Detection of Barrett's Esophagus by Transepithelial Leak of Sucrose

Abstract

An inexpensive test for Barrett's esophagus in the general population and among patients with gastroesophageal reflux disease is described. Patients swallow a concentrated solution of sucrose (100 gms in 200 cc of water) at bedtime, and collect any urine voided for 7 hrs. Urine sucrose is determined by HPLC. The amount of sucrose voided (urine volume x sucrose concentration) equals the amount of sucrose that leaked transepithelially out of the upper gastrointestinal (GI) tract. Unlike, glucose or fructose, the disaccharide sucrose cannot transit through cells, since it lacks a membrane transport protein. However any paracellular leak in the upper GI tract will allow sucrose to leave the luminal compartment and enter the vasculature. Once in the bloodstream, without a reabsorptive pathway in the kidney, all sucrose will enter the urine. This test has been well described for diagnosis of gastric ulcer disease (Meddings et al., 1993). A test that could cheaply identify: 1) GERD patients most in need of upper endoscopy to diagnose Barrett's, and 2) Barrett's patients who have undetected dysplasia and are in the need of the most frequent repeat endoscopic surveillance, would be clinically valuable. Our group has shown that precancerous epithelium in colon is characterized by transepithelial leaks in tight junctions (Soler et al., 1998) and that Barrett's metaplasia contains different tight junction proteins than in adjacent squamous esophageal mucosa (Rendon Huerta et al., 2003). Claudin-1 is lower in Barrett's epithelium. Claudin-2, nondetectable in normal esophagus, is apparent in Barrett's epithelium. Occludin is not different in the two epithelia on a per mg protein basis. We hypothesized that the esophageal mucosa of Barrett's patients would be leakier than that of healthy controls or GERD patients. Our results indicate that controls and GERD patients manifest the same degree of sucrose leak (66 mg in urine of controls [n = 15, + 39 std dev] vs 62 mg excreted by GERD patients [n = 9, + 39 std dev]). Barrett's patients exhibit greater sucrose leak (177 mg + 102 std. dev., n = 14) which is significantly different from both prior groups (P<0.0002, Wilcoxon). All enrolled patients were on PPI therapy prior to taking the sucrose. Neither the Barrett's nor the GERD patients had clinically detectable esophagitis. The mechanistic significance for promotion of tumorigenesis, of high permeability across the Barrett's epithelium, is discussed. An inexpensive test for Barrett's esophagus in the general population and among patients with gastroesophageal reflux disease is described. Patients swallow a concentrated solution of sucrose (100 gms in 200 cc of water) at bedtime, and collect any urine voided for 7 hrs. Urine sucrose is determined by HPLC. The amount of sucrose voided (urine volume x sucrose concentration) equals the amount of sucrose that leaked transepithelially out of the upper gastrointestinal (GI) tract. Unlike, glucose or fructose, the disaccharide sucrose cannot transit through cells, since it lacks a membrane transport protein. However any paracellular leak in the upper GI tract will allow sucrose to leave the luminal compartment and enter the vasculature. Once in the bloodstream, without a reabsorptive pathway in the kidney, all sucrose will enter the urine. This test has been well described for diagnosis of gastric ulcer disease (Meddings et al., 1993). A test that could cheaply identify: 1) GERD patients most in need of upper endoscopy to diagnose Barrett's, and 2) Barrett's patients who have undetected dysplasia and are in the need of the most frequent repeat endoscopic surveillance, would be clinically valuable. Our group has shown that precancerous epithelium in colon is characterized by transepithelial leaks in tight junctions (Soler et al., 1998) and that Barrett's metaplasia contains different tight junction proteins than in adjacent squamous esophageal mucosa (Rendon Huerta et al., 2003). Claudin-1 is lower in Barrett's epithelium. Claudin-2, nondetectable in normal esophagus, is apparent in Barrett's epithelium. Occludin is not different in the two epithelia on a per mg protein basis. We hypothesized that the esophageal mucosa of Barrett's patients would be leakier than that of healthy controls or GERD patients. Our results indicate that controls and GERD patients manifest the same degree of sucrose leak (66 mg in urine of controls [n = 15, + 39 std dev] vs 62 mg excreted by GERD patients [n = 9, + 39 std dev]). Barrett's patients exhibit greater sucrose leak (177 mg + 102 std. dev., n = 14) which is significantly different from both prior groups (P<0.0002, Wilcoxon). All enrolled patients were on PPI therapy prior to taking the sucrose. Neither the Barrett's nor the GERD patients had clinically detectable esophagitis. The mechanistic significance for promotion of tumorigenesis, of high permeability across the Barrett's epithelium, is discussed.