Gastroesophageal reflux disease (GERD) is one of the most common conditions encountered by a gastroenterologist. Patients with GERD can present with heartburn, regurgitation, and atypical chest pain, among other symptoms.1 The mainstay of treatment includes lifestyle changes such as weight loss, avoiding GERD triggers, waiting at least 3 hours after eating before laying down, head of bed elevation, and smoking cessation. If patients have persistent symptoms despite adopting these lifestyle changes, then medications such as proton pump inhibitors (PPIs) and histamine-type 2 receptor blockers (H2RBs) can be used. Although most patients will achieve symptomatic relief with PPIs or H2RBs, there are certain patients that may have refractory GERD.  In these situations, additional diagnoses should be considered, including esophageal dysmotility, gastroparesis or delayed gastric emptying, nonerosive reflux disease (NERD), eosinophilic esophagitis, functional heartburn, esophageal cancer (rarely), and biliary reflux. 

Biliary reflux occurs when the bile secreted into the duodenum moves retrograde into the stomach and potentially into the esophagus.2 Biliary reflux has also been called duodeno-gastroesophageal reflux (DGER), biliary gastritis, or alkaline reflux gastritis.1,3 In certain patients with DGER, it has been postulated that a weak or widely patent pylorus could predispose patients to this condition.3 DGER may also be more common in patients with motility disorders, especially in those whose gastric or duodenal motility is reduced, including certain patients with type 2 diabetes mellitus or those taking chronic opioid medications.3 Patients who have undergone gastric surgeries where the pylorus is bypassed or disrupted may be predisposed to developing DGER as well.3 Additional risk factors include gallbladder dysfunction, cholecystectomy (CCY), and biliary sphincterotomy.3

Bile reflux is typically alkaline in nature, compared with the acidic environment found in the stomach.2,3 Despite this difference in pH, patients can experience similar symptoms, making DGER and GERD difficult to distinguish.4 Patients with DGER may complain of bilious vomiting; however, this symptom is relatively nonspecific. There are certain endoscopic and histopathological changes that may help attribute a patient’s symptoms to DGER.3,5 Gastric and esophageal exposure to bile has been associated with histologic changes in the stomach and esophagus, including intestinal metaplasia.5 Bile reflux into the stomach can also lead to mucin depletion and influx of hydrogen ions.4  


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DGER is often seen in patients with Barrett esophagus (BE) and severe esophagitis, both of which can be identified during an esophagoduodenoscopy (EGD).5 Certain patients may develop biliary reflux based on having an “acid-bile” pocket in the proximal part of the stomach; this leads to a collection of bile and may predispose the patient to esophageal reflux.3-5 Bile reflux may also be a component in patients who are identified as having nonacidic reflux on pH monitoring.3-5

When performing an EGD, there should typically be no bile found in the stomach based on the required prolonged fasting state prior to the procedure. Therefore, identification of bile in the stomach should place bile reflux on the differential diagnosis. As there are no formal definitions for how to diagnose bile reflux, it is typically done based on locating pooling of bile in the stomach along with histologic changes consistent with bile-induced gastritis.3 Additional endoscopic findings are relatively nonspecific and include gastric erosions, atrophy, and thickened folds.3 Histologic changes include foveolar hyperplasia and acute and/or chronic inflammation, which can also be seen in NSAID-induced and other chemically-induced injuries.3 There are biochemical analyses and monitoring systems to formally diagnose the presence of bile in the stomach if the endoscopic findings are not clear; however, they are not used in routine practice and may not be readily available at many facilities.

Identification of biliary reflux is important, as patients experiencing this can have more severe mucosal damage in the esophagus, including BE.2,5 A study conducted by Dixon et al found that patients with BE had more evidence of bile related gastritis compared with those reported as having only GERD or nonulcer dyspepsia.5 This study, along with others, raises the question as to whether there is a carcinogenic role of bile reflux. Therefore, patients with evidence of bile reflux should be considered for more aggressive therapy, in the hopes of potentially preventing negative sequelae such as BE.

A study conducted by Lake et al evaluated 262 patients to determine if bile reflux could contribute to functional dyspepsia symptoms.4 The authors examined endoscopic and histopathological findings, as well as motility testing (gastric emptying). In total, 34% (90/262) of patients were found to have bile gastropathy (BG) vs 46% (121/262) with nonbile gastropathy (NBG) and 19% with no gastropathy (NG). Patients with BG were more likely to have severe abdominal symptoms and higher prevalence of CCY (68%) compared with NBG (35%) and NG (22%). Patients with BG were also significantly more likely to have gastric erythema (88.9% vs 63.6%; P <.001) compared with NBG. Interestingly, there was a higher prevalence of erosions (22.3% vs 8.9%; P =.016) and polyps (8.3% vs 0.0%; P =.046) in the NBG compared with the BG group. There were no statistically significant differences in prevalence of ulcers, atrophy, or gastropathy location (more common in antrum for both groups). 

Presence of BG was associated with more severe gastric histopathologic changes including edema and chronic active inflammation compared with NBG. Patients with CCY had significantly higher odds of having BG (odds ratio [OR], 6.60; 95% CI, 1.87-23.30; P =.003). It is important to note that this study found that a history of CCY was associated with bile reflux, which is most likely secondary to the unregulated and more pronounced delivery of bile into the duodenum. Increased levels of bile could reduce duodenal motility, making patients more prone to develop DGER. The authors concluded that duodeno-gastric bile reflux was present in at least 1/3 of patients with functional dyspepsia. 

There are no formal guidelines for treating patients with DGER; therefore, they are typically treated similarly to those with traditional GERD. Treatment options include PPIs, H2RBs, prokinetics (metoclopramide), and baclofen (to reduce relaxation of the lower esophageal sphincter via gamma-aminobutyric acid B agonist action).1 It is also important to review a patient’s medication list and limit medications that could impair gastroduodenal motility, such as opioids and anticholinergics. Agents such as ursodeoxycholic acid (UDCA), cholestyramine, misoprostol, and sucralfate have also been studied, with limited data to support their routine use.3

When PPIs are used to treat DGER, the mechanism may be secondary to reducing gastric acid volume and overall acidity, although the alkaline nature of the bile reflux can still cause irritation of the esophagus.1 In addition, DGER should be considered in patients with persistent GERD symptoms, despite maximum PPI dosing. 

As with refractory GERD, surgery can also be considered in those patients with DGER who fail medical management. Surgeries such as the Roux-en-Y are options, although there are less supportive data than in patients with classic GERD; these surgeries also come with complications. Therefore, surgery is not frequently pursued for patients solely diagnosed with DGER.6

References

  1. Tack J. Review article: the role of bile and pepsin in the pathophysiology and treatment of gastro-esophageal reflux disease. Aliment Pharmacol Ther. 2006;24(2):10-16. doi: 10.1111/j.1365-2036.2006.03040.x
  2. Richter J. Advances in GERD: current developments in the management of acid-related GI disorders.  Gastroenterol Hepatol. 2010;6(5):297-299.
  3. McCabe ME, Dilly CK. New causes for the old problem of bile reflux gastritis. Clin Gastroenterol Hepatol. 2018;16(9):1389-1392. doi: 10.1016/j.cgh.2018.02.034
  4. Lake A, Rao SSC, Larion S, Spartz H, Kavuri S. Bile reflux gastropathy and functional dyspepsia. J Neurogastroenterol Motil. 2021;27(3):400-407. doi: 10.5056/jnm20102
  5. Dixon MF, Neville PM, Mapstone NP, Moayyedi P, Axon AT. Bile reflux gastritis and Barrett’s oesophagus: further evidence of a role for duodenogastro-oesophageal reflux? Gut. 2001;49(3):359-63.  doi: 10.1136/gut.49.3.359
  6. Madura JA. Primary bile reflux gastritis: diagnosis and surgical treatment. Am J Surg. 2003;186(3):269-73. doi: 10.1016/s0002-9610(03)00213-7