GASTROENTEROLOGY
1992;103:775-780
Effect of Acute Hyperglycemia on Esophageal Motility and Lower Esophageal Sphincter Pressure in Humans SIJBRAND Y. DE BOER, AD A. M. MASCLEE, WA1 F. LAM, and CORNELIS B. H. W. LAMERS Department
of Gastroenterology-Hepatology,
University
The effect of acute hyperglycemia on esophageal motility and lower esophageal sphincter pressure (LESP) was investigated. Esophageal manometry was performed for 1211 minutes in seven healthy volunteers on two separate occasions during euglycemia and during hyperglycemia with blood glucose levels stabilized at 15 mmol/L. At 90 minutes, motility was stimulated with edrophonium chloride (0.08 mg/kg intravenously). Pancreatic polypeptide (PP) secretion was determined as an indirect measure of vagal-cholinergic tone. During hyperglycemia the LESP decreased significantly (P < 0.05) from 20.1 f 1.6 mm Hg to 10.7 + 0.6 mm Hg; plasma PP levels were also significantly (P < 0.05) decreased during hyperglycemia. Edrophonium induced significant (P < 0.05) increases in LESP and PP levels in both experiments. However, LESP and PP levels after edrophonium stimulation remained significantly (P < 0.05) reduced during hyperglycemia compared with euglycemia. During hyperglycemia a significant (P < 0.05) increase in peristaltic wave duration and a decrease in peristaltic velocity were observed in the distal part of the esophagus. It is concluded that blood glucose levels affect esophageal motility, acute hyperglycemia reduces LESP and impairs esophageal motility under both basal and edrophonium-stimulated conditions, and hyperglycemia reduces plasma PP levels, suggesting impaired vagal-cholinergic activity during hyperglycemia.
Hospital, Leiden, The Netherlands
reported in these patients include reduced lower esophageal sphincter pressure (LESP) and a decrease in coordinated peristalsis with an increase in nonperistaltic contractions.4-7 The pathogenesis of gastrointestinal motor dysfunction in diabetics has not been clearly elucidated. Abnormal gastrointestinal motility in diabetics is usually associated with the presence of autonomic neuropathy.“’ Apart from neural dysfunction, however, other factors such as glycemic control and metabolic derangements secondary to diabetes mellitus may be involved.8 The role of serum glucose in the regulation of gastrointestinal motility has not been well defined. The present study was undertaken to investigate the influence of serum glucose concentrations on esophageal body motility and LESP. Esophageal manometry was performed during both euglycemia (5 mmol/L) and hyperglycemia (15 mmol/L). Healthy volunteers were studied to preclude the influence of alterations in esophageal motility secondary to autonomic neuropathy. A second goal of the study was to examine the tone of the vagal cholinergic nerve system during hyperglycemia. This was accomplished (a) indirectly by measuring pancreatic polypeptide (PP) secretion, which is known to be dependent on vagal cholinergic tone, and (b) by infusion of edrophonium chloride, a cholinergic stimulant that acts as choline esterase inhibitor. Materials and Methods Subjects
n patients with diabetes mellitus, gastrointestinal motility disturbances, especially of the stomach, the small bowel, and the large bowel, occur frequent1y.l.’ Until recently, little was known about esophageal motility in diabetic patients. Although typical symptoms of esophageal dysfunction such as dysphagia, chest pain, and heartburn are uncommon, abnormal esophageal motor function is demonstrable in more than 50% of diabetic patients.2-5 Abnormal manometric findings that have been
I
Seven healthy male volunteers (age 19-25 years) participated in the study. None was taking chronic medication or had a history of gastrointestinal disease, surgery, or diabetes mellitus. Informed consent was obtained from each person, and the protocol had been approved by the ethics committee of the University Hospital, Leiden, The Netherlands. 0
1992 by the American
Gastroenterological 0016-5095/92/$3.00
Association
776 DE BOER ET AL.
Equipment Esophageal body motility and LESP were recorded with a small polyvinyl four-lumen composite side-hole catheter. The orifices were 5 cm apart and oriented radially at 90’ to each other. Each lumen was perfused with mL/min) using a low-compliance capildistilled water (0.5 lary tube infusion pump (Arndorfer Medical Specialists, Greendale, WI). A rapid pull-through technique was used to record endexpiratory LESP. Two pull-through measurements were made for each time point except during the first 10 minutes after administration of edrophonium, when LESP was recorded in 2-minute intervals and only one pull-through measurement was performed. Intraluminal esophageal pressures were recorded at 5, 10,15, and 20 cm above the upper margin of the lower esophageal sphincter (LES). At each time point the manometric responses to at least two, but usually five, standardized wet swallows (5-mL water bolus) were recorded. The peristaltic wave amplitude and duration of contraction were calculated for the proximal (20 cm above the LES), mid (10 and 15 cm above the LES), and distal (5 cm above the LES) parts of the esophagus. Velocity of peristalsis for the proximal, mid, and distal parts of the esophagus was calculated from the time of onset between peristaltic wave peaks between adjacent transducers. It was measured over three 5-cm intervals in the proximal (20-15cm above the LES), mid (15-10cm above LES), and distal (10-s cm above the LES) parts of the esophagus. Test Procedure Each subject participated in two experiments, performed in random order during euglycemia or during hyperglycemia with blood glucose levels stabilized at 15 mmol/L. After an overnight fast the four-lumen catheter was passed through the nose with the distal tip into the proximal part of the stomach for esophageal manometry. All studies were started at 9 AM with subjects in the semirecumbent position lying in comfortable chair. Acute hyperglycemia at (15 mmol/L) was obtained using a modified glucose clamp technique.g*‘O The acute increase in blood glucose level was induced by an intravenous bolus injection of 20% glucose. The amount of glucose administered was calculated from the body weight. After the bolus injection, 20% glucose was infused at varying rates guided by serum glucose measurements every 2.5-5minutes (glucose oxidase method, Beckman glucose analyzer; Beckman Instruments, Palo Alto, CA). Serum glucose levels were maintained within &lo% of the desired level. Esophageal manometry was performed before initiating the glucose clamp and for 120 minutes during euglycemia or clamping when glucose levels were stable for at least 30 minutes. During the first 90 minutes the influence of serum glucose levels on esophageal motility was studied. Manometry was recorded every 10 minutes for 90 minutes. At 90 minutes a bolus injection of edrophonium chloride, 0.08 mg/kg body wt, was administered intravenously. Esophageal manometry was recorded for an additional 30 minutes at 1, 3,5,7.5,10, 20,and 30 minutes after edrophonium stimulation. Edrophonium chloride
GASTROENTEROLOGYVol.103,No.3
(Tensilon; Roche Products Ltd., Welwyn Garden City, England) is a short-acting acetylcholinesterase inhibitor that prevents acetylcholine destruction and thus enhances vagal-cholinergic effects.” Blood samples for measurement of plasma PP were collected before clamping, at lo-minute intervals during clamping, and 0, 1, 3,5,7.5,10,20,and 30 minutes after administration of edrophonium. Plasma PP concentrations were measured by a sensitive and specific radioimmunoassay as described previously.” Statistical
Analysis
All results are expressed as mean + SEM. The integrated incremental PP secretion in response to edrophonium was determined by calculating the area under the plasma concentration-time curve after subtraction of the basal value. Data were analyzed for the significance of differences by analysis of variance (ANOVA). When this indicated a probability of ~0.05 for the null hypothesis, Student-Newman-Keuls analyses were performed to determine which values differed significantly between the euglycemic and hyperglycemic experiments or within experiments in response to hyperglycemia or administration of edrophonium.
Results Serum Glucose Levels Fasting serum glucose levels in the euglycemia and hyperglycemia experiments were 5.2 f 0.3 mmol/L and 5.0 * 0.3 mmol/L, respectively. Serum glucose levels during euglycemia and during clamping aimed at 15 mmol/L are shown in Figure 1. LESP The basal LESP during euglycemia was not significantly different from the basal LESP before hyper-
glucose (mm&l)
1 damp
Okc
;o
;o
90
time(min)120
Figure 1. Serum glucose concentrations (mmol/L; mean +_SEM) reached during clamping aimed at 5 mmol/L and 15 mmol/L in seven
healthy
subjects.
September
ESOPHAGEAL
19%
glycemia: 19.3 + 1.6 mm Hg vs. 20.1 f 1.6 mm Hg. During the euglycemia experiment, no significant differences in LESP from basal values were observed from 0 to 90 minutes (Figure 2).During hyperglycemia, LESP was significantly (P < 0.05) reduced compared with basal levels or with euglycemia, beginning at 20 minutes and continuing during the first part of the experiment until 90 minutes. During hyperglycemia the LESP gradually declined reaching a minimum value of 10.7 + 0.6 mm Hg at 90 minutes. Administration of edrophonium resulted in significant (P < 0.05)increases in LESP from 1 to 5 minutes after infusion in the euglycemia experiment and from 1 to 10 minutes in the hyperglycemia experiment (Figure 2). Thereafter the LESP returned to pre-edrophonium levels. The mean of the individual peak LESPs after edrophonium administration was significantly (P < 0.05) lower during hyperglycemia (31.9 ? 3.1 mm Hg) than during euglycemia (39.4 + 3.7 mm Hg); the mean of the individual peak increments in LESP after edrophonium administration was not significantly different between the two experiments (euglycemia, 20.0 + 3.4 mm Hg; hyperglycemia, 21.2 k 3.0 mm Hg). Esophageal
Body Motility
Peristaltic wave amplitude, duration, and velocity measured in the upper and mid portions of the esophagus during hyperglycemia were not significantly different from those measured during euglycemia (Table 1). Significant differences in peristaltic wave duration and velocity between euglycemia and hyperglycemia were observed only in the distal portion of the esophagus. Peristaltic wave amplitude and duration increased
LESP (mm Hg)
.
.
90 Ume(min)
lx)
t
eaophonlum II
I,
0
30
60
Figure 2. LESP (mm Hg; mean ? SEM) during euglycemia (A) and hyperglycemia (0) in seven healthy subjects: O-90 minutes, unstimulated; 90-120 minutes, after intravenous administration of edrophonium, 0.08 mg/kg. *Significant differences in LESP between euglycemia and hyperglycemia (P < 0.05); ‘significant increase in LESP after edrophonium administration (P < 0.05).
MOTILITY
DURING ACUTE
HYPERGLYCEMIA
777
after edrophonium administration in both the euglycemia and the hyperglycemia experiment, but the differences were significant only for peristaltic wave duration. Peristaltic wave velocity was not affected by edrophonium administration during hyperglycemia or during euglycemia. Plasma PP Levels Basal plasma PP levels before clamping were not significantly different between the two experiments: 21 + 4 pmol/L vs. 21 k 3 pmol/L (Figure 3). From 0 minutes, when blood glucose levels had been stabilized for at least 30 minutes, until 90 minutes, when edrophonium was administered, PP levels were already significantly (P < 0.115)reduced in the hyperglycemia experiment. Significant (P < 0.05) increases in plasma PP concentrations were observed in both the euglycemia and the hyperglycemia experiment from 3 to 20 minutes after administration of edrophonium (Figure 3). Neither the peak increments in plasma PP (euglyce10 + 1 pmol/L) mia, 13 k 4 pmol/L; hyperglycemia, nor the integrated incremental PP secretion (183 f 65 pmol/L - 30 min vs. 145 +- 26 pmol/L - 30 min) were significantly different between the two experiments. Despite significant increases in plasma PP levels over basal values after edrophonium administration, PP levels during hyperglycemia remained significantly (P < 0.05) reduced compared with those during euglycemia from 0 to 30 minutes after edrophonium administration. Discussion The results of this study indicate that in healthy humans, blood glucose levels affect esophageal motility. During acute hyperglycemia [l5 mmol/L (270 mg/dL)], basal LESP was significantly decreased. Hyperglycemia influenced motility in the distal part of the esophagus by significantly increasing peristaltic wave duration and by slowing the velocity of peristalsis. Although to our knowledge this study is the first to show that hyperglycemia impairs esophageal motility, an inhibitory effect of glucose on the function of other gastrointestinal organs has been recognized for several years.13-16 McGregor et al. have shown that gastric emptying is delayed during intravenous infusion of glucose.14 Hyperglycemia suppresses both gastric acid and pancreatic enzyme secretion.‘5a16 Unfortunately, in these studies13-“j performed in healthy volunteers, serum glucose levels were not determined. Because glucose was administered by either bolus injection or constant-rate infusion, glucose levels may have varied markedly as a result of reactive insulin secretion. In more recent studies,
778
DE BOER ET AL.
GASTROENTEROLOGY Vol. 103, No. 3
Table 2. Manometric Data of Esophageal Peristalsis in Seven Healthy Subjects During Euglycemia Hyperglycemia (15 mmol/L) Under Basal Conditions Proximal, Mid, and Distal Parts of the Esophagus
and After Administration
Euglycemia Basal” Amplitude (mm Hg) Proximal Mid Distal Duration (s) Proximal Mid Distal Velocity (cm/s) Proximal Mid Distal
Hyperglycemia
Edrophonium
39 + 2 50 f 3 45 * 4
(5 mmol/L) and of Edrophonium for the
stimulatedb
44 f 2 59 + 3 50 + 6
Basal”
36 + 2 54 + 3 53 f 4
Edrophonium
stimulatedb
38 + 4 59 * 4 57 f 6
2.2 f 0.1 2.6 + 0.1 2.8 + 0.1
2.7 + 0.2” 3.3 f 0.4” 4.0 + 0.7”
2.4 + 0.1 2.8 + 0.1 3.2 f O.ld
2.7 f 0.2’ 3.5 + o.4c 4.0 _+0.8”
3.4 f 0.1 4.3 f 0.1 4.7 + 0.3
3.2 + 0.2 4.5 f 0.3 4.5 f 0.4
3.0 + 0.1 4.3 zk 0.1 3.9 zk 0.3d
3.2 ?I 0.2 4.6 f 0.2 3.9 + 0.5
“Mean + SEM, from 0 to 90 minutes. bMean + SEM, from 0 to 5 minutes after stimulation, “P < 0.05, edrophonium stimulated vs. basal. dP < 0.05, hyperglycemia vs. euglycemia.
however, hyperglycemia has been obtained by clamp techniques, thus stabilizing serum glucose levels. Using these techniques it has been confirmed that hyperglycemia inhibits gastric motor function as shown by a significant reduction in antral motility during hyperglycemia at 13.9 mmol/L (250 mg/ dL).17 Gastrointestinal motor dysfunction, and more recently abnormal esophageal motility, have been well documented in patients with diabetes mellitus.‘-8 The pathogenesis of esophageal dysmotility in diabetes has not been clearly elucidated. It has been
PP (pmolli)
30
20 -
10 -
edrophonium Ok’
b
,b
Gb
90
time (min)
120
Figure 3. Plasma PP concentrations (pmol/L; mean + SEM) during euglycemia (A) and hyperglycemia (0) in seven healthy subjects; O-90 minutes, unstimulated; 90-120 minutes, after intravenous administration of edrophonium, 0.09 mg/kg. *Significant differences in PP concentrations between euglycemia and hyperglycemia (P < 0.05); *significant increases in PP concentrations in response to edrophonium (P < 0.05).
suggested that neural impairment, especially autonomic nerve dysfunction, is an important factor.l” Evidence for this hypothesis is derived from studies indicating that esophageal motor abnormalities are more prevalent in diabetic patients with than in those without clinical signs of neuropathy.3-7s18 In addition, the degree of esophageal dysmotility appears to correlate with the severity of autonomic neuropathy.4,18 On the other hand, abnormal esophageal peristalsis does occur in the absence of demonstrable neuropathy.3p4 It has therefore been questioned whether other factors such as glycemic control or metabolic derangements secondary to diabetes may influence gastrointestinal function in these patients. As shown in this study, acute hyperglycemia in healthy subjects induced several esophageal motor abnormalities that have been described in diabetic patients: reduced LESP, prolonged duration of peristaltic waves, and decreased peristaltic velocity. Infusion of glucose in healthy subjects may induce several metabolic changes apart from hyperglycemia. It is therefore possible that metabolic changes secondary to hyperglycemia, rather than glucose itself, are responsible for the inhibitory effect on esophageal motility. For instance, high glucose concentrations stimulate insulin secretion, and hyperinsulinemia affects gastrointestinal motility. However, previous studies have shown that insulin exerts a stimulatory rather than an inhibitory effect on intestinal motilhyperglycemia reduces gastric ity. “*‘OFurthermore, emptying in patients with type I diabetes, indicating that insulin is not responsible for the inhibitory effect of hyperglycemia on gastrointestinal function.21 In experimental diabetes, and more recently also
September
1992
ESOPHAGEAL
in human diabetes,” delayed nerve-conduction velocity during hyperglycemia has been shown. It has also been shown that infusion of glucose suppresses efferent vagus nerve activity.23 In the present study, hyperglycemia significantly reduced plasma PP levels. The secretion of PP from the pancreas is known to be under vagal cholinergic contro1.24 For instance, insulin-induced hypoglycemia is a potent stimulus of PP secretion through vagal cholinergic activation of PP-secreting cells. Hyperglycemia, on the other hand, is known to suppress PP release through inhibition of vagal-cholinergic activity because the inhibitory effect of hyperglycemia on PP secretion is blunted by truncal vagotomy.25 Previous studies have indicated that vagal-cholinergic innervation plays an important role in the regulation of esophageal motility.26 Significant reductions in LESP and esophageal peristalsis during cholinergic blockade with atropine have been shown.26,27 The inhibitory effects of hyperglycemia on esophageal motility observed in this study resemble those seen during cholinergic blockade with atropine. Based on these observations and the suppression of PP secretion, it is postulated that hyperglycemia influences esophageal motility, at least in part, through inhibition of vagal-cholinergic neural activity. Administration of edrophonium resulted in transient but significant effects on LESP and esophageal body motility. Edrophonium significantly increased LESP during both euglycemia and hyperglycemia. Increments in LESP were not significantly different between euglycemia and hyperglycemia, but the maximum LESP after edrophonium administration was significantly lower during hyperglycemia than during euglycemia. In accordance with the results of previous studies,“*” edrophonium produced a stimulatory effect on esophageal body motility characterized by significant increases in the duration and amplitude of peristaltic contractions. After edrophonium administration, plasma PP levels increased significantly from basal levels, suggesting an increase in cholinergic activity. In the hyperglycemia experiment, however, plasma PP levels after edrophonium administration were significantly lower than those in the euglycemia experiment. These results are in accordance with a significantly lower LESP after edrophonium administration during hyperglycemia. Thus, the inhibitory, possibly vagal-cholinergic-mediated effect of hyperglycemia on esophageal motility and PP secretion is present not only under basal conditions but also during stimulation with edrophonium. We conclude that blood glucose levels affect esophageal motor function, as demonstrated by a reduction in LESP and esophageal motility during acute
MOTILITY DURING ACUTE HYPERGLYCEMIA
779
hyperglycemia (15 mmol/L). Plasma PP levels were significantly reduced during hyperglycemia, pointing to impaired vagal-cholinergic activity. An inhibitory effect of hyperglycemia on esophageal motility and PP secretion was seen not only under basal conditions but also during stimulation with edrophonium. References 1.
2. 3.
4. 5.
6.
7.
8.
9.
10.
11.
12.
Feldman M, Schiller LR. Disorders of gastrointestinal motility associated with diabetes mellitus. Ann Intern Med 1983;98:378-384. Rothstein RD. Gastrointestinal motility disorders in diabetes mellitus. Am J Gastroenterol 1990;85:782-785. Russell COH, Gannan R, Coatsworth J, Nielsen R, Allan F, Hill LD, Pope CE. Relationship among esophageal dysfunction, diabetic gastroenteropathy, and peripheral neuropathy. Dig Dis Sci 1983;28:289-293. Stewart IM, Hosking DJ, Preston BJ, Atkinson M. Oesophageal motor changes in diabetes mellitus. Thorax 1976;31:278-283. Hollis JB, Caste11 DO, Braddom RL. Esophageal function in diabetes mellitus and its relation to peripheral neuropathy. Gastroenterology 1977;73:1098-1102. Mandelstam P, Siegal CI, Lieber A, Siegel M. The swallowing disorder in patients with diabetic neuropathy-gastroenteropathy. Gastroenterology 1969;56:1-12. Loo DF, Dodds WJ, Soergel KH, Arxdorfer RC, Helm JF, Hogan WJ. Multipeaked esophageal pressure waves in patients with diabetic neuropathy. Gastroenterology 1985;88:485-494. Horowitz M, Harding PE, Maddox AF, Wishart JM, Akkermans LMA, Chatterton BF, Shearman DJC. Gastric and oesophageal emptying in patients with type 2 diabetes mellitus. Diabetologia 1989:32:151-159. Ward WK, Halter JB, Beard JB, Porte D. Adaptation of B and A cell function during prolonged glucose infusion in human subjects. Am J Physiol 1984;246:E405-E411. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-E223. Lee CA, Reynolds JC, Ouyang A, Baker L, Cohen S. Esophageal chest pain. Value of high-dose provocative testing with edrophonium chloride in patients with normal esophageal manometries. Dig Dis Sci 1987;32:682-688. Lamers CBHW, Diemel C, van Leer E, van Leusen R, Peetoom JJ. Mechanism of elevated pancreatic polypeptide concentrations in chronic renal failure. J Clin Endocrinol Metab 1982:55:922-926.
13. 14.
15.
16.
17.
18.
Aylett P. Gastric emptying and changes of glucose level, as affected by glucagon and insulin. Clin Sci 1962;22:171-178. MacGregor IL, Gueller, Watts HD, Meyer JH. The effect of acute hyperglycemia on gastric emptying in man. Gastroenterology 1976:70:190-196. MacGregor IL, Deveney C, Way LW, Meyer JH. The effect of acute hyperglycemia on meal-stimulated gastric, biliary, and pancreatic secretion and serum gastrin. Gastroenterology 1976:70:197-202. Niederau C, Sonnenberg A, Erckenbrecht J. Effects of intravenous infusion of amino acids, fat, or glucose on unstimulated pancreatic secretion in healthy humans, Dig Dis Sci 1985;30:445-455. Barnett JL, Owyang C. Serum glucose concentration as a modulator of interdigestive gastric motility. Gastroenterology 1988;94:739-744. Murray FE, Lombard MC, Ashe J. Lynch D, Drury MI,
780
DE BOER ET AL.
O’Moore B, Lennon J, Crowe J. Esophageal function in diabetes mellitus with special reference to acid studies and relationship to peripheral neuropathy. Am J Gastroenterol 1987;82:840-843. 19. Prasad KR, Sarna SK. The central and peripheral effects of insulin on migrating myoelectric complexes (abstr). Gastroenterology 1986;90:1589. 20. Bueno L, Ruckebusch M. Insulin and jejunal electrical activity in dog and sheep. Am J Physiol 1976;230:1538-1544, 21. Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, Dent J. Hyperglycemia slows gastric emptying in type I [insulin-dependent] diabetes mellitus. Diabetologia 1990;33: 675-680. 22. Sindrup SH, Ejlertsen B, Gjessing H, Svendsen A, Froland A. Peripheral nerve function during hyperglycemic clamping in insulin-dependent diabetic patients. Acta Neurol Stand 1989;79:412-418. 23. Hirano T, Niijima A. Effects of 2-deoxy-o-glucose, glucose and insulin on efferent activity in gastric vagus nerve. Experientia 1980;36:1197-1198,
GASTROENTEROLOGY Vol. 103,No. 3
24. Schwartz TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 1983;85:1411-1425. 25. Tsuda K, Seino Y, Mori K, Seino S, Takemura J, Kuzuya H, Yamamura T, Kotoura Y, Ito N, Imura H. Effect of truncal vagotomy on pancreatic polypeptide response after intravenous glucose administration. Regul Pept 1981;1:347-352. 26. Christensen J. Motor-functions of the pharynx and esophagus. In: Physiology of the gastrointestinal tract. Johnson LR, et al., eds. New York: Raven, 1987;595-612. 27. Dodds WJ, Dent J, Hogan WJ, Arndorfer RC. Effect of atropine on esophageal motor function in humans. Am J Physiol 1981;240:G290-G296. 28. Richter JE, Hackshaw BT, Wu WC, Caste11 DO. Edrophonium: a useful provocative test for esophageal chest pain. Ann Intern Med 1985;103:14-21.
Received February 1, 1991. Accepted February 24,1992. Address requests for reprints to: A. A. M. Masclee, M.D., Department of Gastroenterology-Hepatology, University Hospital, Building 1, C4-P, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
1992;103:775-780
Effect of Acute Hyperglycemia on Esophageal Motility and Lower Esophageal Sphincter Pressure in Humans SIJBRAND Y. DE BOER, AD A. M. MASCLEE, WA1 F. LAM, and CORNELIS B. H. W. LAMERS Department
of Gastroenterology-Hepatology,
University
The effect of acute hyperglycemia on esophageal motility and lower esophageal sphincter pressure (LESP) was investigated. Esophageal manometry was performed for 1211 minutes in seven healthy volunteers on two separate occasions during euglycemia and during hyperglycemia with blood glucose levels stabilized at 15 mmol/L. At 90 minutes, motility was stimulated with edrophonium chloride (0.08 mg/kg intravenously). Pancreatic polypeptide (PP) secretion was determined as an indirect measure of vagal-cholinergic tone. During hyperglycemia the LESP decreased significantly (P < 0.05) from 20.1 f 1.6 mm Hg to 10.7 + 0.6 mm Hg; plasma PP levels were also significantly (P < 0.05) decreased during hyperglycemia. Edrophonium induced significant (P < 0.05) increases in LESP and PP levels in both experiments. However, LESP and PP levels after edrophonium stimulation remained significantly (P < 0.05) reduced during hyperglycemia compared with euglycemia. During hyperglycemia a significant (P < 0.05) increase in peristaltic wave duration and a decrease in peristaltic velocity were observed in the distal part of the esophagus. It is concluded that blood glucose levels affect esophageal motility, acute hyperglycemia reduces LESP and impairs esophageal motility under both basal and edrophonium-stimulated conditions, and hyperglycemia reduces plasma PP levels, suggesting impaired vagal-cholinergic activity during hyperglycemia.
Hospital, Leiden, The Netherlands
reported in these patients include reduced lower esophageal sphincter pressure (LESP) and a decrease in coordinated peristalsis with an increase in nonperistaltic contractions.4-7 The pathogenesis of gastrointestinal motor dysfunction in diabetics has not been clearly elucidated. Abnormal gastrointestinal motility in diabetics is usually associated with the presence of autonomic neuropathy.“’ Apart from neural dysfunction, however, other factors such as glycemic control and metabolic derangements secondary to diabetes mellitus may be involved.8 The role of serum glucose in the regulation of gastrointestinal motility has not been well defined. The present study was undertaken to investigate the influence of serum glucose concentrations on esophageal body motility and LESP. Esophageal manometry was performed during both euglycemia (5 mmol/L) and hyperglycemia (15 mmol/L). Healthy volunteers were studied to preclude the influence of alterations in esophageal motility secondary to autonomic neuropathy. A second goal of the study was to examine the tone of the vagal cholinergic nerve system during hyperglycemia. This was accomplished (a) indirectly by measuring pancreatic polypeptide (PP) secretion, which is known to be dependent on vagal cholinergic tone, and (b) by infusion of edrophonium chloride, a cholinergic stimulant that acts as choline esterase inhibitor. Materials and Methods Subjects
n patients with diabetes mellitus, gastrointestinal motility disturbances, especially of the stomach, the small bowel, and the large bowel, occur frequent1y.l.’ Until recently, little was known about esophageal motility in diabetic patients. Although typical symptoms of esophageal dysfunction such as dysphagia, chest pain, and heartburn are uncommon, abnormal esophageal motor function is demonstrable in more than 50% of diabetic patients.2-5 Abnormal manometric findings that have been
I
Seven healthy male volunteers (age 19-25 years) participated in the study. None was taking chronic medication or had a history of gastrointestinal disease, surgery, or diabetes mellitus. Informed consent was obtained from each person, and the protocol had been approved by the ethics committee of the University Hospital, Leiden, The Netherlands. 0
1992 by the American
Gastroenterological 0016-5095/92/$3.00
Association
776 DE BOER ET AL.
Equipment Esophageal body motility and LESP were recorded with a small polyvinyl four-lumen composite side-hole catheter. The orifices were 5 cm apart and oriented radially at 90’ to each other. Each lumen was perfused with mL/min) using a low-compliance capildistilled water (0.5 lary tube infusion pump (Arndorfer Medical Specialists, Greendale, WI). A rapid pull-through technique was used to record endexpiratory LESP. Two pull-through measurements were made for each time point except during the first 10 minutes after administration of edrophonium, when LESP was recorded in 2-minute intervals and only one pull-through measurement was performed. Intraluminal esophageal pressures were recorded at 5, 10,15, and 20 cm above the upper margin of the lower esophageal sphincter (LES). At each time point the manometric responses to at least two, but usually five, standardized wet swallows (5-mL water bolus) were recorded. The peristaltic wave amplitude and duration of contraction were calculated for the proximal (20 cm above the LES), mid (10 and 15 cm above the LES), and distal (5 cm above the LES) parts of the esophagus. Velocity of peristalsis for the proximal, mid, and distal parts of the esophagus was calculated from the time of onset between peristaltic wave peaks between adjacent transducers. It was measured over three 5-cm intervals in the proximal (20-15cm above the LES), mid (15-10cm above LES), and distal (10-s cm above the LES) parts of the esophagus. Test Procedure Each subject participated in two experiments, performed in random order during euglycemia or during hyperglycemia with blood glucose levels stabilized at 15 mmol/L. After an overnight fast the four-lumen catheter was passed through the nose with the distal tip into the proximal part of the stomach for esophageal manometry. All studies were started at 9 AM with subjects in the semirecumbent position lying in comfortable chair. Acute hyperglycemia at (15 mmol/L) was obtained using a modified glucose clamp technique.g*‘O The acute increase in blood glucose level was induced by an intravenous bolus injection of 20% glucose. The amount of glucose administered was calculated from the body weight. After the bolus injection, 20% glucose was infused at varying rates guided by serum glucose measurements every 2.5-5minutes (glucose oxidase method, Beckman glucose analyzer; Beckman Instruments, Palo Alto, CA). Serum glucose levels were maintained within &lo% of the desired level. Esophageal manometry was performed before initiating the glucose clamp and for 120 minutes during euglycemia or clamping when glucose levels were stable for at least 30 minutes. During the first 90 minutes the influence of serum glucose levels on esophageal motility was studied. Manometry was recorded every 10 minutes for 90 minutes. At 90 minutes a bolus injection of edrophonium chloride, 0.08 mg/kg body wt, was administered intravenously. Esophageal manometry was recorded for an additional 30 minutes at 1, 3,5,7.5,10, 20,and 30 minutes after edrophonium stimulation. Edrophonium chloride
GASTROENTEROLOGYVol.103,No.3
(Tensilon; Roche Products Ltd., Welwyn Garden City, England) is a short-acting acetylcholinesterase inhibitor that prevents acetylcholine destruction and thus enhances vagal-cholinergic effects.” Blood samples for measurement of plasma PP were collected before clamping, at lo-minute intervals during clamping, and 0, 1, 3,5,7.5,10,20,and 30 minutes after administration of edrophonium. Plasma PP concentrations were measured by a sensitive and specific radioimmunoassay as described previously.” Statistical
Analysis
All results are expressed as mean + SEM. The integrated incremental PP secretion in response to edrophonium was determined by calculating the area under the plasma concentration-time curve after subtraction of the basal value. Data were analyzed for the significance of differences by analysis of variance (ANOVA). When this indicated a probability of ~0.05 for the null hypothesis, Student-Newman-Keuls analyses were performed to determine which values differed significantly between the euglycemic and hyperglycemic experiments or within experiments in response to hyperglycemia or administration of edrophonium.
Results Serum Glucose Levels Fasting serum glucose levels in the euglycemia and hyperglycemia experiments were 5.2 f 0.3 mmol/L and 5.0 * 0.3 mmol/L, respectively. Serum glucose levels during euglycemia and during clamping aimed at 15 mmol/L are shown in Figure 1. LESP The basal LESP during euglycemia was not significantly different from the basal LESP before hyper-
glucose (mm&l)
1 damp
Okc
;o
;o
90
time(min)120
Figure 1. Serum glucose concentrations (mmol/L; mean +_SEM) reached during clamping aimed at 5 mmol/L and 15 mmol/L in seven
healthy
subjects.
September
ESOPHAGEAL
19%
glycemia: 19.3 + 1.6 mm Hg vs. 20.1 f 1.6 mm Hg. During the euglycemia experiment, no significant differences in LESP from basal values were observed from 0 to 90 minutes (Figure 2).During hyperglycemia, LESP was significantly (P < 0.05) reduced compared with basal levels or with euglycemia, beginning at 20 minutes and continuing during the first part of the experiment until 90 minutes. During hyperglycemia the LESP gradually declined reaching a minimum value of 10.7 + 0.6 mm Hg at 90 minutes. Administration of edrophonium resulted in significant (P < 0.05)increases in LESP from 1 to 5 minutes after infusion in the euglycemia experiment and from 1 to 10 minutes in the hyperglycemia experiment (Figure 2). Thereafter the LESP returned to pre-edrophonium levels. The mean of the individual peak LESPs after edrophonium administration was significantly (P < 0.05) lower during hyperglycemia (31.9 ? 3.1 mm Hg) than during euglycemia (39.4 + 3.7 mm Hg); the mean of the individual peak increments in LESP after edrophonium administration was not significantly different between the two experiments (euglycemia, 20.0 + 3.4 mm Hg; hyperglycemia, 21.2 k 3.0 mm Hg). Esophageal
Body Motility
Peristaltic wave amplitude, duration, and velocity measured in the upper and mid portions of the esophagus during hyperglycemia were not significantly different from those measured during euglycemia (Table 1). Significant differences in peristaltic wave duration and velocity between euglycemia and hyperglycemia were observed only in the distal portion of the esophagus. Peristaltic wave amplitude and duration increased
LESP (mm Hg)
.
.
90 Ume(min)
lx)
t
eaophonlum II
I,
0
30
60
Figure 2. LESP (mm Hg; mean ? SEM) during euglycemia (A) and hyperglycemia (0) in seven healthy subjects: O-90 minutes, unstimulated; 90-120 minutes, after intravenous administration of edrophonium, 0.08 mg/kg. *Significant differences in LESP between euglycemia and hyperglycemia (P < 0.05); ‘significant increase in LESP after edrophonium administration (P < 0.05).
MOTILITY
DURING ACUTE
HYPERGLYCEMIA
777
after edrophonium administration in both the euglycemia and the hyperglycemia experiment, but the differences were significant only for peristaltic wave duration. Peristaltic wave velocity was not affected by edrophonium administration during hyperglycemia or during euglycemia. Plasma PP Levels Basal plasma PP levels before clamping were not significantly different between the two experiments: 21 + 4 pmol/L vs. 21 k 3 pmol/L (Figure 3). From 0 minutes, when blood glucose levels had been stabilized for at least 30 minutes, until 90 minutes, when edrophonium was administered, PP levels were already significantly (P < 0.115)reduced in the hyperglycemia experiment. Significant (P < 0.05) increases in plasma PP concentrations were observed in both the euglycemia and the hyperglycemia experiment from 3 to 20 minutes after administration of edrophonium (Figure 3). Neither the peak increments in plasma PP (euglyce10 + 1 pmol/L) mia, 13 k 4 pmol/L; hyperglycemia, nor the integrated incremental PP secretion (183 f 65 pmol/L - 30 min vs. 145 +- 26 pmol/L - 30 min) were significantly different between the two experiments. Despite significant increases in plasma PP levels over basal values after edrophonium administration, PP levels during hyperglycemia remained significantly (P < 0.05) reduced compared with those during euglycemia from 0 to 30 minutes after edrophonium administration. Discussion The results of this study indicate that in healthy humans, blood glucose levels affect esophageal motility. During acute hyperglycemia [l5 mmol/L (270 mg/dL)], basal LESP was significantly decreased. Hyperglycemia influenced motility in the distal part of the esophagus by significantly increasing peristaltic wave duration and by slowing the velocity of peristalsis. Although to our knowledge this study is the first to show that hyperglycemia impairs esophageal motility, an inhibitory effect of glucose on the function of other gastrointestinal organs has been recognized for several years.13-16 McGregor et al. have shown that gastric emptying is delayed during intravenous infusion of glucose.14 Hyperglycemia suppresses both gastric acid and pancreatic enzyme secretion.‘5a16 Unfortunately, in these studies13-“j performed in healthy volunteers, serum glucose levels were not determined. Because glucose was administered by either bolus injection or constant-rate infusion, glucose levels may have varied markedly as a result of reactive insulin secretion. In more recent studies,
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Table 2. Manometric Data of Esophageal Peristalsis in Seven Healthy Subjects During Euglycemia Hyperglycemia (15 mmol/L) Under Basal Conditions Proximal, Mid, and Distal Parts of the Esophagus
and After Administration
Euglycemia Basal” Amplitude (mm Hg) Proximal Mid Distal Duration (s) Proximal Mid Distal Velocity (cm/s) Proximal Mid Distal
Hyperglycemia
Edrophonium
39 + 2 50 f 3 45 * 4
(5 mmol/L) and of Edrophonium for the
stimulatedb
44 f 2 59 + 3 50 + 6
Basal”
36 + 2 54 + 3 53 f 4
Edrophonium
stimulatedb
38 + 4 59 * 4 57 f 6
2.2 f 0.1 2.6 + 0.1 2.8 + 0.1
2.7 + 0.2” 3.3 f 0.4” 4.0 + 0.7”
2.4 + 0.1 2.8 + 0.1 3.2 f O.ld
2.7 f 0.2’ 3.5 + o.4c 4.0 _+0.8”
3.4 f 0.1 4.3 f 0.1 4.7 + 0.3
3.2 + 0.2 4.5 f 0.3 4.5 f 0.4
3.0 + 0.1 4.3 zk 0.1 3.9 zk 0.3d
3.2 ?I 0.2 4.6 f 0.2 3.9 + 0.5
“Mean + SEM, from 0 to 90 minutes. bMean + SEM, from 0 to 5 minutes after stimulation, “P < 0.05, edrophonium stimulated vs. basal. dP < 0.05, hyperglycemia vs. euglycemia.
however, hyperglycemia has been obtained by clamp techniques, thus stabilizing serum glucose levels. Using these techniques it has been confirmed that hyperglycemia inhibits gastric motor function as shown by a significant reduction in antral motility during hyperglycemia at 13.9 mmol/L (250 mg/ dL).17 Gastrointestinal motor dysfunction, and more recently abnormal esophageal motility, have been well documented in patients with diabetes mellitus.‘-8 The pathogenesis of esophageal dysmotility in diabetes has not been clearly elucidated. It has been
PP (pmolli)
30
20 -
10 -
edrophonium Ok’
b
,b
Gb
90
time (min)
120
Figure 3. Plasma PP concentrations (pmol/L; mean + SEM) during euglycemia (A) and hyperglycemia (0) in seven healthy subjects; O-90 minutes, unstimulated; 90-120 minutes, after intravenous administration of edrophonium, 0.09 mg/kg. *Significant differences in PP concentrations between euglycemia and hyperglycemia (P < 0.05); *significant increases in PP concentrations in response to edrophonium (P < 0.05).
suggested that neural impairment, especially autonomic nerve dysfunction, is an important factor.l” Evidence for this hypothesis is derived from studies indicating that esophageal motor abnormalities are more prevalent in diabetic patients with than in those without clinical signs of neuropathy.3-7s18 In addition, the degree of esophageal dysmotility appears to correlate with the severity of autonomic neuropathy.4,18 On the other hand, abnormal esophageal peristalsis does occur in the absence of demonstrable neuropathy.3p4 It has therefore been questioned whether other factors such as glycemic control or metabolic derangements secondary to diabetes may influence gastrointestinal function in these patients. As shown in this study, acute hyperglycemia in healthy subjects induced several esophageal motor abnormalities that have been described in diabetic patients: reduced LESP, prolonged duration of peristaltic waves, and decreased peristaltic velocity. Infusion of glucose in healthy subjects may induce several metabolic changes apart from hyperglycemia. It is therefore possible that metabolic changes secondary to hyperglycemia, rather than glucose itself, are responsible for the inhibitory effect on esophageal motility. For instance, high glucose concentrations stimulate insulin secretion, and hyperinsulinemia affects gastrointestinal motility. However, previous studies have shown that insulin exerts a stimulatory rather than an inhibitory effect on intestinal motilhyperglycemia reduces gastric ity. “*‘OFurthermore, emptying in patients with type I diabetes, indicating that insulin is not responsible for the inhibitory effect of hyperglycemia on gastrointestinal function.21 In experimental diabetes, and more recently also
September
1992
ESOPHAGEAL
in human diabetes,” delayed nerve-conduction velocity during hyperglycemia has been shown. It has also been shown that infusion of glucose suppresses efferent vagus nerve activity.23 In the present study, hyperglycemia significantly reduced plasma PP levels. The secretion of PP from the pancreas is known to be under vagal cholinergic contro1.24 For instance, insulin-induced hypoglycemia is a potent stimulus of PP secretion through vagal cholinergic activation of PP-secreting cells. Hyperglycemia, on the other hand, is known to suppress PP release through inhibition of vagal-cholinergic activity because the inhibitory effect of hyperglycemia on PP secretion is blunted by truncal vagotomy.25 Previous studies have indicated that vagal-cholinergic innervation plays an important role in the regulation of esophageal motility.26 Significant reductions in LESP and esophageal peristalsis during cholinergic blockade with atropine have been shown.26,27 The inhibitory effects of hyperglycemia on esophageal motility observed in this study resemble those seen during cholinergic blockade with atropine. Based on these observations and the suppression of PP secretion, it is postulated that hyperglycemia influences esophageal motility, at least in part, through inhibition of vagal-cholinergic neural activity. Administration of edrophonium resulted in transient but significant effects on LESP and esophageal body motility. Edrophonium significantly increased LESP during both euglycemia and hyperglycemia. Increments in LESP were not significantly different between euglycemia and hyperglycemia, but the maximum LESP after edrophonium administration was significantly lower during hyperglycemia than during euglycemia. In accordance with the results of previous studies,“*” edrophonium produced a stimulatory effect on esophageal body motility characterized by significant increases in the duration and amplitude of peristaltic contractions. After edrophonium administration, plasma PP levels increased significantly from basal levels, suggesting an increase in cholinergic activity. In the hyperglycemia experiment, however, plasma PP levels after edrophonium administration were significantly lower than those in the euglycemia experiment. These results are in accordance with a significantly lower LESP after edrophonium administration during hyperglycemia. Thus, the inhibitory, possibly vagal-cholinergic-mediated effect of hyperglycemia on esophageal motility and PP secretion is present not only under basal conditions but also during stimulation with edrophonium. We conclude that blood glucose levels affect esophageal motor function, as demonstrated by a reduction in LESP and esophageal motility during acute
MOTILITY DURING ACUTE HYPERGLYCEMIA
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hyperglycemia (15 mmol/L). Plasma PP levels were significantly reduced during hyperglycemia, pointing to impaired vagal-cholinergic activity. An inhibitory effect of hyperglycemia on esophageal motility and PP secretion was seen not only under basal conditions but also during stimulation with edrophonium. References 1.
2. 3.
4. 5.
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Feldman M, Schiller LR. Disorders of gastrointestinal motility associated with diabetes mellitus. Ann Intern Med 1983;98:378-384. Rothstein RD. Gastrointestinal motility disorders in diabetes mellitus. Am J Gastroenterol 1990;85:782-785. Russell COH, Gannan R, Coatsworth J, Nielsen R, Allan F, Hill LD, Pope CE. Relationship among esophageal dysfunction, diabetic gastroenteropathy, and peripheral neuropathy. Dig Dis Sci 1983;28:289-293. Stewart IM, Hosking DJ, Preston BJ, Atkinson M. Oesophageal motor changes in diabetes mellitus. Thorax 1976;31:278-283. Hollis JB, Caste11 DO, Braddom RL. Esophageal function in diabetes mellitus and its relation to peripheral neuropathy. Gastroenterology 1977;73:1098-1102. Mandelstam P, Siegal CI, Lieber A, Siegel M. The swallowing disorder in patients with diabetic neuropathy-gastroenteropathy. Gastroenterology 1969;56:1-12. Loo DF, Dodds WJ, Soergel KH, Arxdorfer RC, Helm JF, Hogan WJ. Multipeaked esophageal pressure waves in patients with diabetic neuropathy. Gastroenterology 1985;88:485-494. Horowitz M, Harding PE, Maddox AF, Wishart JM, Akkermans LMA, Chatterton BF, Shearman DJC. Gastric and oesophageal emptying in patients with type 2 diabetes mellitus. Diabetologia 1989:32:151-159. Ward WK, Halter JB, Beard JB, Porte D. Adaptation of B and A cell function during prolonged glucose infusion in human subjects. Am J Physiol 1984;246:E405-E411. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-E223. Lee CA, Reynolds JC, Ouyang A, Baker L, Cohen S. Esophageal chest pain. Value of high-dose provocative testing with edrophonium chloride in patients with normal esophageal manometries. Dig Dis Sci 1987;32:682-688. Lamers CBHW, Diemel C, van Leer E, van Leusen R, Peetoom JJ. Mechanism of elevated pancreatic polypeptide concentrations in chronic renal failure. J Clin Endocrinol Metab 1982:55:922-926.
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Aylett P. Gastric emptying and changes of glucose level, as affected by glucagon and insulin. Clin Sci 1962;22:171-178. MacGregor IL, Gueller, Watts HD, Meyer JH. The effect of acute hyperglycemia on gastric emptying in man. Gastroenterology 1976:70:190-196. MacGregor IL, Deveney C, Way LW, Meyer JH. The effect of acute hyperglycemia on meal-stimulated gastric, biliary, and pancreatic secretion and serum gastrin. Gastroenterology 1976:70:197-202. Niederau C, Sonnenberg A, Erckenbrecht J. Effects of intravenous infusion of amino acids, fat, or glucose on unstimulated pancreatic secretion in healthy humans, Dig Dis Sci 1985;30:445-455. Barnett JL, Owyang C. Serum glucose concentration as a modulator of interdigestive gastric motility. Gastroenterology 1988;94:739-744. Murray FE, Lombard MC, Ashe J. Lynch D, Drury MI,
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O’Moore B, Lennon J, Crowe J. Esophageal function in diabetes mellitus with special reference to acid studies and relationship to peripheral neuropathy. Am J Gastroenterol 1987;82:840-843. 19. Prasad KR, Sarna SK. The central and peripheral effects of insulin on migrating myoelectric complexes (abstr). Gastroenterology 1986;90:1589. 20. Bueno L, Ruckebusch M. Insulin and jejunal electrical activity in dog and sheep. Am J Physiol 1976;230:1538-1544, 21. Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, Dent J. Hyperglycemia slows gastric emptying in type I [insulin-dependent] diabetes mellitus. Diabetologia 1990;33: 675-680. 22. Sindrup SH, Ejlertsen B, Gjessing H, Svendsen A, Froland A. Peripheral nerve function during hyperglycemic clamping in insulin-dependent diabetic patients. Acta Neurol Stand 1989;79:412-418. 23. Hirano T, Niijima A. Effects of 2-deoxy-o-glucose, glucose and insulin on efferent activity in gastric vagus nerve. Experientia 1980;36:1197-1198,
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24. Schwartz TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 1983;85:1411-1425. 25. Tsuda K, Seino Y, Mori K, Seino S, Takemura J, Kuzuya H, Yamamura T, Kotoura Y, Ito N, Imura H. Effect of truncal vagotomy on pancreatic polypeptide response after intravenous glucose administration. Regul Pept 1981;1:347-352. 26. Christensen J. Motor-functions of the pharynx and esophagus. In: Physiology of the gastrointestinal tract. Johnson LR, et al., eds. New York: Raven, 1987;595-612. 27. Dodds WJ, Dent J, Hogan WJ, Arndorfer RC. Effect of atropine on esophageal motor function in humans. Am J Physiol 1981;240:G290-G296. 28. Richter JE, Hackshaw BT, Wu WC, Caste11 DO. Edrophonium: a useful provocative test for esophageal chest pain. Ann Intern Med 1985;103:14-21.
Received February 1, 1991. Accepted February 24,1992. Address requests for reprints to: A. A. M. Masclee, M.D., Department of Gastroenterology-Hepatology, University Hospital, Building 1, C4-P, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
