Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome

One of the hallmarks of the mammalian stomach is its ability to secrete large quantities of concentrated (0.16 mol/L) hydrochloric acid (HCl).1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Although it is generally assumed that gastric acid and the proteolytic enzyme pepsin are required to initiate digestion, achlorhydric individuals generally do not develop malabsorption unless small bowel bacterial overgrowth is present. It is thus likely that the ability of the stomach to secrete acid evolved primarily from a need to sustain a sterile intragastric milieu. Organisms that possessed the capacity to kill ingested bacteria and other microbes were able to avoid the development of enteric colonization, and thereby ensure both efficient absorption of nutrients and prevention of systemic infections.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Nevertheless, when present, gastric acid does play a significant role in protein hydrolysis and other aspects of the digestive process, and under various conditions, acid may play an etiologic role in producing various forms of discomfort and inciting esophageal and gastroduodenal mucosal injury. The normal human stomach contains approximately 1 billion parietal cells that secrete hydrogen ions into the gastric lumen in response to various physiological stimuli. The generation of H+ ions is mediated by 3 pathways: neurocrine, paracrine, and endocrine (Figure 1). The principal neurocrine transmitter is acetylcholine, which is released by vagal postganglionic neurons and appears to stimulate H+ ion generation directly via a parietal cell muscarinic M3 receptor. Histamine is the primary paracrine transmitter that binds to H2-specific receptors on parietal cells. Adenylate cyclase is then activated, leading to an increase in adenosine 3′,5′-cyclic monophosphate (cAMP) levels and subsequent generation of H+ ions. The secretion of gastrin from antral G cells comprises the endocrine pathway and stimulates H+ ion generation both directly and indirectly, the latter by stimulating histamine secretion from enterochromaffin-like (ECL) cells of the corpus and fundus. Interactions among neurocrine, paracrine, and endocrine pathways are coordinated to promote or inhibit H+ ion generation. Histamine appears to represent the dominant route, because gastrin stimulates acid secretion principally by promoting histamine release from ECL cells.2Waldum HL Sandvik AK. The enterochromaffin-like (ECL) cells.Acta Oncol. 1993; 32: 141-147Crossref PubMed Google Scholar, 3Prinz C Scott DR Hurwitz D Helander HF Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary culture.Am J Physiol. 1994; 267: G663-G675PubMed Google Scholar Thus, ECL cells are often referred to as "controller" cells in the process of gastric acid secretion. A negative feedback loop governs both gastrin release and the return of acid secretion to basal level.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar, 4Van Dam J Wolfe MM. Gastrin and other peptide hormones. In Pharmacology of peptic ulcer disease.in: eds Collen MJ Benjamin SB Springer-Verlag,, Berlin1991: 55-58Google Scholar, 5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 6Schubert ML Saffouri B Makhlouf GM. Identical patterns of somatostatin secretion from isolated antrum and fundus of rat stomach.Am J Physiol. 1988; 254: G20-G24PubMed Google Scholar This autoregulatory mechanism prevents postprandial acid hypersecretion. After ingestion of a meal, gastrin release stimulates secretion of gastric acid. The intraluminal pH begins to decrease, which stimulates release of somatostatin from antral D cells, possibly through the activation of calcitonin gene-related peptide (CGRP) neurons.5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 7Ren J Dunn ST Tang Y Wang Y Gao J Brewer K Harty RF. Effects of calcitonin gene-related peptide on somatostatin and gastrin gene expression in rat antrum.Regul Pep. 1998; 73: 75-82Crossref PubMed Scopus (9) Google Scholar Somatostatin then appears to act via a paracrine mechanism to inhibit further release of gastrin from G cells.8Wolfe MM Jain DK Reel GM McGuigan JE. Effects of carbachol on gastrin and somatostatin release in rat antral tissue culture.Gastroenterology. 1984; 87: 86-93Abstract Full Text PDF PubMed Google Scholar Somatostatin produced by D cells in the gastric corpus and fundus may also directly inhibit acid secretion from parietal cells and may suppress histamine release from ECL cells (Figure 1).6Schubert ML Saffouri B Makhlouf GM. Identical patterns of somatostatin secretion from isolated antrum and fundus of rat stomach.Am J Physiol. 1988; 254: G20-G24PubMed Google Scholar, 9Short GM Reel GM Doyle JW Wolfe MM. Effect of GRP on β-adrenergic-stimulated gastrin and somatostatin release in the isolated rat stomach.Am J Physiol. 1985; 249: G197-G202PubMed Google Scholar Other recent observations indicate that several other neurotransmitters, including vasoactive intestinal peptide (VIP), galanin, and pituitary adenylate cyclase-activating peptide, may play important roles in regulating gastric acid secretion, both directly and indirectly, under physiological conditions.10Athmann C Zeng N Sachs G. An integrated model of paracrine regulation of acid secretion.Gastroenterology. 1999; 116 (abstr): A590Google Scholar The treatment of duodenal ulcer (DU) has served as the basis (correctly or incorrectly) for the management of nearly all acid-related disorders. This supposition in all likelihood contributed to delays in the optimal management of other gastrointestinal (GI) disorders in which acid plays an etiologic role in producing symptoms and causing mucosal injury, such as gastroesophageal reflux disease (GERD). Although patients with gastric ulcers (GUs) tend to have normal or reduced levels of acid secretion,11Feldman M Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy.Gastroenterology. 1986; 90: 540-544Abstract Full Text PDF PubMed Google Scholar the average DU patient is an acid hypersecretor. When compared with age-matched controls, DU patients secrete ~70% more acid during the day (meal-stimulated) and about 150% more acid at night (basal secretion) (Figure 2).11Feldman M Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy.Gastroenterology. 1986; 90: 540-544Abstract Full Text PDF PubMed Google Scholar Postprandial gastric acid secretion is regulated primarily by increases in gastrin expression, which is controlled by a negative feedback loop. Individuals infected with Helicobacter pylori have been shown to have a diminished number of somatostatin-secreting D cells, which decreases the magnitude of the response to luminal acidification.12Moss SF Legon S Bishop AE Polak JM Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease.Lancet. 1992; 340: 930-932Abstract PubMed Scopus (187) Google Scholar, 13Graham DY Lew GM Lechago J. Antral G-cell and D-cell numbers in Helicobacter pylori infection: effect of H. pylori eradication.Gastroenterology. 1993; 104: 1655-1660PubMed Google Scholar, 14Odum L Petersen HD Andersen IB Hansen BF Rehfeld JF. Gastrin and somatostatin in Helicobacter pylori infected antral mucosa.Gut. 1994; 35: 615-618Crossref PubMed Google Scholar Thus, in patients with H. pylori infection limited to the antrum, the negative feedback inhibition of gastrin release is attenuated, resulting in higher postprandial gastrin levels and hypersecretion of acid. Despite the existence of meal-induced hyperchlorhydria in DU patients, the presence of food in the stomach has a buffering effect that may protect the gastroduodenal mucosa from acid-induced injury. However, at night and during other prolonged periods of fasting, acid bathes the "bare" mucosa, and in DU patients, the increase in nocturnal acid secretion magnifies this effect. Duodenal bicarbonate secretion also appears to be impaired in patients with DU,15Isenberg JI Selling JA Hogan DL Koss MA. Impaired proximal duodenal mucosa bicarbonate secretion in patients with duodenal ulcer.N Engl J Med. 1987; 316: 374-1379Crossref PubMed Google Scholar as well as in those infected with H. pylori, making the mucosal exposure to acid even greater. These observations, as discussed below, form the rationale for single nocturnal dosing of H2-receptor antagonists in the treatment of DU, a mode of therapy that is at least as effective as multiple dosing regimens. Clearly, factors other than acid and pepsin are involved in the pathogenesis of peptic ulcer disease (PUD), because only 30% of patients with DUs and very few patients with GUs are hyperchlorhydric.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar The balance between aggressive factors that act to injure the gastroduodenal mucosa and defensive factors that normally protect against corrosive agents is also important. When this delicate balance is disrupted for any reason, mucosal injury may ensue.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar These defensive properties appear to be mediated to a large extent by endogenous prostaglandins, nitric oxide, and trefoil proteins, and when the synthesis of any or all are diminished, the ability of the gastroduodenal mucosa to resist injury is decreased. Thus, even normal rates of acid secretion may be sufficient to injure the mucosa and produce gastroduodenal ulcers. Nevertheless, even in DU patients who are normal secretors of acid, a reduction in the rate of acid secretion is the most efficient means of healing ulcers.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Although a large number of gastroduodenal ulcers are associated with H. pylori infection, at least 60% of individuals with complicated ulcers (e.g., hemorrhage or perforation) report the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin.16Wolfe MM Lichtenstein DR Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1372) Google Scholar Mucosal injury associated with NSAID use is initiated topically by the acidic nature of NSAIDs.17Schoen RT Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.Am J Med. 1989; 86: 449-459Abstract Full Text PDF PubMed Google Scholar Topical mucosal injury may also occur as a result of indirect mechanisms, mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites.18Graham DY Smith JL Holmes GI Davies RO. Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa.Clin Pharmacol Ther. 1985; 38: 65-70Crossref PubMed Google Scholar, 19Carson JL Strom BL Morse L West Sl Soper KS Stolley PD Jones JK. The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.Arch Intern Med. 1987; 147: 1054-1059Crossref PubMed Google Scholar Topical injury caused by NSAIDs certainly contributes significantly to the development of gastroduodenal mucosal injury, but the systemic effects of these agents appear to play the predominant role,17Schoen RT Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.Am J Med. 1989; 86: 449-459Abstract Full Text PDF PubMed Google Scholar, 20Soll AH Weinstein WM Kurata J McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 114: 307-319Crossref PubMed Google Scholar, 21Needleman P Isakson PC. The discovery and function of COX-2.J Rheumatol. 1997; 24: 6-8PubMed Google Scholar largely through the decreased synthesis of mucosal prostaglandins.22Lanza FL Royer GL Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa.N Engl J Med. 1980; 303: 136-138Crossref PubMed Google Scholar Avoidance of topical mucosal injury by enteric-coated aspirin preparations22Lanza FL Royer GL Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa.N Engl J Med. 1980; 303: 136-138Crossref PubMed Google Scholar or by the parenteral23Lanza FL Karlin DA Yee JP. A double-blind placebo controlled endoscopic study comparing the mucosal injury seen with orally and parenterally administered nonsteroidal analgesic ketorolac tromethamine at therapeutic and supratherapeutic doses.Am J Gastroenterol. 1987; 82: 939Google Scholar or rectal24Henry D Dobson A Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.Gastroenterology. 1993; 105: 1078-1088Abstract PubMed Google Scholar administration of NSAIDs does not prevent the development of ulcer complications. Moreover, doses of aspirin as low as 10 mg are sufficient to significantly suppress gastric mucosal prostaglandin synthesis.25Cryer B Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.Gastroenterology. 1999; 117: 17-25Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar A decrease in the above protective mechanisms normally stimulated by prostaglandins enables endogenous gastric acid to incite mucosal injury. In recent years, it has become evident that the actual percentage of ulcers associated with H. pylori may not be 90%–95% as often reported, but may be as low as 32% in non-referral-based populations.26Kurata JH Nogawa AN. Meta-analysis of risk factors for peptic ulcers.J Clin Gastroenterol. 1997; 24: 2-17Crossref PubMed Scopus (174) Google Scholar Furthermore, despite the inclination to ascribe the etiology of ulcers in such individuals to NSAIDs, the use of these agents clearly does not account for the balance of the cases. Finally, the vast majority of remaining individuals do not have the Zollinger-Ellison syndrome (ZES) or another unusual cause of gastroduodenal ulcer. Thus, while peptic ulceration involves the participation of several factors, as first stated by Karl Schwarz27Schwarz K. Über penetrierende magen-und jejunalgeschwüre.Beitr Klin Chirurgie. 1910; 5: 96-128Google Scholar in 1910: "Ohne sauren Magensaft, kein peptisches Geschwür," i.e., "No acid, no ulcer." The erosive properties of acid continue to play a central role in the pathogenesis of gastroduodenal mucosal ulceration, and conversely, acid suppression therapy remains the cornerstone of therapy. Although the principal aggressive factor involved in causing heartburn and the other clinical manifestations of GERD is the presence of acid in the esophagus, the disorder does not usually result from the hypersecretion of gastric acid.28Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis.Gastroenterology. 1991; 101: 1149-1158PubMed Google Scholar Rather, GERD occurs as a result of several abnormalities in motor function of the lower esophagus and the lower esophageal sphincter (LES). Despite the etiologic role played by these important motor abnormalities, the severity of symptoms, most notably heartburn, and esophageal mucosal injury can be correlated with the total time that the esophageal mucosa is exposed to acid. Gastric acid thus also constitutes a critical element in the pathogenesis of GERD, and acid suppression comprises the principal mechanism for therapy. However, the optimal timing and degree of acid suppression differ significantly in GERD patients compared with the treatment of gastroduodenal ulcer (see below). Many terms have been used to describe this entity, including stress ulcer syndrome, stress gastritis, stress-related mucosal disease, and stress-related erosive syndrome (SRES).29Lucas CE Sugawa C Riddle J Rector F Rosenberg B Wah AJ. Natural history and surgical dilemma of "stress" gastric bleeding.Arch Surg. 1971; 102: 266-273Crossref PubMed Google Scholar, 30Goldin GF Perra DA. Stress-related mucosal damage. What to do or not to do.Gastrointest Clin North Am. 1996; 6: 505-526PubMed Google Scholar The principal feature of SRES is its relationship to serious systemic disease, such as sepsis, massive burn injury, head injury associated with increased intracranial pressure, severe trauma, and multiple-system organ failure. A meta-analysis of 2252 patients by Cook et al.31Cook DJ Fuller HD Guyatt GH Marshall JC Leasa D Hall R Winton TL Rutledge F Todd TJR Roy P LaCroix J Griffith L Willan A. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian critical care trials group.N Engl J Med. 1994; 330: 377-381Crossref PubMed Scopus (474) Google Scholar identified mechanical ventilation and coagulopathy as the 2 singlemost important risk factors. Although the pathophysiology is multifactorial and definitely includes a component of ischemia, which compromises gastric mucosal integrity, luminal acid plays a dominant role in producing the multiple erosive lesions characteristic of the entity. Fiddian-Green et al.32Fiddian-Green RG McGough E Pittenger G Rothman E. Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration.Gastroenterology. 1983; 85: 613-620PubMed Google Scholar emphasized the importance of H+ ion back-diffusion by demonstrating a high correlation between the degree of intramural pH and the development of SRES. Furthermore, most, but not all, methods for preventing massive hemorrhage-associated SRES include the alkalinization of gastric contents.33Wolfe M. Stress-related erosive syndrome. In Current therapy in gastroenterology and liver disease.in: ed Bayless T Mosby-Year Book,, St. Louis1994: 139-143Google Scholar The parietal cell possesses a unique morphology that differs markedly between the resting and stimulated states.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Mitochondria occupy 34% of its cell volume, indicative of the importance of adenosine triphosphate (ATP) synthesis as an energy source required for the active transport of H+ ions out of the cell against a 3,000,000:1 ionic gradient. A large percentage of resting cell volume is also occupied by tubulovesicles, which are elongated tubes with smooth surface membranes, and by the secretory canaliculus, a small invaginated area of the apical membrane. Upon stimulation, which is generally accomplished by eating a meal, the tubulovesicles decrease in number and become transformed into microvilli around the secretory canaliculus, which serves to greatly expand the surface area of the parietal cell in preparation for the secretion of large quantities of HCl. The parietal cell also possesses several different receptors for stimulatory and inhibitory ligands on its basolateral membrane (Figure 1). The histamine receptor belongs to a large family of G protein-linked receptors possessing 7 transmembrane domains.34Ganz I Schaeffer M Del Valle J Logsdon C Campbell V Uhler M Yamada T. Molecular cloning of a gene encoding the histamine H2-receptor.Proc Natl Acad Sci USA. 1991; 488: 429-433Crossref Scopus (104) Google Scholar Despite the recognition that histamine stimulates gastric acid secretion, it was not until 1966, when Ash and Schield35Ash A Schild H. Receptors mediating some of the actions of histamine.Br J Pharmacol. 1996; 27: 427-439Google Scholar described H1 and receptors for that the of acid secretion with histamine antagonists was In et JW and of histamine PubMed Scopus Google Scholar described histamine H2-receptor inhibition and initiated the for agents that suppress the secretion of acid. 10 of the release of cimetidine in the in 3 H2-receptor and for use the drugs (Figure suppress basal and acid secretion, to a degree than discussed Despite therapeutic some do with to the properties most of which are DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM Scholar The of these drugs occurs by a of and and does not dose are for all individuals with of DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM Scholar H2-receptor antagonists as a an and in for use in the of the Histamine effect on and with DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM in a for gastroduodenal and with DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM for gastroduodenal ulcer. in a and with DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM Scholar and with DR Wolfe MM. Histamine H2-receptor In Gastrointestinal ed Wolfe MM Scholar The central via the plays a dominant role in regulating basal acid secretion, as well as the of acid secretion. of were used to the time of the and in the recent agents such as and were used as of gastric acid secretion. These drugs were associated with including and and as a result are used muscarinic receptors have been and and all are G protein different In of gastric acid secretion has that the parietal cell normally the M3 M M Sachs G. The muscarinic receptor gene in parietal cells is the M3 1992; Google Scholar the and are effective of acid secretion and effect by with a MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar These 2 agents are in other for the treatment of duodenal but have not been for use in the stated gastrin stimulates acid secretion via an endocrine pathway and H+ ion generation both directly and The and of the gastrin receptor have been subjects of and may be in and other have that gastrin stimulates acid secretion by the release of histamine from ECL R G F P M M T Histamine in endocrine cells in the 1986; 86: PubMed Scopus Google Scholar, C M Scott DR F Helander HF Sachs G. Histamine secretion from rat enterochromaffin-like 1993; 105: PubMed Scopus Google Scholar receptors for gastrin receptors on parietal cells have been by Soll et AH DA Gastrin receptors on isolated parietal Clin Invest. 1984; 73: PubMed Google Scholar by the and by et M M. cloning and of the parietal cell gastrin Natl Acad Sci USA. 1992; PubMed Google Scholar who and the gastrin receptor from a parietal cell Moreover, has for a gastrin receptor on the parietal cells of and J R I Sachs G. in in rat parietal 1992; PubMed Google Scholar The gastrin receptor belongs to the family of G protein-linked receptors possessing 7 transmembrane M M. cloning and of the parietal cell gastrin Natl Acad Sci USA. 1992; PubMed Google Scholar It is to the receptor for or and is thus often referred to as the or receptor. receptor antagonists have been which include and RG In of a Pharmacol Ther. 1987; Google Scholar The is a that was from the and has been to gastric acid RG In of a Pharmacol Ther. 1987; Google Scholar Despite this these antagonists have not been used as of acid secretion. However, may in the treatment of and disorders by of to gastrin receptors in the M B of the in 1999; Full Text Full Text PDF PubMed Scopus Google Scholar Other receptors on the parietal cell basolateral membrane have been by the ability of various agents to inhibit gastric acid secretion. prostaglandins inhibit H+ ion generation by to G protein-linked receptor on the parietal which appears to inhibit adenylate and thereby decrease generation when DA M MJ Soll AH. inhibition of parietal by the inhibitory protein of adenylate 1988; PubMed Scopus Google Scholar discussed below, the properties of prostaglandin such as while not are critical for any clinical MM Lichtenstein DR Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1372) Google Scholar The gastric enzyme is a