Megaloblastic anemia

◉ Causes of megaloblastic anemia

There are a few factors that contribute to this condition, but the most common cause of megaloblastic anemia is a deficiency of vitamin B12 and folic acid.

These two vitamins play a significant role in DNA synthesis and the development of all body cells, especially red blood cells.

Sometimes, it occurs as a side effect of medications that affect the bone marrow, like methotrexate, or as a result of an autoimmune disorder such as pernicious anemia.

Here are a few of the main causes:

◉ Pathophysiology of megaloblastic anemia

Folate and vitamin B12 deficiencies cause defective synthesis of DNA leading to errors in DNA replication and arrested division and therefore apoptosis of hematopoietic stem cells causing ineffective and incomplete erythropoiesis.

◉ Pathophysiology of megaloblastic anemia

Symptoms of megaloblastic anemia vary from one patient to another. If anemia develops gradually and patient is compensated it may be asymptomatic. While patients with severe anemia will have cardiac, neurological and gastrointestinal symptoms.

◉ How to diagnose megaloblastic anemia?

The diagnosis of megaloblastic anemia depends on obtaining a detailed medical and familial history from the patient, along with an assessment of the clinical presentation and characteristic findings in blood tests. Additionally, patients should be evaluated for underlying conditions that may contribute to megaloblastic anemia.

1- Complete blood count (CBC):

Mean corpuscular volume (MCV): greater than 100FL is diagnostic for megaloblastic anemia. And if MCV if greater than 115FL is more specific to vitamin B12 deficiency or cobalamin deficiency than other causes of macrocytosis. On the other side low MCV doesn’t exclude megaloblastic anemia.

2- Peripheral blood smear

Peripheral blood smear shows macro-ovalocyte which is specific to megaloblastic anemia. Also smear shows anisocytosis (variation in red blood cells size) and poilkocytosis (variation in RBCs shape).

3- Serum vitamin B12 (cobalamin): can be measured by ELISA (enzyme linked immuno-sorbent assay) if level below 200pg/ml it is diagnostic for deficiency.

4- Serum folate level: less than 2ng/ml (< 4.53nmol/L).

5- Red blood cell folate (RBCs folate): if level is less than 150ng/ml that is diagnostic. This test is not recommend in most of patients.

6- Serum level of methyl malonic acid (MMA) and homocysteine (HCY) both are elevated in vitamin B12 deficiency, while in folate deficiency only homocysteine is elevated.

7- Holotranscobalamine (Holo Tc): this is the active fraction of serum cobalamin which is more specific than serum cobalamin level.

8- Serum LDH: markedly elevated in severe megaloblastic anemia.

9- Bone marrow aspiration (BM aspiration):

bone marrow aspiration is not an important study in evaluation of vitamin B12 or folate deficiency, but it helps exclude other causes of megaloblastic anemia such as myelodysplastic syndrome and assess iron stores.

Aspiration show enlarged and immature RBCs in bone marrow which confirms diagnosis.

◉ Treatment of megaloblastic anemia

Treatment of megaloblastic anemia can be done by many ways depending on the underlying cause of anemia and symptoms that patient is presented with.

◉ Conclusion

In conclusion there are plenty of causes that result in megaloblastic anemia, moreover, depending on the cause the management plan is decided accordingly.


  1. Hariz A, Bhattacharya PT. Megaloblastic Anemia. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
  2. Facp, S. N. M. M. (n.d.). Megaloblastic anemia Treatment & Management: Approach considerations, Cobalamin therapy, folate Therapy.
  3. Moawad, H., MD. (2022, February 14). What is megaloblastic anemia? Verywell Health.
  4. Arora, H. (2015, September 9). Megaloblastic anemia. Medindia.
  5. Gerber, G. F. (2023, December 8). Megaloblastic macrocytic anemias. Merck Manuals Professional Edition.
  6. National Organization for Rare Disorders. (2023b, August 23). Megaloblastic anemia - Symptoms, causes, treatment | NORD.