Correspondence

Gastroesophageal Reflux Disease

N Engl J Med 2009; 360:729-730February 12, 2009

Article

To the Editor:

In his article about gastroesophageal reflux disease, Kahrilas (Oct. 16 issue)1 describes the potential risks of prolonged use of proton-pump inhibitors. However, the author does not call attention to the important relation between sustained hypochlorhydria and vitamin B₁₂ and iron deficiency.

Vitamin B₁₂ deficiency is a major public health problem in the elderly population. Long-standing administration of proton-pump inhibitors can result in malabsorption of cobalamin in food2 and contribute, along with conditions such as autoimmune gastritis and lifestyle choices such as vegetarianism, to the development of clinically manifest vitamin B₁₂ deficiency.3 Moreover, it is well known that hypochlorhydria secondary to early or full-blown autoimmune atrophic gastritis is one of the main causes of refractory iron-deficiency anemias in the absence of chronic gastrointestinal bleeding.4 The causal mechanism is closely related to the persistently low production of hydrochloric acid.5 Hypochlorhydria caused by treatment with proton-pump inhibitors could have similar consequences. Therefore, in patients treated over the long term with proton-pump inhibitors, close clinical vigilance is warranted for the early detection and correction of vitamin B₁₂ and iron deficiency.

Ciriaco Aguirre, M.D., Ph.D.
Guillermo Ruiz-Irastorza, M.D., Ph.D.
University of the Basque Country, 48903 Barakaldo, Spain
r.irastorza@euskalnet.net

Maria-Victoria Egurbide, M.D., Ph.D.
Hospital de Cruces, 48903 Barakaldo, Spain

5 References

1. 1

   Kahrilas PJ. Gastroesophageal reflux disease. N Engl J Med 2008;359:1700-1707
   Full Text | Web of Science | Medline

2. 2

   Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med 2000;51:357-375
   CrossRef | Web of Science | Medline

3. 3

   Andres E, Noel E, Abdelghani MB. Vitamin B(12) deficiency associated with chronic acid suppression therapy. Ann Pharmacother 2003;37:1730-1730
   CrossRef | Web of Science | Medline

4. 4

   Hershko C, Hoffbrand AV, Keret D, et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica 2005;90:585-595
   Web of Science | Medline

5. 5

   Annibale B, Capurso G, Delle Fave G. The stomach and iron deficiency anaemia: a forgotten link. Dig Liver Dis 2003;35:288-295
   CrossRef | Medline

To the Editor:

As Kahrilas notes, maintenance acid-suppressing therapy is often necessary in patients with gastroesophageal reflux disease. A troublesome issue regarding indefinite treatment with proton-pump inhibitors is the propensity for chronic atrophic gastritis to develop in patients infected with Helicobacter pylori.1 Atrophic gastritis could theoretically lead to an increased risk of gastric cancer. On the other hand, some studies have shown that eradication of H. pylori in patients with reflux esophagitis who are receiving proton-pump inhibitors can decrease inflammation and reverse corpus gastritis.2 As a result, the current guidelines of the European Helicobacter Study Group suggest that H. pylori testing be considered in patients receiving long-term maintenance treatment with proton-pump inhibitors.3

Francisco José Fernández-Fernández, M.D.
Hospital Arquitecto Marcide, 15405 Ferrol, Spain
fjf-fernandez@terra.es

3 References

1. 1

   Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996;334:1018-1022
   Full Text | Web of Science | Medline

2. 2

   Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217-1221
   CrossRef | Web of Science | Medline

3. 3

   Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-781
   CrossRef | Web of Science | Medline

Author/Editor Response

Proton-pump inhibitors are highly efficacious in maintaining remission in patients with gastroesophageal reflux disease or peptic ulcer disease, as well as in providing protection against ulcers in patients taking nonsteroidal antiinflammatory drugs. As evidence of the efficacy of proton-pump inhibitors, billions of doses have been taken, in the form of prescription drugs, generic drugs, and over-the-counter trade-name and generic drugs. Clearly, there is a strong consensus that these drugs are reasonably safe. However, no drug is perfectly safe. In the case of the proton-pump inhibitors, most safety considerations pertain to unwanted effects of long-term hypergastrinemia, hypochlorhydria, or even achlorhydria.1

Aguirre and colleagues highlight selected risks of nutrient malabsorption. Hypochlorhydria prevents the reduction of nonabsorbable iron to its absorbable ferrous form, leading to iron-deficiency anemia. Similarly, hypochlorhydria impairs the release of vitamin B₁₂ from binding proteins and food, leading to deficiency. Both deficiencies are encountered with atrophic gastritis or after partial gastrectomy. However, there are only a few case reports of iron deficiency or vitamin B₁₂ deficiency potentially linked to the use of proton-pump inhibitors. Evidently, the degree and constancy of acid suppression associated with the use of these agents is usually not similar to those in atrophic gastritis. A possible exception might be in association with H. pylori gastritis, which is pertinent to the comments of Fernández-Fernández. H. pylori can cause atrophic gastritis, which increases the risk of gastric cancer. Long-term use of proton-pump inhibitors accelerates the progression to atrophic gastritis,2 an observation that led to the Maastricht III Consensus recommendation that an H. pylori test-and-treat strategy be considered for patients receiving long-term treatment with proton-pump inhibitors.3 However, there are no data from either clinical trials or population databases to substantiate an increased risk of H. pylori–associated gastric cancer with the use of proton-pump inhibitors, leaving this recommendation in the realm of the theoretical.

In summary, there is currently inadequate evidence to mandate H. pylori screening or any other routine precaution with long-term use of proton-pump inhibitors. That said, proton-pump inhibitors should be used at dose levels and in conditions for which they have proven efficacy; in the absence of a benefit, any drug-associated risks are unacceptable.

Peter J. Kahrilas, M.D.
Northwestern University Feinberg School of Medicine, Chicago, IL 60611-2951
p-kahrilas@northwestern.edu

3 References

1. 1

   Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1392-1413
   CrossRef | Web of Science | Medline

2. 2

   Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217-1221
   CrossRef | Web of Science | Medline

3. 3

   Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-781
   CrossRef | Web of Science | Medline