What is Megaloblastic Anemia?
Megaloblastic anemia (MA) is a heterogeneous group of anemias characterized by the presence of large red blood cell precursors in the bone marrow, which are referred to as megaloblasts.
Megaloblastic erythroid precursors are larger than normal and their nuclei are larger and appear immature with granular chromatin.
Causes of Megaloblastic Anemia
The most common causes of megaloblastic anemia are vitamin B12 or folate deficiencies within a long list that includes deficiency of other micronutrients, congenital disorders, myelodysplastic syndromes, and acquired DNA synthesis defects seen during chemotherapy.
Ineffective DNA synthesis in hematopoietic precursor cells is the primary cause of megaloblastic anemia.
Causes:
Vitamin deficiencies
Deficiency of folate
1. Decreased intake
a. Nutritional deficiency (elderly, alcoholics, poverty).
b. Diet induced: goat’s milk, synthetic diets.
c. Infants with prematurity.
d. Hyperalimentation.
2. Decreased absorption
a. Celiac disease and tropical sprue.
3. Increased demand
a. Pregnancy.
b. Puberty.
c. Chronic hemolytic anemia.
d. Exfoliative dermatitis.
e. Hemodialysis.
Deficiency of vitamin B12
1. Impaired absorption
a. Pernicious anemia.
b. After gastrectomy or ileal resection.
c. Zollinger-Ellison syndrome.
d. Blind loop syndrome.
e. Fish tapeworm infestation.
f. Pancreatic insufficiency.
2. Decreased intake
a. Vegans.
b. Vegetarians
Other causes
1. Drugs (eg, antibiotics, anticancer agent, anticonvulsants and oral contraceptives)
2. Inborn errors of metabolism
3. Acute megaloblastic anemia
a. Nitrous oxide exposure.
b. Acute illness.
4. Idiopathic (congenital dyserythropoietic anemia, erythroleukemia, and refractory
megaloblastic anemia)
5. Thiamine-responsive megaloblastic anemia
Pathophysiology of Megaloblastic Anemia
The pathophysiology of this type of anemia is ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic cell precursors as a result of DNA synthesis errors.
Defective DNA synthesis can be caused by both vitamin B12 and folate deficiency.
As a result, the nucleus and cytoplasm do not mature simultaneously.
The cytoplasm (which has normal hemoglobin synthesis) matures normally, but the nucleus (which has DNA impairment) is not fully mature.
Symptoms of Megaloblastic Anemia
Anemia develops gradually, giving enough time for cardiopulmonary and intraerythrocytic compensation to occur before symptoms appear.
Symptoms usually appear in patients who are severely anemic.
The main symptoms include the following: –
-
- Weakness.
- Palpitation.
- Fatigue.
- Light-headedness.
- Shortness of breath caused by low hematocrit.
- Jaundice can occur from intramedullary and extravascular hemolysis.
- Leukopenia or thrombocytopenia is generally present but does not typically cause any clinical concern.
Vitamin B12 deficiency is frequently associated with neurologic symptoms as well as autonomic gastrointestinal disturbances.
The neurologic symptoms are caused by symmetric paresthesia, numbness, and impaired vibration and position sense, which causes gait disturbances.
About 10% of B12-deficient patients have hyperpigmentation, and some pernicious anemia patients have autoimmune vitiligo.
There may be cerebral manifestations in B12 deficiency including: –
-
- Mental confusion.
- Paranoia.
- Dementia, and even frank psychosis.
Rare symptoms encountered with vitamin B12 deficiency include: –
-
- Generalized malabsorption caused by intestinal megaloblastosis.
- Infertility.
- Glossitis.
- Cerebral venous thrombosis.
In severe B12 deficiency, hyperhomocysteinemia may increase the risk of thrombosis.
Complications of Megaloblastic Anemia
Megaloblastic anemia complications can vary depending on the cause.
Deficiency in vitamin B12 can lead to the following complications:
-
- Neurological problems, including memory impairment, paresthesia, compromised vision, ataxia, and peripheral neuropathy. These may be irreversible once they appear.
- Infertility
- Gastric cancer
- Neural tube defects in developing fetus, leading to spina bifida or anencephaly
Folate deficiency complications include:
-
- Infertility
- Cardiovascular disease
- Cancer
- Premature childbirth
- Neural tube defects in the fetus during pregnancy
All types of anemia can lead to tachycardia and heart failure.
Read Also: Pernicious Anemia | Causes, Symptoms, and Treatments
Laboratory Investigation of Megaloblastic Anemia
Whether due to cobalamin or folic acid deficiency, all types of megaloblastic anemia have the same laboratory findings.
The most notable finding in a complete blood count (apart from anemia) is macrocytosis. In addition, leuko-neutropenia and thrombocytopenia in varying degrees can be present, especially in the case of chronic deficiencies. The number of reticulocytes is low.
Megaloblasts in a peripheral blood smear (PBS), while not pathognomic, are highly suggestive of megaloblastic anemia. The changes are not limited to red blood cells; hyper-segmented neutrophils with six or more lobes may also be present.
Howell-Jolly bodies, anisocytosis, and poikilocytosis are among the other findings.
If there are megaloblasts on PBS with a high reticulocyte count, the first-line investigation includes a red blood cell assay for vitamin B12 and folate.
Vitamin B12 deficiency is indicated by levels less than 200 pg/ml.
Laboratory Findings
A- Complete blood count and blood film
-
- Anemia is usually preceded by a high MCV.
- Low red blood cell, hemoglobin, and reticulocyte counts are common.
- In moderate to severe deficiency, low white cell and platelet counts can occur.
- The blood film reveals macro-ovalocytes and hyper-segmented neutrophils.
B- Bone marrow analysis
-
- Hypercellularity is prominent in all three cell lines.
- The erythroid hyperplasia is more marked than the others.
- Abnormal erythropoiesis, characterized by abnormally large red cell precursors (megaloblasts) with less mature nuclei.
C- Serum cobalamin (Vitamin B12) levels.
-
- Normal levels: 120 – 680 pmol/L measured using Immunoassay.
- Serum cobalamin level limitations include falsely low levels (in patients with normal cobalamin), falsely normal or high levels, myeloproliferative disorders, and acute liver disease.
D- Other tests
-
- Schilling test: It assesses cobalamin absorption by measuring increased urine radioactivity following an oral dose of radioactive cobalamin.
- Serum homocysteine and methylmalonic acid: Patients with cobalamin deficiency have elevated serum methylmalonic acid and homocysteine levels. Anemia is caused by hereditary vitamin B12 deficiency.
| Patient Condition | Homocysteine | Methylmalonic Acid |
|---|---|---|
|
Healthy |
Normal |
Normal |
|
Vitamin B12-Defeciency |
Increased |
Increased |
|
Folate Deficiency |
Increased |
Normal |
Differential Diagnosis
In non-megaloblastic macrocytic anemias, a complete blood count may reveal macrocytosis.
The number of reticulocytes will aid in differentiating between two primary conditions.
There are two main conditions for which the clinician must look if reticulocytosis is present: hemolytic anemia and acute hemorrhage.
If reticulocytopenia is present, the underlying conditions may be evident in hypothyroidism, alcoholism, liver dysfunction, and certain drugs.
When vitamin B12 or folate deficiency has been ruled out by laboratory tests, bone marrow aspiration should be performed.
Indeed, myelodysplastic disorders and sideroblastic anemia can manifest as refractory megaloblastic anemia.
Related Content: Anemia and Heavy Menstruation Relationship, and Treatments
Treatment of Megaloblastic Anemia
Treatment for vitamin B12 deficiency involves intramuscular injections of hydroxocobalamin. During the first week of treatment, patients usually receive 1000 ug of vitamin B12 daily.
The following month, they will receive weekly injections, followed by monthly injections. Reticulocytosis usually develops within 3 to 5 days.
Hemoglobin levels begin to increase by the tenth day, and anemia usually resolves completely after two months of treatment.
The reversal of neurological changes usually takes longer, and some symptoms will persist even if treatment is started right away.
At a monthly dose of 1000 ug, the treatment should be continued indefinitely. Preventive treatment with vitamin B12 may be necessary for life in some cases, particularly in patients with prior total gastrectomy or extensive ileal resection.
Before starting treatment for folate deficiency, it is essential to rule out concomitant vitamin B12 deficiency. Large doses of folic acid may worsen neuropathy in the presence of vitamin B12 deficiency.
Folic acid supplementation, 1 to 5 mg/day, is usually given orally. Parenteral preparation is recommended for patients with malabsorption. Treatment should be continued for a minimum of two years to prevent relapse.
Transfusions
During transfusions, complications can occur, including congestive heart failure in the elderly.
Transfusion should be limited to cases of symptomatic anemia rather than low hemoglobin levels.
Summary
Megaloblastic anemia (MA) is a heterogeneous group of anemias characterized by the presence of large red blood cell precursors in the bone marrow, which are referred to as megaloblasts.
Megaloblastic erythroid precursors are larger than normal and their nuclei are larger and appear immature with granular chromatin.
The most common causes of megaloblastic anemia are vitamin B12 or folate deficiencies within a long list that includes deficiency of other micronutrients, congenital disorders, myelodysplastic syndromes, and acquired DNA synthesis defects seen during chemotherapy.
The pathophysiology of this type of anemia is ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic cell precursors as a result of DNA synthesis errors.
Defective DNA synthesis can be caused by both vitamin B12 and folate deficiency.
The main symptoms include weakness, palpitation, fatigue, light-headedness, shortness of breath caused by low hematocrit and jaundice can occur from intramedullary and extravascular hemolysis.
Megaloblastic anemia complications can vary depending on the cause, neurological problems including memory impairment, paresthesia, compromised vision and ataxia.
All types of megaloblastic anemia have the same laboratory findings, the most notable finding in a complete blood count (apart from anemia) is macrocytosis.
Treatment for vitamin B12 deficiency involves intramuscular injections of hydroxocobalamin. During the first week of treatment, patients usually receive 1000 ug of vitamin B12 daily.
Folic acid supplementation, 1 to 5 mg/day, is usually given orally. Parenteral preparation is recommended for patients with malabsorption. Treatment should be continued for a minimum of two years to prevent relapse.
References
- Hariz, A. (2020, October 23). Megaloblastic anemia. StatPearls [Internet]. PubMed
- A;, G. R. D. M. (2017, March). Megaloblastic anemias: Nutritional and other causes. The Medical clinics of North America. PubMed
- (PDF) nutritional anaemia. ResearchGate. (2012, February). Researchgate
