Rapid Gastric Emptying of Fatty Meals in Pancreatic Insufficiency

GASTROENTEROLOGY 67:920-925, 1974 Copyright© 1974 by The Williams & Wilkins Co.

Vol. 67, No.5 Printed in U.S.A.

RAPID GASTRIC EMPTYING OF FATTY MEALS IN PANCREATIC INSUFFICIENCY WILLIAM B. LONG, M.D., AND JORDAN B. WEISS, M.D.

Gastrointestinal Section of the University of Pennsylvania Division, the Philadelphia General Hospital, Philadelphia, Pennsylvania

To ascertain whether maldigestion leads to aberrations in gastric emptying of liquid fatty meals, gastric emptying was studied in 7 patients with pancreatic insufficiency and in 10 normal volunteers. Gastric emptying of meals was determined by serial dilutions of phenol red given by gastric tube. One hour after ingestion, 36.8 ± 5.1% (mean ± SE) of fatty meals remained in the stomach of normal subjects, whereas only 3.9 ± 1.1% remained in the stomach of patients (P < 0.001). The amount remaining at 30 min in normal subjects also exceeded that in patients (75.8 versus 27.8%, P < 0.01). A heat-labile factor in desiccated porcine pancreas (Viokase, Viobin Corp., Monticello, Ill.) retarded (P < 0.001) emptying of fatty meals in patients (40.3 ± 6.3% of the meal remained at 60 min). Viokase increased gastric pH 60 min after a fatty meal from a mean of 4.6 to 5.2 (P < 0.05). Viokase did not alter emptying of 5% glucose in water meals. We conclude that in pancreatic insufficiency gastric emptying of fatty meals is abnormally rapid, probably because of maldigestion, and that pancreatic enzyme replacement retards gastric emptying and increases gastric pH after liquid fatty meals. Fatty food normally empties from the gastric emptying by fat within the small stomach more slowly than carbohydrate or bowel, mediated perhaps by an intestinal protein foods. The slow emptying of fat has hormone. 3 Fat may require digestion to been attributed to a feedback inhibition of have this inhibitory effect. To see if malReceived February 11, 1974. Accepted April 4, digestion would lead to alterations in gastric emptying of liquid fatty meals, we 1974. This work was presented in part at the American studied gastric emptying in normal volunGastroenterological Association meetings in New teers and in patients with pancreatic inYork City on May 24, 1973, and at the Eastern sufficiency. The effect of treatment of Section of the American ~deration for Clinical Re- patients with pancreatic enzyme replacesearch, Boston, Massachusetts, January 12, 1973. 2 ment was also determined. 1

Address requests for reprints to: Dr. William B. Long, Gastrointestinal Research Laboratories, University of Pennsylvania Division, The Philadelphia General Hospital, 700 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. This work was supported in part by General Research Support Grant 5S01 RR 05508 and General Clinical Research Center Grant 5 M01-RR-00107, Philadelphia General Hospital; Training Grant 5T01-8M5462-08, University of Pennsylvania; National Institutes of Health, Bethesda, Maryland . The authors wish to express their thanks to Nan L . Ward, Doris Carangian, Joel Raichlen, and Nancy Van Sten for their valuable assistance.

Methods Seven patients with chronic calcific pancreatitis and steatorrhea of 15 to 52 g per day on 100-g fat diet, and 10 normal volunteers with no history of gastrointestinal disorder, were studied. The age range of the patients was 29 to 55 (mean ± SE, 41.7 ± 3.8) and that of control subjects 21 to 55 (32.2 ± 3.6) years. Six patients were male, and one female; 6 control subjects were male and 4 were female. In the 5 patients in whom daily stool fat was measured while they were taking pancreatic enzymes (Viokase, Vi-

9:20

obin Corp., Monticello, Ill.), stool fat (mean ± fell from 40.6 ± 5.4 g to 14.1 ± 3.9 g (P < 0.005). All patients had diabetes mellitus well controlled with insulin at the time of the tests . A no. 16 French tube was passed by mouth and positioned fluoroscopically in the dependent portion of the greater curvature of the stomach of test subjects after an overnight fast. The stomach was washed with water and evacuated. While comfortably seated, the subjects swallowed an homogenized fatty meal composed of 650 ml of water, 50 g of corn oil, 42 g of nonfat Carnation dry milk (13.8 g of protein, 23 g of carbohydrate), two packages of an artificial sweetener (Sweet 'n Low, Cumberland Packing Corp., Brooklyn, N. Y.), 0.5 ml of vanilla extract, and 20 ml of phenol red marker solution. The osmolality of the meal was 200 ± 5 (mean ± SE) milliosmolar and its pH was adjusted to 6.8 with a few drops of 1 N NaOH. The meal was given at room temperature . Ingestion took about 3 to 4 min . All patients had an initial study using a fatty meal without Viokase, followed on another day by a meal with Viokase; 4 patients then had studies using fatty meals with Viokase boiled for 10 min, and nonfat water meals with, and then without Viokase. Each study was performed on a sepa: rate day. Nonfat water meals consisted of 700 ml of 5% glucose in water, pH 7.0. Volumes of gastric contents at 30, 45, and 60 min after the beginning of the meal were determined according to a modification of a method described by George . • A sample of 5 ml of gastric contents was withdrawn, and 10 ml of phenol red solution were introduced into the stomach and mixed vigorously by withdrawing and injecting syringefuls of gastric contents. The 1-min mixing period used by George for water meals was lengthened because of the increased viscosity of the fatty meal; the total time required for introduction of phenol red and mixing was 2 min. A 1-min mixing period was used for glucose in water meals. A second 5-ml sample was then withdrawn. The volume at any time (V,) was calculated from the following equation: SE)

VPR"CPR

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GASTRIC EMPTYING IN PANCREATIC INSUFFICIENCY

November 1974

=

(Ct+2- C,)V,

where VPR = the volume of phenol red marker added; CPR, = the concentration of phenol red added; C, = the concentration of phenol red in gastric contents at time t; ct +2 = concentration of phenol red after 2 min mixing; and V, = the gastric volume at time t. The percentage of water phase of the original meal left at 60 min was calculated from the following equation:

% original meal =

~: 0

X

Cso/C.7

X

c.siC32

X

CaoiCo

X

100

where V and C are volumes and concentrations at the indicated times . Percentages of the meal remaining 30 and 45 min after ingestion were calculated by a similar procedure . The actual calculations were performed by a programmed Monroe desk top calculator. Only 30-min residuals were calculated for 5% glucose in water meals. After the 62-min sample of fatty meals, the stomach was evacuated completely via the gastric tube, and the volume obtained was recorded. The pH of samples was determined by glass electrode and osmolality by freezing point depression. The marker solution of phenol red contained 750 mg of phenol red made up to 500 ml with distilled water and adjusted to pH 7.0. Phenol red in the gastric aspirate and original meal was determined after precipitation of protein by mixing 1-ml sample, 0.5 ml of 10% (w/v) BaC1 2, 1 ml of 0.3 N Ba(OH 2), 1 ml of 5% (w/v) ZnSO., and 2.5 ml of distilled water . 5 The cloudy mixture was centrifuged 10 min at 3000 rpm, and 1 ml of the clear supernatant was combined with 1 ml of a NaOH-boric acid KCl buffer (0.05 M boric acid, 0.05 M KCl, 0.37 M NaOH, pH 9.2) and 1 ml of H.O. 6 The solution was then read at 560 nm on a Beckman DB spectrophotometer and compared with appropriate standards. Pancreatic enzymes were given in the form of desiccated porcine pancreas (Viokase). When used, six Viokase tablets (0.3 g each) were crushed and mixed with the meal just before consumption. Statistical comparisons were performed by Student's t-test; intragastric pH of patients was also analyzed by paired analysis. 7

Results

The accuracy of determining the volume of a fatty meal by phenol red dilution was determined in vitro using meal volumes of 50 to 500 ml. Phenol red was added and mixed over 2 min through a no. 16 French tube as in vivo. The resulting ratio of calculated to measured volumes was 1.01 ± 0.03 (mean± sn). Further in vivo verification of the technique was obtained by correlating the calculated 60-min gastric volumes with the volumes evacuated at 62 min (fig. 1). Regression analysis showed a linear regression coefficient of 0.91 with the calculated volume = 9.9 ml + 0.88 x measured volume.

LONG AND WEISS

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The conclusions of our studies were the same, whether calculated or measured volumes were considered. However, the phenol red dilution technique allowed us to determine gastric volumes at 30, 45, and 60 min during a single experiment. Therefore, all results reported here were determined by the phenol red dilution technique. Because phenol red marks the water phase of fatty meals, and water and fat may leave the stomach at different rates, our studies determined only the gastric emptying of the water phase of fatty meals. The water phase of fatty meals emptied

more rapidly from the stomachs of patients with pancreatic insufficiency than from the stomachs of control subjects (table 1) . The percentage of meals remaining at 60 min in individual control subjects and patients is illustrated in figure 2. Significant differences (P < 0.001) were observed at 30, 45, and 60 min after the meal. Administration of ground Viokase significantly (P < 0.001) retarded emptying of the fatty meals in patients. There were no significant differences of residual meals at 30, 45, and 60 min between control subjects and patients whose meals contained Viokase. Boiling Viokase in water for 10 min abolished its activity (P < 0.005). One patient (G. R.) • was studied three times with no therapy, three times with active Viokase, and three • times with heat-inactivated Viokase (table • 2). The results were quite reproducible • • • from 1 day to the next . • •• Viokase had no effect (P > 0.4) on the emptying of 5% glucose in water meals • • •• •• • (table 1). In contrast, the percentage of normals • fatty meals remaining at 30 min in the 4 patients 0~ 0 0 patients whose emptying of water meals untreated o 00 was studied, was 27.4 ± 4.0 without Viotreated • 0 0 00 kase and 58.4 ± 11.9 with Viokase (P < 0 0.05). 400 0 200 600 Intragastric pH 60 min after a fatty meal evacuated volume (ml) in patients was slightly lower without VioFIG. 1. Comparison of the volume of gastric conkase than with Viokase (paired analysis, t tents 60 min after fatty meals in patients with and without pancreatic enzyme treatment and in normal = 2.78, p < 0.05). The gastric pH tended to volunteers, as determined by gastric evacuation (x be higher in control subjects than in unaxis) or as calculated by dye dilution (y axis) (r = treated patients at 60 min, but this was not significant (P > 0.2). No significant differ0.91, y = 9.9 + 0.88 x).

..

. .:· .

TABLE

1. Gastric retention( %) of meals 30, 45, and 60 min after ingestion in control subjects and patients

Control subjects Fatty meals . ... . . . . . . ... ... . ...... .. . Patients Fatty meals No Viokase . . . . . .. . . . ... . . .. . . .. Viokase .... .. . .. . . ... ... .. . . . . . .. Heated Viokase .. ..... . ... . ... . . . .. Water meals< No Viokase .. . . ... .... .. . ... . . .. . .. Viokase . . . . .. .. . .. ..... . .. . ......

N•

30min

45min

60min

10

78.8 ± 6.9•

51.7 ± 6.5

36.8 ± 5.1

7 7 4

27 .8 ±4.6 60.2 ± 8.6 27.9 ± 8.9

10.7 ± 2.1 54.5 ± 9.9 10.1 ± 2.8

3.9 ± 1.1 40.3 ± 6.3 5.6 ± 2.3

4 4

33.9 ± 9.8 25.7 ± 3.0

a Number of subjects studied (N). • Mean ± SE of percentage of water phase of meals remaining in groups of control subjects and patients. c 5% glucose in water.

November 1974 100 Normal

Pancreatic

Insufficiency

"' ::

.<;::

"'E: "''..... "'"'E:

50

u

...

I

..

~

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GASTRIC EMPTYING IN PANCREATIC INSUFFICIENCY

. I

0 No

R,.

Viokose

Heated Viokose

FIG. 2. Percentage of the water phase of fatty meals remaining 60 min after the meal in stomachs of normal volunteers and patients. Patients received either no treatment (No Rz), Viokase, or heated Viokase with the meals. The percentage remaining in normal subjects differed from that of untreated patients (P < 0.001), but not from that of treated patients . Boiling Viokase abolished its ability to inhibit emptying of fatty meals (P < 0.005).

ence of gastric osmolality was found between patients and control subjects or between treated and untreated patients (table 3). Discussion Our finding' · 2 of rapid gastric emptying of liquid fatty meals in patients with chronic pancreatitis and steatorrhea implies an interrelation of intraluminal digestion and gastric emptying. Menguy 8 showed that exclusion of bile and lipase from the duodenum abolished the inhibitory effect of intraduodenal fat on rat gastric motility. In dogs, intraduodenal fatty acids are more potent than whole fat in inhibiting antral contraction. 9 These studies suggest that fat must be digested or absorbed to inhibit gastric motility. Our data show that addition of pancreatic enzymes (Viokase) to fatty meals slowed their emptying in pancreatic insufficiency, that the action of Viokase was heat-labile, and that Viokase had no effect on gastric emptying of a 5% glucose in water meal. These observations imply that Viokase has no direct effect on gastric emptying, but that a heat-labile factor, probably pancreatic enzymes, improves digestion, and that the products of digestion, in turn, inhibit gastric emptying. Our meal contained a small

amount of protein, and improved digestion of protein, as well as digestion of fat, may have contributed to inhibition of gastric emptying. Digestion of carbohydrates may affect gastric emptying. Carbohydrate is thought to inhibit gastric emptying by affecting duodenal osmoreceptors. Hunt 10 observed that starch meals emptied from the stomach of normal individuals as slowly as glucose meals of equal carbohydrate content but greater osmolality; he postulated that starch affects duodenal osmoreceptors after intraduodenal hydrolysis. In contrast, starch meals empty more rapidly than isocaloric glucose meals in newborn infants;" this may reflect a deficiency of pancreatic amylase, leading to maldigestion of starch. The sugar in our meal was mainly lactose, which should not be affected by the presence or absence of pancreatic amylase, or by the addition of Viokase. The mechanism whereby intraduodenal fat inhibits gastric emptying is not clear. The effects of vagotomy on gastric motility indicate that a neural mechanism could be involved. 12 • 13 However, intestinal hormones released by fat appear to be the principal mediators of this inhibition. Farrell and lvy 14 observed inhibition of the motility of a transplanted gastric pouch after intraduodenal fat administration. They ascribed this affect to a hormone released from the duodenum. In man, Chey TABLE

2. Reproducibility of gastric emptying of fatty meals in I patient (G. R.)

No Viokase•

Viokase

30min

45min

20' 23 35 86

15 10 24 67 47 56 5 7 7

72

Heated Viokase

81 31 15 27

60min

2 1 9

56 21 41 4 3 4

a Three studies were performed without Viokase, three with Viokase, and three with heated Viokase. 0 Percentage of water phase of meals remaining in the stomach 30 , 45, and 60 min after ingestion .

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LONG AND WEISS TABLE

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3. lntragastric pH and osmolality after fatty meals• Osmolality

Gastric pH 30min

60min

30min

60min

milliosmoles

Control subjects ... . .. . . ... . . . . . . ... . ... Patients No Viokase . . ..... .. .... . . . . . .... .. . Viokase . . ... .... . ....... ······ ..... ..

6.1 ± 0.2

5.1 ± 0.4

209 ± 8

222 ± 9

6.1 ± 0.2 6.0 ± 0.1

4.6 ± 0.5• 5.2 ± 0.1

206 ± 6 226 ± 5

227 ± 12 227 ± 5

• Mean ± SE 30 and 60 min after meal. • Paired analysis shows intragastric pH lower at 60 min in untreated t han in treated patients (t = 2.78, p < 0.05) . No other significant differences are noted between treated and untreated patients or between patients and control subjects.

et al. 15 demonstrated inhibition of gastric emptying of water meals by intravenous cholecystokinin-pancreozymin (CCK-PZ), and Fisher et al. 16 found augmentation of pyloric sphincter pressure by intravenous CCK-PZ or secretin. Identification of which intestinal hormone may be involved awaits application of sensitive assays after meals in normal individuals and patients. Recently, Harvey et al., 17 using a radioimmunoassay, reported that patients with pancreatic insufficiency have very high fasting levels of CCK-PZ; fasting CCK-PZ levels approached those found after meals in normals. The response of serum CCK-PZ to meals in patients was not reported. If confirmed, high serum immunoreactive CCK-PZ seems paradoxical in patients with rapid gastric emptying of fatty meals. Perhaps, fasting serum CCK-PZ in such patients is biologically inactive. An alternative explanation may be that neural or hormonal factors other than CCK-PZ are the principal mediators of the inhibition of gastric emptying of fat. The gastric pH, 60 min after a fatty meal, was lower (P < 0.05) without Viokase (4.6 ± 0.5) than with Viokase (5.2 ± 0.1). This difference may reflect either retention of a greater amount of buffer or increased small bowel inhibition of gastric acid secretion after pancreatic enzyme replacement. Intraduodenal fat reduces pentagastrin-stimulated acid secretion in man. 18 The effect of intra duodenal fat on gastric acid secretion, as well as its effect on gastric motility, may depend on adequate digestion. The inhibitory effect of

Viokase therapy on gastric emptying of fatty meals is probably not mediated by the observed increase in gastric pH because more neutral meals tend to empty more rapidly than acid meals. 19 Gastric pH did not differ significantly between control subjects and patients ; perhaps a larger series or one matched for maximal acid secretory ability would show a difference. Gastric osmolality was not affected by Viokase therapy and did not differ between patients and control subjects. Although our patients had diabetes mellitus as well as steatorrhea, diabetes probably does not explain their rapid gastric emptying of fatty meals. Gastric retention during upper gastrointestinal X-rays is more characteristic of diabetes than is rapid emptying. 20 Other than by improving digestion, Viokase would not be expected to have an effect on an abnormality of gastric motility, but, if so, would have affected emptying of glucose in water meals, as well as fatty meals, and this did not occur. On the other hand, rapid gastric emptying of high calorie meals in pancreatic insufficiency may render control of diabetes more difficult. Enzyme supplementation could influence control of diabetes, not only by improving digestion and increasing caloric absorption, but also by slowing gastric emptying of meals and distributing caloric loads over longer periods. Steatorrhea does not appear until the majority of pancreatic enzyme secretion is lost, and then increases rapidly with further loss of secretion. 21 Why steatorrhea

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GASTRIC EMPTYING IN PANCREATIC INSUFFICIENCY

appears only in severe pancreatic insufficiency, and whether aberrations in gastric emptying also appear only with severe enzyme deficiencies are not clear. If rapid evacuation of the stomach overwhelmed limited pancreatic reserves it might contribute to maldigestion. Below a certain level of pancreatic enzyme secretion, a vicious cycle could develop where maldigestion led to rapid emptying, which in turn intensified the digestive abnormality. This could account for the sudden appearance of steatorrhea in severe pancreatic disease. REFERENCES 1. Long WB, Weiss JB: Rapid gastric emptying of fatty meals in pancreatic insufficiency (abstr). Gastroenterology 64:763, 1973 2. Long WB, Weiss JB: Inhibition of gastric emptying by desiccated hog pancreas (abstr). Clin Res 20:871, 1972 3. Hunt JN, Knox MT: Regulation of gastric emptying. In Handbook of Physiology, sect 6: Alimentary Canal, vol 4. Edited by CF Code. Washington DC, American Physiological Society, 1969, p 1917- 1935 4. George JD: New clinical method for measuring the rate of gastric emptying: the double sampling test meal. Gut 9:237-242, 1968 5. Boulter JM , McMichael HB: Modification of polyethylene glycol estimation suitable for small animals. Gut 11:268-270, 1970 6. Schedl HP, Miller D, WhiteD: Use of polyethylene glycol and phenol red as unabsorbed indicators for intestinal absorption studies in man. Gut 7:159-163, 1966 7. Snedecor GW, Cochran WG : Statistical Methods . Sixth edition, Ames, Iowa State University Press, 1967 8. Menguy R: Role of biliary and pancreatic secre-

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