FIGURE 17 Mechanisms inhibiting gastric acid secretion. Blanks indicate actions that either do not occur or are not significant physiologically.

FIGURE 17 Mechanisms inhibiting gastric acid secretion. Blanks indicate actions that either do not occur or are not significant physiologically.

additional enzyme from pepsinogen. At an intragastric pH of 2 or less, the conversion of pepsinogen to pepsin is almost instantaneous. Pepsin begins the digestion of protein by splitting interior peptide bonds.

There are two main groups of pepsinogens. Group I pepsinogens are secreted by peptic (chief) and mucous cells of the oxyntic glands. Group II pepsinogens come from mucous cells of the pyloric gland area and the duodenum as well as the oxyntic gland mucosa. Pepsino-gens can be measured in the blood, where their quantities correlate with the presence of duodenal ulcer disease.

Acetylcholine is the strongest and most important stimulator of pepsin secretion. Vagal stimulation during both the cephalic and gastric phases results in the majority of the pepsin response to a meal. Acid is necessary not only for the activation of pepsin but also because it initiates at least two other mechanisms stimulating pepsin secretion. First, acid triggers a local cholinergic reflex that stimulates the chief cells to secrete. This mechanism is sensitive to atropine and local anesthetics and is mediated by the enteric nervous system. Second, acid releases secretin from the duodenum, and secretin stimulates pepsin secretion. There is also evidence that cholinergic stimulation results in more pepsin secretion when the intragastric pH is low. These mechanisms ensure that large amounts of pepsi-nogen are not secreted unless sufficient acid is present to convert it to the active enzyme.


The cells of the gastric mucosa secrete two types of mucus. Vagal nerve stimulation and acetylcholine stimulate soluble mucus secretion from the mucous neck cells.

Soluble mucus mixes with the other secretions of the glands and lubricates the gastric chyme. Surface mucous cells secrete visible or insoluble mucus in response to chemical or physical irritation. Chemicals, such as ethanol, and friction with ingested material stimulate the release of visible mucus, which is secreted as a gel forming an unstirred layer over the mucosa. This layer traps dead cells as they are sloughed from the mucosa and forms a protective lubricating coat. In addition, bicarbonate ions from the alkaline component of secretion are trapped within this layer and maintain the pH at the surface of the stomach near neutrality despite luminal pHs of less than 2. During the digestion of a meal, this physical and alkaline barrier prevents damage from friction and keeps the mucosal cells from coming into contact with pepsin and high concentrations of acid.

Intrinsic Factor

Intrinsic factor is secreted by the parietal cells in humans as a 55,000-molecular-weight mucoprotein. It combines with dietary vitamin B12, forming a complex necessary for the absorption of the vitamin by an active process that is located in ileal mucosa. The absence of intrinsic factor results in the condition known as pernicious anemia, a disease associated with achlorhy-dria and the absence of parietal cells. The development of this disease is poorly understood because the liver stores vitamin B12 in amounts sufficient for several years. Therefore, the developmental stages of the disease occur a number of years before the condition is recognized. The secretion of intrinsic factor is the only reason the stomach is necessary for life, and patients

TABLE 1 Basal and Maxim (Histamine-Stimulated) Acid Outputs From Normal Humans and Those With Conditions Affecting Acid Secretion

Normal 1-5 6-40

Pernicious anemia 0 0

Gastric cancer 0-5 0-40

Gastric ulcer 0-3 1-20

Duodenal ulcer 2-10 15-60

Gastrinoma 10-30 30-80

with pernicious anemia or after gastrectomy must take injections of vitamin B12.

Acid Secretion and Serum Gastrin

Table 1 shows the basal and maximal rates of gastric acid secretion for normal humans and for patients having clinical conditions in which acid secretion is usually altered. Basal acid output is that which occurs during the interdigestive period when the stomach is empty. Maximal acid output is measured in response to a maximal dose of histamine. It is important to note the degree of overlap between acid outputs in the various groups. Thus, although these values indicate that, in general, a patient with duodenal ulcer secretes more acid than a normal individual, such measurements have little meaning in the diagnosis of individual cases.

Because of the feedback mechanism whereby acid inhibits the release of gastrin, serum gastrin values are, in general, inversely related to acid secretory rates. In other words, patients with gastric cancer or gastric ulcer disease usually have higher than normal serum gastrin levels. Patients with pernicious anemia, who secrete no acid, often have astronomically high serum gastrins. The obvious exceptions are gastrinoma (Zollinger-Ellison syndrome) patients, who have both high rates of acid production and extremely high gastrin levels. In this group of patients, however (as discussed in Chapter 32), the gastrin is being released from a tumor and is not subject to acid feedback inhibition.

Acid output (mmol/hr)

Condition Basal Maximal

Clinical Note

Peptic Ulcer

Gastric and duodenal ulcers form when the respective mucosal linings of the gastrointestinal tract are digested by acid and pepsin. The presence of acid and pepsin are normally required for ulcer formation and, as such, both diseases are classified as peptic ulcers. Despite being classified under one heading, however, the etiologies of the two conditions are quite different. Put simply, an ulcer forms when damaging factors such as acid and pepsin overcome the mucosal protective factors such as bicarbonate secretion, mucus, and cell renewal. In the case of duodenal ulcer, there is good evidence that the defect is increased amounts of acid and pepsin. In the case of gastric ulcer, the defect appears to be in the mucosa itself, so that its defense mechanisms have been weakened. This analysis is oversimplified and generalized, and both factors no doubt play some role in most cases of ulcer.

Increased acid and pepsin secretion have been implicated in duodenal ulcer disease. As shown in Table 1, as a group, these patients have higher than normal rates of secretion. In general, duodenal ulcer disease patients have higher than normal serum gastrin levels in response to a meal and about double the normal number of gastric parietal cells. Whether the increased number of parietal cells is due to the trophic effect of gastrin is unknown. Increased serum gastrin levels are due in part to a defective mechanism for the inhibition of gastrin release by mucosal acidification. There is also evidence that parietal cells in patients with duodenal ulcer are actually more sensitive to gastrin as well. In addition, the secretion of pepsin, as determined from serum pepsinogen levels, is almost doubled in the duodenal ulcer group. The ability of increased acid secretion to produce duodenal ulcer disease is dramatically demonstrated in patients with gastrinoma. These patients always develop duodenal ulcers, never gastric ulcers.

The lower than normal rate of acid secretion in gastric ulcer is believed to be due in part to the inability to collect acid that has been secreted and then has leaked back into the damaged mucosa. The normal gastric mucosa is relatively impermeable to acid, but a number of events may cause this so-called gastric mucosal barrier to become weakened. These include abnormalities

Clinical Note (continued)

in mucosal blood flow, altered rates of cell renewal, decreased mucus secretion, bacterial infection, and damaging agents such as alcohol, bile acids, and aspirin.

The exact nature of the barrier is unknown, and mucosal resistance to acid probably includes physiologic processes as well as morphologic entities. Cell membranes and junctional complexes prevent normal back-diffusion of H+. Diffused H+ is normally transported back into the lumen. Processes that no doubt have some role in maintaining the barrier also include cell renewal and migration, blood flow, and mucous and bicarbonate secretion. Chemical factors such as gastrin, epidermal growth factor, and prosta-glandin have all been shown to decrease the severity and promote the healing of ulcers.

It has now been established that the major acquired causative factor in the genesis of both gastric and duodenal ulcer is infection with the bacteria Helicobacter pylori. Virtually 100% of gastric ulcer patients, excluding those whose ulcers were caused by chronic aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), are infected, whereas 95% of duodenal ulcer patients are H. pylori positive. The major characteristic of H. pylori is high urease activity and the production of NH3 from urea, which allows the bacteria to survive and colonize in the acid environment of the gastric mucosa. NH3 directly damages the epithelial cells, breaking the gastric mucosal barrier and allowing H+ to diffuse back into cells. Although NH3 is the major cytotoxic agent, the bacterium also releases a variety of factors and cytokines that damage cells and contribute to gastric ulcer formation.

Recent evidence also suggests that H. pylori is responsible for the increased acid secretion found in duodenal ulcer patients. After eradication of the bacteria from a group of duodenal ulcer patients, their increased basal acid output, increased GRP-stimulated acid output, increased ratio of basal to gastrin-stimulated maximal acid output, and increased ratio of GRP-stimulated maximal acid output to gastrin-stimulated maximal acid output returned to normal. Only the increased maximal acid output in response to gastrin failed to return to normal. Because the maximal acid output is probably due to an increased number of parietal cells from the trophic action of the gastrin, this too may return to normal after serum gastrin levels have been reduced. Increased acid secretory and serum gastrin responses appear to be related in part to a decreased inhibition of gastrin release and parietal cell secretion by somatostatin in H. pylori-infected individuals. There is also evidence that NH^ directly stimulates gastrin release. All of the effects of H. pylori on the mucosa have not been elucidated, but the treatment of gastric and duodenal ulcer diseases involves the eradication of the infection.

Why H. pylori infection causes gastric ulcer in one person and duodenal ulcer in another has not been firmly established. However, strong evidence indicates that H. pylori infection of the corpus of the stomach results in gastric ulcer, while a primarily antral infection causes duodenal ulcer. In the corpus, gastritis results in decreased acid secretion, damage, gastric ulcer, and the risk of neoplasia. In the antrum, gastritis inhibits somatostatin release, increases gastrin release, increases acid secretion, and results in a duodenal ulcer.

The treatment of peptic ulcer disease is based entirely on its pathophysiology. Medical treatment usually consists of administering antisecre-tory drugs such as a histamine H -receptor blocking agent. The most potent antisecretory drugs are those like omeprazole that inhibit the (H+,K+)-ATPase. These compounds are substituted benzimidazoles that accumulate in acid spaces and are activated at low pH. Once activated, these drugs bind irreversibly to sulfhydryl groups present on the active site of the (H+,K+)-ATPase, inhibiting the enzyme. Omeprazole effectively treats peptic ulcer, even duodenal ulcers caused by gastrinoma (Zollinger-Ellison syndrome). Medical treatment includes the eradication of H. pylori, which is extremely effective in preventing recurrence of the ulcer. Effective medical treatment has made surgery for peptic ulcer disease all but disappear. When done, however, surgery usually consisted of vagotomy and/or antrectomy. These procedures decrease acid secretion by 60-80% by removing one or both major stimulants of acid secretion and their potentiating interactions with histamine.

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