How can the frequent absence of symptoms in severe reflux esophagitis be explained?
F. Mearin, J.R. Malagelada (Barcelona)
The role of esophageal acid exposure, mucosal resistance
and visceral sensitivity in the development of esophagitis and symptoms
The manifestations of gastroesophageal reflux disease (GERD) include both a wide range of symptom severity and variable degrees of esophageal inflammation. Clinical and research experience show that although endoscopic grade and symptom severity tend to increase in proportion to each other, there is no strict parallelism. In fact, about half of the patients with heartburn may have a normal appearing esophagus on endoscopy  and, conversely, patients with severe esophagitis may be asymptomatic [2, 3]. These discrepancies highlight the individual importance of esophageal acid exposure, mucosal resistance and visceral sensitivity in the developement of esophagitis and symptomatic GERD (Table I).
GERD symptoms in patients with severe reflux esophagitis
From a clinical point of view, symptom severity is a poor predictor of the presence or grade of esophagitis. This seems to be especially true for complicated GERD. When healthy subjects have been investigated only minor forms of esophagitis have been detected, but occasionally cases of erosive esophagitis have been reported . At the same time, it is well known that patients with Barrett's esophagus (BE) or peptic strictures, who represent severe and chronic forms of GERD, may lack of a history of reflux symptoms. Clinical studies have shown that up to 25% of patients with BE are symptom-free  and that only one-third of patients with esophageal strictures have a history of GERD . Moreover, when ClH is perfused into the esophagus about one third of patients with Barrett's esophagus are acid insensitive . Twenty four hour pHmetry studies have also shown that esophageal acid sensitivity is decreased in patients with BE despite more prolonged acid exposure. Hence, although esophageal acid exposure in BE is higher than in GERD patients with normal endoscopy or with erosive esophagitis and no Barrett, the frequency of symptoms, as well as the proportion of reflux episodes causing symptoms is much smaller .
Esophageal perception in severe reflux esophagitis
(including Barrett's esophagus)
Some spatiotemporal characteristics of reflux such as extension into the proximal esophagus, duration and acidity, seem to influence symptom occurrence mainly when esophagitis is present .
All these factors are increased in patients with BE. Therefore, lack of symptomatic manifestations is probably related to decreased esophageal perception. This could be due to a selective decrease in sensitivity to acid stimulation, to a more generalized esophageal hypoalgesia or to a generalized increase in the perception threshold (both visceral and somatic). According to the first hypothesis, mucosal damage and/or modifications of permeability to hydrogen ions might be responsible for decrease in sensitivity. Esophageal transmucosal potential difference (PD) reflects in part the functional properties of the mucosa with respect to H+ permeability. If the low PD found in some patients with esophagitis is related to an increased H+ permeability and, therefore, to enhanced sensitivity  it could be speculated that the increased PD found in BE may be associated with lower H+ permeability and decreased acid perception . This latter finding may be in accordance with the presence (as in early esophagitis) or absence (as in Barrett's) of dilated intercellular spaces observed by transmission electron microscopy. Dilated intercellular spaces are an early marker of acid reflux damage, and appear to be related to the development of symptoms since dilated spaces are detectable in patients with heartburn without endoscopic evidence of esophagitis .
Against the hypothesis of a selective acid hyposensitivity are data obtained from laboratory studies showing that patients with BE, when compared with healthy controls and GERD patients without Barrett, have an increased threshold for perception. This is true not only in relation to acid contact but also to esophageal distension . Another interesting finding of this study was that, in most cases, esophageal hypoalgesia was detected above the level of columnar mucosa . Somatic sensitivity, at least when investigated by electrocutaneous stimulation, is normal in patients with BE .
In summary, patients with severe reflux esophagitis, mainly those with BE or peptic strictures, may not have GERD symptoms. A decreased sensitivity to both chemical and mechanical stimulation seems to be involved in the symptoms absence, and may become clinically relevant.
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