Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome

Am J Med. 1998 May;104(5):422-30. doi: 10.1016/s0002-9343(98)00087-4.


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.

MeSH terms

  • Achlorhydria / chemically induced*
  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adolescent
  • Adult
  • Aged
  • Anti-Ulcer Agents / adverse effects*
  • Drug Monitoring
  • Female
  • Folic Acid / blood
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Omeprazole / adverse effects*
  • Time Factors
  • Vitamin B 12 / blood
  • Vitamin B 12 Deficiency / blood
  • Vitamin B 12 Deficiency / chemically induced*
  • Zollinger-Ellison Syndrome / drug therapy*


  • Anti-Ulcer Agents
  • Folic Acid
  • Adenosine Triphosphatases
  • Omeprazole
  • Vitamin B 12