Setting: office
CC: “Why do my ulcers keep coming back?”
VS: BP:114/74 mm Hg; P: 88 beats/minute; T: 97.8°F; R: 14 breaths/minute
HPI: A 43-year-old man who was recently tested and treated for a gastric ulcer now comes to your office with recurrence of epigastric pain. The eradication of the last gastric ulcer was confirmed by repeat endoscopy several weeks after treatment. A biopsy showed no cancer at the time. Testing for active Helicobacter infection was negative as well. He restarted a PPI 2 weeks ago but still has epigastric discomfort. He took ibuprofen for a few days for the pain.
ROS:
Diarrhea several times a day
Medications:
Esomeprazole
Ibuprofen
Nonsteroidal antiinflammatory drugs (NSAIDs) are the second most common cause of ulcers.
1. NSAIDs inhibit prostaglandins.
2. Prostaglandins make gastric mucus.
3. Gastric mucus protects against acid.
PE:
Abdomen: soft, nontender, hyperactive bowel sounds
Skin: vesicular lesions on extensor surfaces
Which of these tests cannot determine if H. pylori infection is current and active?
a. Stool antigen
b. Breath testing
c. Serology
d. Biopsy
Answer c. Serology
The presence of immunoglobulin G (IgG) alone for serology for H. pylori cannot show that the infection is active. Serology cannot tell old versus new infection. We tend to use the stool antigen test more often for technical reasons—it is easier to do and no equipment is needed—in an office. Biologically, carbon-labeled urea and stool antigen testing are equal.
Breath Test Mechanism
1. The patient drinks urea that is labeled with radioactive carbon.
2. Urease splits off the ammonia.
3. Ammonia (NH3) binds to acid and stays in the gut as NH4+.
4. Carbon dioxide (CO2) with label (C13 or C14) is exhaled and detected.
Initial Orders:
Do a Helicobacter stool antigen test.
Continue esomeprazole.
Stop ibuprofen.
Exclude persistent Helicobacter infection as a cause of treatment failure first.
If Helicobacter was not eradicated with PPI, amoxicillin, and clarithromycin, what would be the first step?
a. Retreat with the same regimen.
b. Continue PPI; switch antibiotics to metronidazole, tetracycline, and bismuth subsalicylate.
c. Obtain sensitivity testing of the organism.
d. Repeat the endoscopy.
e. Add an H2-blocker.
Answer b. Continue PPI; switch antibiotics to metronidazole, tetracycline, and bismuth subsalicylate.
Manage persistent Helicobacter infections as a failure of antibiotics and possible resistance to the original antibiotics. Switching the medications and trying that for 2 to 3 weeks is easier than waiting for sensitivity testing. Bismuth’s effect is to suppress Helicobacter infection.
The Interval History shows that the patient says his pain persists. He saw another clinician, who ordered a serum gastrin level, which is elevated.
What is the meaning of the elevated gastrin?
a. Everyone on a PPI has an elevated gastrin, it means nothing at this time.
b. He has Zollinger-Ellison syndrome (ZES).
c. The patient must have a pancreatic lesion.
Answer a. Everyone on a PPI has an elevated gastrin, it means nothing at this time.
Gastrin levels should not be evaluated while patients are on PPIs. Every time you lower gastric acidity with a PPI, H2-blocker, or liquid antacid, the gastrin level will rise. To diagnose ZES or gastrinoma, you need to evaluate the gastrin level after stopping PPI therapy.
Acid is feedback inhibition on gastrin.
NORMAL: Low Acid = High Gastrin
Have the patient return to discuss the results of Helicobacter testing.
Also, any time you have a complicated case that fails primary therapy, order a consultation in the area. This shows that you know when you need help.
Report:
Stool antigen is negative for Helicobacter.
Order:
Upper endoscopy
Move the clock forward to get the endoscopy done. If pain persists after NSAIDs are stopped and persistent Helicobacter infection has been excluded, you need to scope the patient.
Report:
Upper endoscopy: multiple, large ulcers in second and third portions of duodenum
Evaluate gastrin level after stopping PPI therapy when the patient has
• Large ulcers (>1 cm)
• Multiple ulcers
• A recurrence of symptoms after Helicobacter eradication
• Distal ulcers (past the first part of the duodenum)
Hold the PPIs for a day and recheck the gastrin level or measure gastric acid output with a tube.
High Acid + High Gastrin = ZES
The patient comes to the office after not taking a PPI for 2 days and has both the gastrin level and the gastric acid output measured. Both are elevated, but the gastrin level is only marginally elevated and not higher than 1000 pg/mL.
When gastrin levels are equivocally elevated, what test will confirm gastrinoma?
a. Ultrasound
b. CT
c. Magnetic resonance imaging (MRI)
d. Secretin suppression test
e. Endoscopic ultrasound (EUS)
Answer d. Secretin suppression test
Secretin should normally lower gastrin levels. Secretin decreases acid by releasing bicarbonate-rich fluid from the pancreas. Secretin also shuts off acid production by decreasing gastrin by a direct suppressive effect. In gastrinoma, the gastrin level will not go down with secretin.
Endocrine disorders must always be confirmed with a function test before an imaging test. You cannot tell the functional content of a lesion by ultrasound (US), CT, or MRI. EUS is an excellent test for locating lesions in the pancreas, but it cannot show the functional content of the lesion.
1. Gastrin stimulates parietal cells to make acid.
2. Acid in the duodenum makes secretin.
3. Secretin releases 2 to 3 L/day of bicarbonate-rich fluid from the pancreas.
Normal: Secretin suppresses gastrin to stop acid production.
Gastrinoma: Secretin cannot suppress gastrin.
The patient returns earlier than expected because of sudden worsening of diarrhea during the test for gastric acid output and gastrin levels while stopping the PPI. Both gastrin and acid levels were high. In addition, there was a change in stool “character.”
What is the mechanism of the diarrhea?
a. Acid inactivates lipase.
b. Acid increases GI tract motility.
c. Gastrin opens sphincters.
d. It is caused by bacterial overgrowth from long-term PPI use.
e. Pepsin deactivation
Answer a. Acid inactivates lipase.
Lipase in the duodenum works at a pH >4. When acid is massively overproduced as it is in gastrinoma, you frequently get diarrhea. It is effectively a steatorrhea. Pepsin that is made in the stomach is inactivated by basic pH in the duodenum. This is why the physiologic effect of pepsin is limited and it is not necessary for life.
Acid in the duodenum actually decreases gastric motility. Gastrin directly stimulates stomach motility and growth. The acid the gastrin makes slows the small bowel motility.
Normal GI tract physiology:
• Acid in the duodenum slows stomach emptying.
• Acid inactivates lipase.
• Base inactivates pepsin.
Gastric acid output and gastrin level are high. The patient’s diarrhea resolves with restarting a PPI. You can cure gastrinoma by surgical removal if the lesion is solitary. If it is metastatic, the patient will need lifelong PPIs and there is no cure.
Orders:
Abdominal CT
Calcium level
The abdominal CT and MRI do not show metastatic disease. The calcium level is normal. There was actually an increase in the gastrin level with the use of secretin. High calcium level with gastrinoma would have meant hyperparathyroidism. Hyperparathyroidism with gastrinoma means possible multiple endocrine neoplasia (MEN) syndrome.
When do you look for MEN?
• Hypercalcemia
High Calcium + Gastrinoma = Look for MEN
Why is there a paradoxical rise in gastrin with the use of secretin in gastrinoma (ZES)?
a. Secretin directly stimulates gastrin in gastrinoma.
b. Cholecystokinin level increases.
c. Bicarbonate release raises pH and removes any residual feedback inhibition on G cells.
Answer c. Bicarbonate release raises pH and removes any residual feedback inhibition on G cells.
Gastrinoma is an adenoma. Adenomas can return some residual normal feedback inhibition sensitivity. When secretin causes the ductal cells of the pancreas to release bicarbonate-rich fluid, there is loss of the normal feedback inhibition provided by acid.
If the abdominal CT does not show metastases, order an EUS and nuclear somatostatin scan. When using both modalities, you exceed 95% sensitivity in finding metastatic gastrinoma. You want to be sure the disease is local before you go in and resect it.
Orders:
EUS
Nuclear somatostatin scan
Both tests have negative results. The patient should undergo surgical resection of the gastrinoma and the disorder will resolve.
Gastrinoma leads to increased somatostatin receptors in the GI tract.