The absence of changes in the distal esophagus on conventional endoscopy does not rule out the diagnosis of GERD. It is estimated that upto 70% of patients with typical symptoms of GERD have normal esophageal mucosa on upper endoscopy (NERD) , , . At least, two different approaches have been attempted in these patients: biopsies of the normal appearing squamous mucosa and evaluation of the distal esophagus with newer techniques such as high resolution and magnification endoscopy.
Histologically, acute reflux damage consists of superficial epithelial swelling and/or necrosis accompanied by intraepithelial neutrophilic infiltrates. Chronic reflux induces eosinophilic infiltrates, basal cell hyperplasia, epithelial thickening, and elongation of the vascular papillae (Ismail-Beigi Criteria) , . Basal hyperplasia in excess of 15% and papillary elongation in excess of 2/3 of the epithelial thickness have been proposed as criterion to diagnose reflux esophagitis (Fig. 2). The number of eosinophils in reflux esophagi-tis is usually 1-20/high power field. More than 20 eosinophils/HPF should alert the clinician to the possibility of an alternative diagnosis such as eosinophilic esophagitis . However, the lack of eosinophils does not rule out reflux esophagitis .
Although, initial reports in 1970s suggested that histologic features of basal cell hyperplasia and location of the papillae close to the epithelial surface correlated well with the presence of GERD , , other studies directly comparing esophageal 24-hr pH results to histology have attested to the lack of discriminatory value of these histological criteria. In a report of 100 patients, (69 with positive pH studies), Johnson et al  found a significant correlation between esophageal acid exposure and the length of both the papillary and basal cell zones, although the correlation coefficients were low (none exceeding 0.33). In
another study, Schindlbeck and colleagues found only minor differences in the prevalence of histological features between 13 NERD patients, 11 patient controls, and 7 healthy controls .
In a recent study, the correlation between the histological criteria and 24 hour pH testing was predominantly negative, with the exception of neutrophil inflammation . However, another recent study, which analyzed data from a large prospective GERD trial (the ProGERD study; n = 1475), found that elongation of papillae and basal cell hyperplasia were seen in 40.7% and 12.7% of NERD patients and 46.1% and 15.7% of patients with erosive esophagitis, respectively, at 2 cm above the z-line. The presence of intraepithelial inflammatory cells showed a high specificity but very low sensitivity . However, the lack of a clearly defined control group makes it hard to make conclusive recommendations as some of these histological findings may be observed in biopsies from asymptomatic individuals.
Some other groups have evaluated the presence of dilated intercellular spaces (DIS) as a marker for GERD. Calabrese et al used transmission electron microscopy to study DIS in patients with GERD and duodenal gastro-esophageal reflux disease (DGER). Patients with GERD and DGER had intercellular spaces dilated to at least two times greater than controls and there was no significant difference in DIS between patients with erosive esophagitis and NERD .
At this time, unless histological criteria are updated or better correlated to either symptoms, 24 h pH results or response to acid suppressive therapy, biopsies of the distal normal appearing distal esopha-geal mucosa cannot be routinely recommended for the diagnosis of GERD.
High resolution and magnification endoscopy has recently been used to develop endoscopic criteria for non-erosive esophageal injury from gastroesopha-geal reflux . Lugol's Iodine was used in 13 patients with heartburn and pathologic 24-hour esophageal acid exposure but with no erosions on standard endoscopy and in 10 asymptomatic volunteers with normal esophageal acid exposure. A few subtle endoscopic findings, such as pin-point vessels and triangular indentation of the squamocolumnar junction upward into the squamous mucosa, were found in NERD patients using high-resolution magnification chromoendoscopy with Lugol's staining . These preliminary findings demonstrate that NERD patients may show minimal mucosal changes on high-resolution endoscopy.
A recent elegant study correlated histologic and endoscopic findings in patients with NERD with the help of magnification endoscopy before and after PPI treatment . Patients with NERD, more often than controls, showed endoscopic changes of minimal change esophagitis with punctate erythema as the most important finding, which resolved after PPI therapy. A sensitivity of 64%, specificity of 85% and a positive predictive value of 80% were determined for these findings on magnifying endoscopy. In the same study, an increased length of papillae (14/39 with NERD vs. 2/39 in controls; p < 0.005) and basal cell hyperplasia (17/39 vs. 4/39; p < 0.009) were seen in the NERD group which resolved in the majority of patients after PPI therapy. These new techniques appear very promising for the future but are not yet ready for routine clinical practice.
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Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.