Zollinger-Ellison syndrome

* EVIDENCE-BASED ANSWER

Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.

* EVIDENCE SUMMARY

The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.

Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochromaffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors. (1) Three other nonsystematic reviews support these findings. (2-4) In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes. (5)

Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis. (1) The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma. (1) Three other nonsystematic reviews support these findings. (2,3,5) The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.

Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections. (6)

Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate nonsystematic reviews showed no problems with malabsorption of these micronutrients. (1,3)

B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome). (1,2) This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.

* RECOMMENDATIONS FROM OTHERS

A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted. (7) The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use. (8,9)

REFERENCES

(1.) Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14:651-668.

(2.) Garnett WR. Considerations for long-term use of proton-pump inhibitors. Am J Health Syst Pharm 1998; 55:2268-2279.

(3.) Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997; 92(4 Suppl):51S-57S.

(4.) Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999; 20:195-205.

(5.) Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003; 17:343-351.

(6.) Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997; 8:571-574.

(7.) Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996; 58(Nov 11):T&G:1-2.

(8.) Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.

(9.) DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999; 94:1434-1442.

* CLINICAL COMMENTARY

No evidence of long-term adverse health effects from PPIs, but cost still a problem

Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.

Richard A. Guthmann, MD, Illinois Masonic Family Practice Residency, University of Illinois at Chicago

Wail Malaty, MD, Mountain Area Health Education Center Rural Track Family Practice Residency, Hendersonville, NC; Sue Stigleman, MLS, Mountain Area Health Education Center, Asheville, NC; Jill Mayer, MLIS, Health Sciences Library, University of North Carolina at Chapel Hill

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