GI - Gastric Secretion and Hyperacidity Workshop

What options exist for the long-term management of a patient with a gastronoma?

The first priority is to locate the gastrinoma(s) in this patient with Zollinger-Ellison syndrome. If gastrinomas can be identified, they should be removed. Because over half of the gastrinomas in Zollinger-Ellison patients are malignant, chemotherapy may be appropriate. Zollinger-Ellison patients often become refractory to treatment with H2 receptor antagonists. Other treatments that may be used include proximal vagotomy (sectioning the vagal branches to the fundus and the body of the stomach) and partial or total gastrectomy.

What does the gastric mucosal barrier consist of?

-an unstirred, bicarbonate rich mucus layer which maintains pH 7 at cell surfaces and protects the gastric mucosa from gastric juice (pH 2) -tight junctions between gastric mucosal cells that prevent penetration of HCl between cells -luminal membranes of gastric mucosal cells that are impermeable to protons (H+).

How might a cholinergic antagonist enhance the effectiveness of cimetidine in reducing HCl secretion by the patient's gastric mucosa?

Acetylcholine is a secretagogue at the parietal cell and also elicits secretion of histamine by gastric ECL cells (Fig. 33-12). There is a potentiation between gastrin and acetylcholine at both cell types. Suppression of cholinergic tone with an anticholinergic drug lessens the response to the elevated gastrin at the levels of the parietal cell and the ECL cell. In this way, the anticholinergic drug enhances the effectiveness of cimetidine in this patient. However, these drugs are much less used since the arrival of H2 receptor blockers and omeprazol (and other proton pump inhibitors).

In a person with extremely high serum gastrin, why would a test meal not elevate serum gastrin further?

After a meal, peptides and amino acids in the stomach and duodenum, as well as distension of the gut, stimulate antral and duodenal G cells to release gastrin. If the patient's high serum gastrin were caused by hyperplasia of antral or jejunal G cells, a significant rise in gastrin after a meal would be expected. If, on the other hand, the high serum gastrin is caused by an independent and autonomous source of gastrin, no significant rise in gastrin is expected after a meal. This finding raises the suspicion that the patient might have a gastrinoma or Zollinger-Ellison syndrome.

What is the most common cause of gastric ulcers not due to NSAIDs?

Almost all patients with gastric ulcers that are NOT related to non-steroidal anti-inflammatory drugs (NSAIDs) test positive for Helicobacter Pylori. H. Pylori positive individuals can be without symptoms or suffer from anything between relatively mild gastritis and gastric ulcer(s).

How often are gastric ulcers associated with hypersecretion of HCl?

Gastric ulcers are rarely associated with hypersecretion of HCl. The gastric mucosal barrier (mucus and bicarbonate) normally suffices to protect the stomach even in hypersecretors.

What, if not hypersecretion of HCl, causes gastric ulcers?

Gastric ulcers are usually the result of a defect in the gastric mucosal barrier. In fact, patients with gastric ulcers are usually hyposecretors of HCl; this is because of the strong inhibitory effect of the low pH at the surface of the antral mucosa on secretion of HCl.

Why might a person with increased gastrin levels have an increased density of parietal cells in the gastric mucosa?

Gastrin has a trophic effect on the oxyntic mucosa. The constant high level of serum gastrin in this patient is responsible for the increased number of gastric glands and the increased density of parietal cells. The increased density of gastric glands and increased population of parietal cells within the glands (visible in the biopsy specimen) might also contribute to elevated HCl secretion.

Why can cimetidine provide relief from ulcers?

Gastrin is a relatively weak secretagogue at the parietal cell. Gastrin mostly effects HCl secretion by releasing histamine from ECL (enterochromaffin-like) cells in the gastric mucosa (see figure). Hence, cimetidine, which blocks the histamine H2 receptors on the parietal cells, blocks much of the effect of the elevated serum gastrin in this patient. The binding of cimetidine to H2 receptors is reversible. Moreover, cimetidine is degraded at a fairly high rate. For this reason, and because of the very high gastrin levels in the patient, large and frequent doses of cimetidine are required to suppress HCl secretion sufficiently to allow the patient's ulcer to heal.

How does omeprazole decrease the patient's rate of HCl secretion? Why is only one dose per day required?

Omeprazole (Prilosec) inhibits the H+/K+-ATPase in parietal cells (see Fig.). It is a potent inhibitor of gastric acid secretion evoked by any secretagogue. Omeprazole forms a covalent bond with the H+/K+-ATPase and inhibits it irreversibly. The inhibition is only relieved by the synthesis of new H+/K+-ATPase molecules and replacing inhibited pump molecules. For this reason, the inhibition of HCl secretion by omeprazole in this patient is longer lasting than that by other drugs. Prilosec is contraindicated in patients taking coumarins (anticoagulant) where it can increase the bleeding tendency because of a drug interaction.

Why might a person with acid in the duodenum have steatorrhea?

Pancreatic lipase is extremely pH-sensitive and can be rapidly and irreversibly denatured at acidic pH. The inactivation of lipase because of the low duodenal pH in this patient is the most likely cause of her steatorrhea (= excess fat in the stool).

What stimulates the release of pepsinogen?

Pepsinogen secretion is stimulated by HCl, acetylcholine and the hormones gastrin, secretin and cholecystokinin.

What physiological mechanisms protect against ulcer formation?

Protection is provides by the gastric mucosal barrier. The gastric epithelium establishes a protective barrier (mucus gel) to protect from self-digestion.

Why might a patient have a large increase in serum gastrin after an intravenous infusion of secretin?

Secretin strongly suppresses gastric HCl secretion, primarily by a direct inhibition of the parietal cells, but also indirectly through inhibition of gastrin release. In a normal individual, the latter effect on the secretion of gastrin is minimal. By mechanisms that have not been fully elucidated, secretin stimulates gastrinoma cells to release gastrin. This finding pretty well clinches the diagnosis of Zollinger-Ellison syndrome. Gastrinomas originate with a high incidence from the pancreas. Secretin is a strong secretory and trophic stimulus to the pancreas and exocrine pancreatic cells carry a high density of secretin receptors. Thus, it is conceivable that gastrinoma cells of pancreatic origin are also equipped with such secretin receptors.

What does increase in serum gastrin lead to?

Since gastrin is a secretagogue for parietal cells, it leads to increased rate of HCl secretion.

Why might the duodenum have ulcers due to HCl but not gastric ulcers?

The rate at which HCl enters the duodenum could be too high for it to be neutralized there by pancreatic, biliary and duodenal secretions, and thereby causes the pH in the duodenum to be much lower than normal. In addition to the low pH, elevated levels of pepsin may contribute to the damage of the duodenal mucosa. Gastric pepsin secretion is elevated and enters the duodenum as part of chyme. The lower than normal pH in the duodenum allows pepsin to remain active and pepsin can contribute to ulcer formation through its proteolytic activity.

What abnormalities might lead to elevated serum gastrin levels?

There are several possible causes of high serum gastrin: a) Patients who are hyposecretors of gastric acid for any reason (such as pernicious anemia or achlorhydria = inability to lower gastric juice pH below 6.5 despite maximal stimulation of HCl secretion) have elevated serum gastrin. Normally, a low pH in the antrum inhibits gastrin secretion by G cells in the antrum and duodenum (negative feedback mechanism). In our case the patient is a hypersecretor of HCl (low antral and duodenal pH), so those causes can be ruled out. b) The most prominent possibilities that remain are hyperplasia of antral G cells or the presence (not in the stomach) of a gastrinoma (a gastrin-secreting tumor). Gastrinomas occur most frequently in the pancreas and are the cause of the disorder known as Zollinger-Ellison syndrome.

Why would a person with steatorrhea and diarrhea due to increased acid have weight loss?

Weight loss is due to malabsorption. Several factors contribute to malabsorption: - acid (low pH) damages the mucosa of the small intestinal and impairs the absorption process - inactivation of pancreatic enzymes in an acidic environment - precipitation of bile salts interferes with lipid absorption process.

What causes Zollinger-Ellison Syndrome?

Zollinger-Ellison Syndrome is caused by a non-beta islet cell gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration. The primary tumor is usually located in the pancreas, the duodenum, and abdominal lymph nodes. The disease is rare (~1 in a million) but affects 0.1-1% of all patients with duodenal ulcers.

Why might a person with acid reaching the duodenum have diarrhea?

a) The increased fat in the GI tract (seen as steatorrhea) is osmotically active (pulling fluid into the gut). b) Certain fatty acids are hydroxylated by intestinal bacteria to form compounds that induce secretion of fluid and electrolytes by colonic epithelial cells. c) Gastrin at high levels induces fluid secretion by the intestinal mucosa and inhibits absorption of fluid and electrolytes in the small intestine.