How high are serum gastrin levels in case of esophageal alkaline reflux exposure?
T.N. Walsh (Dublin)
Only one study to date has addressed the question of serum gastrin levels in alkaline esophageal reflux. DeMeester's group measured fasting serum gastrin levels in 22
Barrett's patients and compared 11 patients who had increased esophageal alkaline exposure with 11 who had normal alkaline exposure [1]. The mean (SEM) gastrin level in the former group were 59 pg/ml compared with 35 (7.5) pg/ml in patients with normal alkaline exposure (p < 0.05). No comparable data were available from patients with reflux but without Barrett's esophagus, or from normal controls. Gastric hypersecretion was also identified in 10 of 23 Barrett's patients tested. It is not clear whether these had normal or elevated levels of gastrin or how many were represented in the alkaline reflux group.
There is no evidence that alkaline or acid reflux into the esophagus influences gastrin secretion. Gastrin, produced by the G cells of the lateral walls of the antral portion of the gastric mucosa, is secreted in response to stimuli from receptors in the microvilli which mediate the gastrin response to changes in the gastric lumen. Its release is also stimulated by increased vagal discharge and blood-borne factors such as calcium and epinephrine. It is inhibited by luminal acid, and by secretin, GIF, VIP, glucagon and calcitonin.
The effect of alkaline duodenogastric reflux on gastrin secretion was the subject of considerable debate as some workers could detect no increase in serum gastrin in response to an acute change in gastric antral alkalinisation [2-4]. Peters et al. [5] found, however, that when the antrum was exposed to alkaline perfusate for up to 5 h, serum gastrin levels rose significantly from 25 to 37 pg/ml (p < 0.05). In the clinical context of chronic duodenogastric alkaline reflux the findings have been less clear. Wilson et al [6] could find no difference between basal gastrin levels in bile reflux patients (18.8 pmol/1), bile diverted patients (20.6 pmol/1) and normal controls (16.0 pmol/1) while Niemela [7] has shown a positive correlation between the degree of duodenogastric reflux as measured by isotope studies and serum gastrin levels. In animal studies an amplified serum gastrin response to food was identified in animals with bile reflux, even where basal fasting levels were normal [8,9].
In our unit, the effect of cholecystectomy on alkaline duodenogastric reflux, serum gastrin levels and gastroesophageal reflux (GER) was examined in a series of studies. Nine patients were studied before and 3 months after cholecystectomy by dual channel gastric and esophageal pH monitoring, esophageal manometry and fasting blood sampling for gastrin, substance P and neurotensin [10]. Mean ± SEM gastrin levels increased significantly following cholecystectomy from 8.9 ± 1.8 ng/1 to 17.9 ± 3.4 ng/1 while substance P and neurotensin levels were unchanged. This was paralleled by a significant increase in gastric alkalinisation detected by the gastric pH probe and by an insignificant drop in the LES pressure from 15.4 ± 0.7 mmHg to 14.3 ± 0.9 mmHg. Further studies established that following cholecystectomy, alkaline duodenogastric reflux was associated with a significant increase in mixed GER [11]. While there was no change in the basal lower esophageal sphincter pressure, there was a significant reduction in the sphincter function index. This does not imply that the reduction was mediated through gastrin. McCallum demonstrated a rise in basal LES pressures in response to 0.4 M NaHCO3 bolus ingestion which was not associated with alteration in serum gastrin levels [12].
The definition of esophageal alkaline reflux as pH > 7.0 reflects the lack of sophistication of the facilities hitherto available for monitoring duodenal contents,
necessitating reliance on the pH of the refluxate to determine its presence. It does not reflect any belief in alkalinity per se as the source of esophageal pathology. While the term seems to imply that acid and alkaline reflux are mutually exclusive or that mixed alkaline and acid reflux is not as harmful as acid or alkaline reflux alone, there is obviously a continuum from pure acid reflux, to mixed reflux which is clinically significant, to alkaline reflux.
Serum gastrin levels in GERD are of interest because of the role of gastrin LES pressure modulation, in gastric acid secretion, and in the gastrin response to acid reduction. McCallum et al. found no difference between patients with GER and normal subjects with respect to serum gastrin levels, endogenous gastrin response, or antral gastrin concentration and concluded that gastrin played no role in the development of LES incompetence, or the pathophysiology of GER [13]. No correlation was observed between LES pressure and gastrin levels in patients with Zollinger-Ellison syndrome [14], or in patients with pernicious anaemia [15]. Despite elevated gastrin levels in Barrett's patients with alkaline GER LES pressures are invariably lower than normal [1]. These findings are in keeping with the observations that the dose of gastrin required to elevate LES pressure to the equivalent of that seen after a meal, would require serum gastrin levels 10 times greater than physiological values [16]. It is likely that while gastrin has a potential role in pharmacological doses, the complex interplay of other hormonal, neural and myogenic effects reduces this effect to insignificance.
In patients with GER, acid blockade with omeprazole therapy results in a significant elevation of serum gastrin levels from 8.6 to 16.9 ptnol/l (p < 0.05) [17]. In another study cessation of long-term omeprazole therapy resulted in a rapid reduction in gastrin levels from 160 to 42 ng/1 within 10 days and a parallel increase in gastric acid production with a rapid recurrence of esophagitis [18]. Robertson et al. described a predictive role for gastrin as patients who responded to ranitidine 300 mg had a mean (range) serum gastrin level of 4.52 (2.4-10) pmol/1, while patients with a level of 11.1 (3.5-21) pmol/1 did not [19].
The introduction of monitoring equipment such as the Bilitec 2000 (Synectics Medical AB, Sweden) which can detect bile in the esophagus [20], the development of probes that can detect other duodenal constituents, and the availability of ambulatory manometry should shed further light on esophageal alkaline reflux and the effects of gastrin in a more physiological context.
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