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Gastric emptying and duodeno-gastro-oesophageal reflux in gastro-oesophageal reflux disease
ALIMENTARYTRACT
DIGEST LIVER OIS 2002:34:477-83
Gastric emptying and duodeno-gastro-oesophageal in gastro-oesophageal reflux disease J. Freedman I? Grybtickl M. Lindqvist* L. Granstrijm J. Lagergren3 P. M. Hellstrt3m4 H. Jacobssonl E. N&And
5
Background, Previous studies present conflicting results regarding relationship between gastric emptying and gastro-oesophageal reflux disease. Reflux of duodenal content to oesophagus is generally considered to be associated with more severe disease. Aim. To assess presence of a gastric emptying disorder in persons with reflux of duodenal contents to oesophagus and to identify any correlation with gastric emptying and oesophageal motility Methodology. A total of 15 subjects with [B+) and 15 subjects without (B-1 bile reflux to oesophagus determined by 24-hour bilirubin monitoring were studied with scintigraphic solid gastric emptying and 24hour oesophageal manometry Results. There was no difference 10.844.0]
Division of Surgery and 2 Division of Clinical Physiology, Karolinska Institutet, Danderyd Hospital; Departments of 1Radiology, 3 Surgery, 4 Gastroenteroiogy end Hapatology, 5Nuclear Medicine, Karolinske Hospital, Stockholm, Sweden. AddiwsfDrc~I? Dr. J. Freedman Department of Surgery, Oanderyd Hospital, SE- 182 88 Danderyd, Sweden. Fax: +46-8-6557766. E-mail: Jacob.Freedman@kir da sll. se. L. Svensson, medical technician, did an excellent job with oesophageal physiology studies. Study supported by Swedish Medical Research Council, funds of Karolinska Institutet, The Swedish Society for Medicine, N. Svartz Foundation, M. Bergwall Foundation, H. Jeansson Foundation and AMF Sjukfdrsakringar Jubileums Foundation Ruth end Rickerd Juhlin Foundation, Eirs 50-&a Foundation and Minerva Foundation. Submitted November 29# 2001. Accepted after revision January 29, 2002.
reflux
vs 24.6
(8.140.
in lag phase
I] min],
half
emptying
[median
23.7
[range
time
[74.6
148.0
93.6) vs 82.8 [54.4- 153.91 min] or emptying rate [O. 89 [0.59- I.341 vs 0.83 [O. 36- I. 1 S)%/min] for B- and B+ subjects, respectively In addition, there was no difference in emptying rate of gastric fundus between B- and B+ subjects. Subjects with bile reflux had less effective oesophageal contractions of oesophageal body [9.4[3.3-37]%] compared to subjects without bile reflux [32[1947]%, p=O.O02]. However: there was no correlation between oesophageal motility and gastric emptying. Conclusion. Results suggest that a gastric emptying disorder is a less likely contributing cause of bile reflux to the oesophagus, but bile reflux is associated with less effective oesophageal motility
Digest
Liver
Key words:
8is 2002;34:477-83 bile reflux;
gastric
emptying:
gastro-oesophageal
reflux
disease
Introduction Results regarding gastric emptying time in subjects with gastro-oesophageal reflux disease (GERD) have been conflicting. Some studies have demonstrated a delayed gastric emptying ’ 2 while other studies have not confirmed this 3 4. Other reports have shown that subjects with GERD have slower clearance and increased compliance of the gastric fundus 5 with a concomitant increase in visceral sensitivity 6 and a high frequency of disturbed myoelectrical activity ‘. The increase in fundic relaxation has been proposed as a major cause of GERD by applying a force of traction on the lower oesophageal sphincter (LES), thereby reducing its length and pressure ’ causing transient lower oesophageal relaxations (TLESRs) y. It has been proposed that pharmacological treatment of dysmotility in the proximal stomach could be effective in the treatment of GERD “‘. Recent studies with ambulatory bilirubin measurements in the oesophagus have demonstrated that there may be an association between reflux of duodenal contents to the oesophagus and more severe disease, such as Barrett’s oesophagus ” 12, a premalignant condition with intestinal metaplasia of the distal oesophagus, correlated with GERD IX. Bile acids and pancreatic
477
Gastric emptying and bile reflun
trypsin have been shown to be cytotoxic and cancerpromoting in vitro and in animal studies i4-i8. The mechanism behind duodenogastro-oesophageal reflux (DGER) is not known. There is a physiological backwash of duodenal contents to the stomach during the fasting state i9-*‘. In most healthy subjects, this backwash does not contain bile. It has been shown that only 17% of healthy individuals have bile markers in the duodenum during the postprandial phase, when the duodenogastric reflux occurs, probably caused by incomplete bile duct closure by the sphincter of Oddi 22. The aim of the present study was to investigate whether there is a disturbed gastric emptying in subjects with DGER and if there is any correlation between oesophageal motility and gastric emptying, suggesting an abnormal upper gastrointestinal motility.
Methods Subjects A total of 15 subjects undergoing evaluation for GERD with reflux of bile (B+) to the oesophagus and 15 subjects without GERD and with normal bilirubin monitoring (B-) were included in the study. GERD was delined as typical symptoms of heartburn or regurgitation at least twice per week. The B- subjects were healthy individuals without gastrointestinal symptoms and free of any medication. The B+ subjects had an oesophagogastro duodenoscopy performed with classification of oesophagitis according to Savary-Miller. 5 had no oesophagitis, 5 had grade 1, 1 had grade 2 and 4 had grade 4 (of which all had intestinal metaplasia). Previous studies have shown that postmenopausal women and men have similar gastric emptying rates in contrast to premenopausal women who have a slower rate of gastric emptying 23. Therefore, the two groups were matched not only by gender, but also according to menopausal status. The demographics of the two subject groups are shown in Table I. The study was approved by the Ethics Committee and the Radiation Protection Committee of the Karolinska Hospital and all subjects gave informed consent. Study protocol 24-hour ambulatory combined pH, bilirubin and oesophageal manometry All subjects were off proton pump inhibitors and Hz-blockers for a week prior to the examination. The left nostril was anaesthetised using lignocaine gel. A calibrated combined pH and 3-channel micro transducer manometry catheter was then introduced and passed to the stomach (Koenigsberg Instruments Inc., Pasadena, CA, USA). A pull-through manometric detection of the LES was performed with all three pressure sensors. The pH-sensor was positioned 5 478
kble I. Characteristics of subjects with [B+l or without [B-l reflux of bile to oesophagus.
Age (years1 Male sex Gastric emptying sex (male1 BMI (kg/m21
B- Ill=151
E+ In&l
33 123-70)
54 [34-781" 8
:: 25.2 [19.6-30.91
::.I
(20-37.4)
Data shown as median Irangel. Gastric emptying sex lmalal equals males and postmenopausal females as they have same reference values for gastric emptying. Mann-Whitney U-test, ~~0.05 (7. Abbreviations: see list.
cm, and the pressure tip transducers 3, 8 and 13 cm, above the upper border of the LES. The bile detection catheter (Bilitec 2000, Medtronic Functional Diagnostics A/S, Copenhagen, Denmark) was then introduced next to the pH-catheter and positioned at the same level as the pH-sensor. Both catheters were then tethered to the nose and cheek with adhesive tape and connected to the portable recording units. The subjects were instructed to abstain from alcohol, tobacco, carbohydrated drinks and foodstuffs known to disturb readings of the Bilitec system (i.e., coloured food, for example coffee and tomatoes). The Bilitec works by measuring absorbance of yellow light between the tip of the catheters optic fibres and a small reflective mirror and has previously been validated 24. To minimize the risk of obstructing the reflective mirror of the Bilitec catheter, only liquid food was allowed. The subjects were prompted to keep a diary, noting the time of episodes of reflux symptoms, food intake and laying down. They returned the next day for removal of the catheter assembly. The stationary manometry, pH- and bile data was analysed using Polygram for Windows software, version 2.1 (Medtronics Synectics, Stockholm, Sweden). All tracings were also examined visually for exclusion of possibly erroneous recordings. For the bilirubin study, periods with increased absorption, which occurred during eating, with an instantaneous rise to absorption >O. 14 were excluded from the analysis. Acid reflux was defined as periods when pH fell below 4, as is generally accepted. Bilirubin reflux was defined as periods when the absorbance was greater than 0.14. Pathologic bilirubin reflux was defined as greater than 7.7% of the time with bilirubin reflux. The normal range for bilirubin was based on the 951h percentile of 20 healthy subjects previously examined at Danderyd Hospital (unpublished data). The ambulatory manometry data was analysed using Multigram for DOS software (Synectics Medtronics, Stockholm, Sweden). All readings were first examined visually to ensure correct baseline settings for detection
.I. Freedman et al.
of oesophageal contractions but not pressure changes due to breathing, and were, if needed, corrected. The software was set to detect an oesophageal contraction if the pressure rose above 20 mm Hg for a minimum duration of 1 s. The recording was divided into periods of pain, meal, postprandial (O-30 minutes after meal intake), upright and supine. Propagated contractions were defined as a peristaltic wave passing all three pressure sensors. An effective propagation was defined as a propagated contraction with a contractile pressure of at least 30 mm Hg at all three recording points.
90, TsO,gastric emptying rate and fundus emptying rate, with percent of time with pH <4 or percent of time with bilirubin absorbance >0.14 as the dependent variable. The natural log of bilirubin and pH were used for all statistical analyses. A power analysis showed 80% probability of detecting an 11 minutes difference in lag 90, 0.2%/minute in gastric emptying rate and 21 minutes in half emptying time. ~~0.05 was considered significant.
Gastric emptying Scintigraphy is a practical way to study gastric motility 25.The scintigraphic gastric emptying test used in this paper has previously been described in detail 23. In brief, a test meal with a technetium-99, labelled, 1300 kJ, omelette and an unlabelled low-calorie, 290 kJ drink was ingested after an overnight fast. Tobacco use was not allowed after midnight before the examination. Immediately upon finishing the meal, the soft drink was taken and imaging was started. The subjects were investigated in a standing position. Successive l-minute frontal and dorsal registrations were made every 5 minutes during the first 50 minutes, followed by imaging every 10 minutes for a total of 120 minutes. The subjects were allowed to move between the registrations, but were usually sitting comfortably close to the camera. The activity in the stomach was outlined by a region of interest in each of the images and geometric mean values calculated. After correction for physical decay, the total activity in the stomach was converted to percent of the maximum count rate recorded in each investigation and the values were plotted against time. The same procedure was done for regions of interest in the proximal and distal stomach 2h. A linear fit computation by least-square regression was performed and applied to the linear part of the curve. This was manually defined in all investigations. In most subjects, the linear phase lasted between 30 and 120 minutes. The linear emptying was defined as the slope of the fitted curve (%/minute). The lag phase (lag 90) and half-emptying time (T& were defined by the intercepts of the regression line with the 90% and 50% levels, respectively. In addition, the linear fit was used to define the percentage gastric retention of the meal at 60, 90 and 120 minutes by using the values of the regression lines at these positions. The area under the curve (AUC) was calculated for fundic and antral activity over time to assess proximal gastric emptying.
24-hour pH- and bilirubin monitoring The median (range) percent time with bilirubin >0.14 and pH was greater in the B+ subjects [20.8 (7.7-80.7) and 15.3 (O-55)%, respectively] than in the B- subjects [0 (O-5.8) and 2.7 (1.5-9.0)%, respectively] (both ~~0.05).
Statistical methods Data are shown as median (range). Comparisons between groups were performed with the Mann-Whitney U-test. A univariate regression analysis was performed for lag
Results
24-hour manometry There was no difference in LES pressure or length in the B+ and B- subjects [pressure; 13.5 (7.0-31.0) vs 18.5 (6.0-28.0) mmHg, p=O.78, length; 4.0 (2.0-6.0) vs 4.0 (2.0-7.0) cm, p=O.66, respectively]. Complete 24hour recordings were obtained in 10 of the B+ and 14 of the B- subjects, the remaining six were studied before the ambulatory manometry test became available. The percent effective contractions were significantly lower in the B+ group [9.4(3.3-37)%] compared to the B- subjects [32(19-47)%, p=O.O02] (Fig. 1). Similar
*** -0 0r T 0 1
I
I
B+
B-
Fig.1. Boxplot of percent effective oesophageal contractions in subjects with and without duodenogastm-oesohageal mflux. Percertt [Median, 25 md 90 percentiles, circles represent o&tiers1 effective contractions in Iesophagus during 24 hours in subjects with tB+l and without (B-1 duolenogastm-oesophagaeal reflux. p=O.O02 I”‘“], Mann-Whitney U-test.
479
Gastric emptying and bile r&n
We
II. Results of solid gastric emptying in subjects with LB+1 or without (8-l reflux of bile to oesophagus B+ In451
Lag SO fminl Tsa fminl Gastric emptying rate, Wmin Retention total 60 min Retention total SO min Retention total 120 min Tso fminl fundus Retention fundus 60 min Retention fundus SO min Retention fundus 120 min AUC fundus AUC antrum Data shown
as median
(range).
25 83 0.83 66 44 17 47 40 24 IO 4839 2419 Retained
gastric
content
B- In451
ELI-401 (54-l 501 (0.36-l .21 (44-841 (I I-731 LO-621 [I .O-981 (9.4-761 (2.1-481 fl.l-411 [I 934-84661 [I 186-44791
24 75 0.89 60 38 14 44 35 17 3.3 4789 2174
over time. No significant
differences,
Mann-Whitney
U-test,
[I I-441 [48-941 (0.59-I .31 [36-751 [0.9-531 (O-301 (0.6-641 [I .2-521 (0.86-331 (0.32-171 (2427-61571 [I 239-3581 I
p~O.05.
Abbreviations:
see
list.
Univeriate analysis with percent of time with bilirubin co.14 end % time with pH<4 as dependent factors in 30 subjects with and without duodenogastro-oesophageal reflux.
Table III.
Variable
Bile Reflux
Acid refh
Uniuariate
hivariate
B
Lag 90 fminl Gastric emptying rate [Wminl TXI fminl AUC fundus
-0.06 -21 .I 0.28 0.002
Gastric emptying over time. No significant breviations: see list.
correlation
II'
p-value
0.001 0.05 0.07 0.01 between
bile reflux
significant results were obtained if the postprandial, supine or upright periods were examined (data not shown). There was no correlation between the percent effective contractions in the oesophagus over the whole 24-hour period or the postprandial period versus the gastric emptying rate (%/min) (R2=0.12, p=O.56 and R*=O. 16, p=O.45, respectively).
B
0.86 0.26 0.15 0.57 or acid reflux
-0.007 -0.4 0.001 0.001 to oesophagus
and different
II2
0.006 0.008 0.001 0.003 parameters
p-value
0.68 0.64 0.85 0.92 of gastric
emptying.
Ab-
sophagus (Table III). Of the 30 subjects in this study, two with GERD had delayed gastric emptying as compared to normal data earlier presented by Gryback et al. 23. Both these subjects had normal pH values and bile exposure was just above the normal limit. Discussion
Solid
gastric
emptying
There was no difference between the B+ and the Bsubjects with regard to any of the parameters of gastric emptying studied [lag 90, TX,, gastric emptying rate and amount retained in the stomach at 60, 90 and 120 min (Table II)]. Similarly, there was no difference in the emptying rate from the gastric fundus to the antrum (Table II). In a univariate analysis, there was no association between the percent of time with bilirubin >0.14 in the oesophagus and any of the gastric emptying parameters (Table III). Similarly, no association was found between any of the gastric emptying parameters and the percent of time with pH <4 in the oe480
This study demonstrates that subjects with DGER have less effective contractions in the oesophagus, but there is no difference in gastric emptying compared to subjects without DGER. In previous studies of gastric emptying and GERD, no assessment had been made of DGER. This study did not detect any correlation between different gastric emptying parameters and degree of DGER and there was no difference in gastric emptying between subjects with and without DGER. As gastric emptying was studied using a labelled omelette, no conclusion can be drawn regarding capacity for liquid emptying. No as-
_ - - - - - I
J. Freedman et al.
sociation was found between acid reflux and gastric emptying. This is in contrast to some studies demonstrating that subjects with GERD have slower gastric emptying rates, as studied with scintigraphy ’ 2 or ultrasound 27, compared to normal subjects. However, the results presented are in agreement with other studies that found no correlation between GERD and gastric emptying 3 4. In a previously published multivariate analysis, including gastric emptying, oesophageal pH- and manometry data and gastric secretion, it was found that oesophageal clearance, LES pressure and, to some extent, peak acid output were important predictors for GERD 28. In contrast with the findings of the present study, Stacher et al. 29 have shown that an impaired proximal, but not total, gastric emptying is seen in subjects with GERD. A multiple regression analysis demonstrated that LES pressure accounted for 22% of the correlation with oesophageal exposure to acid, whereas proximal gastric emptying only accounted for 8%. These factors may be associated as it has been found that subjects with reflux disease have a slower recovery of gastric tone in response to distension 5 ‘j. In a study using ultrasonography, it was found that 70% of GERD subjects have a slow reflux of gastric contents over the oesophageal sphincter with slow clearance by oesophageal peristalsis after 30 seconds to 2 minutes, a pattern of motility that was not seen in controls, thus providing further evidence of a disturbed motility pattern in the proximal stomach 30. Our normal value for bile exposure, ~7.7% percent time with bilirubin absorbance ~0.14, compares well with data presented by Marshall et al. 3’ (<7%), but is somewhat higher than those presented by Vaezi and Richter 32 (< 1.8% in 20 controls, 13 male) and Kauer et al. (~2.9% in 25 controls) j3, but lower than another study by Kauer et al. j4. The reasons for this are unclear, albeit the groups studied are small and dietary restrictions were different, as were the catheter setups in the different studies. There is a strong correlation between acid and bile reflux to the oesophagus, and previous studies have shown a correlation between acid reflux and reduced efficiency of oesophageal peristalsis 35-40.Bile reflux has been shown to increase the permeability of the oesophageal epithelium by disruption of the cellular membranes 4’-43. It is possible that the noxious damage caused by acid and bile reflux induces irreversible changes in terms of motility, possibly by thickening of submucosal collagen and loss of muscle fibres as proposed by Stein et al. 35, thereby worsening the disease by impairment of oesophageal clearance. The present study demonstrates that subjects with DGER have less effective oesophageal motility over a period of 24 hours. Whether an impaired oesophageal motility re-
sults in GERD or whether the damage caused by chronic reflux on the oesophagus results in an impaired oesophageal motility can not be answered by the present study. It has been suggested that GERD is a part of a more generalized disorder of motility in the whole gastrointestinal tract, and perhaps also linked to autonomic dysfunction 44. GERD is more common in subjects with irritable bowel disease 4s46, dyspepsia 47 and gallstone disease 48. It has also been shown that total gastric emptying time is correlated to impaired oesophageal clearance of a solid bolus, as well as to failed oesophageal peristalsis in subjects with GERD 49. Yet, in the present study, oesophageal motility was measured with ambulatory oesophageal manometry, optimising conditions for evaluation of oesophageal body motility, but no correlation was found between 24-hour motility parameters and gastric emptying, neither proximal nor total. A critique against this study may be that it only includes 15 subjects in each group. Yet, a power analysis demonstrates sufficient power to detect a difference of more than 21 minutes in gastric emptying between the groups, and smaller differences probably lack clinical significance. In summary, the present study did not identify disturbed gastric emptying in subjects with DGER compared to subjects without DGER. The only significant determinate of bile reflux being the impaired oesophageal motility as determined by 24-hour oesophageal monitoring. It remains to be determined whether this is a pre-existing condition or if it is due to the noxious effects of duodenal contents and acid on he oesophagus. list
of abbreviations
AUC: area under the curve; BMI: body mass index: DGER: duodenogastro-oesophageal reflux; GERD: gastro-oesophageal reflux disease; LES: lower oesophageal sphincter; TLESR: transient lower oesophageal relaxation.
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46 Smart HL, Nicholson DA, Atkinson M. Gastro-oesophageal reflux in the irritable bowel syndrome. Gut 1986;27: 1127-31. 47 Haque M, Wyeth JW, State NH, Talley NJ, Green R. Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study. N Z Med J 2000;113:178-81. 48 Portincasa P, Di Ciaula A, Palmieri V, Velardi A, VanBerge-Henegouwen GP, Palasciano G. Impaired gallbladder and gastric motility and pathological gastro-oesophageal reflux in gallstone patients. Eur J Clin Invest 1997;27:653-61. 49 Lundell L, Myers JC, Jamieson GG. Is motility impaired in the entire upper gastrointestinal tract in patients with gastro-oesophageal reflux disease? Stand J Gastroenterol 1996;3 1: 13 l-5.
/
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483
DIGEST LIVER OIS 2002:34:477-83
Gastric emptying and duodeno-gastro-oesophageal in gastro-oesophageal reflux disease J. Freedman I? Grybtickl M. Lindqvist* L. Granstrijm J. Lagergren3 P. M. Hellstrt3m4 H. Jacobssonl E. N&And
5
Background, Previous studies present conflicting results regarding relationship between gastric emptying and gastro-oesophageal reflux disease. Reflux of duodenal content to oesophagus is generally considered to be associated with more severe disease. Aim. To assess presence of a gastric emptying disorder in persons with reflux of duodenal contents to oesophagus and to identify any correlation with gastric emptying and oesophageal motility Methodology. A total of 15 subjects with [B+) and 15 subjects without (B-1 bile reflux to oesophagus determined by 24-hour bilirubin monitoring were studied with scintigraphic solid gastric emptying and 24hour oesophageal manometry Results. There was no difference 10.844.0]
Division of Surgery and 2 Division of Clinical Physiology, Karolinska Institutet, Danderyd Hospital; Departments of 1Radiology, 3 Surgery, 4 Gastroenteroiogy end Hapatology, 5Nuclear Medicine, Karolinske Hospital, Stockholm, Sweden. AddiwsfDrc~I? Dr. J. Freedman Department of Surgery, Oanderyd Hospital, SE- 182 88 Danderyd, Sweden. Fax: +46-8-6557766. E-mail: Jacob.Freedman@kir da sll. se. L. Svensson, medical technician, did an excellent job with oesophageal physiology studies. Study supported by Swedish Medical Research Council, funds of Karolinska Institutet, The Swedish Society for Medicine, N. Svartz Foundation, M. Bergwall Foundation, H. Jeansson Foundation and AMF Sjukfdrsakringar Jubileums Foundation Ruth end Rickerd Juhlin Foundation, Eirs 50-&a Foundation and Minerva Foundation. Submitted November 29# 2001. Accepted after revision January 29, 2002.
reflux
vs 24.6
(8.140.
in lag phase
I] min],
half
emptying
[median
23.7
[range
time
[74.6
148.0
93.6) vs 82.8 [54.4- 153.91 min] or emptying rate [O. 89 [0.59- I.341 vs 0.83 [O. 36- I. 1 S)%/min] for B- and B+ subjects, respectively In addition, there was no difference in emptying rate of gastric fundus between B- and B+ subjects. Subjects with bile reflux had less effective oesophageal contractions of oesophageal body [9.4[3.3-37]%] compared to subjects without bile reflux [32[1947]%, p=O.O02]. However: there was no correlation between oesophageal motility and gastric emptying. Conclusion. Results suggest that a gastric emptying disorder is a less likely contributing cause of bile reflux to the oesophagus, but bile reflux is associated with less effective oesophageal motility
Digest
Liver
Key words:
8is 2002;34:477-83 bile reflux;
gastric
emptying:
gastro-oesophageal
reflux
disease
Introduction Results regarding gastric emptying time in subjects with gastro-oesophageal reflux disease (GERD) have been conflicting. Some studies have demonstrated a delayed gastric emptying ’ 2 while other studies have not confirmed this 3 4. Other reports have shown that subjects with GERD have slower clearance and increased compliance of the gastric fundus 5 with a concomitant increase in visceral sensitivity 6 and a high frequency of disturbed myoelectrical activity ‘. The increase in fundic relaxation has been proposed as a major cause of GERD by applying a force of traction on the lower oesophageal sphincter (LES), thereby reducing its length and pressure ’ causing transient lower oesophageal relaxations (TLESRs) y. It has been proposed that pharmacological treatment of dysmotility in the proximal stomach could be effective in the treatment of GERD “‘. Recent studies with ambulatory bilirubin measurements in the oesophagus have demonstrated that there may be an association between reflux of duodenal contents to the oesophagus and more severe disease, such as Barrett’s oesophagus ” 12, a premalignant condition with intestinal metaplasia of the distal oesophagus, correlated with GERD IX. Bile acids and pancreatic
477
Gastric emptying and bile reflun
trypsin have been shown to be cytotoxic and cancerpromoting in vitro and in animal studies i4-i8. The mechanism behind duodenogastro-oesophageal reflux (DGER) is not known. There is a physiological backwash of duodenal contents to the stomach during the fasting state i9-*‘. In most healthy subjects, this backwash does not contain bile. It has been shown that only 17% of healthy individuals have bile markers in the duodenum during the postprandial phase, when the duodenogastric reflux occurs, probably caused by incomplete bile duct closure by the sphincter of Oddi 22. The aim of the present study was to investigate whether there is a disturbed gastric emptying in subjects with DGER and if there is any correlation between oesophageal motility and gastric emptying, suggesting an abnormal upper gastrointestinal motility.
Methods Subjects A total of 15 subjects undergoing evaluation for GERD with reflux of bile (B+) to the oesophagus and 15 subjects without GERD and with normal bilirubin monitoring (B-) were included in the study. GERD was delined as typical symptoms of heartburn or regurgitation at least twice per week. The B- subjects were healthy individuals without gastrointestinal symptoms and free of any medication. The B+ subjects had an oesophagogastro duodenoscopy performed with classification of oesophagitis according to Savary-Miller. 5 had no oesophagitis, 5 had grade 1, 1 had grade 2 and 4 had grade 4 (of which all had intestinal metaplasia). Previous studies have shown that postmenopausal women and men have similar gastric emptying rates in contrast to premenopausal women who have a slower rate of gastric emptying 23. Therefore, the two groups were matched not only by gender, but also according to menopausal status. The demographics of the two subject groups are shown in Table I. The study was approved by the Ethics Committee and the Radiation Protection Committee of the Karolinska Hospital and all subjects gave informed consent. Study protocol 24-hour ambulatory combined pH, bilirubin and oesophageal manometry All subjects were off proton pump inhibitors and Hz-blockers for a week prior to the examination. The left nostril was anaesthetised using lignocaine gel. A calibrated combined pH and 3-channel micro transducer manometry catheter was then introduced and passed to the stomach (Koenigsberg Instruments Inc., Pasadena, CA, USA). A pull-through manometric detection of the LES was performed with all three pressure sensors. The pH-sensor was positioned 5 478
kble I. Characteristics of subjects with [B+l or without [B-l reflux of bile to oesophagus.
Age (years1 Male sex Gastric emptying sex (male1 BMI (kg/m21
B- Ill=151
E+ In&l
33 123-70)
54 [34-781" 8
:: 25.2 [19.6-30.91
::.I
(20-37.4)
Data shown as median Irangel. Gastric emptying sex lmalal equals males and postmenopausal females as they have same reference values for gastric emptying. Mann-Whitney U-test, ~~0.05 (7. Abbreviations: see list.
cm, and the pressure tip transducers 3, 8 and 13 cm, above the upper border of the LES. The bile detection catheter (Bilitec 2000, Medtronic Functional Diagnostics A/S, Copenhagen, Denmark) was then introduced next to the pH-catheter and positioned at the same level as the pH-sensor. Both catheters were then tethered to the nose and cheek with adhesive tape and connected to the portable recording units. The subjects were instructed to abstain from alcohol, tobacco, carbohydrated drinks and foodstuffs known to disturb readings of the Bilitec system (i.e., coloured food, for example coffee and tomatoes). The Bilitec works by measuring absorbance of yellow light between the tip of the catheters optic fibres and a small reflective mirror and has previously been validated 24. To minimize the risk of obstructing the reflective mirror of the Bilitec catheter, only liquid food was allowed. The subjects were prompted to keep a diary, noting the time of episodes of reflux symptoms, food intake and laying down. They returned the next day for removal of the catheter assembly. The stationary manometry, pH- and bile data was analysed using Polygram for Windows software, version 2.1 (Medtronics Synectics, Stockholm, Sweden). All tracings were also examined visually for exclusion of possibly erroneous recordings. For the bilirubin study, periods with increased absorption, which occurred during eating, with an instantaneous rise to absorption >O. 14 were excluded from the analysis. Acid reflux was defined as periods when pH fell below 4, as is generally accepted. Bilirubin reflux was defined as periods when the absorbance was greater than 0.14. Pathologic bilirubin reflux was defined as greater than 7.7% of the time with bilirubin reflux. The normal range for bilirubin was based on the 951h percentile of 20 healthy subjects previously examined at Danderyd Hospital (unpublished data). The ambulatory manometry data was analysed using Multigram for DOS software (Synectics Medtronics, Stockholm, Sweden). All readings were first examined visually to ensure correct baseline settings for detection
.I. Freedman et al.
of oesophageal contractions but not pressure changes due to breathing, and were, if needed, corrected. The software was set to detect an oesophageal contraction if the pressure rose above 20 mm Hg for a minimum duration of 1 s. The recording was divided into periods of pain, meal, postprandial (O-30 minutes after meal intake), upright and supine. Propagated contractions were defined as a peristaltic wave passing all three pressure sensors. An effective propagation was defined as a propagated contraction with a contractile pressure of at least 30 mm Hg at all three recording points.
90, TsO,gastric emptying rate and fundus emptying rate, with percent of time with pH <4 or percent of time with bilirubin absorbance >0.14 as the dependent variable. The natural log of bilirubin and pH were used for all statistical analyses. A power analysis showed 80% probability of detecting an 11 minutes difference in lag 90, 0.2%/minute in gastric emptying rate and 21 minutes in half emptying time. ~~0.05 was considered significant.
Gastric emptying Scintigraphy is a practical way to study gastric motility 25.The scintigraphic gastric emptying test used in this paper has previously been described in detail 23. In brief, a test meal with a technetium-99, labelled, 1300 kJ, omelette and an unlabelled low-calorie, 290 kJ drink was ingested after an overnight fast. Tobacco use was not allowed after midnight before the examination. Immediately upon finishing the meal, the soft drink was taken and imaging was started. The subjects were investigated in a standing position. Successive l-minute frontal and dorsal registrations were made every 5 minutes during the first 50 minutes, followed by imaging every 10 minutes for a total of 120 minutes. The subjects were allowed to move between the registrations, but were usually sitting comfortably close to the camera. The activity in the stomach was outlined by a region of interest in each of the images and geometric mean values calculated. After correction for physical decay, the total activity in the stomach was converted to percent of the maximum count rate recorded in each investigation and the values were plotted against time. The same procedure was done for regions of interest in the proximal and distal stomach 2h. A linear fit computation by least-square regression was performed and applied to the linear part of the curve. This was manually defined in all investigations. In most subjects, the linear phase lasted between 30 and 120 minutes. The linear emptying was defined as the slope of the fitted curve (%/minute). The lag phase (lag 90) and half-emptying time (T& were defined by the intercepts of the regression line with the 90% and 50% levels, respectively. In addition, the linear fit was used to define the percentage gastric retention of the meal at 60, 90 and 120 minutes by using the values of the regression lines at these positions. The area under the curve (AUC) was calculated for fundic and antral activity over time to assess proximal gastric emptying.
24-hour pH- and bilirubin monitoring The median (range) percent time with bilirubin >0.14 and pH was greater in the B+ subjects [20.8 (7.7-80.7) and 15.3 (O-55)%, respectively] than in the B- subjects [0 (O-5.8) and 2.7 (1.5-9.0)%, respectively] (both ~~0.05).
Statistical methods Data are shown as median (range). Comparisons between groups were performed with the Mann-Whitney U-test. A univariate regression analysis was performed for lag
Results
24-hour manometry There was no difference in LES pressure or length in the B+ and B- subjects [pressure; 13.5 (7.0-31.0) vs 18.5 (6.0-28.0) mmHg, p=O.78, length; 4.0 (2.0-6.0) vs 4.0 (2.0-7.0) cm, p=O.66, respectively]. Complete 24hour recordings were obtained in 10 of the B+ and 14 of the B- subjects, the remaining six were studied before the ambulatory manometry test became available. The percent effective contractions were significantly lower in the B+ group [9.4(3.3-37)%] compared to the B- subjects [32(19-47)%, p=O.O02] (Fig. 1). Similar
*** -0 0r T 0 1
I
I
B+
B-
Fig.1. Boxplot of percent effective oesophageal contractions in subjects with and without duodenogastm-oesohageal mflux. Percertt [Median, 25 md 90 percentiles, circles represent o&tiers1 effective contractions in Iesophagus during 24 hours in subjects with tB+l and without (B-1 duolenogastm-oesophagaeal reflux. p=O.O02 I”‘“], Mann-Whitney U-test.
479
Gastric emptying and bile r&n
We
II. Results of solid gastric emptying in subjects with LB+1 or without (8-l reflux of bile to oesophagus B+ In451
Lag SO fminl Tsa fminl Gastric emptying rate, Wmin Retention total 60 min Retention total SO min Retention total 120 min Tso fminl fundus Retention fundus 60 min Retention fundus SO min Retention fundus 120 min AUC fundus AUC antrum Data shown
as median
(range).
25 83 0.83 66 44 17 47 40 24 IO 4839 2419 Retained
gastric
content
B- In451
ELI-401 (54-l 501 (0.36-l .21 (44-841 (I I-731 LO-621 [I .O-981 (9.4-761 (2.1-481 fl.l-411 [I 934-84661 [I 186-44791
24 75 0.89 60 38 14 44 35 17 3.3 4789 2174
over time. No significant
differences,
Mann-Whitney
U-test,
[I I-441 [48-941 (0.59-I .31 [36-751 [0.9-531 (O-301 (0.6-641 [I .2-521 (0.86-331 (0.32-171 (2427-61571 [I 239-3581 I
p~O.05.
Abbreviations:
see
list.
Univeriate analysis with percent of time with bilirubin co.14 end % time with pH<4 as dependent factors in 30 subjects with and without duodenogastro-oesophageal reflux.
Table III.
Variable
Bile Reflux
Acid refh
Uniuariate
hivariate
B
Lag 90 fminl Gastric emptying rate [Wminl TXI fminl AUC fundus
-0.06 -21 .I 0.28 0.002
Gastric emptying over time. No significant breviations: see list.
correlation
II'
p-value
0.001 0.05 0.07 0.01 between
bile reflux
significant results were obtained if the postprandial, supine or upright periods were examined (data not shown). There was no correlation between the percent effective contractions in the oesophagus over the whole 24-hour period or the postprandial period versus the gastric emptying rate (%/min) (R2=0.12, p=O.56 and R*=O. 16, p=O.45, respectively).
B
0.86 0.26 0.15 0.57 or acid reflux
-0.007 -0.4 0.001 0.001 to oesophagus
and different
II2
0.006 0.008 0.001 0.003 parameters
p-value
0.68 0.64 0.85 0.92 of gastric
emptying.
Ab-
sophagus (Table III). Of the 30 subjects in this study, two with GERD had delayed gastric emptying as compared to normal data earlier presented by Gryback et al. 23. Both these subjects had normal pH values and bile exposure was just above the normal limit. Discussion
Solid
gastric
emptying
There was no difference between the B+ and the Bsubjects with regard to any of the parameters of gastric emptying studied [lag 90, TX,, gastric emptying rate and amount retained in the stomach at 60, 90 and 120 min (Table II)]. Similarly, there was no difference in the emptying rate from the gastric fundus to the antrum (Table II). In a univariate analysis, there was no association between the percent of time with bilirubin >0.14 in the oesophagus and any of the gastric emptying parameters (Table III). Similarly, no association was found between any of the gastric emptying parameters and the percent of time with pH <4 in the oe480
This study demonstrates that subjects with DGER have less effective contractions in the oesophagus, but there is no difference in gastric emptying compared to subjects without DGER. In previous studies of gastric emptying and GERD, no assessment had been made of DGER. This study did not detect any correlation between different gastric emptying parameters and degree of DGER and there was no difference in gastric emptying between subjects with and without DGER. As gastric emptying was studied using a labelled omelette, no conclusion can be drawn regarding capacity for liquid emptying. No as-
_ - - - - - I
J. Freedman et al.
sociation was found between acid reflux and gastric emptying. This is in contrast to some studies demonstrating that subjects with GERD have slower gastric emptying rates, as studied with scintigraphy ’ 2 or ultrasound 27, compared to normal subjects. However, the results presented are in agreement with other studies that found no correlation between GERD and gastric emptying 3 4. In a previously published multivariate analysis, including gastric emptying, oesophageal pH- and manometry data and gastric secretion, it was found that oesophageal clearance, LES pressure and, to some extent, peak acid output were important predictors for GERD 28. In contrast with the findings of the present study, Stacher et al. 29 have shown that an impaired proximal, but not total, gastric emptying is seen in subjects with GERD. A multiple regression analysis demonstrated that LES pressure accounted for 22% of the correlation with oesophageal exposure to acid, whereas proximal gastric emptying only accounted for 8%. These factors may be associated as it has been found that subjects with reflux disease have a slower recovery of gastric tone in response to distension 5 ‘j. In a study using ultrasonography, it was found that 70% of GERD subjects have a slow reflux of gastric contents over the oesophageal sphincter with slow clearance by oesophageal peristalsis after 30 seconds to 2 minutes, a pattern of motility that was not seen in controls, thus providing further evidence of a disturbed motility pattern in the proximal stomach 30. Our normal value for bile exposure, ~7.7% percent time with bilirubin absorbance ~0.14, compares well with data presented by Marshall et al. 3’ (<7%), but is somewhat higher than those presented by Vaezi and Richter 32 (< 1.8% in 20 controls, 13 male) and Kauer et al. (~2.9% in 25 controls) j3, but lower than another study by Kauer et al. j4. The reasons for this are unclear, albeit the groups studied are small and dietary restrictions were different, as were the catheter setups in the different studies. There is a strong correlation between acid and bile reflux to the oesophagus, and previous studies have shown a correlation between acid reflux and reduced efficiency of oesophageal peristalsis 35-40.Bile reflux has been shown to increase the permeability of the oesophageal epithelium by disruption of the cellular membranes 4’-43. It is possible that the noxious damage caused by acid and bile reflux induces irreversible changes in terms of motility, possibly by thickening of submucosal collagen and loss of muscle fibres as proposed by Stein et al. 35, thereby worsening the disease by impairment of oesophageal clearance. The present study demonstrates that subjects with DGER have less effective oesophageal motility over a period of 24 hours. Whether an impaired oesophageal motility re-
sults in GERD or whether the damage caused by chronic reflux on the oesophagus results in an impaired oesophageal motility can not be answered by the present study. It has been suggested that GERD is a part of a more generalized disorder of motility in the whole gastrointestinal tract, and perhaps also linked to autonomic dysfunction 44. GERD is more common in subjects with irritable bowel disease 4s46, dyspepsia 47 and gallstone disease 48. It has also been shown that total gastric emptying time is correlated to impaired oesophageal clearance of a solid bolus, as well as to failed oesophageal peristalsis in subjects with GERD 49. Yet, in the present study, oesophageal motility was measured with ambulatory oesophageal manometry, optimising conditions for evaluation of oesophageal body motility, but no correlation was found between 24-hour motility parameters and gastric emptying, neither proximal nor total. A critique against this study may be that it only includes 15 subjects in each group. Yet, a power analysis demonstrates sufficient power to detect a difference of more than 21 minutes in gastric emptying between the groups, and smaller differences probably lack clinical significance. In summary, the present study did not identify disturbed gastric emptying in subjects with DGER compared to subjects without DGER. The only significant determinate of bile reflux being the impaired oesophageal motility as determined by 24-hour oesophageal monitoring. It remains to be determined whether this is a pre-existing condition or if it is due to the noxious effects of duodenal contents and acid on he oesophagus. list
of abbreviations
AUC: area under the curve; BMI: body mass index: DGER: duodenogastro-oesophageal reflux; GERD: gastro-oesophageal reflux disease; LES: lower oesophageal sphincter; TLESR: transient lower oesophageal relaxation.
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. X EUROPEAN COURSE ON THERAPEUTIC DIGESTIVE ENDOSCOPY AND RADIOLOGY LIVE VIDEO DEMONSTRATIONS Rome, Italy, 24-25 October, 2002 Course Directoc Coordinators:
Aula Brasca, Universith
G. Costamagna
M. Mutignani,
V. Perri
Congress venue Cattolica de1 Sacro Cuore, Policlinico Universitario Largo A. Gemelli 8, 00168 Rome, Italy
“A. Gemelli”,
Organizing secretariat SC Studio Congressi, Via Francesco Ferrara 40, 00191 Rome, Italy. Tel. +39-06-3290250 - Fax +39-06-36306897 E-mail: [email protected] - www.scstudiocongressi.it
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