Content:
◉ Introduction
Megaloblastic anemia is a form of anemia in which the bone marrow produces abnormally large and immature red blood cells (megaloblasts) into the blood stream in inadequate amounts, leading to an impairment in red blood cells function and oxygen delivery to the tissues and organs.
◉ 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:
- Dietary: Eating very small amounts of vitamin B12 or folate-containing foods causes a deficiency over a period of time.
- Digestion: Conditions that affect the small intestine, specifically the ileum, such as celiac disease or Crohn's disease, are prone to developing vitamin B12 deficiency due to malabsorption.
- Autoimmune: Antibodies attack parietal cells of the stomach, affecting intrinsic factor production and vitamin B12 absorption.
- Demand: Increased demand in cases such as pregnancy, hemolysis, malabsorption, and hemodialysis can cause symptoms of megaloblastic anemia.
- Medication: Drugs like anticancer and anticonvulsants affect folate metabolism and bone marrow function.
◉ 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.
- Symptoms of anemia: fatigue, pallor (pale skin), palpitations, dizziness, headache, hypersomnia (heavy sleepiness) and difficulties in concentration.
- Gastrointestinal symptoms: decreased appetite, weight loss and diarrhea.
- Jaundice: it is a yellowish discoloration of skin and mucous membranes due to increased production of indirect bilirubin because of intramedullary hemolysis.
- Glossitis: it is a smooth swollen tongue due to loss of papillae which occurs in cobalamin deficiency.
- Neurological manifestations: peripheral neuropathy is apparent especially in patients affected by vitamin B12 deficiency, this is characterized by paresthesia (patient develops lancinating pain in lower extremities) and disturbed gait (problem in balance). These symptoms could occur in both folate and vitamin B12 deficiency but they are more evident in cobalamin deficiency.
- Subacute combined degeneration: it is a degeneration of spinal cord posterolateral Column occurring in cobalamin deficiency. Patient is presented with abnormal gait, loss of proprioceptive and vibratory sense.
- Patients with tropical or non-tropical sprue may have signs of malabsorption such as weight loss, diarrhea, abdominal distention and steatorrhea.
- Cardiopulmonary: in severe anemic patients dyspnea, tachypnea and cardiopulmonary insufficiency may happen.
- Mild liver enlargement (hepatomegaly).
◉ 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.
- Reticulocyte count: reticulocytopenia (low).
- Red blood cell distribution width (RDW): high.
- Platelet count: thrombocytopenia may be present in severe cases.
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).
- Nucleated RBCs and megaloblasts may be present.
- Howell-jolly bodies are commonly found in the smear.
- Hyper-segmented neutrophils found early in disease but later on neutropenia manifests. This can be masked if patient has macrocytosis due to cobalamin deficiency associated with iron deficiency anemia.
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.
- If a vitamin B12 and folic acid deficiency is identified due to a reduction in the contribution without proof of malabsorption syndrome or any underlying disorder, the patient must take vitamin B12 and Folic acid by oral or parenteral.
- For folic acid supplementation, a dose of 5 to 15 mg per day is sufficient. It is important to continue treatment for 4 months.
- If patients have symptoms of severe anemia, rapid blood transfusion is necessary, as supplements of vitamin B12 and folic acid did not quickly relieve symptoms of anemia.
◉ Conclusion
In conclusion there are plenty of causes that result in megaloblastic anemia, moreover, depending on the cause the management plan is decided accordingly.
