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The noxious agents responsible for injuring the oesophageal mucosa in patients with gastro-oesophageal reflux disease (GORD) may originate from two possible sources, the stomach and the duodenum. Hydrochloric acid and pepsin are the important gastric contents, whereas conjugated and unconjugated bile acids and trypsin are the proposed duodenal ingredients predisposing to the development of oesophageal symptoms and mucosal injury.1 The regurgitation of these duodenal contents into the stomach followed by reflux into the oesophagus is known as duodenogastro-oesophageal reflux (DGOR).
To date, the controversy in the literature regarding the specific agents responsible for oesophageal damage centres around the relative importance of acid/pepsin reflux versus DGOR. Early animal studies have clearly shown that acid alone, and in combination with various pepsin concentrations, is damaging to the oesophagus.2-5 For example, Goldberg and colleagues2 showed oesophageal mucosal damage in the intact feline oesophagus with either very high acid concentrations (pH 1.0–1.3) or lower acid concentrations (pH 1.6–2.0) in the presence of pepsin. Additionally, human studies3-5 have clearly delineated a positive correlation between the degree of abnormal acid reflux and the severity of oesophagitis. These studies show that more than 90% of patients with oesophagitis and Barrett’s oesophagus have increased oesophageal exposure to acid on pH monitoring.5 Additionally, Bremner and colleagues6 observed that patients with increased oesophageal exposure to pH 1–2, corresponding to the known pKa of pepsin, had the most significant degrees of oesophagitis; an indirect inference to the possible importance of pepsin. Therefore, the role of acid and pepsin in causing oesophageal mucosal injury is irrefutable.
The role of duodenal contents in the development of oesophageal mucosal injury is controversial and the subject of many animal and human studies. Animal studies show that oesophageal mucosal damage caused by bile acids is dependent on both the conjugation state of bile acids and the pH of the refluxate. Using net acid flux (NAF) across the oesophageal lumen as an index of mucosal injury, Harmon and colleagues7 showed that taurine conjugated bile salts, taurodeoxycholate and taurocholate, increased NAF at pH 2, whereas the unconjugated forms increased NAF at pH 7 and not at pH 2. Hence, animal studies show that conjugated bile acids are more injurious to the oesophageal mucosa at acidic pH, whereas unconjugated bile acids are more harmful at pH 5–8. Additionally, Kivilaakso and colleagues8 found that in addition to bile acids, the pancreatic enzyme trypsin causes oesophageal mucosal damage at pH 7.0.
Prior to the advent of the new bilirubin monitoring device (Bilitec), the majority of human evidence for the role of DGOR in oesophageal damage was acquired by prolonged pH monitoring using pH>7 (“alkaline reflux”) as a marker of DGOR.9-11 However, the measurement of oesophageal pH>7 as a marker of DGOR is confounded by several problems. Precautions must be taken to use glass electrodes, dietary restriction of food with pH<7, inspection of patients with periodontal disease, and dilatation of strictures to avoid pooling of saliva.1 Furthermore, several studies using triple-probe pH monitoring placed in the oesophagus, gastric fundus and antrum found that oesophageal exposure to pH>7 does not originate from the stomach but rather was due to saliva or bicarbonate production by the oesophageal submucosal glands.12 ,13 Additionally, recent studies14 ,15 with the Bilitec show no correlation between DGOR and “alkaline reflux”. Using simultaneous Bilitec and oesophageal pH monitoring, Champion and colleagues14 found a graded increase in acid and DGOR from controls to patients with oesophagitis with the highest value in patients with Barrett’s oesophagus. Although DGOR had a strong correlation with acid reflux (r = 0.78), it had a poor correlation with pH>7 (r = 0.06). We reported similar findings15 in patients with complicated and uncomplicated Barrett’s oesophagus. Therefore, these studies suggest that pH>7—“alkaline reflux”—is a poor marker for oesophageal exposure to duodenal contents and should not be used to assess DGOR.
One of the earliest methods used to evaluate DGOR was the aspiration of gastric or oesophageal contents with fluid analysis for bile acids. The results from the gastric aspiration studies are conflicting. Kaye and Showalter16 found no significant difference between fasting gastric bile acid concentrations of patients with oesophagitis compared with controls. Similarly, studies by Gillen and colleagues17 found no difference in the fasting bile acid concentrations of patients with complicated or uncomplicated Barrett’s oesophagus compared with normal controls. However, we18found that fasting bile acid concentrations were higher in patients with complicated Barrett’s oesophagus compared with those with uncomplicated disease, with both being higher than in patients with GORD and controls. A limitation of gastric aspiration studies is the presumption that the presence of bile acids in the stomach is a good indicator of oesophageal exposure to duodenal contents and therefore DGOR. However, only half of DGOR episodes into the antrum reach the fundus of the stomach, and then all that is present in the fundus may not reflux into the oesophagus.19
Similarly to studies of gastric aspirates, studies with oesophageal aspiration techniques in humans show conflicting results regarding the role of DGOR in oesophageal mucosal injury. On the one hand Mittal and colleagues20 found no bile acids in either the fasting or postprandial oesophageal aspirates of patients with GORD. On the other, Gotley and colleagues21 studied 45 patients with oesophagitis and 10 controls using continuous collection of oesophageal aspiration over 16 hours and found increased amounts of conjugated bile acids, measured by high performance liquid chromatography (HPLC), in the majority (87%) of aspirates. Most bile acid reflux in this study occurred at night with 7% of samples having bile acid concentrations above 1.0 mmol/l, the usually toxic concentration producing oesophageal mucosal damage. However, a later study by the same group22found that the oesophageal aspirates of patients with oesophagitis only rarely (2%) had conjugated bile acid concentrations high enough (>1.0 mmol/l) to cause oesophageal mucosal damage. Additionally, they found no unconjugated bile acids or trypsin in the aspirates, whereas acid and pepsin was found in almost all specimens. Thus, supporting the animal studies, they concluded that reflux oesophagitis was caused by acid and pepsin with bile acids and trypsin having insignificant roles. Similarly, a recent study by Kauer and colleagues23 in 43 normal subjects and 37 patients with GORD found higher concentrations of glycocholic and glycochenodeoxycholic bile acids in the oesophageal aspirates of patients with GORD. However, only two of 37 patients had bile acid concentrations above 1.0 mmol/l.
In this issue (see page 598), Nehra et alused a new oesophageal aspiration technique in an attempt to clarify further the role of DGOR in patients with acid reflux disease. They studied 10 asymptomatic subjects and 30 patients with symptoms of GORD including 10 patients with Barrett’s oesophagus. All patients underwent 15 hour continuous oesophageal aspiration with simultaneous pH monitoring. Using a newly modified HPLC technique, they found significantly (p<0.05) higher concentrations of bile acids in patients with oesophagitis (124 μmol/l) and Barrett’s oesophagus (181 μmol/l) than controls (0 μmol/l). Furthermore, they showed that the predominant bile acids detected were cholic, taurocholic and glycocholic acids. Importantly, they were able to correlate the degree of bile acid reflux with the pH of the refluxate, finding a temporal relation between acid and taurine conjugated bile acid reflux in the distal oesophagus of patients with GORD (r = 0.58, p = 0.009). This finding confirms our recent report18 in which we found that the most (70–90%) DGOR measured by the Bilitec in patients with GORD or Barrett’s oesophagus occurs in an acidic (pH<4) milieu, suggesting that acid and DGOR may both be important in causing oesophageal mucosal damage. Furthermore, we18 showed that acid and DGOR occur simultaneously more commonly in patients with Barrett’s oesophagus (90–100%) than patients with GORD but without Barrett’s oesophagus (50–80%), suggesting an important synergistic role for acid and DGOR in patients with Barrett’s oesophagus. Additionally, the study by Nehraet al confirmed the results from animal studies showing that the taurine conjugated bile acids may be the important bile constituents responsible for oesophageal damage in an acidic milieu.
However, several important points discussed by these authors require further clarification. Nehra et al found that up to 20% of their patients with GORD have DGOR without acid reflux. Therefore, they concluded that DGOR without acid reflux is damaging to the oesophageal mucosa, and “explains why 15–20% of patients with GORD fail to respond to acid suppression therapy.” However, this conclusion is beyond the scope of their study and is not supported by other reports. We18 did not find a significant degree of DGOR without acid reflux in patients with GORD or Barrett’s oesophagus. Furthermore, studies show that nearly all patients with GORD and oesophagitis can be treated successfully with adequate acid suppression.24 ,25 The 15–20% treatment failure rate reported in the literature is usually the result of inadequate acid suppression25 in drug studies using fixed doses of proton pump inhibitors (PPIs) and is not a function of bile induced oesophageal damage. Furthermore, several studies show that acid suppression with omeprazole reduces oesophageal exposure to acid reflux and also decreases DGOR, most likely by reducing the gastric volume available to reflux into the oesophagus.14 ,26 Outside isolated case reports, there is currently little convincing human evidence for the damaging potential of DGOR without acid reflux. For example, studies by Sears and colleagues27 in patients with a partial gastrectomy who had prolonged and significant DGOR measured by the Bilitec found that only the patients with concomitant acid reflux had oesophagitis. In this study, the group of patients with DGOR without acid reflux had upper gastroinestinal symptoms (regurgitation, bloating, nausea, and vomiting) but did not have any signs of oesophageal mucosal damage, suggesting that DGOR without acid reflux may cause oesophageal symptoms but does not frequently cause oesophagitis in humans. The symptoms in these patients were successfully treated in 70% of cases using high dose propulsid (20 mg po qid).28 In those unresponsive to this medical therapy, surgical intervention (Roux-en-Y diversion) can result in adequate symptom relief.
Therefore, currently the literature suggests that both acid and DGOR in patients with GORD and an intact stomach may be important in causing oesophageal mucosal damage. Based on the currently available data, there is no evidence for the damaging potential of DGOR alone without acid reflux in the human oesophagus. Additionally, studies now show that, in an acidic refluxate, taurine conjugated bile acids are the important human bile constituents causing oesophageal damage. In this group of patients, acid suppression with PPIs can reduce both oesophageal acid exposure and DGOR. The reduction in DGOR is most likely related to the reduction in gastric volume secondary to inhibition of acid release by the gastric PPIs. Additionally, conjugated bile acids are precipitated out of solution and pepsin is inactivated at the higher intragastric and intra-oesophageal pH environments created by the PPIs. Therefore, medical treatment with PPIs or antireflux surgery seems to offer equal protection against the damaging effects of both acid and DGOR in patients with complicated GORD or Barrett’s oesophagus.