Abstract
Background and aims: Long-term treatment with H+-K+-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for
severe gastroesophageal reflux disease is now widely used. Whether such treatment
will result in vitamin B12 deficiency is controversial. We studied whether long-term treatment with omeprazole
alters serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.
Methods:
In 131 consecutive patients treated with either omeprazole (n = 111) or histamine
H2-receptor antagonists (n = 20), serum vitamin B12 and folate levels and complete blood counts were determined after acid secretion
had been controlled for at least 6 months. These studies were repeated yearly. Serum
vitamin B12 and folate levels were correlated with the type of antisecretory drug and the extent
of inhibition of acid secretion.
Results:
The mean duration of omeprazole treatment was 4.5 years, and for H2-receptor antagonists 10 years. Vitamin B12 levels, but not serum folate levels or any hematological parameter, were significantly
(P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced
sustained hyposecretion (P = 0.0014) or complete achlorhydria (P <0.0001). In 68 patients with two determinations at least 5 years apart, vitamin
B12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment
was inversely correlated with vitamin B12 levels (P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B12 levels during follow-up.
Conclusions:
Long-term omeprazole treatment leads to significant decreases in serum vitamin B12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome
treated with H+-K+-ATPase inhibitors should have serum vitamin B12 levels monitored. Furthermore, these results raise the possibility that other patients
treated chronically with H+-K+-ATPase inhibitors may develop B12 deficiency.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Omeprazole.Drugs. 1986; 32: 15-47
- Omeprazole. An update of its pharmacology and therapeutic use in acid-related disorders.Drugs. 1994; 48: 91-132
- Lansoprazole.A reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders. Drugs. 1994; 48: 404-430
- Gastroesophageal reflux disease.in: Sleisenger M.H Fordtran J.S Gastrointestinal Disease. 5th ed. WB Saunders, Philadelphia, Pa1993: 378-401
- Healing and relapse of severe peptic esophagitis after treatment with omeprazole.Gastroenterology. 1988; 95: 903-912
- Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis.Gastroenterology. 1990; 99: 621-628
- Long-term omeprazole therapy in peptic ulcer disease.Gastroenterology. 1993; 104: 1356-1370
- Vitamin B12 malabsorption and omeprazole therapy.J Am Coll Nutr. 1994; 13: 544-545
- Risks of hypergastrinemia.Dig Dis Sci. 1995; 13: 1-2
Maton PN, Dayal Y. Clinical implications of hypergastrinemia. In: Zakim D, Dannenberg AJ, eds. Peptic Ulcer Disease and Other Acid-related Disorders. Armonk, NY: Academic Research Associates;1991;213–246.
- Toxicological studies on omeprazole.Scand J Gastroenterol. 1985; 20: 53-69
- Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy.J Clin Gastroenterol. 1992; 14: 288-292
- Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption.J Am Coll Nutr. 1994; 13: 584-591
- Gastrointestinal absorption and transport of cobalamin (vitamin B12).in: Johnson L.R Alpers D.H Christensen J Physiology of the Gastrointestinal Tract. 3rd ed. Raven Press, New York1994: 1997-2026
- Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract.Scand J Gastroenterol. 1991; 26: 1-7
- Metabolic aspects of folic acid and cobalamin.in: Beutler E Lichtman M.A Coller B.S Kipps T.J William’s Hematology. 5th ed. McGraw-Hill, New York1996: 380-393
- Metabolic consequences of long-term inhibition of acid secretion by omeprazole.Aliment Pharmacol Ther. 1992; 6: 399-406
- Omeprazole therapy causes malabsorption of cyanocobalamin (Vitamin B12).Ann Intern Med. 1994; 120: 211-215
Festen H, Tertoolen J. Malabsorption of protein-bound but not unbound cobalamin during treatment with omeprazole. Gastroenterology 1988;94:A125. Abstract.
- The effect of omeprazole on gastric acidity and the absorption of liver cobalamins.Scand J Gastroenterol. 1987; 22: 156-160
- Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome.Gastroenterology. 1989; 97: 827-836
- Use of omeprazole in Zollinger-Ellison.Aliment Pharmacol Ther. 1993; 7: 597-610
- Advances in gastric antisecretory therapy in Zollinger-Ellison syndrome.in: Mignon M Jensen R.T Endocrine Tumors of the Pancreas Recent Advances in Research and Management. Frontiers of Gastrointestinal Research. S Karger, Basel, Switzerland1995: 240-257
- Zollinger-Ellison syndrome.JAMA. 1994; 271: 1-7
- Gastrinoma.in: Go V.L.W DiMagno E.P Gardner J.D The Pancreas Biology, Pathobiology and Disease. 2nd ed. Raven Press, New York, NY1993: 931-978
- Assessment and prediction of long-term cure in patients with Zollinger-Ellison syndrome.Ann Intern Med. 1993; 119: 199-206
- Secretin and calcium provocative tests in the Zollinger-Ellison syndrome.Ann Intern Med. 1989; 111: 713-722
- Control of gastric acid hypersecretion in the management of patients with Zollinger-Ellison syndrome.World J Surg. 1993; 17: 468-480
- Imaging for pancreatic endocrine tumor localization.in: Mignon M Jensen R.T Endocrine Tumors of the Pancreas Recent Advances in Research and Management. Frontiers of Gastrointestinal Research. S Karger, Basel, Switzerland1995: 268-281
- Selective venous sampling for gastrin to localize gastrinomas. A prospective study.Ann Intern Med. 1986; 105: 841-847
- Zollinger-Ellison syndrome can be the initial endocrine manifestation in patients with multiple endocrine neoplasia-type 1.Am J Med. 1994; 97: 436-444
- Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high.Gastroenterology. 1992; 103: 1498-1508
- Reflux esophagitis in patients with Zollinger-Ellison syndrome.Gastroenterology. 1990; 98: 341-346
- Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome.Gastroenterology. 1995; 108: 1637-1649
Dawson-Saunders B, Trapp RG. Basic and Clinical Biostatistics. Norwalk, Conn: Appleton & Lange; 1990:1–329.
- Effect of omeprazole on the secretion of intrinsic factor, gastric acid and pepsin in man.Gut. 1985; 26: 594-598
- The Zollinger-Ellison syndrome with steatorrhea. II. The mechanism of fat and vitamin B 12 malabsorption.Gastroenterology. 1968; 55: 705-723
- Hematologic alterations following partial gastrectomy.Am J Med Sci. 1973; 266: 240-248
- Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery.Ann Intern Med. 1996; 124: 469-476
- Prevalence of cobalamin deficiency in the Framingham elderly population.Am J Clin Nutr. 1994; 60: 2-11
- Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people.Am J Clin Nutr. 1993; 58: 468-476
- Impaired assimilation of egg CO57 vitamin B12 in patients with hypochlorhydria and achlorhydria and after gastric resection.Gastroenterology. 1973; 64: 913-919
- Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12.Dig Dis Sci. 1979; 24: 397-402
- Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis.Gastroenterology. 1991; 101: 1039-1045
- Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects.Gastroenterology. 1994; 106: 615-623
- Bacterial overgrowth during treatment with omeprazole compared with cimetidine.Gut. 1996; 39: 54-59
- Cimetidine and malabsorption of cobalamin.Dig Dis Sci. 1982; 27: 13-16
- Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration.Dig Dis Sci. 1980; 25: 188-191
- Effect of cimetidine on the absorption of vitamin B12.Scand J Gastroenterol. 1982; 17: 129-131
Belaiche J, Cattan D, Zittoun J, et al. Effect of ranitidine on cobalamin absorption. Dig Dis Sci 1983;28:667–668. Letter.
- Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole.Aliment Pharmacol Ther. 1987; 1: 239-251
- Famotidine in the therapy of gastric hypersecretory states.Am J Med. 1986; 81: 49-59
- Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states.in: Misiewicz J.J Wood J.R Ranitidine Therapeutic Advances. Excerpta Medica, Amsterdam, Netherlands1984: 168-198
- Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome.Gastroenterology. 1987; 93: 69-76
- Effects of omeprazole on acid secretion and acid related symptoms in patients with Zollinger-Ellison syndrome.Scand J Gastroenterol. 1989; 166: 95-100
- Use of omeprazole in patients with the Zollinger-Ellison syndrome.Dig Dis Sci. 1991; 36: 394-404
- Prospective study of the long-term efficacy and safety of lansoprazole in patients with Zollinger-Ellison syndrome.Aliment Pharmacol Ther. 1993; 7: 41-50
- Curative resection in Zollinger-Ellison syndrome.Ann Surg. 1992; 215: 8-18
- Gastrin-producing tumors.Cancer Treat Res. 1997; 89: 293-334
- Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis.NEJM. 1988; 318: 1720-1728
- Pernicious anemia.The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med. 1988; 148: 1712-1714
- Atypical cobalamin deficiency. Subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption.J Lab Clin Med. 1987; 109: 454-463
- Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels.Ann Intern Med. 1996; 124: 299-304
- The role of cobalamin in synthesis of protein and immunoglobulins by human peripheral lymphocytes.Nutr Res. 1981; 1: 349-361
- Reversible hypogammaglobulinaemia in cyanocobalamin (B12) deficiency.Acta Med Scand. 1963; 174: 193-200
- Immunoglobulin deficiency responding to vitamin B12 in two elderly patients with megaloblastic anaemia.Postgrad Med J. 1985; 61: 1065-1066
- Subtle cobalamin deficiency.Ann Intern Med. 1996; 124: 338-340
- Long term omeprazole treatment in man.Digestion. 1988; 39: 126-135
Article Info
Publication History
Published online: August 16, 2004
Accepted:
February 25,
1998
Received in revised form:
February 25,
1998
Received:
July 21,
1997
Identification
Copyright
© 1998 Excerpta Medica Inc. Published by Elsevier Inc. All rights reserved.
