Pathophysiology of Gastroesophageal Reﬂux Disease: Offensive Factors and Tissue Resistance (2000)

Gastroesophageal (acid) reﬂux is an almost universal and daily occurrence, even in asymptomatic healthy subjects. Nevertheless, only a small percentage of the population at risk-which is everyone-develops gastroesophageal reﬂux disease (GERD), the latter heralded by symptoms, such as heartburn, or (microscopic and/or macroscopic) signs of damage to the esophageal mucosa (1). This attests to the effectiveness of the three-tiered esophageal defense against injury to the esophageal mucosa from the noxious factors within gastric juice (Fig. 1). The ﬁrst, and most well-studied, tier of the defense is the antireﬂux barrier. Comprised primarily of the lower esophageal sphincter and diaphragmatic support, the antireﬂux barriers are designed to limit the frequency and volume of contact between reﬂuxate and esophageal epithelium. When these barriers fail, the second tier of defense, known as the esophageal luminal clearance mechanisms come into play to limit the duration of contact between reﬂuxate and esophageal epithelium. These consist of esophageal peristalsis and gravity, for volume clearance, and swallowed salivary secretions and secretions from esophageal submucosal glands, for acid clearance and restoration of a neutral pH. However, esophageal clearance, even under optimum circumstances, is not instantaneous, usually requiring 3-5 min to restore pH to neutrality after a single episode of reﬂux (2). Moreover clearance of the reﬂuxate is often considerably slower at night since all166 OrlandoFigure 1 The esophagus protects itself from reﬂux-induced mucosal injury through a three-tiered system: antireﬂux barriers, luminal clearance mechanisms, and epithelial resistance. (Reprinted with permission from Orlando RC. Reﬂux esophagitis. In: Yamada T, Alpers DH, Laine L, Owyang G, Powell DW, eds. Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins, 1999:1235-1263.)investigated components (submucosal glands are yet to be studied) are inoperable during rapid-eye-movement sleep (3-5). On average, the daily dwell time for acid within the lumen of the esophagus is on the order of 2 h or more. For this reason, a third tier of defense is needed to maintain the health and integrity of the esophageal epithelium; this is known as ‘‘tissue resistance.’’ Tissue resistance includes those factors associated with the mucosa that are designed to limit damage during contact of reﬂuxate with esophageal epithelium (6). Ultimately, the interplay between the noxious luminal factors and epithelium are the ﬁnal arbitersPathophysiology of GERD 167of disease-disease heralded clinically by heartburn and morphological changes within the epithelium. This chapter reviews the mechanisms comprising tissue resistance and their respective roles in preventing injury during contact with noxious elements in the reﬂuxate. It also describes the pathophysiological sequence by which acid and acid-pepsin overcomes tissue resistance to lead to esophagitis and, based on this knowledge, provides an alternative hypothesis to lower esophageal sphincter (LES) dysfunction to account for the development of GERD in patients with normal acid contact time on 24-h pH monitoring.