Introduction

In Japan, the number of patients with gastroesophageal reflux disease (GERD) has been rapidly increasing since 1990, and approximately 10% of patients who undergo endoscopic examinations have reflux esophagitis [1]. While GERD including reflux esophagitis is a benign disease, the problem is what the quality of life in patients with GERD is impaired. An increase in GERD patients not infected by Helicobacter pylori, a Westernized diet, and obesity has been suggested as factors that have increased the prevalence of reflux esophagitis. The severity of reflux esophagitis is mild, i.e., grade A or B by the LA classification, in approximately 90% of patients, and endoscopic healing of more than 90% is achieved with a standard dose of PPI [1]; however, an increase in severe reflux esophagitis not healed by standard-dose PPI therapy has recently been reported in Japan [2]. The cause of esophageal mucosa breaks in reflux esophagitis is excessive esophageal acid exposure, which significantly increases in severe reflex esophagitis [3]. This review summarizes excessive esophageal acid exposure as a cause of reflux esophagitis.

Esophageal motility after swallowing in healthy subjects

The lower esophageal sphincter (LES) relaxes after swallowing to clear solid and liquid contents from the esophagus and then contracts at an LES pressure of 15–20 mmHg to prevent reflux from the stomach into the esophagus [4]. LES relaxation starts after swallowing and primary peristalsis appears in the upper esophagus, and ends when primary peristalsis reaches the LES [4]. The duration of LES relaxation associated with swallowing is 5–8 s [5]. Since gastric pressure is approximately 5 mmHg higher and esophageal pressure is approximately 5 mmHg lower than atmospheric pressure during inspiration, a pressure gradient of approximately 10 mmHg exists between the stomach and esophagus [6]. Therefore, acid reflux may occur if LES pressure is very low. Besides swallowing, LES relaxation occurs via esophagus-distending stimuli (liquid or air reflux and food residue in the esophagus).

Mechanisms underlying excessive esophageal acid exposure in reflux esophagitis patients

Reflux esophagitis is caused by excessive esophageal acid exposure [3], and factors related to excessive esophageal acid exposure include acid reflux, the esophageal bolus clearance of acid, and esophageal hiatal hernia.

Acid reflux

The continuous measurement of LES pressure revealed that acid reflux occurs when LES pressure is markedly reduced. Conditions with markedly reduced LES pressure are caused by (a) relaxation of the LES (LES pressure is nearly zero) or (b) intrinsically very low LES pressure.

Acid reflux during LES relaxation

  1. (a.1)

    LES relaxation not associated with swallowing (transient LES relaxation)

    More than 95% of acid reflux occurring during LES relaxation is not accompanied by swallowing. LES relaxation unrelated to swallowing is called transient LES relaxation (TLESR) [7] (Fig. 1). TLESR is also the physiological mechanism responsible for belching and is not a pathological phenomenon. TLESR is commonly accompanied by air reflux, and sometimes by acid reflux. Between 80 and 100% of acid reflux episodes in healthy subjects and 56–73% in GERD patients are caused by TLESR, which is one of the main mechanisms responsible for acid reflux in healthy subjects and GERD patients [8,9,10,11,12,13]. Although the mechanisms underlying acid reflux in patients with endoscopically demonstrated non-erosive reflux disease (NERD) have not yet been elucidated in detail, we previously demonstrated that all acid reflux episodes were caused by TLESR in NERD patients [14]. TLESR is defined as (i) no swallowing during the 4 s before or 2 s after the beginning of LES relaxation, (ii) a residual pressure during LES relaxation of <2 mmHg, (iii) an LES relaxation rate of ≥1 mmHg/s, and (iv) an LES relaxation time of ≥10 s [7]. While the duration of LES relaxation associated with swallowing is 5–8 s, the average duration of TLESR is approximately 15–20 s, with a maximum of approximately 30 s [7]. Furthermore, while the crural diaphragm is not inhibited during LES relaxation with swallowing, it is suppressed during TLESR [15]. In addition, intense contractions of the LES and primary or secondary peristalsis are often observed at the end of TLESR.

    1. a.1.1

      Frequency of TLESR and proportion of acid reflux episodes during TLESR.

      Since the frequency of TLESR was reported to be significantly higher in GERD patients than in healthy subjects by Dodds et al. [9], GERD may be associated with a high frequency of TLESR. The study by Dodds et al. [9] was performed using subjects in the recumbent position; however, acid reflux often occurs postprandially in the vertical position. An evaluation of the frequency of TLESR in the vertical position revealed no significant differences between healthy subjects and reflux esophagitis patients [13, 16,17,18,19]. These findings indicate that the frequency of TRESR is unrelated to excessive esophageal acid exposure.

      Although TLESR is not necessarily accompanied by acid reflux, the proportion of acid reflux episodes during TLESR at 5 cm above the LES was found to be higher in reflux esophagitis patients than in healthy subjects [7, 9,10,11,12,13, 16, 17]. Based on these findings, excessive esophageal acid exposure is considered to be caused by a high proportion of acid reflux episodes during TLESR rather than a high frequency of TLESR. The higher proportion of acid reflux episodes during TLESR in reflux esophagitis patients may be explained by differences in the volume of acid reflux and the gastroesophageal pressure gradient; however, this needs to be clarified in more detail.

      As for differences between Japan and Western countries, the proportion of acid reflux episodes during TLESR was previously reported to be higher in reflux esophagitis patients than in healthy subjects in Japan and Western countries, but was lower in reflux esophagitis patients and healthy subjects in Japan than in Western countries [16]. These findings may explain the lower prevalence of severe reflux esophagitis in Japan than in Western countries.

    2. a.1.2

      Factors that affect the frequency of TLESR.

      Gastric distension by a balloon [20], gas [21], or food [22, 23] is a factor that increases the frequency of TLESR. An increase in intra-abdominal gastric pressure by obesity also increases the frequency of TLESR [24]. The site of the reception of these gastric distension stimuli is considered to be near the cardia [25]. Although many patients develop heartburn after the intake of a high-fat meal, there is currently no consensus on the relationship between a high-fat diet and gastric acid reflux [26,27,28,29]. Regarding the relationship between fat intake and TLESR, no significant differences were reported in the frequency of TLESR [28, 29], whereas acid reflux occurred more frequently during TLESR after the ingestion of a high-fat meal [28]. As for other food items, beer, coffee, chocolate, and onions have been reported to increase esophageal acid exposure; however, their relationships with the frequency of TLESR currently remain unclear. On the other hand, the recumbent position [22, 30], sleep [31, 32], and anesthesia [33] have been identified as factors that suppress the frequency of TLESR.

    3. a.1.3

      Neural reflex arcs of TLESR.

      Since the frequency of TLESR is reduced by suppressing excitation of the vagal reflex, TLESR is considered to be mediated by the vagus nerve [34]. Furthermore, splanchnic nerve section has no effect on the frequency of TLESR; therefore, the splanchnic nerve is not considered to be involved in TLESR [35]. The reflex arc of TLESR begins with the afferent fibers of the vagus nerve, which are distributed in the gastric muscle layer and sense gastric distension. This signal of gastric distension is sent to the solitary nucleus of the brainstem via the afferent fibers of the vagus nerve and transferred to the dorsal motor nucleus of the vagus nerve from the pattern generator, which controls the frequency of TLESR. This signal is considered to be sent to the intramural plexuses of the LES via the efferent fibers of the vagus nerve and induce TLESR (Fig. 2) [36,37,38,39,40,41,43]. As previously reported, neurotransmitters and their receptors are located in afferent fibers of the vagus nerve, arc nucleus, and dorsal motor nucleus of the vagus nerve. Acetylcholine, cholecystokinin (CCK), gamma amino butyric acid (GABA), glutamic acid, nitric oxide (NO), and opiates may be involved in transient LES relaxation in animals and humans [6]. Acetylcholine, NO, GABA-B, 5-hydroxytryptamine (5HT3), opiates, and CCK receptors are located in the vagus nerve nucleus within the brainstem and its surroundings, whereas CCK, 5HT3, and GABA-B receptors are in the afferent vagus nerve [40]. The crural diaphragm is inhibited during TLESR, presumably via the afferent vagus nerve, which mediates TLESR [44]. While afferent fibers are considered to suppress the nuclei of the respiratory centers, further studies are needed to obtain more detailed information.

      Fig. 1
      figure 1

      High-resolution manometric and esophageal pH recordings at 5 cm above the LES. There is no pharyngeal swallow signal from 4 s before to 2 s after the onset of LES relaxation; therefore, this is transient LES relaxation. During transient LES relaxation, regular increases are not observed in diaphragmatic hiatal pressure due to diaphragmatic contractions during inspiration, and acid reflux is detected approximately 10 s after the beginning of LES relaxation. LES lower esophageal sphincter, UES upper esophageal sphincter

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      Fig. 2
      figure 2

      Triggering and control of transient lower esophageal sphincter relaxation

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  2. a.2

    Acid reflux during LES relaxation associated with swallowing.

    Acid reflux during LES relaxation associated with swallowing accounts for less than 5% of acid reflux during LES relaxation and is a rare mechanism of acid reflux. Acid reflux occurring after swallowing is often observed when primary peristalsis is defective or incomplete [10, 45]. On the other hand, acid reflux is rarely observed when normal primary peristalsis occurs after swallowing. The rareness of acid reflux during LES relaxation after swallowing is ascribed to (i) the shorter duration of LES relaxation (5–8 s) than TLESR, (ii) the absence of crural diaphragm inhibition, unlike TLESR, and (iii) occlusion of the esophageal lumen due to the appearance of primary peristalsis after swallowing.

Acid reflux associated with low LES pressure

Acid reflux due to low LES pressure occurs when intrinsic LES pressure is extremely low. Free reflux and strain reflux are the mechanisms responsible for acid reflux in this state. Free reflux occurs when LES pressure is nearly zero (<2 mmHg). Strain reflux is induced by a rapid increase in abdominal pressure when LES pressure is low (commonly <5 mmHg). These mechanisms of acid reflux are observed in patients with low LES pressure and are mostly responsible for severe reflux esophagitis. Acid reflux due to low LES pressure is observed in 15–45% of patients with severe reflux esophagitis [16, 17, 46], but rarely in healthy subjects, NERD patients, and patients with mild reflux esophagitis [14, 46].

Esophageal bolus clearance of acid

The delayed esophageal bolus clearance of acid may cause excessive esophageal acid exposure. Esophageal peristalsis plays a key role in the clearance of refluxed acid from the esophagus. The esophageal bolus clearance of acid is a two-step process of bolus clearance and acid neutralization [47, 48]. If a 15-ml or smaller bolus of acid is instilled into the esophagus, most of the acid may be cleared from the esophagus by peristaltic contractions; the remainder of the acid lining the esophagus mucosa is neutralized by saliva traversing the esophagus during subsequent swallow-induced peristaltic contractions. Seven to ten swallows following esophageal acidification are needed to restore esophageal pH to normal—between 5 and 7. Hypotensive and failed peristalsis are ineffective at clearing acid from the esophagus [49, 50].

The factors that constitute peristaltic waves are the amplitude of esophageal contractions and frequency of normal peristalsis, and are significantly lower in patients with severe reflux esophagitis (grades C and D by the LA classification) than in healthy subjects and patients with mild reflux esophagitis, resulting in the delayed esophageal bolus clearance of acid [51, 52]. This delay in acid clearance is one of the causes of excessive esophageal acid exposure observed in patients with reflux esophagitis. While no significant difference has been reported in primary peristalsis between patients with mild reflux esophagitis and healthy subjects, an evaluation by the classification of mild reflux esophagitis into grades A and B revealed a significant decrease in the amplitude of primary peristalsis in the lower esophagus in patients with grade B than grade A reflux esophagitis [52]. However, a recent study showed that the propagation of contraction waves in the entire esophagus with a pressure of 20 mmHg or higher was necessary for esophageal clearance [53]; therefore, differences in the amplitude of contraction waves between grades A and B are not considered to be clinically significant.

Secondary peristalsis is also important for the esophageal bolus clearance of acid. Secondary peristalsis is characterized by peristaltic waves induced by the esophageal distention (liquid reflux and air reflux) and is important for refluxed liquid and food clearance in the esophagus not cleared by primary peristalsis. Since swallowing frequently occurs during the daytime, defective secondary peristalsis is not a major issue. However, salivary secretion is suppressed during the nighttime and primary peristalsis does not occur; therefore, secondary peristalsis is important for the esophageal bolus clearance of acid in nighttime reflux. The frequency of secondary peristalsis has been reported to be significantly lower in GERD and NERD patients than in healthy subjects [54, 55].

Esophageal hiatal hernia

Regarding the relationship between TLESR and esophageal hiatal hernia, the frequency of TLESR was previously reported to be significantly higher in the condition of the continuous infusion of a small amount of air into the stomachs of patients with than in those without hiatal hernias [56]. However, 24-h esophageal manometry and pH monitoring under physiological conditions revealed that the number of acid reflux episodes during TLESR did not significantly differ according to the presence or absence of a hiatal hernia, whereas acid reflux during LES relaxation after swallowing and that associated with low LES pressure were significantly greater in patients with than in those without hiatal hernias [57].

The layer of acid that appears postprandially above the dietary layer immediately below the esophagogastric junction (EGJ) has been identified as a source of postprandial acid reflux [58]. This layer of acid immediately below the EGJ is called the “acid pocket” [59]. The acid pocket migrates upward, reaches the esophageal side of the EGJ, and may cause mucosal damage to the lower esophagus [60,61,62]. This upward migration of the acid pocket, sometimes referred to as an “acid film”, is more likely to occur in GERD patients, particularly in the supine position [61]. The length of the acid pocket has been reported to be long in GERD patients [60], and its location is of particular importance [62]. When the acid pocket is located in the hernia sac (supradiaphragmatic location), the proportion of acid reflux episodes during TLESR (70–85%) is significantly higher than when it is located below the diaphragm (7–20%) [62].

In healthy subjects, acid reflux mostly occurs when the acid pocket is present in the hernia [63]. Although hiatal hernias are often absent in healthy subjects, a previous study that evaluated the postprandial location of the EGJ showed that it was elevated by 4.3 cm (median) during TLESR. Therefore, even in healthy subjects without hiatal hernias, temporary hiatal hernias occur during TLESR [64]. Regarding other mechanisms responsible for acid reflux besides TLESR (swallow-induced, strain, and free reflux), acid reflux increases when the acid pocket is present in the hernia sac [64]. Thus, the acid pocket is considered to be closely related to postprandial acid reflux, and evaluations to make the “acid pocket” a target for the treatment of GERD have begun.

Regarding the relationship between hiatal hernias and esophageal acid clearance, the esophageal bolus clearance of acid was found to be significantly delayed in patients with a hernia sac [65]. The acid pocket in the hernia sac is also considered to be involved in the delayed esophageal bolus clearance of acid. As shown in the Fig. 3, pressure is higher in the hernia sac than in the esophagus. If the acid pocket is present in the hernia sac, acid easily refluxes into the esophagus during LES relaxation after swallowing due to the pressure gradient between the hernia sac and esophagus. The repetition of this phenomenon with each swallow delays the esophageal bolus clearance of acid.

Fig. 3
figure 3

High-resolution manometric recordings after water swallowing (WS) in a patient with a hiatal hernia. The pressure in the hernia sac after swallowing is higher than esophageal pressure. If acid is present in the hernia sac, it easily refluxes into the esophagus during LES relaxation after swallowing due to the pressure gradient between the sac and esophagus. This is a factor involved in excessive esophageal acid exposure, which is a cause of reflux esophagitis

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Conclusions

TLESR is a major mechanism responsible for acid reflux, but is not necessarily accompanied by acid reflux. Acid reflux during TLESR and the delayed esophageal bolus clearance of acid are important causes of excessive esophageal acid exposure. The presence of an acid pocket in the hernia sac has been identified as a factor that contributes to acid reflux episodes during TLESR. In GERD patients, the acid pocket may migrate upwards and reach the esophageal side of the EGJ.