My Patient Has Reflux Esophagitis in Spite of Daily Omeprazole. His Serum Gastrin on Omeprazole Is 750. What Is the Next Step in Evaluation for Gastrinoma?
Susan
Truong,
HMS
Alphonso
Brown,
MD, MS Clin Epi
Reflux esophagitis is best treated with anti-secretory therapy, proton pump inhibitors (PPIs). The step-up approach for heartburn, reflux esophagitis, beginning with over-the-counter antacids, progressing to H2 blockers, and then PPIs, has been replaced with a step-down approach. As the cost of PPIs, with the advent of generic omeprazole, has decreased, this approach is not effective and not cost effective. PPIs are considered just as safe as H2 blockers, yet they are far more effective.
Years prior, when PPIs were first introduced as omeprazole (Prilosec [AstraZeneca, Wilmington, DE), safety was a concern. As omeprazole resulted in a profound decrease in acid secretion, the cells responsible for stimulating acid secretion, sensing the absence of acid, increased release of the stimulatory hormone, gastrin. Although gastrin levels normally rise in patients taking PPIs, the elevation is typically not of clinical significance. Animal studies, especially murine models, given PPIs have shown a proliferation of gastrin-secreting cells and even the development of gastrinomas. The fear has been that the elevated gastrin level (hypergastrinemia) often seen in patients on PPIs will pose a risk for persons to develop gastrinomas.
Hypergastrinemia can be caused by several entities (Table 36-1) with gastrinoma, or Zollinger-Ellison syndrome (ZES), the most feared the diagnosis. A normal fasting serum gastrin level typically is below 110 to 150 pg/mL. Antisecretory medications can moderately raise the gastrin level to approximately 200 to 400 pg/mL. It has been shown, however, that a group of approximately 5% of patients on PPI therapy have gastrin levels greater than 400 pg/mL. With gastrinomas, one typically sees fasting gastrin levels greater than 1000 pg/mL but it is important to remember that as many as 10% of ZES patients have serum gastrins well below 1000 pg/mL.
ZES typically presents with recurrent multiple peptic ulcer disease due to acid hypersecretion. Approximately 90% of patients develop multiple ulcers with the majority located in the first portion of the duodenum. ZES can also present with diarrhea as the predominant symptom as excess acid secretion can lead to inactivation of pancreatic enzymes resulting in malabsorption and steatorrhea. Signs suggestive of acid hypersecretion, such as multiple recurrent peptic ulcer disease, diarrhea, or history of multiple endocrine neoplasia type I, should prompt work-up for ZES. This includes fasting serum gastrin concentration off of PPIs, secretin stimulation test, and gastric acid secretion studies. The first 2 tests are routinely used to aid in diagnosis.
The first step is to obtain a fasting gastrin level off of PPI therapy for at least 1 week. As mentioned above, a gastrin greater than 1000 pg/mL is typically seen in ZES. It is, however, not diagnostic of the disease as patients with pernicious anemia can also have serum gastrin levels in that range. It is, therefore, important to keep the patient’s clinical picture in mind when evaluating for gastrinoma. For patients with serum gastrins greater than 1000 pg/mL, a gastric pH probe can help to distinguish between chronic atrophic gastritis and other causes. An elevated pH would suggest pernicious anemia. For patients with gastrin levels between 110 pg/mL and 1000 pg/mL, a secretin stimulation test can help guide further work-up. This test is based on the fact that a normal gastrin-secreting cell will be inhibited by the infustion of secretin (a normally acting inhibitor of gastrin secretion). Patients with ZES, with a gastrinoma, have an uncoupling of the secretin inhibitory receptor. Thus, these patients should have a persistent or significant elevation of serum gastrin levels after secretin stimulation while patients with other causes for hypergastrinemia should not have a rise in serum gastrin. A decrease should be noted. If a patient has no inhibitory response to the secretin, one should pursue imaging to try to localize the tumor. This can be done either with an octreotide scan or an endoscopic ultrasound (EUS). Octreoscan is best for metastatic disease or lymph node involvement. EUS images the pancreas with great accuracy and can allow a fine needle aspiration of small suspected tumors to confirm the diagnosis (Figure 36-1).
Figure 36-1. Endoscopic ultrasound showing a small 1.5-cm mass consistent with an islet cell tumor. Fine needle aspiration shown revealed gastrinsecreting cells on immunostain consistent with gastrinoma.
For this particular patient, an elevated serum gastrin of 750 pg/mL on PPI therapy is not strong enough evidence to suggest gastrinoma. Several options exist, including a secretin stimulation test. With ZES being such a rare entity, one should consider all other causes for his PPI resistant reflux esophagitis before pursuing this pathway. The first reasonable step would be for the patient to have endoscopy to evaluate his reflux and to determine if he has gastritis or ulcer disease as well. Should this reveal multiple duodenal ulcers, one may pursue a repeat gastrin level after stopping PPI for 1 week. Computed tomography, magnetic resonance imaging, and EUS should be performed for imaging if a gastrinoma is suspected.
Bibliography
Koop HAR. Long-term maintenance treatment of reflux esophagitis with omeprazole: prospective study in patients with H2-blocker-resistant esophagitis. Dig Dis Sci. 1991;36;552-557.
Lamberts R, Brunner G, Solcia E. Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion. 2001;64:205-213.
Orlando LA, Lenard L, Orlando RC. Chronic hypergastrinemia: causes and consequences. Dig Dis Sci. 2007;52:2482-2489.
Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684.