Can omeprazole cause anemia, and how does it occur?

Can Omeprazole Cause Anemia?

Yes, omeprazole can cause anemia, primarily through two mechanisms: impaired iron absorption leading to iron deficiency anemia, and impaired vitamin B12 absorption leading to megaloblastic anemia.

Mechanisms of Anemia Development

Iron Deficiency Anemia

Omeprazole causes iron deficiency anemia by creating a hypochlorhydric or achlorhydric gastric environment that impairs the absorption of oral iron supplementation. 1, 2

• Gastric acid is essential for converting ferric iron (Fe³⁺) to the more absorbable ferrous form (Fe²⁺), and PPIs suppress this critical step 3, 4
• The FDA drug label includes precautionary notices regarding risks for anemia and specifically notes that PPI use decreases iron absorption and may cause iron deficiency anemia 1, 2
• A dose-dependent association exists between continuous PPI use and risk of iron deficiency, though this typically requires ≥1 year of use 1

Clinical evidence demonstrates that iron-deficient patients taking omeprazole have markedly suboptimal responses to oral iron supplementation:

• In a study of 50 iron-deficient anemic patients on omeprazole, only 16% achieved a normal hemoglobin response (rise >2 g/dL) and only 40% achieved a normal ferritin response (rise >20 μg/dL) after 3 months of ferrous sulfate therapy 3
• The mean hemoglobin change was only 0.8 ± 1.2 g/L, and mean ferritin change was only 10.2 ± 7.8 μg/L—both far below expected responses 3
• Case reports document iron deficiency anemia developing after as long as 25 years of omeprazole use, even without any identifiable gastrointestinal blood loss 5

Vitamin B12 Deficiency Anemia

Daily treatment with omeprazole over a long period (longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. 2

• Gastric acid and pepsin are required to cleave vitamin B12 from food proteins, and PPIs suppress this process 1
• In patients with Zollinger-Ellison syndrome treated with omeprazole for a mean duration of 4.5 years, vitamin B12 levels were significantly lower (P = 0.03), especially in those with sustained hyposecretion (P = 0.0014) or complete achlorhydria (P < 0.0001) 6
• Vitamin B12 levels decreased significantly (30%; P = 0.001) in patients rendered achlorhydric over at least 5 years of follow-up 6
• The duration of omeprazole treatment was inversely correlated with vitamin B12 levels (P = 0.013) 6
• Eight percent of patients developed subnormal B12 levels during long-term follow-up 6

Clinical Implications and Management

Iron-deficient patients taking omeprazole may require high-dose oral iron therapy for longer duration or intravenous iron therapy to overcome the absorption impairment. 3

• Standard oral iron supplementation is often insufficient in the presence of PPI-induced achlorhydria 3, 4
• Consider temporarily discontinuing the PPI if clinically feasible, or switching to H2-receptor antagonists which have less profound effects on gastric pH 1
• Intravenous iron bypasses the gastric absorption problem entirely and may be the most effective option for refractory cases 3

For vitamin B12 deficiency, patients on long-term omeprazole should have serum vitamin B12 levels monitored periodically. 6

• This is particularly important for patients treated for longer than 3 years 2
• The FDA drug label specifically recommends considering this diagnosis if clinical symptoms consistent with cyanocobalamin deficiency are observed 2

Important Caveats

The American Gastroenterological Association does not currently recommend routine screening for nutritional deficiencies or providing supplementation to all individuals taking PPIs, given the lack of causal evidence from randomized controlled trials and heterogeneous findings from observational studies. 1

• However, the FDA drug label does include precautionary notices regarding these risks 1, 2
• Well-controlled, long-term (≥1 year) randomized controlled trials accounting for supplement use and dietary intake are needed to conclusively determine the effects 1
• Some large RCTs (Safety of Omeprazole in Peptic Reflux Esophagitis and Long-Term Usage of Esomeprazole versus Surgery) reported no significant differences in iron or vitamin B12 at 5 years, though these were not structured to detect clinically relevant changes 1

The risk is highest in patients with:

• Pre-existing iron deficiency or vitamin B12 deficiency 3, 4
• Complete achlorhydria induced by high-dose or long-term PPI therapy 6
• Advanced age 3
• Duration of therapy exceeding 1 year for iron deficiency and 3 years for B12 deficiency 1, 2