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Interdigestive gastroduodenal motility and serum motilin levels in patients with idiopathic delay in gastric emptying
GASTROENTEROLOGY 1986;90:20-6
Interdigestive Gastroduodenal Motility and Serum Motilin Levels in Patients With Idiopathic Delay in Gastric Emptying G. LAB6, M. BORTOLOTTI, and G. BERSANI
P. VEZZADINI,
G. BONORA,
Department of Medicine and Gastroenterology, University of Bologna, Bologna, Italy
The interdigestive gastroduodenal motor activity and serum motilin levels were studied in 22 dyspeptic patients with markedly delayed gastric emptying not due to diseases known to impair gastroduodenal motility and in 7 control subjects with normal gastric emptying. Motor activity was recorded using a manometric probe positioned in the gastric antrum and in the proximal duodenum, and blood samples for radioimmunoassay of motilin were taken every 1.5 min during the recording period. The control subjects showed gastroduodenal activity fronts of the migrating motor complex associated with motilin peaks. Almost all patients with delayed gastric emptying showed no activity fronts in the stomach, and only half of them showed activity fronts starting in the duodenum. In these patients a significant reduction in the number of motilin peaks and in the integrated motilin output during the identified peaks was also observed. The results of this study indicate that most dyspeptic patients with idiopathic delay in gastric emptying may also have an alteration in interdigestive gastroduodenal motility, mainly characterized by a lack of gastric activity fronts, associated with an impaired motilin release. In a number of patients with nonspecific functional dyspeptic symptoms, including epigastric fullness or distention after a meal and a feeling of prolonged digestion, no organic disease of the gastrointestinal tract is demonstrable. In these patients, in whom gastric emptying is frequently delayed (l), an abnorReceived October 1, 1984. Accepted June 25, 1985. Address requests for reprints to: M. Bortolotti, M.D., Via Massarenti, 48, Bologna 40138, Italy. This study was supported in part by grant CT 83.02876.56 from the National Research Council of Rome (Italy). 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
ma1 interdigestive myoelectric activity of the distal stomach has been described (2). A preliminary report from our group (3) showed that alterations in the gastroduodenal interdigestive migrating motor complex are also present in most patients with idiopathic gastroparesis. In that study we did not evaluate the pattern of circulating motilin, a hormone that fluctuates with the various phases of the migrating motor complex [J-7). Therefore, the present study was designed to investigate the interdigestive gastroduodenal motor activity and the associated changes of circulating motilin in dyspeptic patients with abnormally delayed gastric emptying of unknown origin (idiopathic gastroparesis).
Subjects and Methods Subjects Twenty-two patients (6 men and 16 women, mean age 34 yr, range 18-60 yr) who complained of epigastric fullness or distention after a meal and a feeling of prolonged digestion and who had a markedly slow gastric emptying were studied. In particular, the half-emptying
time of a semiliquid meal, evaluated by using a scintigraphic method (8), was above the mean +3 SD of the normal subjects. Half-emptying time was calculated from time-activity curves obtained with a computer-assisted LFOV y-camera positioned over the gastric area after ingestion of a 300-ml semisolid meal (500 kcal provided by 55% carbohydrates, 25% fat, and 20% protein) mixed with 5 mCi of sQ”Tc-sulfur colloid. Seven healthy volunteers matched for age and sex (3 men and 4 women, mean age 34 yr, range 18-60 yr) who had no specific symptoms related to gastrointestinal disorders and had half-emptying times within the normal range were also investigated. No subject entering this study had a history of gastrointestinal surgery. Organic lesions and diseases known to affect gut motility (e.g., diabetes, scleroderma) were excluded in all cases by a diagnostic workup including
INTERJXGESTIVEMOTIWTY, MOTILIN, GAS’I’ROPARESIS 21
January 1986
Table
1. Activity
Fronts and Motilin
Case No. Healthy subjects 1 2 3 4 5 6 7 patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Peaks Observed
in Healthy Recording time (min)
Subjects
and in Dyspeptic
Patients
Activity fronts Gastroduodenal
Motilin peaks
Age (ur)
Sex
30 18 26 35 60 29 41
F F M M F M F
200 200 200 220 200 240 200
I”; II”
I”; II” I”; II” I”; II” 10; II”
I”; II” I”: II” I”; II” I”; II” I”; II” I”; II” I”; II”
48 20 60 25 33 45 36 22 18 29 55 44 38 22 25 27 23 35 42 34 37 21
M F M M F F F F M M F F M M M F F F F F F F
200 240 300 250 240 300 240 300 240 200 240 200 250 200 260 200 200 300 300 200 300 300
I”; II” -
I”; II” I”; II”; III
Duodenal
I”: II” I”. II”
Dyspeptic
I; III; III are subsequent
Recording
-
I; II I”; II” I” I”
-
of Motor Activity
The interdigestive motor activity in the stomach and in the proximal duodenum was recorded during a period of 200-300 min after a 14-h fast. The study was carried out using a four-lumen probe (external diameter 4.5 mm) with lateral holes 5 cm apart. The catheters were perfused with an Arndorfer pump (Arndorfer Medical Specialties, Greensdale, Wis.) and connected to Statham P 23 DB external pressure transducers (Statham Laboratories Inc., Puerto Rico) and to a Beckman R 612 polygraph (Beckman Instruments, Stiller Park, Ill.). The recording holes, indicated by radiopaque markers, were positioned
-
-
activity fronts or motilin peaks observed in each subject. a Association
routine laboratory tests and radiologic and ultrasonographic examinations of the digestive system. No subject exceeded 10% of the ideal body weight. Pentagastrinstimulated gastric acid secretion and fasting serum gastrin concentrations were within the normal range for our laboratory in all cases. None of the subjects had taken any drugs during the week preceding the examination nor had they smoked for at least 10 h before the test. Written informed consent was obtained from all subjects.
I; II; III I I” -
-
between activity front and motilin peak.
under fluoroscopic control (two in the gastric antrum and two in the proximal half of the duodenum). During the recording of motor activity, 3-ml blood samples were drawn at 15-min intervals for motilin assay. Radioimmunoassay
of Serum
Motilin
Serum immunoreactive motilin concentration was measured by a specific radioimmunologic method previously described (9). Briefly, the antiserum TS-6 specific for the N-terminal region of the motilin molecule (gift from Dr. N. S. Track, Laboratory of Gastrointestinal Hormones, University of Toronto, Canada) was used in a final dilution of 1: 50,000. Natural porcine motilin (obtained from Quadra Logic Technologies Inc., Vancouver, Canada) was used as a standard. Serum samples (O&ml duplicates) were assayed at a final dilution of 1: 10 in a total volume of 2 ml. After a 5-day incubation at 4”C, free and bound hormones were separated by dextran-coated charcoal. No cross-reactivity was found with physiologically related peptides. The mean concentration of motilin required to reduce the binding of labeled motilin to 50% was 9 fmol/ml assay tube, equivalent to 90 pmol/L serum. With-
22 LABbETAL.
Figure
GASTROENTEROLOGY Vol. 90, No. 1
1. Interdigestive gastroduodenal motor activity recorded manometrically in a healthy subject with normal gastric emptying. AP, proximal antrum; AD, distal antrum; D, and D2, proximal half of the duodenum; Pn, pneumogram. Note that the activity front propagates from the antrum to the duodenum, is preceded by phase II activity with irregular pressure waves, and is followed by phase I activity characterized by motor quiescence.
in-assay and between-assay coefficients of variation were 5.1% and 8.5% at mean serum motilin levels of 70 and 72 pmol/L, respectively (n = 10). All samples from the same subject were assayed simultaneously.
Analysis
and Calculations
According to other investigators (10-12), three different phases of each interdigestive cycle were visually identified: phase I is characterized by motor quiescence, phase II by irregular motor activity, and phase III (activity front) by a short burst of rhythmic contractions. The duration of cycles [time interval between the end of one duodenal activity front and the end of the next) and the percentage of time occupied by each phase of the cycle were determined. When the interdigestive cycles were not regular and there was a lack of activity fronts, the phases of motor quiescence (phase I-like activity) and the phases of irregular contractions (phase II-like activity) were identified and the percentage of the recording time occupied by each phase was measured. Serum motilin levels were evaluated as the mean concentration during the periods of motor quiescence and during the periods of irregular motor activity, and as the maximum value during the entire recording time. A mean baseline concentration of serum motilin during the recording of motor activity was also calculated. A motilin peak was identified when one or more contiguous values exceeded the mean + 3 SD baseline concentration. The integrated motilin output (IMO) during each peak, expressed in nanomoles * minutes per liter, was calculated using the following formula: IMO = $ (M, + M&t, + + (M2 + M&
+
.,
where M1, MZ, . . . are the serum motilin concentrations at the different points identifying a peak (including the origin and the end of the peak on the baseline) minus the mean
baseline
motilin concentration in picomoles per liter, and the time intervals in minutes between M1 and Mz,MzandMB,. . . . An activity front was considered to be associated with a motilin peak when it occurred during the same time period also used for the calculation of the integrated motilin output. The statistical analysis was performed using appropriate tests (Student’s t-test, Wilcoxon’s rank-file test, x2 test]. t1, tz, . . * are
Results Motor Activity Table 1 shows the incidence of gastric and duodenal activity fronts in healthy subjects and in dyspeptic patients. All healthy subjects showed regular interdigestive motor cycles (Figure l),with phase III activity propagated distally from the antral region to the duodenum. A total of 14 gastroduodenal activity fronts were observed during the whole recording period of 24.3 h. The mean duration of the cycles, calculated from the duodenal record, was 93 min (range 69-113 min), 38.6% (range 35%-58%) of which was occupied by phase I, 55.7% (range 38%62%) by phase II,
and 5.7% (range 3%7%) by phase III activity. In 20 of 22 dyspeptic patients no activity front was observed in the stomach during the entire recording period. In 11 of these 20 patients there was a lack of activity fronts also in the proximal duodenum (Figure ZA), whereas in the remaining 9 patients, activity
fronts starting in the proximal duodenum were recorded (Figure 2B). Only 2 patients in the entire group had activity fronts propagating from the
January 1986
INTERDIGESTIVE MOTILITY, MOTILIN, GASTROPARESIS
23
A
P---‘-
Pn
tmin
mmHg
I 20
B rrlrr_r--Pn
1 min
120mmHg
L
.
-
A
AP
-A-
_
AD
Figure 2. Manometric recordings of interdigestive gastroduodenal motor activity carried out in 2 patients (A and B) with idiopathic delay in gastric emptying. In each recording: AP, proximal antrum; AD, distal antrum; D1 and D2, proximal half of the duodenum; Pn, pneumogram. A. In this patient no activity front was recorded either in the stomach or in the duodenum during the entire recording period. Only periods of irregular motor activity or quiescence were observed. B. In this patient activity fronts were recorded only in the duodenum and not in the antrum during the entire recording period. The stomach showed only periods of irregular motor activity alternating with phases of motor quiescence.
antrum to the duodenum, with a time interval of 110 and 154 min, respectively. A total of four gastroduodenal and 19 duodenal activity fronts were recorded in the 22 dyspeptic patients during the whole 91-h recording period. The mean duration of the duodenal cycles recorded in the 9 patients with
activity fronts starting in the duodenum was 115 min (range 65-156 min), 46% (range 22%_71%) of which was occupied by phase I, 49% range (23%-Z%) by phase II, and 5% (range 2%-7’%) by phase III activity. The incidence of either gastroduodenal or duodenal activity fronts in dyspeptic patients was signifi-
24
LAB0
GASTROENTEROLOGY Vol. 90, No. 1
ET AL.
Figure 3. Individual values of mean serum motilin concentrations during the periods of motor quiescence (A) and during the periods of irregular motor activity (B), and the maximum value measured during the entire recording time (C) in normal subjects (N) and in dyspeptic patients (PI. 0, Subject with both gastric and duodenal phase III activity; 0, subject with phase III activity beginning in the duodenum; 0, subject without gastric and duodenal phase III activity. 01 P
cantly lower than in healthy subjects (p < 0.001 and p < 0.05,respectively). No significant difference was found between the duration of cycles in the 9 dyspeptic patients with activity fronts originating in the proximal duodenum and that in normal subjects. Serum Motilin Figure 3 shows the individual values of mean serum motilin concentration during the periods of motor quiescence and during the periods of irregular contractions, and the maximum value measured during the entire recording time in healthy subjects and in dyspeptic patients. In these two groups mean serum motilin concentration during the phase of motor quiescence was 42 + 23 pmol/L (3 + SD) and 36 + 22 pmol/L, respectively (p not significant). The mean concentration of circulating motilin during the phase of irregular motor activity was higher in healthy subjects (81 + 43 pmol/L) than in dyspeptic patients (54 f 42 pmol/L). This difference, however, did not reach statistical significance. The mean maximhm value of serum motilin registered during the entire recording period in healthy subjects (123 + 48 pmol/L) was significantly higher (p < 0.05) than in dyspeptic patients (57 t 25 pmol/L). The 2 patients with activity fronts propagating from the antrum to the duodenum had serum motilin concentrations near the upper limit of the range. Table 1 reports the incidence of motilin peaks observed in the two groups. All healthy subjects showed fluctuations of serum motilin, whereas only 11 of 22 dyspeptic patients (50%) showed motilin
NS
peaks. In the whole group of normal subjects a total of 14 peaks were recognized during the whole recording time of 24.3 h. On the contrary, the whole group of 22 dyspeptic patients showed a total of 19 motilin peaks during the whole recording time of 91 h. In these patients the incidence of motilin peaks was significantly lower than in controls (p < 0.05). The mean + SD integrated motilin output calculated during the motilin peaks in dyspeptic patients (1.3 k 0.94 nmol - min/L) was significantly lower (p < 0.05) than in healthy subjects (3.8 * 2.70 nmol * min/L).
Association Between Activity Motilin Peaks
Fronts and
The association between activity fronts and motilin peaks in each subject is indicated in Table 1. Fourteen of 14 activity fronts propagating from the antrum to the duodenum (100%) were associated with a motilin peak in healthy volunteers and 4 of 4 (100%) in dyspeptic patients. In the 9 patients with phase III activity starting only in the duodenum, 8 of 19 activity fronts (42%) were associated with a motilin peak, whereas the remaining 11 activity fronts (58%) did not occur with a motilin peak. In control subjects all motilin peaks were associated with an activity front. In dyspeptic patients 12 of 19 motilin peaks (63%) were associated with gastroduodenal or duodenal activity fronts, whereas 7 (37%) occurred without the presence of a related activity front.
January 1986
Discussion The results of this study confirm our preliminary observation that dyspeptic patients with marked delay in gastric emptying may also have abnormalities in interdigestive motor activity (3). The absence of activity fronts in the stomach was the most characteristic feature of these patients. This motor disorder was associated with an impaired cyclic rise in fasting serum motilin, the peaks being small or absent during the recording of motor activity. On the contrary, healthy subjects showed the typical fluctuations of serum motilin related to phase III activity, as already described by others (4-i’). At present, it is not completely known whether fluctuations of endogenous circulating motilin in humans modulate or are modulated by the interdigestive migrating motor complex. Previous studies have shown that plasma motilin peaks precede the occurrence of phase III activity in huFurthermore, physiologic doses of mans (4,6,7,13). exogenous motilin induce and motilin antiserum abolish the migrating motor complex (4,14,15). Conversely, another study suggests that the cyclic increase of circulating motilin is an epiphenomenon, the hormone being released into the circulation by the contractile activity of the duodenum and upper jejunum (16).Our investigation was not designed to evaluate the cause-effect relationship between these two events. It is of interest to note, however, that in our dyspeptic patients without gastric phase III activity the motilin peaks were small or absent, whereas the only 2 patients with activity fronts starting in the stomach showed values of serum motilin near the upper limit of the range and similar to the mean values in normal subjects. These results seem to be in agreement with previous studies suggesting the existence of a threshold concentration of motilin above which gastric fronts occur (17) and showing that higher motilin peaks are associated with the cycles starting in the stomach (11). On the basis of these considerations, we do not know whether the absence or the smallness of motilin fluctuations in our dyspeptic patients is the cause of the absence of phase III activity in the stomach or is secondary to the interdigestive motility dysfunction in the upper small intestine. In patients with phase III activity starting in the proximal duodenum, the majority of activity fronts were not associated with motilin peaks and one-half of the motilin peaks were not associated with activity fronts. Furthermore, small motilin peaks were also observed in 3 of half the dyspeptic patients with absence of complexes either in the antrum or in the proximal duodenum. As the motor activities of the distal duodenum and the upper jejunum were not
INTERDIGESTIVE
MOTILITY,
MOTILIN,
GASTROPARESIS
25
recorded in this study, we cannot exclude the possible occurrence of complexes starting in these more distal parts, as observed by others (4,11,13,17). The difficulty in correlating motility events in the human duodenum with cyclic rises of plasma motilin has been already noted (16).Previous studies (13,18) have demonstrated that the complexes that originate in the stomach, but not those starting in the small intestine, are regularly associated with well-defined motilin peaks. Other groups have observed that a relationship does not always exist between plasma motilin and the initiation of spontaneous activity fronts in the upper small intestine (19). The etiology of the motor disorder observed in our patients is unknown. The diseases that are thought to alter the gastric motility (20) were excluded on the basis of an extensive clinical and laboratory workup. In particular, we have excluded the presence of diabetes, a disease in which a motility dysfunction similar to that observed in our patients has been described (21). Acid hypersecretive or hyposecretive states and hypergastrinemic conditions were also excluded in order to avoid the possible influence of abnormal gastroduodenal acidity (22) or circulating gastrin concentration (23)on the interdigestive motility pattern. However, the presence of a lesion in the enteric smooth muscle or intrinsic innervation, or both, indiscernible with the conventional diagnostic examinations, cannot be ruled out. In conclusion, our study shows that dyspeptic patients with abnormally delayed gastric emptying of unknown origin may also have a dysfunction in the interdigestive motor activity. The most characteristic feature, and possibly a marker, of this functional disorder is the absence of phase III activity in the gastroduodenal area associated with the absence or smallness of motilin fluctuations. Taking into account that activity fronts are thought to play an important role in sweeping gastric content during the last postprandial period (24),it can be suggested that the absence of phase III activity in the stomach may contribute to the induction of gastric stasis and, consequently, to the typical dyspeptic symptoms in these patients.
References Pellegrini CA, Broderik WC, Van Dyke D, Way LW. Diagnosis and treatment of gastric empyting disorders (clinical usefulness of radionuclide measurement of gastric emptying). Am J Surg 1983;145:143-51. Chey WY, You CH, Lee KY, Menguy R. Gastric dysrhythmia: clinical
aspects.
In: Chey WY, ed. Functional
disorders
of the
digestive tract. New York: Raven, 1983:175-80. Bortolotti M, Foschi S, Galletti M, Labb G. Interdigestive migrating motor complex (MMC) restored by an Hz antagonist
26 LAB0 ET AL.
(ranitidine) in gastroparesis (abstr). Stand J Gastroenterol 1962;17(Suppl 78):234. 4. Vantrappen G, Janssens J, Peeters TL, Bloom SR, Cristofides ND, Hellemans J. Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci 1979;24:497-500. 5. Itoh 2, Takeuchi S, Aizawa I, et al. Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs. Am J Dig Dis 1978;23:929-35. 6. You CH, Chey WY, Lee KY. Studies on plasma motilin concentration and interdigestive motility of the duodenum in humans. Gastroenterology 1980;79:62-6. 7. Peeters TL, Vantrappen G, Janssens J. Fasting plasma motilin levels are related to the interdigestive motor complex. Gastroenterology 1960;79:716-9. 8. Jacobs F, Akkermans LMA, Oli Hong-Yore, Hoekstra F, Wittebol P. A radioisotopic method to quantify the function of fundus, antrum and their contractile activity in gastric emptying of a semisolid and solid meal. In: Wienbeck M, ed. Motility of the digestive tract. New York: Raven, 1982: 23390. 9. Vezzadini P, Bonora G, Bernardini S, Ecchia R, Toni R, Labo G. Radioimmunoassay of mdtilin in human plasma: interdigestive levels in normal subjects and in patients with hypergastrinemic chronic atrophic gastritis. J Nucl Med Allied Sci 1984;28!197-2Oi. 10. Vantrappen G, Janssens J, Peeters TL. The migrating motor complex. Med Clin North Am 1981;65:1311-29, 11. Rees WDW, Malagelada JR, Miller LJ. Human interdigestive and postprandial gastrointestinal motor and gastrointestinal hormone patterns. Dig Dis Sci 1982;27:321-9. 12. Wingate DL. Backwards and forwards with the migrating complex. Dig Dis Sci 1981;26:641-66. 13. Janssens J, Vantrappen G, Peeters TL. The activity front of the migrating motor complex of the human stomach but not of
GASTROENTEROLOGY
vol.
90,NO. 1
the small intestine is motilin-dependent. Regul Pept 1983;6: 363-9. 14. Thomas PA, Kelly KA, Go VLW. Does motilin regulate canine interdigestive gastric motility? Dig Dis Sci 1979;24:577-82. 15. Lee KY, Chang TM, Chey WY. Effect of rabbit antimotilin serum on myoelectric activity and plasma mdtiiin concentration in fasting dog. Am J Physiol 1983;245:G547-53. 16. Sarna S, Chey WY, Condon RE, Dodds WJ, Meyers T, Chang TM. Cause-and-effect relationship between motilin and migrating myoelectfic complexes. Am J Physiol 1983;245: G277-84. 17. Itoh Z, Aizawa I, Seguchi T. The interdigestive migrating complex and its significance in man. Clin Gastroenterol 1982;11:497-521. 18. Poitras P, Steinbach JH, Van Deventer G, Code CF, Walsh JH. Motilin-independent ectopic fronts of the interdigestive myoelectric complex in dogs. Am J Physiol 1980;216:215-20. 19. Fox JET. Motilin-an update. Life Sci 1984;35:695-7O6. 20. Caniilleri M, Malagelada JR. Gastric motility in disease. In: Akkermans LMA, Johnson AG, Read NW, eds. Gastric and gastroduodenal motility. New York: Praeger, 1984:201-32. 21. Malagelada JR, Rees, WDW, Mazzotta LJ, Go VLW. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol. Gastrdenterology 1980;78:286-93. 22. Peeters TL, Vantrappen G, Janssens J. Sham feeding amplifies the secretory component of interdigestive activity (abstr). Gastroenterol Clin Biol 1983;7:722. 23. Lee HY, Kim MS, Chey WY. Effects of a meal and gut hormones on plasma motilin and duodenal motility in dog. Am J Physiol 1980;238:G28O-3. 24. Itoh Z. Hormones, peptides, opioids and prostaglandins in normal gastric contractions. In: Akkermans LMA, Johnson AG, Read NW, eds. Gastric and gastroduodenal motility. New York: Praeger, 1984:41-59.
Interdigestive Gastroduodenal Motility and Serum Motilin Levels in Patients With Idiopathic Delay in Gastric Emptying G. LAB6, M. BORTOLOTTI, and G. BERSANI
P. VEZZADINI,
G. BONORA,
Department of Medicine and Gastroenterology, University of Bologna, Bologna, Italy
The interdigestive gastroduodenal motor activity and serum motilin levels were studied in 22 dyspeptic patients with markedly delayed gastric emptying not due to diseases known to impair gastroduodenal motility and in 7 control subjects with normal gastric emptying. Motor activity was recorded using a manometric probe positioned in the gastric antrum and in the proximal duodenum, and blood samples for radioimmunoassay of motilin were taken every 1.5 min during the recording period. The control subjects showed gastroduodenal activity fronts of the migrating motor complex associated with motilin peaks. Almost all patients with delayed gastric emptying showed no activity fronts in the stomach, and only half of them showed activity fronts starting in the duodenum. In these patients a significant reduction in the number of motilin peaks and in the integrated motilin output during the identified peaks was also observed. The results of this study indicate that most dyspeptic patients with idiopathic delay in gastric emptying may also have an alteration in interdigestive gastroduodenal motility, mainly characterized by a lack of gastric activity fronts, associated with an impaired motilin release. In a number of patients with nonspecific functional dyspeptic symptoms, including epigastric fullness or distention after a meal and a feeling of prolonged digestion, no organic disease of the gastrointestinal tract is demonstrable. In these patients, in whom gastric emptying is frequently delayed (l), an abnorReceived October 1, 1984. Accepted June 25, 1985. Address requests for reprints to: M. Bortolotti, M.D., Via Massarenti, 48, Bologna 40138, Italy. This study was supported in part by grant CT 83.02876.56 from the National Research Council of Rome (Italy). 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
ma1 interdigestive myoelectric activity of the distal stomach has been described (2). A preliminary report from our group (3) showed that alterations in the gastroduodenal interdigestive migrating motor complex are also present in most patients with idiopathic gastroparesis. In that study we did not evaluate the pattern of circulating motilin, a hormone that fluctuates with the various phases of the migrating motor complex [J-7). Therefore, the present study was designed to investigate the interdigestive gastroduodenal motor activity and the associated changes of circulating motilin in dyspeptic patients with abnormally delayed gastric emptying of unknown origin (idiopathic gastroparesis).
Subjects and Methods Subjects Twenty-two patients (6 men and 16 women, mean age 34 yr, range 18-60 yr) who complained of epigastric fullness or distention after a meal and a feeling of prolonged digestion and who had a markedly slow gastric emptying were studied. In particular, the half-emptying
time of a semiliquid meal, evaluated by using a scintigraphic method (8), was above the mean +3 SD of the normal subjects. Half-emptying time was calculated from time-activity curves obtained with a computer-assisted LFOV y-camera positioned over the gastric area after ingestion of a 300-ml semisolid meal (500 kcal provided by 55% carbohydrates, 25% fat, and 20% protein) mixed with 5 mCi of sQ”Tc-sulfur colloid. Seven healthy volunteers matched for age and sex (3 men and 4 women, mean age 34 yr, range 18-60 yr) who had no specific symptoms related to gastrointestinal disorders and had half-emptying times within the normal range were also investigated. No subject entering this study had a history of gastrointestinal surgery. Organic lesions and diseases known to affect gut motility (e.g., diabetes, scleroderma) were excluded in all cases by a diagnostic workup including
INTERJXGESTIVEMOTIWTY, MOTILIN, GAS’I’ROPARESIS 21
January 1986
Table
1. Activity
Fronts and Motilin
Case No. Healthy subjects 1 2 3 4 5 6 7 patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Peaks Observed
in Healthy Recording time (min)
Subjects
and in Dyspeptic
Patients
Activity fronts Gastroduodenal
Motilin peaks
Age (ur)
Sex
30 18 26 35 60 29 41
F F M M F M F
200 200 200 220 200 240 200
I”; II”
I”; II” I”; II” I”; II” 10; II”
I”; II” I”: II” I”; II” I”; II” I”; II” I”; II” I”; II”
48 20 60 25 33 45 36 22 18 29 55 44 38 22 25 27 23 35 42 34 37 21
M F M M F F F F M M F F M M M F F F F F F F
200 240 300 250 240 300 240 300 240 200 240 200 250 200 260 200 200 300 300 200 300 300
I”; II” -
I”; II” I”; II”; III
Duodenal
I”: II” I”. II”
Dyspeptic
I; III; III are subsequent
Recording
-
I; II I”; II” I” I”
-
of Motor Activity
The interdigestive motor activity in the stomach and in the proximal duodenum was recorded during a period of 200-300 min after a 14-h fast. The study was carried out using a four-lumen probe (external diameter 4.5 mm) with lateral holes 5 cm apart. The catheters were perfused with an Arndorfer pump (Arndorfer Medical Specialties, Greensdale, Wis.) and connected to Statham P 23 DB external pressure transducers (Statham Laboratories Inc., Puerto Rico) and to a Beckman R 612 polygraph (Beckman Instruments, Stiller Park, Ill.). The recording holes, indicated by radiopaque markers, were positioned
-
-
activity fronts or motilin peaks observed in each subject. a Association
routine laboratory tests and radiologic and ultrasonographic examinations of the digestive system. No subject exceeded 10% of the ideal body weight. Pentagastrinstimulated gastric acid secretion and fasting serum gastrin concentrations were within the normal range for our laboratory in all cases. None of the subjects had taken any drugs during the week preceding the examination nor had they smoked for at least 10 h before the test. Written informed consent was obtained from all subjects.
I; II; III I I” -
-
between activity front and motilin peak.
under fluoroscopic control (two in the gastric antrum and two in the proximal half of the duodenum). During the recording of motor activity, 3-ml blood samples were drawn at 15-min intervals for motilin assay. Radioimmunoassay
of Serum
Motilin
Serum immunoreactive motilin concentration was measured by a specific radioimmunologic method previously described (9). Briefly, the antiserum TS-6 specific for the N-terminal region of the motilin molecule (gift from Dr. N. S. Track, Laboratory of Gastrointestinal Hormones, University of Toronto, Canada) was used in a final dilution of 1: 50,000. Natural porcine motilin (obtained from Quadra Logic Technologies Inc., Vancouver, Canada) was used as a standard. Serum samples (O&ml duplicates) were assayed at a final dilution of 1: 10 in a total volume of 2 ml. After a 5-day incubation at 4”C, free and bound hormones were separated by dextran-coated charcoal. No cross-reactivity was found with physiologically related peptides. The mean concentration of motilin required to reduce the binding of labeled motilin to 50% was 9 fmol/ml assay tube, equivalent to 90 pmol/L serum. With-
22 LABbETAL.
Figure
GASTROENTEROLOGY Vol. 90, No. 1
1. Interdigestive gastroduodenal motor activity recorded manometrically in a healthy subject with normal gastric emptying. AP, proximal antrum; AD, distal antrum; D, and D2, proximal half of the duodenum; Pn, pneumogram. Note that the activity front propagates from the antrum to the duodenum, is preceded by phase II activity with irregular pressure waves, and is followed by phase I activity characterized by motor quiescence.
in-assay and between-assay coefficients of variation were 5.1% and 8.5% at mean serum motilin levels of 70 and 72 pmol/L, respectively (n = 10). All samples from the same subject were assayed simultaneously.
Analysis
and Calculations
According to other investigators (10-12), three different phases of each interdigestive cycle were visually identified: phase I is characterized by motor quiescence, phase II by irregular motor activity, and phase III (activity front) by a short burst of rhythmic contractions. The duration of cycles [time interval between the end of one duodenal activity front and the end of the next) and the percentage of time occupied by each phase of the cycle were determined. When the interdigestive cycles were not regular and there was a lack of activity fronts, the phases of motor quiescence (phase I-like activity) and the phases of irregular contractions (phase II-like activity) were identified and the percentage of the recording time occupied by each phase was measured. Serum motilin levels were evaluated as the mean concentration during the periods of motor quiescence and during the periods of irregular motor activity, and as the maximum value during the entire recording time. A mean baseline concentration of serum motilin during the recording of motor activity was also calculated. A motilin peak was identified when one or more contiguous values exceeded the mean + 3 SD baseline concentration. The integrated motilin output (IMO) during each peak, expressed in nanomoles * minutes per liter, was calculated using the following formula: IMO = $ (M, + M&t, + + (M2 + M&
+
.,
where M1, MZ, . . . are the serum motilin concentrations at the different points identifying a peak (including the origin and the end of the peak on the baseline) minus the mean
baseline
motilin concentration in picomoles per liter, and the time intervals in minutes between M1 and Mz,MzandMB,. . . . An activity front was considered to be associated with a motilin peak when it occurred during the same time period also used for the calculation of the integrated motilin output. The statistical analysis was performed using appropriate tests (Student’s t-test, Wilcoxon’s rank-file test, x2 test]. t1, tz, . . * are
Results Motor Activity Table 1 shows the incidence of gastric and duodenal activity fronts in healthy subjects and in dyspeptic patients. All healthy subjects showed regular interdigestive motor cycles (Figure l),with phase III activity propagated distally from the antral region to the duodenum. A total of 14 gastroduodenal activity fronts were observed during the whole recording period of 24.3 h. The mean duration of the cycles, calculated from the duodenal record, was 93 min (range 69-113 min), 38.6% (range 35%-58%) of which was occupied by phase I, 55.7% (range 38%62%) by phase II,
and 5.7% (range 3%7%) by phase III activity. In 20 of 22 dyspeptic patients no activity front was observed in the stomach during the entire recording period. In 11 of these 20 patients there was a lack of activity fronts also in the proximal duodenum (Figure ZA), whereas in the remaining 9 patients, activity
fronts starting in the proximal duodenum were recorded (Figure 2B). Only 2 patients in the entire group had activity fronts propagating from the
January 1986
INTERDIGESTIVE MOTILITY, MOTILIN, GASTROPARESIS
23
A
P---‘-
Pn
tmin
mmHg
I 20
B rrlrr_r--Pn
1 min
120mmHg
L
.
-
A
AP
-A-
_
AD
Figure 2. Manometric recordings of interdigestive gastroduodenal motor activity carried out in 2 patients (A and B) with idiopathic delay in gastric emptying. In each recording: AP, proximal antrum; AD, distal antrum; D1 and D2, proximal half of the duodenum; Pn, pneumogram. A. In this patient no activity front was recorded either in the stomach or in the duodenum during the entire recording period. Only periods of irregular motor activity or quiescence were observed. B. In this patient activity fronts were recorded only in the duodenum and not in the antrum during the entire recording period. The stomach showed only periods of irregular motor activity alternating with phases of motor quiescence.
antrum to the duodenum, with a time interval of 110 and 154 min, respectively. A total of four gastroduodenal and 19 duodenal activity fronts were recorded in the 22 dyspeptic patients during the whole 91-h recording period. The mean duration of the duodenal cycles recorded in the 9 patients with
activity fronts starting in the duodenum was 115 min (range 65-156 min), 46% (range 22%_71%) of which was occupied by phase I, 49% range (23%-Z%) by phase II, and 5% (range 2%-7’%) by phase III activity. The incidence of either gastroduodenal or duodenal activity fronts in dyspeptic patients was signifi-
24
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GASTROENTEROLOGY Vol. 90, No. 1
ET AL.
Figure 3. Individual values of mean serum motilin concentrations during the periods of motor quiescence (A) and during the periods of irregular motor activity (B), and the maximum value measured during the entire recording time (C) in normal subjects (N) and in dyspeptic patients (PI. 0, Subject with both gastric and duodenal phase III activity; 0, subject with phase III activity beginning in the duodenum; 0, subject without gastric and duodenal phase III activity. 01 P
cantly lower than in healthy subjects (p < 0.001 and p < 0.05,respectively). No significant difference was found between the duration of cycles in the 9 dyspeptic patients with activity fronts originating in the proximal duodenum and that in normal subjects. Serum Motilin Figure 3 shows the individual values of mean serum motilin concentration during the periods of motor quiescence and during the periods of irregular contractions, and the maximum value measured during the entire recording time in healthy subjects and in dyspeptic patients. In these two groups mean serum motilin concentration during the phase of motor quiescence was 42 + 23 pmol/L (3 + SD) and 36 + 22 pmol/L, respectively (p not significant). The mean concentration of circulating motilin during the phase of irregular motor activity was higher in healthy subjects (81 + 43 pmol/L) than in dyspeptic patients (54 f 42 pmol/L). This difference, however, did not reach statistical significance. The mean maximhm value of serum motilin registered during the entire recording period in healthy subjects (123 + 48 pmol/L) was significantly higher (p < 0.05) than in dyspeptic patients (57 t 25 pmol/L). The 2 patients with activity fronts propagating from the antrum to the duodenum had serum motilin concentrations near the upper limit of the range. Table 1 reports the incidence of motilin peaks observed in the two groups. All healthy subjects showed fluctuations of serum motilin, whereas only 11 of 22 dyspeptic patients (50%) showed motilin
NS
peaks. In the whole group of normal subjects a total of 14 peaks were recognized during the whole recording time of 24.3 h. On the contrary, the whole group of 22 dyspeptic patients showed a total of 19 motilin peaks during the whole recording time of 91 h. In these patients the incidence of motilin peaks was significantly lower than in controls (p < 0.05). The mean + SD integrated motilin output calculated during the motilin peaks in dyspeptic patients (1.3 k 0.94 nmol - min/L) was significantly lower (p < 0.05) than in healthy subjects (3.8 * 2.70 nmol * min/L).
Association Between Activity Motilin Peaks
Fronts and
The association between activity fronts and motilin peaks in each subject is indicated in Table 1. Fourteen of 14 activity fronts propagating from the antrum to the duodenum (100%) were associated with a motilin peak in healthy volunteers and 4 of 4 (100%) in dyspeptic patients. In the 9 patients with phase III activity starting only in the duodenum, 8 of 19 activity fronts (42%) were associated with a motilin peak, whereas the remaining 11 activity fronts (58%) did not occur with a motilin peak. In control subjects all motilin peaks were associated with an activity front. In dyspeptic patients 12 of 19 motilin peaks (63%) were associated with gastroduodenal or duodenal activity fronts, whereas 7 (37%) occurred without the presence of a related activity front.
January 1986
Discussion The results of this study confirm our preliminary observation that dyspeptic patients with marked delay in gastric emptying may also have abnormalities in interdigestive motor activity (3). The absence of activity fronts in the stomach was the most characteristic feature of these patients. This motor disorder was associated with an impaired cyclic rise in fasting serum motilin, the peaks being small or absent during the recording of motor activity. On the contrary, healthy subjects showed the typical fluctuations of serum motilin related to phase III activity, as already described by others (4-i’). At present, it is not completely known whether fluctuations of endogenous circulating motilin in humans modulate or are modulated by the interdigestive migrating motor complex. Previous studies have shown that plasma motilin peaks precede the occurrence of phase III activity in huFurthermore, physiologic doses of mans (4,6,7,13). exogenous motilin induce and motilin antiserum abolish the migrating motor complex (4,14,15). Conversely, another study suggests that the cyclic increase of circulating motilin is an epiphenomenon, the hormone being released into the circulation by the contractile activity of the duodenum and upper jejunum (16).Our investigation was not designed to evaluate the cause-effect relationship between these two events. It is of interest to note, however, that in our dyspeptic patients without gastric phase III activity the motilin peaks were small or absent, whereas the only 2 patients with activity fronts starting in the stomach showed values of serum motilin near the upper limit of the range and similar to the mean values in normal subjects. These results seem to be in agreement with previous studies suggesting the existence of a threshold concentration of motilin above which gastric fronts occur (17) and showing that higher motilin peaks are associated with the cycles starting in the stomach (11). On the basis of these considerations, we do not know whether the absence or the smallness of motilin fluctuations in our dyspeptic patients is the cause of the absence of phase III activity in the stomach or is secondary to the interdigestive motility dysfunction in the upper small intestine. In patients with phase III activity starting in the proximal duodenum, the majority of activity fronts were not associated with motilin peaks and one-half of the motilin peaks were not associated with activity fronts. Furthermore, small motilin peaks were also observed in 3 of half the dyspeptic patients with absence of complexes either in the antrum or in the proximal duodenum. As the motor activities of the distal duodenum and the upper jejunum were not
INTERDIGESTIVE
MOTILITY,
MOTILIN,
GASTROPARESIS
25
recorded in this study, we cannot exclude the possible occurrence of complexes starting in these more distal parts, as observed by others (4,11,13,17). The difficulty in correlating motility events in the human duodenum with cyclic rises of plasma motilin has been already noted (16).Previous studies (13,18) have demonstrated that the complexes that originate in the stomach, but not those starting in the small intestine, are regularly associated with well-defined motilin peaks. Other groups have observed that a relationship does not always exist between plasma motilin and the initiation of spontaneous activity fronts in the upper small intestine (19). The etiology of the motor disorder observed in our patients is unknown. The diseases that are thought to alter the gastric motility (20) were excluded on the basis of an extensive clinical and laboratory workup. In particular, we have excluded the presence of diabetes, a disease in which a motility dysfunction similar to that observed in our patients has been described (21). Acid hypersecretive or hyposecretive states and hypergastrinemic conditions were also excluded in order to avoid the possible influence of abnormal gastroduodenal acidity (22) or circulating gastrin concentration (23)on the interdigestive motility pattern. However, the presence of a lesion in the enteric smooth muscle or intrinsic innervation, or both, indiscernible with the conventional diagnostic examinations, cannot be ruled out. In conclusion, our study shows that dyspeptic patients with abnormally delayed gastric emptying of unknown origin may also have a dysfunction in the interdigestive motor activity. The most characteristic feature, and possibly a marker, of this functional disorder is the absence of phase III activity in the gastroduodenal area associated with the absence or smallness of motilin fluctuations. Taking into account that activity fronts are thought to play an important role in sweeping gastric content during the last postprandial period (24),it can be suggested that the absence of phase III activity in the stomach may contribute to the induction of gastric stasis and, consequently, to the typical dyspeptic symptoms in these patients.
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aspects.
In: Chey WY, ed. Functional
disorders
of the
digestive tract. New York: Raven, 1983:175-80. Bortolotti M, Foschi S, Galletti M, Labb G. Interdigestive migrating motor complex (MMC) restored by an Hz antagonist
26 LAB0 ET AL.
(ranitidine) in gastroparesis (abstr). Stand J Gastroenterol 1962;17(Suppl 78):234. 4. Vantrappen G, Janssens J, Peeters TL, Bloom SR, Cristofides ND, Hellemans J. Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci 1979;24:497-500. 5. Itoh 2, Takeuchi S, Aizawa I, et al. Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs. Am J Dig Dis 1978;23:929-35. 6. You CH, Chey WY, Lee KY. Studies on plasma motilin concentration and interdigestive motility of the duodenum in humans. Gastroenterology 1980;79:62-6. 7. Peeters TL, Vantrappen G, Janssens J. Fasting plasma motilin levels are related to the interdigestive motor complex. Gastroenterology 1960;79:716-9. 8. Jacobs F, Akkermans LMA, Oli Hong-Yore, Hoekstra F, Wittebol P. A radioisotopic method to quantify the function of fundus, antrum and their contractile activity in gastric emptying of a semisolid and solid meal. In: Wienbeck M, ed. Motility of the digestive tract. New York: Raven, 1982: 23390. 9. Vezzadini P, Bonora G, Bernardini S, Ecchia R, Toni R, Labo G. Radioimmunoassay of mdtilin in human plasma: interdigestive levels in normal subjects and in patients with hypergastrinemic chronic atrophic gastritis. J Nucl Med Allied Sci 1984;28!197-2Oi. 10. Vantrappen G, Janssens J, Peeters TL. The migrating motor complex. Med Clin North Am 1981;65:1311-29, 11. Rees WDW, Malagelada JR, Miller LJ. Human interdigestive and postprandial gastrointestinal motor and gastrointestinal hormone patterns. Dig Dis Sci 1982;27:321-9. 12. Wingate DL. Backwards and forwards with the migrating complex. Dig Dis Sci 1981;26:641-66. 13. Janssens J, Vantrappen G, Peeters TL. The activity front of the migrating motor complex of the human stomach but not of
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