely that stirring in the lumen approaches that which can be achieved in a beaker, so the bias may be of a magnitude different from that depicted in Table 1. The relative sampling error would be smaller at the start of a liquid and solid meal, when the ratio of liquid to solid in the stomach is large, but may be worse in later stages as this ratio diminishes. Moreover in sampiing of solid-liquid, nonuniformity cannot be so safely ignored, as in the case of the fat, because several substances being measured bind to, or interact with, the solid phase. For example (Figure 1), trypsin binds avidly and irretrievably to liver particles with a large surface-to-mass ratio. Similarly, we have found the uptake by liver particles of H § ion, some indicators (phenol red, but not PEG), and some isotopic markers (99mTc-DTPA) to be a surface-dependent phenomenon. It is difficult to guess to what extent such problems may have affected the

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SIZE OFLIVER PARTICLESmm Fig 1. Effect of particle size on recovery of trypsin, l g of chicken liver (boiled for 20 or 40 min) was incubated for 5 rain at 37~ C in 25 ml of pH 6.5 solution containing trypsin (100 units/ml) and PEG, then chilled to 0~ C and centrifuged. Supernatant solutions were assayed for trypsin concentration and compared (after correcting for volume changes with PEG analyses) with control solutions (25 ml of trypsin similarly incubated without chicken liver). Percent recovery (mean -+ SE, 5 experiments) varied with particle size. Even with homongenized liver some trypsin was lost on particles that could be centrifuged. Digestive Diseases and Sciences, Vol. 24, No, 2 (February 1979)

DIGESTIVE PHYSIOLOGY current comparisons between solid-liquid vs homogenized meals. Because of incomplete aspiration of the solid phase during the former, intragastric volume might have been somewhat higher than indicated; hence even a larger difference between solid vs homogenized meal might have pertained to H § and pepsin s e c r e t i o n than r e c k o n e d . L i k e w i s e , trypsin output to the solid meal may have been higher than appreciated. The problem is one of guessing the relative effects of sampling error (on volume of distribution) vs binding (on assayed concentration). Despite the inherent problems, the present system is probably as good as there is for studying gastric emptying and secretory outputs under meal conditions which approach those of everyday life. Other potentially accurate methods are available for measuring gastric secretion of acid or gastric emptying that do not depend on sampling from multiple phases, the distribution of particle sizes, or the attainment of steady states. For example, intragastric titration (12) has now been documented (13) as a reliable means of measuring acid secretion. By maintaining intragastric pH at an artificially high level (above a pH allowing peptic digestion or inhibiting of gastrin release), this technique may, however, distort a feeding experiment. Likewise, external gamma counting of food markers to measure gastric emptying should theoretically obviate the problem of sampling intragastric contents. This method is also not free of difficulties. Extinction (14) and overlap (15) c o n t r i b u t e to inaccuracies in gamma counting. The distribution of radiolabels is not precise; that is, labels of the aqueous phase may adhere to the solids or labels of the solid phase may dissociate into the liquid (16, 17). Since the liquid and solid phases of the meal may emigty at very different rates, this imprecise identification of each phase precludes accurate definition of the emptying of either phase or of the total meal. Even when the radiolabel is known to identify accurately a portion of the solid phase, that portion may empty at rates dependent on the size of its particles present in the stomach (18, 19). Since even the same radiolabeled food may empty at different rates, depending on its degree of dispersion, it is open to question whether the emptying of a particular radiolabeled constituent of a test meal may typify the emptying of all the constituents which vary in ease of dispersion. Despite all the various methodological problems, the questions being asked are exceedingly imporDigestive Disease and Sciences, Vol. 24, No. 2 (February 1979)

tant for understanding the working of the gastrointestinal tract. Progress in this rapidly developing field depends on identifying, quantitating and, hopefully, curcumventing troublesome sources of error. JAMES H. MEYER, MD

Associate Professor of Medicine Chief, Gastroenterology UCLA-San Fernando Valley Medical Program

REFERENCES 1. Malagelada JR, Go VLW, Summerskill WHJ: Different gastric, pancreatic, and biliary responses to solid-liquid or homogenized meals. Am J Dig Dis 24:000-000, 1979 2. Malagelada JR, Longstreth GF, Summerskill WHJ, Go VLW: Measurement of gastric functions during digestion of ordinary solid meals in. man. Gastroenterology 70:203-210, 1976 3. MacGregor IL, Gueller R, Watts HD, Meyer JH: The effects of acute hyperglycemia on rates of gastric emptying in man. Gastroenterology 70:190-196, 1976 4. Lagerloff HO, Johansson C, Ekelund K: Human gastric and intestinal response to meals studied by a multiple indicator dilution method. Mt Sinai J Med 43(3): 1-98, 1976 5. Levitt MD, Bond J: Use of the constant perfusion 'technique in the nonsteady state. Gastroenterology 73:1450-1454, 1977 6. Cooper H, Levitan R, Fordtran JH, Ingelfinger FJ: A method for studying absorption of water and solute from the human small intestine. Gastroenterology 50:1-7, 1966 7. MeeroffJC, Go VLW, Phillips SF: Gastric emptying of !iquids in man. Quantification by duodenal recovery marker. Mayo Clin Proc 48:728-732, 1973 8. MacGregor IL, Parent JA, Meyer JH: Gastric emptying of liquid meals and pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and pyloroplasty in man. Gastroenterology 72:195-205, 1977 9. Brunner H, Northfield TC, Hofmann AF, Go VLW, Summerskill WHJ: Gastric emptying and secretion of bile acids, cholesterol, and pancreatic enzymes during digestion. Duodenal perfusion studies in healthy subjects. Mayo Clin Proc 49:851-860, 1974 10. DiMagno EP, Malagelada JR, Go VLW, Moertel CG: Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med 296:13181327, 1977 11. Crosby WH, Crosby WH, Kugler HW: An instrument for serial sampling of intestinal juice. Am J Dig Dis 5:213-216, 1960 12. Fordtran JS, Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 52:645-657, 1973 13. Feldman EJ, Melendez R, Hogan D, Grossman MI: Validation of acid recovery by intragastric titration in dog and man. Gastroenterology 74:1034, 1978 (abstract) 14. Tothill P, McLaughlin GP, Heading RC: Techniques and errors in scintigraphic measurements of gastric emptying. J Nucl Med 19:256-262, 1978

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MEYER 15. Chaudhuri TK: Use of 99mTc-DTPA for measuring gastric emptying time. J Nucl Med 15:391-395, 1974 16. Heading RC, Tothill P, Laidlaw AJ, Shearman DJC: An evaluation of 113mlnDTPa chelate in the measurement of gastric emptying by scintiscanning. Gut 12:611-615, 1971 17. Chaudhuri TK, Greenwald AJ, Heading RC, Chaudhufi TK: A new radioisotope technique for the measurement of gas-

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tric emptying time of solid meal. Am J Gastroenterol 65:4651, 1976 18. Hinder RA, Kelly KA: Canine gastric emptying of solids and liquids. Am J Physiol 233:E335-E340, 1977 19. Meyer JH, Mandiola SA, Shadchehr A, Cohen MB: Dispersion of solid food by the canine stomach. Gastroenterology 72:1102, 1977 (abstract)

Digestive Diseases and Sciences, Vol. 24, No. 2 (February 1979)

New dimensions in digestive physiology.

EDITORIAL New Dimensions in Digestive Physiology Elsewhere in this issue, Malagelada et al (1) have attempted to quantitate secretory responses and...
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