The Role of Bile Reflux in Barrett’s Esophagus


Duodenogastroesophageal Reflux in Synergy with Acid


The mechanism of injury of both pepsin and trypsin relate to their proteolytic activities at different levels of acidity (pH 2–3 and 5–8, respectively), promoting detachment of the surface cells from the epithelium by presumably digesting the structures maintaining cohesion between the cells. The mechanism of HCl relates to impairment of cell volume regulation. The mechanism of bile acid injury is still under investigation. However, the favored hypothesis is that bile acids gain entry across the mucosa, then disrupt the membrane structure or interfere with cellular function, leading to intramucosal damage.8


Studies with the Bilitec device have shown a significant, graded increase in both acid and DGER through the spectrum of esophageal injury, from controls to patients with esophagitis to those with Barrett’s esophagus. The reflux of acid paralleled DGER, and both were significantly higher in patients with complicated Barrett’s than in those with uncomplicated Barrett’s disease.23


Champion and colleagues


demonstrated that bile reflux parallels acid reflux and may have a synergistic effect in the development of Barrett’s disease, but fasting bile acid concentrations did not distinguish patients with Barrett’s from those patients with reflux disease.22


The role of DGER in producing esophageal mucosal injury, without the presence of acid reflux, has been studied as well. Multiple animal studies suggest that bile acids can produce pH-dependent esophageal mucosal injury.11,31,32


However, human evidence has been


Additional reports indicate that bile reflux is at most synergistic with acid to produce esophagitis and does not contribute to the development of Barrett’s esophagus.


Patients with partial gastrectomy represent an outstanding human model for increased DGER as the incompetent pylorus and free regurgitation of duodenal contents into the stomach leads to adequate gastric bile acid concentrations known to cause injury in animal models.8


controversial. Some reports indicate that reflux of duodenal juice contribute to the development of Barrett’s esophagus by the association with increased alkaline pH exposure by ambulatory monitoring.33,34


esophagus, but the amount of injury was less than would be expected if bile reflux was a major contributor to esophageal injury.22 studies by Vaezi and Richter evaluated32


Further partial gastrectomy patients


with upper gastrointestinal (GI) symptoms using pH monitoring and bilirubin monitoring. Those patients with symptoms were shown to have both mixed acid and DGER and as well as DGER only. However, none of the DGER only patients had esophagitis, while there was a significant association with esophagitis for those with mixed reflux.35 Therefore, it is appears that that DGER without the additional component of acid can cause symptoms of reflux but does not usually cause mucosal injury.


A recent study by Bredenoord and colleagues used impedance-pH monitoring to study reflux and short-segment Barrett’s disease. This study found that duration and number of episodes of both acid and weakly acid reflux were higher in those with increasing severity of esophagitis.37


Another trial by Gutschow et al.38 again confirmed the


increase in esophageal acid exposure on pHmetry with increased injury and longer clearance times in those with Barrett’s esophagus. They also found that patients with Barrett’s esophagus had significantly higher exposure to non-acid reflux, especially in supine phase, likely representing an increase in exposure to DGER as this duodenal reflux into the stomach happens normally at night.38


Although this novel


measurement technique can assess a variety of parameters, it should be noted that all weakly acidic or weakly alkaline reflux is not bile reflux, which likely only represents 10 to 15% of the weakly acidic or weakly alkaline reflux.39,40


Future studies employing this device are


ongoing and will add to our current understanding of bile reflux in Barrett’s esophagus.


Conclusions


In addition, >10% of patients with Billroth I and II gastrectomy have reflux symptoms, nausea, vomiting, regurgitation, and distention, but rarely have evidence of mucosal injury.35


For example, Sears et al.


found increased DGER by bilirubin monitoring in 77% of patients with reflux symptoms after partial gastrectomy. Esophagitis and Barrett's esophagus were only seen in those with combined acid reflux.8,36 Studies by Champion et al. found that not only does the total time that pH is <4 increase along the GERD spectrum, but mean percent of total time bilirubin absorbance was ≥0.14 also increased in a graded response with the severity of GERD. The amount of DGER in patients with partial gastrectomy was similar to those patients with Barrett’s


1. Shaheen N, Ransohoff DF, Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review, JAMA, 2002;287(15):1972–81.


2. Naef AP, Savary M, Ozzello L, Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett's esophagus with 12 adenocarcinomas, J Thorac Cardiovasc Surg, 1975;70(5):826–35.


3. Wood RK, Yang YX, Barrett's esophagus in 2008: an update, Keio J Med, 2008;57(3):132–8.


Acidic reflux is a well-accepted factor in causing esophageal injury and a major contributor to the development of Barrett’s esophagus. By contrast, the role of DGER is controversial. Studies with Bilitec have identified DGER as a potential contributor, as the severity of esophagitis parallels the degree of exposure to acid and DGER. In addition, patients with partial gastrectomies reveal that DGER in non-acidic environments rarely causes esophageal injury, revealing more evidence that DGER is synergistic with acid, pepsin, and conjugated bile acids. Impedance-pH studies have revealed a significant association with non-acid reflux and Barrett’s in the supine position as well as increased acid and weakly acidic reflux in those with more severe esophagitis. Studies have also shown that aggressive acid suppression dramatically decreases acid and DGER in patients with severe esophagitis, thought to be secondary to inhibition of gastric acidity and volume. In addition, the more neutral pH leads to inactivation of conjugated bile acids, the component of DGER thought to cause esophageal injury.22,41


Therefore, addition of a


proton pump inhibitor to a patient’s medication regimen appears to effectively reduce the contribution of DGER to Barrett’s esophagus. n


4. Shaheen NJ, Richter JE, Barrett's oesophagus, Lancet, 2009;373(9666):850–61.


5. Vaezi MF, Richter JE, Bile reflux in columnar-lined esophagus, Gastroenterol Clin North Am, 1997;26(3):565–82.


6. Richter JE, Importance of bile reflux in Barrett's esophagus, Dig Dis, 2000;18(4):208–16.


7. Vaezi MF, Singh S, Richter JE, Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies, Gastroenterology, 1995;108(6):1897–907.


8. Vaezi MF, Richter JE, Duodenogastroesophageal reflux and methods to monitor nonacidic reflux, Am J Med, 2001;111(Suppl. 8A(111):160S–8S.


9. Redo SF, Barnes WA, De La Sierra AO, Perfusion of the canine esophagus with secretions of the upper gastro-intestinal tract, Ann Surg, 1959;149(4):556–64.


10. Goldberg HI, Dodds WJ, Gee S, et al., Role of acid and pepsin in acute experimental esophagitis, Gastroenterology, 1969;56(2):223–30.


US GASTROENTEROLOGY & HEPATOLOGY REVIEW 15


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