THE GASTROINTESTINAL SYSTEM

Hyperacidity with Duodenal Ulcer and Gastrinoma

A 25-year-old woman enters the hospital with persistent diarrhea and abdominal pain. An upper
gastrointestinal radiologic series suggests the presence of a duodenal ulcer, which is confirmed by
endoscopy. The patient's basal rate of secretion of gastric HCl is about 12 mmole/hr (the normal range is
1 to 5 mmole/hr). The patient's serum gastrin is 1145 pg/ml (the normal range is 50 to 150 pg/ml). When
the patient's gastric juice is removed via a nasogastric tube during a 24-hour period, the diarrhea is
corrected. The patient also has moderate steatorrhea (excess fat in the stool). A sample of the mucosa of
the patient's gastric fundus is taken via the endoscope. Histologic examination of the mucosal specimen
reveals that the gastric glands are more numerous than normal and have a higher density of parietal cells
than normal. After a test meal, the patient's serum gastrin level does not increase significantly. In the
average normal individual the same meal produces a doubling of serum gastrin. Intravenous infusion of
secretin results in a peak serum gastrin level that is three times the basal level. In normal individuals,
infusion of secretin has little effect on serum gastrin; the most common response is a slight decrease in
serum gastrin. The patient's rate of HCl secretion can be brought to below normal levels by treatment with
the H2 receptor blocker cimetidine. However, the dose of cimetidine required to do this is several times
greater than that usually used for patients with duodenal ulcer, and the drug must be administered four to
six times daily to suppress HCl secretion effectively. Administration of a cholinergic antagonist enhances
the therapeutic effect of the cimetidine. A single daily dose of the H+, K +-ATPase blocker omeprazole is
effective in bringing HCl secretion to below normal rates.

1. Why might the patient have an elevated basal rate of gastric HCl secretion?

2. How would you expect the patient's rate of pepsinogen secretion to compare with normal?

3. Why does the patient have a duodenal ulcer?

4. Why doesn't the patient have a gastric ulcer?

5. What abnormalities might lead to elevated serum gastrin levels?

6. Why does the patient have steatorrhea?

7. What causes the patient to have diarrhea?

8. Why does the patient have an increased density of parietal cells in her fundic mucosa?

9. Why does the patient not have a significant increase in serum gastrin after a test meal?

10. Why does the patient have such a large increase in serum gastrin after intravenous infusion of
secretin?

11. Why is cimetidine effective? Why are such large and frequent doses of cimetidine required?

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

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

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14. What options exist for the long-term management of this patient's care?

1. The dramatically elevated serum gastrin level in the patient might be responsible for the elevated rate
of HCI secretion. The increased density of gastric glands and increased population of parietal cells
within the glands in the biopsy specimen might also contribute to elevated HCI secretion.

2. Because HCl itself promotes the release of pepsinogen, the secretion of pepsinogen by the patient is
expected to be somewhat elevated. This should contribute to the ulceration of the patient's
duodenum.

3. The patient's stomach secretes HCl at rates far above normal. The amount of HCl that enters the
duodenum is probably too great 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, the elevated levels of pepsins may contribute to the damage of the duodenal mucosa.

4. 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. Gastric ulcers are
usually the result of a defect in the gastric mucosal barrier. For this reason, 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.

5. There are several causes of high serum gastrin. Patients who are hyposecretors of gastric acid for any
reason (such as pernicious anemia or achlorhydria) have elevated serum gastrin, because the
negative feedback induced by low pH in the antrum is a major brake on gastrin secretion by antral G
cells. This patient is a hypersecretor of HCI, so those causes can be ruled out. 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.

6. Pancreatic lipase is extremely pH sensitive and can be rapidly and irreversibly denatured at acid pH.
The inactivation of lipase because of the low duodenal pH in this patient is the most likely cause of
her steatorrhea.

7. The patient's steatorrhea probably contributes to the diarrhea. Certain fatty acids are hydroxylated by
intestinal bacteria to form compounds that induce secretion of fluid and electrolytes by colonic
epithelial cells. In addition, gastrin at high levels induces secretion and inhibits absorption of fluid and
electrolytes in the small intestine.

8. Gastrin has a trophic effect on the oxyntic mucosa. The constant high level of serum gastrin in this
patient is probably responsible for the increased number of gastric glands in the fundus and the
increased density of parietal cells in the glands of the fundus.

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 9. After a meal, peptides and amino acids in the stomach and gastric distension stimulate antral and
jejunal 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 a gastrinoma (Zollinger-Ellison syndrome), no significant
rise in gastrin is expected after a meal. This finding suggests that the patient has Zollinger-Ellison
syndrome.

10. Secretin strongly suppresses gastric HCI secretion, primarily by a direct inhibition of the parietal cells.
In a normal individual, secretin has little effect on the secretion of gastrin. 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.

11. Gastrin is a relatively weak secretagogue at the parietal cell. Gastrin mostly effects HCI secretion by
releasing histamine from ECL cells in the gastric mucosa. 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 and excreted at a fairly high rate. For this reason, and because of the very high gastrin
levels in this patient, large and frequent doses of cimetidine are required to suppress HCI secretion
sufficiently to allow the patient's ulcer to heal.

12. Acetylcholine is a secretagogue at the parietal cell and also elicits secretion of histamine by gastric
ECL cells. There is a potentiation between gastrin and acetylcholine at both cell types. Suppression of
cholinergic drive with an anticholinergic drug lessens the effectiveness of 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.

13. Omeprazole inhibits the H+, K+-ATPase in parietal cells. It is thus 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. For this reason, the inhibition of HCI secretion by omeprazole in this patient is longer
lasting than that by other drugs.

14. 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. Omeprazole has been available only recently and it is too
early to determine whether omeprazole therapy will supplant vagotomy and gastrectomy in the long-
term management of Zollinger-Ellison patients.