Physiology of gastric acid secretion

INTRODUCTION — The regulation of acid and pepsin secretion reflects an intricate balance of chemotransmitters delivered to the gastric mucosa by several pathways that mediate both stimulatory and inhibitory mechanisms [1]. Similarly, several mechanisms contribute to the remarkable ability of normal gastroduodenal mucosa to defend itself against injury from the acid/peptic activity in gastric juice and to rapidly repair injury when it does occur. Secretory, defense, and healing mechanisms are regulated by the same type of overlapping neural, endocrine, paracrine, and autocrine control pathways [2].

This topic will review the mechanism and regulation of gastric acid secretion. The physiology of gastrin, somatostatin, and gastric acid hypersecretory states are discussed in detail separately. (See "Physiology of gastrin" and "Physiology of somatostatin and its analogues" and "Pancreatic polypeptide, peptide YY, and neuropeptide Y" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

FUNCTIONAL ANATOMY OF THE STOMACH — The stomach consists of three anatomical (fundus, corpus, and antrum) and two functional areas (oxyntic and pyloric). The oxyntic area comprises approximately 80 percent of the stomach and contains parietal cells that produce gastric acid. Also present in the oxyntic area glands are neuroendocrine cells producing paracrine and hormonal agents that modify parietal cell activity. Oxyntic glands contain ghrelin-containing cells, histamine-containing enterochromaffin-like cells, and somatostatin-secreting D cells. The antrum of the stomach contains pyloric glands, and their main feature is the presence of gastrin-secreting G cells. Somatostatin-secreting D cells are present in the pyloric and oxyntic glands and modulate gastrin release and gastric acid secretion [1]. The cardia region of the stomach is adjacent to the gastro-esophageal junction. Cardia glands are characterized by an absence of parietal cells and chief cells and resemble antral glands.

ROLE OF GASTRIC ACID AND PHASES OF SECRETION — Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, vitamin B12, and is necessary for the absorption of some drugs such as ketoconazole, itraconazole, and thyroid hormone [3]. Gastric acid, by lowering pH, kills ingested microorganisms and limits bacterial growth in the stomach and prevents intestinal infections such as Clostridioides difficile. In addition, gastric acid may have a role in preventing spontaneous bacterial peritonitis [4-6].

The physiologic stimulation of acid secretion has classically been divided into three interrelated phases: cephalic, gastric, and intestinal [2].

Cephalic phase — The cephalic phase is activated by the thought, taste, smell, and sight of food, and swallowing. It is mediated mostly by cholinergic/vagal mechanisms.

Gastric phase — The gastric phase is due to the chemical effects of food and distension of the stomach. Gastrin appears to be the major mediator since the response to food is largely inhibited by blocking gastrin action at its receptors.

Intestinal phase — The intestinal phase accounts for only a small proportion of the acid secretory response to a meal; its mediators remain controversial.

The observation that H2 receptor antagonists block the cephalic and gastric phases underscores the importance of histamine mediation of the stimulatory response, and illustrates the interdependence of the different phases.

REGULATION OF GASTRIC ACID AND PEPSIN — Gastric acid secretion from parietal cells is regulated by redundant, overlapping pathways, which include endocrine (gastrin), paracrine (locally delivered histamine and somatostatin), neural (acetylcholine), and probably autocrine (transforming growth factor-alpha) factors (figure 1) [2,7]. (See 'Somatostatin' below and "Physiology of gastrin".)

Luminal contents have an effect on acid secretion. Proteins stimulate acid secretion, while dietary lipids inhibit acid secretion [8]. The exact mechanisms remain unclear but afferent nerves and enteroendocrine cells that recognize food ingredients may play a role [2].

Gastric acid

Role of the parietal cell — In the resting state, parietal cells are filled with secretory vesicles that coalesce with stimulation to form channels (canaliculi) that drain to the apical lumen [9]. The secretory membrane lining these structures contains the hydrogen-potassium-ATPase acid-secreting pump. This pump is always active, but exists in a short-circuited state in resting vesicles because the pathway necessary for transporting potassium to the apical surface for exchange with hydrogen is not present or active.

With stimulation, this pathway for potassium-chloride cotransport becomes active, allowing hydrogen-potassium exchange to occur [10-13]. Parietal cell activation involves an increase in cytoplasmic calcium or generation of cyclic AMP (cAMP), followed by activation of a cAMP-dependent protein kinase cascade that triggers translocation of proton-pump-containing membranes to the apical surface [2].

The cessation of acid secretion is associated with the re-internalization of the hydrogen-potassium-ATPase pump. This process is mediated by the cytoplasmic tail of the beta subunit of the pump. Transgenic mice with a mutation at this site constitutively secrete acid and continuously express hydrogen-potassium-ATPase at the cell surface [9,14].

Stimulatory factors — The main stimulants of acid secretion are histamine released from the enterochromaffin cells (paracrine secretion), gastrin released from G cells (hormonal secretion), and acetylcholine released from postganglionic enteric neurons (figure 1).  

Mechanical stimuli (distension) and chemical stimuli (food and particularly amino acids) activate afferent vagal neurons expressing glucagon-like peptide 1 (GLP-1) receptor, and these afferent neurons can modulate acid secretion through the dorsal motor nucleus where efferent vagal nerves emanate (figure 1).

Gastrin — Gastrin is the major endocrine regulator of the secretory response to a protein meal. It is released from gastrin-expressing cells (G cells) localized to the antrum. Gastrin enhances gastric acid secretion from parietal cells primarily by stimulating the synthesis and release of histamine from oxyntic mucosal enterochromaffin-like (ECL) cells [15-18]. However, gastrin also has direct actions on parietal cells [19,20].

Gastrin is the best identified trophic regulator of parietal cell mass in humans. This relationship is evidenced by the presence of gastric hypertrophy in gastrinoma patients who have chronic exposure to elevated circulating gastrin levels (picture 1), and atrophy of the parietal cell mass with antrectomy, which decreases circulating gastrin levels.

●Gastrin receptors – Cholecystokinin (CCK) and gastrin have an identical pentapeptide terminal sequence. Gastrin acts via activation of the CCK2 receptor (formerly known as the CCK-B or gastrin receptor), which has equal affinity for CCK and gastrin [21]. These receptors have been localized to parietal and ECL cells, but it is likely that the ECL cell gastrin receptor is of greater importance in regulating acid secretion [18-20].

Gastrin "receptors" have also been found on somatostatin-secreting D cells. However, this receptor is a CCK1 receptor that has much greater affinity for CCK than for gastrin [22]. This difference in receptor affinity may explain why gastrin is so much more effective as a stimulant of acid secretion, while CCK induces greater release of the inhibitor somatostatin [23]. Knockout mice that have been genetically engineered to be deficient in CCK2 receptors have low acid secretion, while double knockout mice (deficient in both gastrin and CCK receptors) have robust acid secretion in response to vagal stimulation or exogenous histamine [24]. These findings are consistent with the conclusion that CCK1 receptors exert inhibitory effects on acid secretion in vivo, mediated by release of endogenous somatostatin. (See "Physiology of gastrin".)

The localization of the receptors responsible for trophic actions of gastrin remains uncertain; the primary receptor appears to be on the ECL cell, although receptors may also be present on gastric stem cells.

●Gastrin release – Complex mechanisms control gastrin release from the antral G cells. Two meal-related factors stimulate gastrin secretion: gastric distention and amino acids.

•The effect of gastric distention varies with the degree of distension [25]. Low-grade distention activates vasoactive intestinal peptide neurons, which stimulates somatostatin release and therefore inhibits gastrin secretion. Higher-grade distention causes cholinergic activation, which reverses the pattern to one of increased gastrin and reduced somatostatin secretion.

•Amino acids induce gastrin release; direct actions on the G cell have been demonstrated but amino acids also activate both cholinergic neurons and bombesin neurons [26]. The release of bombesin (also called gastrin-releasing peptide) from mucosal nerves directly stimulates the G cell [27-29].

•Cholinergic activation after gastric distention or in response to a meal promotes acid secretion by shifting the balance of stimulatory and inhibitory mechanisms toward the stimulatory side, directly activating the parietal cell and stimulating gastrin release while suppressing somatostatin release [1,25,26].

Histamine — Histamine is the major paracrine stimulator of acid secretion. It is localized both in mucosal mast cells and in endocrine cells, the latter called ECL cells because of the silver-staining properties of their granules. The ECL cells are localized to the acid-secreting oxyntic or body mucosa, in direct proximity to the parietal cell.

Gastrin is the primary stimulus to histamine release from ECL cells [15,18,30]. ECL cells are also directly stimulated by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) [31,32]. Somatostatin is a major direct inhibitor of histamine release; calcitonin gene-related peptide (CGRP), peptide YY, prostaglandins, and galanin also inhibit release [1]. Stimulated ECL cells promptly degranulate, with release of histamine and pancreastatin from the vesicles; this is followed by an increase in histamine synthesis [17]. Although gastric mast cells outnumber ECL cells, gastrin has only been demonstrated to release histamine from ECL cells [33].

Several lines of evidence indicate that ECL cell histamine is the major physiologic mediator of acid secretion [18,31,34,35]. Inhibitors of the histamine-forming enzyme histidine decarboxylase (HDC) block the acid secretory response to gastrin, but not to histamine [31]. Furthermore, both H2 receptor deficient mice and HDC-knockout mice have near normal basal acid secretion, a preserved acid secretory response to cholinergic agents, an absent acid secretory response to exogenous gastrin, and hypergastrinemia [31,36]. Mast cells may deliver histamine to parietal cells following exposure to certain antigens (or in patients with systemic mastocytosis), but there is no evidence that they have a role in the normal physiology of acid secretion.

The effects of histamine are largely mediated by the H2 receptors, which explain the efficacy of H2 receptor blockers in the treatment of acid-peptic disease [37]. (See "Peptic ulcer disease: Treatment and secondary prevention" and "Medical management of gastroesophageal reflux disease in adults".) These drugs inhibit acid secretion in response to gastrin, food, and neural stimulation, clearly establishing that histamine plays a role as a universal mediator or modulator of the acid secretory response. Histamine may also act at H3 receptors to increase acid secretion via inhibition of somatostatin release [38].

Vagus nerve/acetylcholine — Neural input is an important integrator of secretory function. Electrical stimulation of the vagus nerve increases acid secretion, pretreatment with atropine decreases acid secretion by 70 percent, and adding an acetylcholine receptor antagonist abolishes acid secretion in rats, suggesting a major role for the muscarinic pathway in acid secretion. Vagotomy decreases basal acid secretion and secretion induced by gastric distention after meals and was the primary mode of treatment for ulcer disease before the advent of antisecretory therapy.

Acetylcholine is the major stimulatory mediator [2]. The major effects of muscarinic receptor activation are to increase gastrin release [15], stimulate parietal cells [2], and inhibit somatostatin secretion [26]. Bombesin, a peptide originally identified in frog skin, also stimulates acid secretion [26], an effect that is mediated at least in part by enhanced gastrin release [27-29]. Bombesin has been shown to closely resemble the structure of a mammalian peptide, a 27-amino acid peptide called gastrin-releasing peptide [39].

Muscarinic receptors on the parietal cells are of the M3 type and these receptors can be stimulated by fermented alcoholic beverages, resulting in increased acid secretion [40]. Vasoactive intestinal peptide release has a dual effect: a weak transient increase in acid secretion, possibly due to direct effects on ECL cells; and a sustained reduction due to enhanced release of somatostatin [41,42].

Other

●Ghrelin – Ghrelin is a 28-amino acid peptide present mainly in the oxyntic mucosa of the stomach. Ghrelin increases food intake and has been reported to stimulate acid secretion via release of histamine from ECL cells [43]. Ghrelin-producing X cells have no direct contact with the gastric lumen, and studies in rats suggest that the effect of ghrelin may be mediated through the vagus nerve. Co-administration of gastrin with ghrelin increases acid production in rats [43].

●Apelin – Apelin is a peptide that in humans is encoded by the APLN gene. Apelin is one of two endogenous ligands for the G-protein-coupled APJ receptor that is expressed at the surface of parietal cells and oxyntic cells. Functional data and immunohistochemical localization suggest that apelin released from parietal cells binds to the APJ receptor expressed in enterochromaffin cells, thereby inhibiting histamine release. This novel negative-feedback regulation might provide a local control of acid secretion in the gastric mucosa. An infusion of apelin increases acid secretion in animal models [44].

Inhibitory mediators — The principal inhibitor of acid secretion is somatostatin, which is released from oxyntic glands and antral D cells (paracrine). Carbohydrates and fat inhibit acid secretion when infused into the duodenum. CCK release in response to duodenal fat inhibits acid secretion [45]. It also releases other potential mediators, and it activates neural responses.

Somatostatin — Somatostatin is a potent inhibitor of acid secretion [41]. It is released from D cells, which are present throughout the gastric mucosa. Although somatostatin has some effects on parietal cells, its major effects are exerted on the inhibition of histamine release and to a lesser extent on gastrin release [2]. The secretion of somatostatin is increased by gastric acid and by gastrin itself, suggesting that a major function of somatostatin is to modulate the feedback inhibition of the acid secretory response to gastrin [46]. Consistent with this hypothesis is the observation that mice lacking the somatostatin receptor have a tenfold increase in basal acid output [47]. This effect can be abolished by gastrin antibody, suggesting that somatostatin suppresses gastric acid secretion via inhibition of the action of gastrin. There may be some effect on gastrin release [28], but it is likely that somatostatin primarily acts by suppressing gastrin-stimulated release of histamine from ECL cells [30]. Somatostatin secretion is also affected by neural inputs. It is suppressed by cholinergic activation and increased by vasoactive intestinal peptide activation [25,26].

Glucagon-like peptide 1 and peptide YY — Intravenous injection of GLP-1 and peptide YY inhibits stimulated gastric acid secretion in humans. Lipid and carbohydrates in the ileum result in release of these peptides corresponding to a time when acid secretion decreases [48,49].

Gaseous inhibitors — Nitric oxide and hydrogen sulfide are gaseous mediators that are known to inhibit gastric acid secretion and enhance mucosal restitution [50].

Neurotensin, xenin, and corticosterone-releasing factor — Neurotensin and its related peptide, xenin, are neuropeptides produced in the brain and small intestine that have an inhibitory effect on acid secretion. Corticosterone-releasing factor is a neuropeptide in the hypothalamus that decreases vagally mediated acid secretion by central mechanisms [2].

Prostaglandins — Prostaglandins are metabolites of arachidonic acid created by the action of cyclooxygenase 1 and 2 (COX-1 and COX-2) in many types of cells in the gastric mucosa. Prostaglandins are autocrine factors that inhibit acid secretion, histamine-stimulated parietal cell function [2], and gastrin-stimulated histamine release [51,52]. The effect on gastrin release is less clear as both inhibitory and stimulatory mechanisms have been described [53]. They are generated from cells in the epithelium and lamina propria. Macrophages and capillary endothelial cells appear to be the primary source [54]. The mechanisms regulating their release in vivo are not well understood. Major prostaglandins in human gastric mucosa are PGE2 and PGI2_. PGE2 inhibits acid secretion in isolated parietal cells. Inhibition of COX-1 by nonsteroidal antiinflammatory drugs increases acid production by parietal cells.

Other secretory regulators

●Transforming growth factor-alpha (TGF-alpha) is an autocrine factor that is present in parietal cells and inhibits gastric acid secretion [55,56]. Administration of fat into the lumen of the small intestine is associated with an inhibition of gastric acid secretion. There are two intestinal peptides that play a role in this phenomenon.

●Peptide YY is released postprandially from cells in the ileum and colon and inhibits the cephalic and gastric phases of acid secretion via central and peripheral effects [57]. Peptide YY binds to receptors on ECL cells and inhibits gastrin-stimulated histamine release [57].

●GLP-1 is the other peptide that inhibits acid secretion. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y".)

Pepsin — Gastric pepsins, which are released as proenzymes (pepsinogen 1 and 2), undergo autoactivation at low pH. At least five different pepsins have been described in the stomach, of which pepsin 3 is the most abundant, but high levels of pepsin 1 have been associated with ulcer disease, and hypoglycemia-induced vagal stimulation and pentagastrin infusion have been shown to increase pepsin 1 levels in the stomach [58]. Pepsinogen secretion is enhanced by acetylcholine and peptides of the CCK/gastrin family [7]. In addition, agents that raise cyclic AMP, such as secretin and vasoactive intestinal peptide, increase pepsinogen secretion in vitro.

Peptic activity is closely linked to acid secretion and gastric pH [59]. This relation is partly due to peptic digests of dietary protein (primarily amino acids), which are potent stimulants of gastrin release and acid secretion [26]. In addition, pepsinogen is converted to the active protease pepsin at low gastric pH; on the other hand, pepsin is inactivated when the pH is increased above 4 [60]. This pH dependence probably accounts for the requirement for elevating the intraluminal pH above 4 to heal refractory ulcers. Acid plus pepsin is much more ulcerogenic than acid alone [60], leaving little question that the "peptic" label appropriately reflects the critical role in ulcer formation of the proteolytic activity in gastric juice. The potentiating effect of pepsin may be due in part to its mucolytic activity [61]. (See "Approach to refractory peptic ulcer disease".)

GASTRIC ACID SECRETION

Normal ranges

Basal acid output — Basal acid output (BAO) is the level of acid secretion when the subject is unstimulated; measurements are widely variable among individuals. Values in normal subjects are less than 10 mEq per hour, averaging about 2 mEq per hour.

Maximal acid output — Maximal acid output is usually measured in response to a maximally effective dose of pentagastrin and averages about 30 mEq per hour. The upper limit of the normal range (95% confidence level) is about 60 mEq per hour, underlining the point that acid secretion between duodenal ulcer patients and normal subjects overlap considerably.

Assessment of acid output — Aspiration of gastric contents via a nasogastric tube is the easiest method of measuring acid secretion, if collections are complete [7]. Basal acid secretion can also be reliably measured through an endoscope during a 15-minute collection period. Alternatively, intragastric titration allows the actual level of acid secretion to be measured by the quantity of base required to hold the gastric pH at a predetermined level. Placement of a gastric pH probe allows hydrogen ion concentration to be measured over a 24-hour period, but measuring hydrogen ion concentration provides only an indirect indicator of the rate of acid secretion.

Factors impacting gastric acid secretion

Medications — Antisecretory agents can alter gastric acid secretion [18,62]. Histamine-2 receptor antagonists (H2RAs) inhibit acid secretion by blocking H2 receptors on the parietal cell. Proton pump inhibitors (PPIs) inhibit hydrogen-potassium-ATPase, the final step of gastric acid secretion by parietal cells. However, prolonged use and discontinuation are associated with tolerance and rebound acid hypersecretion, respectively.

Tolerance — Tolerance to H2RAs develops after as few as seven days of therapy, with diminished effectiveness against nocturnal and pentagastrin-stimulated acid secretion [63,64]. In one study, for example, intravenous H2RAs reduced pentagastrin-stimulated acid secretion by 95 percent prior to oral therapy, compared with only 62 percent inhibition after nine months of oral therapy [64].

The clinical relevance of tolerance has not been established. It may contribute to the poor clinical response to H2RAs in some patients with ulcer disease. Tolerance does not occur with PPIs, probably because they block the final stage of acid secretion, the hydrogen-potassium-ATPase pump. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Antisecretory agents'.)

Rebound acid hypersecretion — Rebound acid hypersecretion occurs after the cessation of one to nine months of H2RA therapy. Increases have been noted in nocturnal acid secretion and in the acid secretory response to a meal [65-67]. In one study, for example, cessation of H2RAs after 25 days of therapy was associated with a significant increase in intragastric acidity (17 percent at day three and 14 percent at day six) compared with pretreatment values; rebound was no longer present after day nine [66]. The magnitude of the rebound appears to reflect the degree and duration of secretory inhibition.

Rebound acid hypersecretion also occurs following treatment with PPIs [68-70]. In a randomized trial in which 120 healthy volunteers were assigned to eight weeks of PPI or placebo, rates of heartburn or dyspepsia in the four weeks after PPI was discontinued were significantly higher in subjects treated with a PPI as compared with placebo (40 versus 15 percent) [70]. The study did not directly relate symptoms to rebound acid hypersecretion, but it suggests that rebound after stopping PPI treatment can provoke symptoms. A meta-analysis showed that rebound results in symptoms in healthy volunteers treated short term with PPIs, but in GERD patients who have been treated chronically with PPIs, no rebound was found; however, these studies had several methodologic limitations [71]. Acid suppression is more profound with potassium-competitive acid inhibitors than with PPIs, but there are no data on rebound with these agents at this time [72]. Rebound appears to be more common in patients not infected with Helicobacter pylori as persisting suppression of acid secretion masks the phenomenon in individuals with H. pylori [68]. (See 'Helicobacter pylori infection' below.)

There are several potential mechanisms of rebound and tolerance, although their relative importance is uncertain [62]:

●Hyperplasia and hyperfunction of histamine-ECL cells presumably in response to relative hypergastrinemia [18,68,69].

●Hyperplasia and hyperfunction of parietal cells presumably in response to hypergastrinemia.

●Upregulation of histamine-independent stimulatory mechanisms mediated by vagal/cholinergic pathways.

●Down-regulation of inhibitory pathways, such as those mediated by endogenous somatostatin.

The observation that antisecretory therapy raises serum gastrin in proportion to the magnitude of acid inhibition led to the hypothesis that hypergastrinemia was the primary factor underlying rebound acid hypersecretion. However, rebound appears to occur on nighttime maintenance doses of H2RAs, which cause only minimal nocturnal and no daytime hypergastrinemia. Furthermore, although sustained, prominent hypergastrinemia causes acid hypersecretion; the threshold duration and magnitude of hypergastrinemia required for a hypersecretory response remains controversial [73].

Helicobacter pylori infection — Acute infection with H. pylori causes a transient hypochlorhydria that may help the organism colonize the stomach. Chronic infection with H. pylori can be associated with increased or decreased acid secretion, depending on the severity of the gastritis and the anatomic distribution of gastritis. Chronic pangastritis is associated with reduced acid production, which initially is caused by a functional inhibition of parietal cells by inflammatory cytokines and products of H. pylori. Over time, chronic H. pylori infection can cause gastric atrophy and irreversible hypochlorhydria and eventually achlorhydria. This pattern of gastritis is seen in approximately 85 percent of patients. A smaller proportion of patients (15 percent) have a pattern of gastritis that involves primarily the antrum (antrum-predominant). This pattern of gastritis is associated with decreased somatostatin levels, high gastrin levels, and increased acid production [74,75].

Other conditions associated with gastric acid hypersecretion — Gastric acid hypersecretion (characterized by a BAO >15 mEq/hour) is observed in approximately 30 percent of patients with duodenal ulcers. H. pylori infection is often a contributing factor, but some patients with duodenal ulcers have acid hypersecretion independent of H. pylori. Other rare conditions associated with acid hypersecretion include Zollinger-Ellison syndrome (due to a gastrinoma), mastocytosis, and a retained antrum following partial gastrectomy.

SUMMARY

●Role of gastric acid – Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, vitamin B12, and is necessary for the absorption of some drugs. Gastric acid, by lowering pH, kills ingested microorganisms and limits bacterial growth in the stomach and prevents intestinal infections. (See 'Role of gastric acid and phases of secretion' above.)

●Phases of acid secretion – The physiologic stimulation of acid secretion has classically been divided into three interrelated phases: cephalic, gastric, and intestinal. (See 'Role of gastric acid and phases of secretion' above.)

●Gastric acid regulation – Gastric acid secretion from parietal cells is regulated by endocrine (gastrin), paracrine (locally delivered histamine and somatostatin), neural (acetylcholine), and autocrine factors (figure 1). (See 'Regulation of gastric acid and pepsin' above.)

•Gastrin is the major endocrine regulator of the secretory response to a protein meal. Gastrin enhances gastric acid secretion from parietal cells largely via the release of histamine from enterochromaffin-like (ECL) cells. Gastrin also exerts trophic action on the gastric mucosa by direct effects on histamine-secreting ECL cells and possibly by effects on gastric stem cells and parietal cells. (See 'Gastrin' above and 'Histamine' above.)

•Somatostatin is the principal inhibitor of acid secretion and is released from oxyntic glands and antral D cells (paracrine). Although somatostatin has some effects on parietal cells, its major effects are exerted on the inhibition of histamine release and to a lesser extent on gastrin release. (See 'Somatostatin' above.)

•The mucosal nerves, containing acetylcholine, gastrin-releasing peptide, and other mediators, mediate the response to the cephalic phase of acid secretion and to gastric distention and amino acids. Acetylcholine is the major stimulatory mediator that increases gastrin release, stimulates parietal cells, and inhibits somatostatin secretion. (See 'Regulation of gastric acid and pepsin' above.)

•Prostaglandins are autocrine factors that inhibit acid secretion, histamine-stimulated parietal cell function, and gastrin-stimulated histamine release. (See 'Prostaglandins' above.)

●Factors impacting gastric acid secretion

•Antisecretory agents – Histamine-2 receptor antagonists (H2RAs) inhibit acid secretion by blocking H2 receptors on the parietal cell. Proton pump inhibitors (PPIs) inhibit hydrogen-potassium-ATPase, the final step of gastric acid secretion by parietal cells. However, prolonged use and then discontinuation are associated with tolerance and rebound acid hypersecretion, respectively.

•Helicobacter pylori – Acute infection with H. pylori causes a transient hypochlorhydria that may help the organism colonize the stomach. Chronic infection with H. pylori can be associated with increased or decreased acid secretion, depending on the severity of the gastritis and the anatomic distribution of gastritis.

●Conditions associated with gastric acid hypersecretion – Gastric acid hypersecretion (basal acid output >15 mEq/hour) may be seen in patients with chronic H. pylori infection, duodenal ulcers (independent of H. pylori infection), Zollinger-Ellison syndrome (due to a gastrinoma), mastocytosis, and a retained antrum following partial gastrectomy. (See 'Other conditions associated with gastric acid hypersecretion' above.)

ACKNOWLEDGMENTS — We are saddened by the death of Mark Feldman, MD, who passed away in March 2024. UpToDate gratefully acknowledges Dr. Feldman’s role as a Section Editor on this topic and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges Andrew H Soll, MD, who contributed to an earlier version of this topic review.