What are the causes of macrocytic anemia (large red blood cell anemia)?

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From the Guidelines

Macrocytic anemia is primarily caused by vitamin B12 deficiency and folate deficiency. The most common causes of megaloblastic, macrocytic anemia are vitamin B12 and folate deficiency, as stated in the British Obesity and Metabolic Surgery Society guidelines 1. These deficiencies can lead to the production of larger, immature red blood cells characteristic of macrocytic anemia. Some key points to consider in the diagnosis and treatment of macrocytic anemia include:

  • Vitamin B12 deficiency can result from inadequate dietary intake, malabsorption, or gastrointestinal disorders, and should be treated immediately with hydroxocobalamin 1 mg intramuscularly administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months 1.
  • Folic acid deficiency may indicate non-adherence with daily multivitamin and mineral supplements, malabsorption, or certain medications, and should be treated with oral folic acid 5 mg daily for a minimum of 4 months after excluding vitamin B12 deficiency 1.
  • It is essential to identify and address the underlying cause of macrocytic anemia, as these vitamins are crucial for proper DNA synthesis and red blood cell maturation. Key considerations in the treatment of macrocytic anemia include:
  • Vitamin B12 injections for B12 deficiency
  • Oral folate supplementation for folate deficiency
  • Addressing underlying causes such as malabsorption, gastrointestinal disorders, or certain medications.

From the Research

Causes of Macrocytic Anemia

  • Macrocytic anemia can be classified into megaloblastic and nonmegaloblastic anemia 2, 3
  • Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate 2, 3, 4
  • Nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and less commonly inherited disorders of DNA synthesis 2, 3, 5
  • Other causes of macrocytosis include reticulocytosis, which is a normal physiologic response to acute anemia 6, 5

Megaloblastic Anemia

  • Vitamin B12 deficiency is the most common cause of megaloblastic anemia 3, 4
  • Folate deficiency can also contribute to megaloblastic anemia 3, 4
  • Lack of vitamin B12 and/or folate can lead to elevated homocysteine levels, which is a key factor responsible for megaloblastic anemia 4

Nonmegaloblastic Macrocytic Anemia

  • Chronic liver dysfunction, hypothyroidism, alcohol use disorder, and myelodysplastic disorders can cause nonmegaloblastic macrocytic anemia 3, 5
  • Alcoholism is the most common form of nonmegaloblastic macrocytic anemia 5
  • Nonmegaloblastic macrocytic anemias may be accompanied by increased reticulocyte counts or by normal or decreased reticulocyte counts 5

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Diagnosis and treatment of macrocytic anemias in adults.

Journal of general and family medicine, 2017

Research

Anemia: Macrocytic Anemia.

FP essentials, 2023

Research

Macrocytic anemia.

American family physician, 1996

Research

Investigation of macrocytic anemia.

Postgraduate medicine, 1979

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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