Duodeno-gastroesophageal reflux
Is the percentage of duodenal marker refluxing into the stomach significantly higher in patients with gastroesophageal reflux than in healthy subjects?
A. Dubois (Bethesda)
Since the first reports that achlorhydric patients could develop severe esophagitis [1-3], the possible role of duodenogastroesophageal reflux in the production of gastroesophageal reflux disease (GERD) has been hotly debated. The attention concentrated initially on bile acids for two main reasons:
1) they are relatively easy to detect;
2) it is logical to assume that the detergent and barrier breaking properties of bile acids are likely to enhance the damage caused by acid and pepsin, or, at neutral or alkaline pH, by trypsin.
Experimental evidence has supported such an effect [4-10], although the damage produced under alkaline conditions is more controversial [11]. This subject was recently reviewed [12].
The question that needs to be addressed, however, is whether duodenal contents (including bile acids, bilirubin and/or, in the presence of achlorhydria, of trypsin) flow back from the duodenum to the stomach in greater amounts in patients with GERD than in healthy controls. Three different techniques are available to assess the presence of duodeno-gastric reflux (DGR).
Aspiration of the gastric or esophageal contents
This represents the oldest technique used to assess DGR. It is based on determination of the concentration and/or output of bile acids in gastric or esophageal contents aspirates.
Esophageal aspirates
Two studies demonstrated the presence of bile acids in esophageal aspirates of some patients with GERD, but the concentrations of bile acids were low (2.5-64.0 mmol.L-1) and they were not significantly different in patients with grade 1 and grade 2 esophagitis and neither were higher than in control subjects [13, 14]. In another study, no bile acids were found in the esophageal aspirates of patients with GERD [15]. On the other hand, a study using a liquid chromatography technique demonstrated the presence of conjugated bile acids in 24-hour esophageal aspirate of 39/45 patients with GERD but in only 2 of
10 controls [16]. In addition, the concentrations of bile salts were lower that 40 µmol/l in controls whereas cytotoxic concentrations (200 mmol.L-1) were observed in 11 patients [16]. In a subsequent study, however, the same group reported that only 2% of GERD patients had concentrations of conjugated bile acids sufficient to cause mucosal damage (> 1,000 mM.L-1) [17]. Thus, these studies demonstrate that bile acids are present in the esophagus of a small fraction of patients with GERD. However, they do not prove that patients with GERD have increased DGR, as these observations could reflect abnormal GER of physiologic intragastric levels of bile acids.
Gastric aspirates
For the reasons discussed in the previous paragraph, determination of the concentration and output of total bile acids in gastric aspirates are also important. In one early study, the concentration and output of total bile acids was found to be increased in the stomach of subject with "symptomatic hiatal hernia" [18]. Although these patients were diagnosed as having only symptomatic sliding hiatal hernia, most subjects were probably true gastroesophageal refluxers because all had heartburn and some subjects also had esophagitis and strictures. Concentration and output of bile acids were not significantly affected by the presence or absence of heartburn, esophagitis and strictures, but the grade of esophagitis correlated with the severity of the illness [18]. Two other studies demonstrated that bile acids concentrations were significantly elevated postprandially, but not during fasting [19, 20]. However, these latter findings may not be valid, as these authors used an enzymatic technique that lacks specificity during the postprandial period. More recent studies in Barrett's esophagus, however, have demonstrated that the concentration of bile acid was more elevated in the presence of complication than in their absence [21]. A general problem of these studies, however, is that by aspirating gastric or esophageal contents, one creates a negative pressure gradient that could facilitate reflux, especially in the presence of weak lower esophageal sphincter (LES) or pylorus. Therefore, the non invasive methods described below are very important.
Scintigraphic studies
Measurement of the amount of 99mTc-HIDA (hepato-iminodiacetic acid) or 99mTc-DISIDA (di-isopropyl-iminodiacetic acid) present in the gastric area allows a tubeless determination of DGR.
DGR as assessed by scintigraphy has been reported to be common in healthy subjects after meals [22]. In patients with esophagitis, however, 99mTc was either not detected [23], or the frequency of its presence in the esophagus was similar to that found in healthy controls [24]. In contrast, the frequency of DGR was reported to be significantly higher in patients with Barrett's esophagus (6/13 patients) than in either GERD patients without Barrett's (3/9 patients) or controls (2/19 subjects), and this frequency tended to be higher if complications were present (4/5 patients) than if they were absent (2/8 patients) [25].
Thus, in contrast to the methods requiring aspiration of esophageal and gastric contents with or without intraduodenal injections of markers, this method does not alter intraluminal pressures. However, it is important to remember that the third and fourth portion of the duodenum, and sometimes the left lobe of the liver, can overlap the stomach area with standard anterior views of the abdomen. Furthermore, duodenoesophageal and/or DGR reflux will be detected only if occurring while the isotope is present in the duodenum, that is during the relatively short time spent by the patient in the stressful environment of the hospital. Finally, "control subjects" are generally patients with a negative scintiscan during the course of an evaluation for acute cholecystitis. Thus, these controls have had, at a minimum, acute abdominal pain which may influence DGR. Therefore, these findings should be taken with caution.
Ambulatory monitoring of DGR
Ambulatory diagnosis of DGR (defined as intragastric pH > 7) was achieved initially by measuring intragastric pH for extended periods of time, and this method was found to be more reliable than scintigraphy [26]. In addition, a good correlation was found between results obtained using this method and direct measurement of intragastric bile acid concentrations [27]. Interpretation of the results obtained during intraesophageal pH monitoring, in contrast, has been more difficult [28], and recording of a pH > 7 in the esophagus is now believed to be often due to saliva, oral infections or consumption of food with pH > 7 [29, 30].
For these reasons, the development of a fiberoptic spectrophotometer allowing ambulatory monitoring of intragastric and intraesophageal reflux of bilirubin (Bilitec 2000, Synectics, Stockholm, Sweden) represents an important advance [31]. A fiberoptic bundle transmits the light emitted by two diodes to the gastric contents and back to an optoelectronic probe. Two wavelength are used, one for bilirubin measurement (at 470 nm) and one for the reference signal (at 565 nm), and an integrated microcomputer then calculates the difference between the absorbance at the two wavelengths. The intraluminal concentration of bilirubin is then calculated using a standard curve. A good correlation was found in vitro between measurements of bilirubin concentration using a spectrophotometer and the Bilitec 2000, and intraluminal measurements also correlated with direct determinations of bilirubin in gastric aspirates [32]. However, the Bilitec 2000 underestimates bilirubin concentration by at least 30% in the presence of free acid [32], and it may be sensitive to the presence of dietary compounds [32] as well as non-specific reduction in light intensity [32]. New probes specifically designed to obviate these problems are currently under development [32, 33]. Nonetheless, the Bilitec 2000 system appears to be a good qualitative method to assess the duration of exposure of the esophagus to bile.
Four recent studies using the Bilitec 2000 demonstrated that patients with Barrett's metaplasia had significantly higher prevalence of abnormal exposure of the esophagus to bilirubin than patients with GERD (with or without erosive esophagitis) or healthy controls [34-37]. In addition, esophageal bilirubin exposure was also greater in patients with Barrett's changes. Interestingly, most of the esophageal bilirubin exposure occurred when the pH of the esophagus was between 4 and 7, i.e. when bile acids, the major component of duodenal juice, are capable of damaging the esophageal mucosa. However, this latter finding could be related to the fact that acid denatures bilirubin to forms that are not detected by the Bilitec [32].
In conclusion, reflux of duodenal juice into the stomach appears to be common in GERD, but it is significantly elevated only in the presence of Barrett's metaplasia.
References