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Volume: Barrett's Esophagus
Chapter: Pathophysiology

How should low prevalence of Barrett's esophagus in patients with Zollinger-Ellison syndrome be interpreted?

E. Sekera, R.T. Jensen, M. Mignon (Geneva, Bethesda, Paris)

Barrett's epithelium development is the most prevalent complication of gastroesophageal reflux disease (GERD) with esophagitis.

The incidence of Barrett's epithelium has been reported to be as high as 1.7/100,000 inhabitants per year [1]. The prevalence of Barrett's epithelium is diversely estimated according to studies ranging between 5% to 22% of patients endoscoped for GERD [1-3].

Barrett's epithelium development is the most serious evolutive event of the natural history of GERD in relation to its malignant potential leading to esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma has considerably increased in the last decades (from 0.13 to 0.7 for 100,000 inhabitants in the Olmsted County in the USA [4]. This phenomenon is also observed in France [5]. Athough Barrett's epithelium is often observed in patients with no past-history of GERD, it is commonly admitted that Barrett's epithelium develops in patients with long-established and severe GERD [3, 6], representing thus the ultimate severity of the GERD clinical spectrum.

In patients with GERD and gastroesophageal junction incompetency, whatever the underlying mechanism is: hiatal hernia (HH), decreased resting lower esophageal sphincter (LES) pressure, intermittent inappropriate LES relaxations or a combination of these factors, it is admitted, indeed, that the greater the gastric acid secretion (GAS) is, the higher the risk of esophagitis [7-10], the longer the duration of esophageal exposure to acid, the larger the mucosal erosive lesions and complications [6, 10-15], the greater the risk of Barrett's epithelium development [3, 6]. Increased pepsin output has also been observed in patients with reflux esophagitis [16].

In contrast to patients with idiopathic GERD, patients with the Zollinger-Ellison (ZE) syndrome have a low prevalence of Barrett's epithelium (3% according to the study of 66 ZE syndrome patients by the NIH group at Bethesda) [17]. Such a prevalence is equivalent to that of the general population [11], lower than in with idiopathic GERD and markedly lower than in patients having GERD together with idiopathic gastric hypersecretion [18].

Patients with ZE syndrome, however, present with a high prevalence of GERD symptoms (up to 60%) [17, 19], high prevalence of esophagitis (up to 40%) [17] and above all high levels of gastric acid [20, 21] and pepsin outputs [20, 22].

How could, thus, be interpreted and explained such discordances between the high prevalence of major aggressive factors and the low prevalence of Barrett's epithelium in ZE syndrome patients? Suggested explanations are: a) clinical, endoscopic and laboratory differences between idiopathic GERD and ZE syndrome patients; b) increased protective mechanisms in ZE syndrome patients.

Clinically the shorter duration of dyspeptic symptoms and/or chronic diarrhea in ZE syndrome patients: 4 to 6,5 years ([23], unpublished personal data) as opposed to 2025 years according to epidemiological studies for patients with Barrett's epithelium complicating GERD [11], leads probably initially to a more rapid institution of adequate acid suppression therapy.

Endoscopically, esophageal erosive lesions, except for some rare cases of acute extensive erosive esophagitis [24], are mild: among 66 ZE syndrome patients there were 12% of grade I and 11% grade II erosive esophagitis according to the Savary-Miller classification [17].

Most ZE syndrome patients studied by Strader et al. [17] had no abnormalities of LES resting pressure and of esophageal motility and only 17% had HH, which is notably less than in patients with idiopathic GERD. The latter finding can be due to the average younger age of the ZE syndrome patients at time of diagnosis (below 50 years) [20, 21] as compared to the GERD patients (above 50-60 years), especially in case of esophagitis.

Although this has not been specifically investigated, the refluxate in ZE syndrome patients is essentially acidic in nature containing no or only a minute quantity of bile, which is confirmed by the aspect and the biochemical characteristics of gastric juice upon gastric aspiration [20, 21].

The increased fractional gastric emptying noticed in ZE syndrome patients, probably contributes also to the milder forms of erosive esophagitis seen in these patients [25]: together with the normality of LES and esophageal motility, this factor favours rapid esophageal clearance of the acidic refluxate.

It is probably also important to remind that ZE syndrome patients usually receive high doses of proton pump inhibitors (PPI's) inducing dramatic acid suppression particularly in those patients presenting with GERD symptoms. In the latter category of ZE syndrome patients, indeed, PPI's regimen must be titrated to leave only very small amount of residual gastric acid secretion (less than 1 mmol H+/h in the hour before next dosing) [26]. Such a therapeutic approach is seldom applied to idiopathic GERD therapy, except perhaps in case of refractory GERD.

Increased protective mechanisms of the esophageal mucosa may also contribute in ZE syndrome patients to the lesser severity of erosive esophagitis and to the low prevalence of Barrett's epithelium.

These protective mechanisms are of salivary and esophageal origin [27].

Saliva contains: water, bicarbonates, mucus and growth factors, notably epidermal growth factor (EGF). Normally salivary secretion increases during food mastication and in response to acidification of the esophagus [28, 29] presumably through vagal neural reflexes [30, 31].

Contrariwise the secretion of salivary protective factors in patients with GERD is impaired particularly of those operating within the pre-epithelial barrier [31].

In addition to alkaline secretion, esophagoprotection includes also organic components: mucus and growth factors. Surgical removal of salivary glands in rats resulted, indeed, in an increase in the rate of permeability of the esophageal mucosa to hydrogen ion accompanied by a marked decrease in the content of mucus within the pre-epithelial mucosal barrier [32].

In asymptomatic volunteers 2- to 4- fold increases in mucin, protein, EGF, prostaglandins (PGE2) and bicarbonates were respectively observed after masticatory stimulation [27]. This was also noted in patients with endoscopic reflux esophagitis even to a greater degree with an increasing trend in salivary viscosity [27].

In contrast to the stimulatory ability of mastication, esophageal mucosal exposition to a pH < 2 entailed a significant decline in the above mentioned protective components [27, 33].

Important defence mechanisms originate also from the extensive network of submucosal glands evidenced in the esophageal epithelium [34].

As saliva, esophageal secretion is made of bicarbonates [35], mucus and growth factors [36] and both are influenced by luminal acidification and pepsin aggression.

Data generated by studies in normal volunteers by Meyers and Orlando showed that the average amount of bicarbonate secreted by the human normal esophagus approximates that reported for basal salivary alkaline secretion [37]. Meyers and Orlando concluded that the human esophagus was secreting bicarbonates in quantities readily capable of acting as an effective mean of clearing acid from the esophageal human completing salivary neutralization [37].

Further experiments in human demonstrated a dramatic increase in esophageal alkali output after esophageal acidification: up to 3- and 32-fold the basal value when the esophagus was acidified with an HCl solution at pH 2 and 1, respectively [29].

Accordingly, the authors considered that esophageal alkaline secretion could be relevant in esophageal mucosal defence, especially during periods of long acid exposure or when salivary secretion is absent such as during sleep [29, 34].

In patients with grade II erosive GERD the basal rate of esophageal mucin was similar to corresponding values recording in controls [38]; this rate however was significantly lower during the mucosal exposure to HCl/pepsin solution which suggests decline of its content within the mucus layer. In patients with even more severe erosive esophagitis (grade III) the decline in esophageal mucin was present in both the basal state and after mucosal exposure to HCl/pepsin [38].

A cornerstone in esophageal defence mechanisms is the production of important growth factors: EGF and transforming growth factor alpha (TGFa) [39, 40].

The distribution and quantity of EGF and EGF receptors (EGF-R) in the esophageal mucosa of control subjects and patients with esophagitis were investigated by Jankowski et al. [41]. Significantly lower EGF levels were found in the inflamed mucosa as compared with the normal uninflamed one [42], together with an increased expression of EGF-R in the proliferative compartment of the esophageal epithelium [42]. More recently, diminished luminal release of EGF has also been demonstrated during esophageal perfusion with saline, HCl, and HCl/pepsin in patients with grade II and III GERD [43]. Collectively, these results strongly suggest, that depletion of EGF may facilitate the development of refluxinduced esophageal lesions and delay healing of already developed mucosal injury.

Moreover and particularly relevant in the context of this discussion, Gray et al. demonstrated a significant decline in salivary EGF concentration in patients with Barrett's epithelium accompanied by severe esophagitis with a long duration of symptoms [44].

In patients with ZE syndrome important data point to increased protective mechanisms of the esophageal mucosa itself. This might result from increased salivary and esophageal bicarbonate and mucins secretion in relation to iterative, but of short duration, esophageal reflux of acid and pepsin [28, 34].

The most fascinating anticipated mechanism, however, concerned growth factors, known as discussed above, as major factors contributing to the maintenance of the integrity of the upper alimentary tract mucosa after injury by acid and pepsin.

It was, indeed, most challenging to assess the role of growth factors in patients with ZE syndrome [45]. Eight patients with ZE syndrome and 17 endoscopically negative patients with non-ulcer dyspepsia were investigated for salivary and gastric EGF content.

All the ZE syndrome patients had a prior history of duodenal ulcer disease, however, each had normal esophageal and gastric mucosa during endoscopy at the time of the study. Saliva and gastric secretions were collected under basal condition and after pentagastrin stimulation while subjects were chewing parafilm.

In patients with ZE syndrome, the concentration of EGF in saliva both in the basal state and during pentagastrin stimulation of gastric secretion were higher (almost double) than innon-ulcer dyspepsia patients (Figure 1). Salivary EGF output both in basal condition and during pentagastrin stimulation were similar in ZE syndrome and non-ulcer dyspepsia patients. In addition basal EGF output in the gastric juice of patients with ZE syndrome was 3-fold higher than in patients with non-ulcer dyspepsia, while pentagastrin stimulated EGF output were identical in both group of patients [45].

If, as in a great majority of EGF-related phenomena, the end-effect evoked at the target tissue is directly related to its concentration at the receptor site [44], the results of Sarosiek et al. [45] are particularly relevant: both salivary and gastric EGF would be retained within the unstirred layer covering the surface of the esophageal epithelium, the former coming from the small portion of saliva not swept by the primary peristalsis from the esophageal lumen, the later reaching the esophageal surface with refluxing gastric juice. In both conditions the high concentration of EGF exerts its biological effects by binding to receptors localized on the luminal aspect of the squamous epithelium [42, 44].

At this level luminal EGF: reinforces mucosal tightness to damaging factors and in case of mucosal damage modulates cellular proliferative capacity leading to the expansion of the epithelial proliferative compartment and mucosal repair.

Figure 1. Salivary EGF concentration in ZE syndrome (ZES) patients versus non-ulcer dyspepsia (NUD) (from [45]).


Low prevalence of Barrett's esophagus in patients with ZE syndrome might be attributable to multiple factors: among them one of most important factors is likely the mucosal protection afforded by an increased content of both salivary and gastric EGF.

Further studies are however warranted in these patients to:
-explore also the pattern of esophageal EGF production,
-understand the underlying mechanism for EGF augmentation: neural reflex, hormonal control from gastrinoma secretory products, adaptative mechanism triggered by local or distant stimulus).

Study of ZE syndrome patients with erosive esophagitis will also be critical to define the kinetics of this presumed adaptative process and may provide important insights into why only some patients with severe idiopathic GERD develop Barrett's esophagitis.


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Publication date: August 2003 OESO©2015