Duodenogastroesophageal reflux and its effect on extraesophageal tissues: a review.

Abstract

We conducted a literature review to identify elements of duodenogastroesophageal reflux (DGER)--namely pancreatic fluids, hydrochloric acid, pepsin, and bile--as to the effects each has when refluxed to the extraesophageal structures. Further, we wished to acquaint clinicians with the possibilities that, in addition to hydrochloric acid, the other components of DGER are likewise contributing to disease in the extraesophageal areas. Our review included studies that have indicated reflux of the above mentioned components of DGER to the pharynx, larynx, tracheobronchial tree, oral cavity, nasopharynx, nose and sinuses, eustachian tube, and middle ear. Findings demonstrate that injury to the upper aerodigestive tract can occur from a variety of substances secreted from the stomach and duodenum. Treatment for DGER is nonspecific. We conclude that patients with an incomplete response to acid suppression may have significant involvement of pepsin, bile, or both. Future studies are needed to clarify the importance of these elements and to suggest more precise treatments.

Introduction

Even though the extraesophageal manifestations of gastroesophageal reflux (GER) are well known to the modern otolaryngologist, the management of some patients with GER still remains elusive. Our armamentarium is primarily directed toward acid suppression; nonacidic reflux is not specifically addressed.

The digestive tract is a continuous valveless tube from the mouth to the anus. Peristalsis and sphincteric zones tend to keep foods and secretions moving in an anterograde direction; however, a variety of chemical and enzymatic agents can still move in a retrograde direction, thus producing "reflux." The upper aerodigestive tract is conjoined at the pharynx, and this refluxate has the potential to reach all subsites: the oral cavity and oropharynx; the sinonasal cavity, nasopharynx, and middle ear; and the larynx and tracheobronchial tree. Major constituents of enteric secretions are listed in the table.

Pancreatic juices consist of an alkaline solution of sodium and calcium bicarbonates and the digestive enzymes of lipase, trypsin, chymotrypsin, and amylase. The alkaline solution neutralizes the acidic, partially digested food from the stomach (chyme). Lipase is responsible for digestion of fats, trypsin and chymotrypsin are responsible for proteins, and amylase is active in carbohydrate digestion. These are secreted into the pancreatic duct, where they are combined with the secretion of the liver, namely bile. Bile principally consists of two bile salts, taurocholic acid and chenodeoxycholic acid, as well as bilirubin. Taurocholic acid is conjugated and is active in an acidic environment of pH 1.2 to 1.5 but is inactivated at a neutral pH. (1) Chenodeoxycholic acid is unconjugated and is active at a neutral pH but not at an acid pH of 2.0. (1) Bilirubin represents the end-product of hemoglobin breakdown and is nontoxic when secreted into the duodenum.

In response to a meal, the stomach secretes gastric juices that consist largely of HCl and pepsin. Pepsinogen is secreted by the chief cells of the stomach and is converted to pepsin in the acid medium. It is active in the digestion of proteins and peptides.

Reflux of acidic gastric contents to the esophagus and extraesophageal structures of the upper aerodigestive tract was demonstrated in Koufman's landmark 1991 study (2) and has been further substantiated over the past 2 decades by multiple clinical and basic scientific studies. (3-8) Recent research also has demonstrated ties between pepsin and inflammation of the laryngopharynx, (9-13) further bridging the reflux of gastric contents to the pathophysiology of aerodigestive tract mucosal injury. A few studies have specifically looked into the reflux of nonacidic duodenogastroesophageal reflux (DGER). The goal of this review article is to familiarize clinicians with those studies as reported in the literature.

Literature search

The U.S. National Library of Medicine's PubMed database was searched using keywords relating to DGER and the anatomic subsites of the upper aerodigestive tract. We limited our search to English language papers published from 1966 to the time of our search. Both clinical and basic scientific articles were reviewed.

Search results

Compared to the body of literature available on GER, there are few studies on the effects of DGER on the upper aerodigestive tract. Sixty-five articles were identified that discussed DGER alone, and 34 additional publications were identified that included the role of pepsin in extraesophageal inflammation. In all, 921 publications were identified that related to the effects of acid reflux on extraesophageal structures when articles about GER (16,099 articles) were excluded.

Duodenal secretions. Little research has been published regarding the effects of pancreatic fluids on the mucosa of the esophagus or extraesophageal structures. Trypsin has been shown to induce ultrastructural changes on rat buccal epithelium, (14) and on esophageal mucosa at alkaline and not acidic pFI, (15) yet in other studies trypsin has been shown not to induce inflammation in the larynx. (16,17) There does not seem to be an efficient assay to clinically evaluate patients for reflux of trypsin or pancreatic fluids. Sodium-ion--selective electrodes placed in the stomach have been used to detect pancreatic fluid, but this method has not been extensively used in an ambulatory clinical setting. (18)

Bile salts have been shown experimentally to induce injury in the larynx (1) and esophagus. (15) Bile reflux can be clinically evaluated in ambulatory patients with Bilitec 2000 (Medtronic Gastroenterology; Minneapolis), a spectrophotometer that detects the presence of bile using the optical properties of bilirubin, the most common pigment present in the secretion. (19,20) This method has been used extensively to evaluate bile reflux into the stomach and esophagus but not the upper esophagus or extraesophageal structures. (21,22)

Tack and colleagues (23) have recommended simultaneous pH and Bilitec monitoring in patients with refractory esophagitis. In their evaluation of 65 patients with symptomatic heartburn who were on proton pump inhibitor therapy, 38% had pathologic DGER alone, and 26% had both HCl reflux and DGER. (23) With respect to extraesophageal manifestations of bile exposure, Poelmans and colleagues performed an interesting study to evaluate throat phlegm with a combination of Bilitec and ambulatory dual-probe 24-hour pH monitoring. (24) They confirmed the presence of bile acids in morning-acquired, fasting samples of throat phlegm using a 3-[alpha]-hydroxysteroid dehydrogenase assay (25) in all patients with yellow-tinged phlegm as opposed to those with "white" or "transparent" phlegm. (24)

Gastric secretions. The literature is replete with evidence of HCl reflux into the extraesophageal structures. A recent meta-analysis of ambulatory dual-probe 24-hour pH monitoring revealed consistencies and reliability in measurements of both normal subjects and those with signs of laryngopharyngeal reflux. (26) There is also evidence of gastric reflux into the tracheobronchial tree, the sinonasal tree, and the middle ear. (27-31)

Pepsin has been identified in the sinonasaltree, (29) saliva, sputum, (11) middle ear effusions, (32) the tracheobronchial tree, (33,34) and in histologic samples of laryngeal tissue in patients with laryngopharyngeal reflux. (9)

Discussion

Acid reflux has been well established in the literature and in the modern clinical practice of the otolaryngologist as a source of extraesophageal inflammation. (35,36) Treatment for reflux is largely based on acid suppression, with many recommending twice-daily dosing with a proton pump inhibitor to minimize any acid reflux events. Other treatment methods include dietary and behavioral modification, as well as using other classes of medicines, including prokinetic agents, antacids, histamine-2 blockers, and mucosal protectants such as sulcralfate. Despite aggressive medical therapy, many patients continue to experience chronic inflammation. (37) Does treatment fail in these patients because of inadequate acid suppression, or could it be that there are other refluxed components that remain medically unaddressed?

Duodenal secretions have been demonstrated in clinical studies to be capable of refluxing into the stomach and esophagus. (23,38) No study has been performed using ambulatory bile monitoring at the level of the upper esophagus or the pharynx. Bile salts have been shown to induce inflammation in the larynges of rats (1) and canines (16) at both acid and neutral pH. Although acid suppression decreases gastric output (and the volume of potential refluxate), there remains no specific medical therapy that neutralizes the activity of bile salts or protects the mucosa from their effects.

In the study of throat phlegm by Poelmans and colleagues, those patients with yellow throat phlegm had a higher incidence of positive pH probe studies and complaints of postnasal drip. (24) The authors suggested that both acidic and nonacidic reflux occur simultaneously in affected patients and only partially neutralize each other. They also suggested that simultaneous acid and alkaline reflux may cause underestimation of reflux exposure in patients who are evaluated with pH probe measurements alone. Combined acid and nonacid reflux has also been shown in other clinical studies that included simultaneous pH probe and Bilitec 2000 monitoring. (22,23,39)

A recent study detailed the use of combined multichannel intraluminal impedance and pH testing on patients with globus sensation whose reflux was refractory to proton pump inhibitor (PPI) therapy. (40) The authors demonstrated continued nonacidic reflux, despite twice-daily PPI therapy, and lack of relief of patients' globus symptoms. This study emphasized that the other elements of DGER were the cause of continued symptomology, explained why acid suppression was not helpful in these cases, and validated the use of impedance in cases where nonacidic reflux is suspected.

Pepsin has been found to be present in multiple extraesophageal sites, and its role in mucosal inflammation has recently been gaining attention. Pepsin has been shown to alter levels of stress-induced proteins (Sep70 and Sep53), as well as depleting levels of E-cadherin and carbonic anhydrase isoenzyme III, (12,13) thus altering the epithelial response to injury.

No specific medical therapy has been directed at the components of DGER. At present, laparoscopic Nissen fundoplication may be the only therapy successful in protecting the upper aerodigestive tract from retrograde flow, (41,42) but a promising medical therapy in the form of liquid alginate may serve as the basis for more conservative management. Alginate is derived from the stem of the seaweed Laminaria hyperborean, harvested off the coast of northern Norway. When taken orally, it forms a strong, cohesive, voluminous, and buoyant gel raft over the gastric mucosa, thus preventing refluxate from leaving the stomach. (43,44) A mucosal protective approach such as this may treat all refluxates in a nonspecific fashion and have the advantage of lacking the toxicities of systemic therapies.

Conclusions

Pepsin and bile salts have been demonstrated to be associated with mucosal inflammation of the esophagus and extraesophageal structures. Clinical monitoring of DGER exposure to the structures proximal to the esophagus has not been performed. DGER may have a role in laryngopharyngeal inflammation and may be a possible source of failure in acid suppression therapy, but no specific medical management for DGER has yet been proven.

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Joel H. Blumin, MD; Albert L. Merati, MD; Robert J. Toohill, MD

From the Division of Laryngology and Professional Voice, Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee (Dr. Merati is now affiliated with the University of Washington, Seattle).

Corresponding author: Joel H. Blumin, MD, 9200 West Wisconsin Ave., Milwaukee W153226. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

Table. Major constituents of enteric secretions

Gastric secretions
   Hydrochloric acid
   Enzymes
      Lipolytic
         Lipase
      Proteolytic
         Pepsin (activated at acid pH)
   Intrinsic factor

Pancreatic secretions
   Sodium and calcium bicarbonate
   Enzymes
      Amylolytic
         Amylase
      Lipolytic
         Lipase
         Phospholipase A (activated by trypsin)
         Cholesterol esterase
         Colipase (activated by trypsin)
      Proteolytic
         Trypsin (activated by enteropeptidase)
         Chymotrypsin (activated by trypsin)
         Carboxypeptidases A and B (activated by trypsin)
         Aminopeptidases (activated by trypsin)
         Elastase (activated by trypsin)
      Ribonucleolytic
         Deoxyribonucleases
         Ribonuclease

Bile
   Bile acids
      Taurocholic acid (conjugated bile acids)
      Chenodeoxycholic acid (unconjugated bile acids)
   Conjugated bilirubin
   Lecithin and traces of other phospholipids
   Unesterified cholesterol
   Proteins and other metabolites