Definition/General
Introduction:
Folate deficiency causes megaloblastic anemia identical to B12 deficiency but without neurological complications
Results from impaired DNA synthesis due to folate coenzyme deficiency
Bone marrow shows megaloblastic changes in all cell lines
Distinguished from B12 deficiency by normal methylmalonic acid levels and absence of neurological symptoms.
Origin:
Results from inadequate dietary intake, increased requirements, or malabsorption
Dietary insufficiency: inadequate green leafy vegetables
Pregnancy and lactation: increased folate requirements
Malabsorption: celiac disease, tropical sprue
Drug interference: methotrexate, phenytoin, trimethoprim
Alcoholism: impaired absorption and utilization.
Classification:
Dietary deficiency: inadequate intake of folate-rich foods
Increased requirements: pregnancy, lactation, hemolysis, malignancy
Malabsorption: celiac disease, tropical sprue, jejunal resection
Drug-induced: antifolate medications, alcohol
Hereditary folate malabsorption: rare genetic disorder
Cerebral folate deficiency: transport defect.
Epidemiology:
Global prevalence: 10-15% in developing countries
Pregnancy: 20-50% affected without supplementation
Alcoholics: 80% have low folate levels
Elderly population: 5-15% prevalence
Neural tube defects: prevented by periconceptional folate
Food fortification: reduced prevalence in developed countries.
Clinical Features
Presentation:
Megaloblastic anemia with high MCV (>100 fL)
Pancytopenia in severe cases
Glossitis and stomatitis
Jaundice from ineffective erythropoiesis
No neurological symptoms (unlike B12 deficiency)
Thrombocytopenia with bleeding.
Symptoms:
Fatigue and weakness
Shortness of breath on exertion
Palpitations
Irritability and mood changes
Poor concentration
Diarrhea (malabsorption cases)
Weight loss.
Risk Factors:
Poor dietary intake (lack of green vegetables)
Pregnancy and lactation
Chronic alcoholism
Malabsorption disorders (celiac disease, Crohn disease)
Antifolate medications (methotrexate, phenytoin)
Chronic hemolysis (increased requirements)
Elderly with poor nutrition.
Screening:
Red blood cell folate (<140 ng/mL suggests deficiency)
Serum folate (<3 ng/mL indicates deficiency)
Homocysteine levels (elevated)
Methylmalonic acid (normal, differentiates from B12 deficiency)
Complete blood count with peripheral smear
Formiminoglutamic acid excretion test.
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Gross Description
Appearance:
Bone marrow shows hypercellularity with increased M:E ratio
Megaloblastic changes identical to B12 deficiency
Giant metamyelocytes and band forms
Large, abnormal megakaryocytes.
Characteristics:
Erythroid hyperplasia with megaloblastic morphology
Nuclear-cytoplasmic asynchrony
Open, lacy chromatin pattern
Multinucleated erythroblasts present.
Size Location:
Increased cellularity throughout bone marrow
Erythroid islands show prominent megaloblastic changes
Diffuse distribution of abnormal cells
Reduced fat spaces due to hyperplasia.
Multifocality:
Hematological effects only (no neurological involvement)
Peripheral blood: oval macrocytes, hypersegmented neutrophils
Gastrointestinal tract: glossitis, stomatitis
Neural tube defects in developing fetus.
Microscopic Description
Histological Features:
Megaloblastic erythropoiesis indistinguishable from B12 deficiency
Nuclear-cytoplasmic asynchrony
Giant metamyelocytes
Hypersegmented neutrophils
Megaloblastic megakaryocytes.
Cellular Characteristics:
Megaloblasts with fine, open chromatin
Mature cytoplasm with immature nuclei
Howell-Jolly bodies
Nuclear fragmentation
Abnormal mitoses.
Architectural Patterns:
Hypercellular bone marrow
Erythroid predominance
Normal architecture preserved
Ineffective erythropoiesis.
Grading Criteria:
Morphologically identical to B12 deficiency
Severity based on degree of megaloblastic changes
Clinical distinction by laboratory tests and neurological examination.
Immunohistochemistry
Positive Markers:
Glycophorin A: positive in megaloblasts
CD71: increased expression
Ki-67: high proliferation with apoptosis.
Negative Markers:
CD34: negative in megaloblasts
Myeloperoxidase: negative in erythroid cells.
Diagnostic Utility:
Morphological features identical to B12 deficiency
Laboratory differentiation essential
Cytogenetics: normal karyotype.
Molecular Subtypes:
Dietary deficiency: low folate intake
Drug-induced: antifolate medications
Malabsorption: GI disorders
Increased requirements: pregnancy, hemolysis.
Molecular/Genetic
Genetic Mutations:
SLC46A1 mutations: hereditary folate malabsorption
MTHFR mutations: methylenetetrahydrofolate reductase deficiency
DHFR mutations: dihydrofolate reductase deficiency.
Molecular Markers:
Homocysteine: elevated
Methylmalonic acid: normal (key difference from B12 deficiency)
Formiminoglutamic acid: increased excretion.
Prognostic Significance:
Excellent response to folate replacement
No permanent sequelae (unlike B12 deficiency)
Rapid improvement with treatment.
Therapeutic Targets:
Oral folic acid: 1-5 mg daily
Dietary counseling: folate-rich foods
Pregnancy supplementation: prevents neural tube defects.
Differential Diagnosis
Similar Entities:
B12 deficiency (elevated methylmalonic acid, neurological symptoms)
Myelodysplastic syndrome
Acute leukemia
Hypothyroidism.
Distinguishing Features:
Folate deficiency: normal MMA, no neurological symptoms
B12 deficiency: elevated MMA, neurological involvement
MDS: dysplastic changes, cytogenetic abnormalities.
Diagnostic Challenges:
Combined B12 and folate deficiency
Masked deficiency with partial treatment
Drug-induced vs nutritional causes.
Rare Variants:
Hereditary folate malabsorption
Cerebral folate deficiency
5,10-methylenetetrahydrofolate reductase deficiency.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Cellularity
Hypercellular bone marrow ([percentage]%) with erythroid predominance
Megaloblastic Changes
Megaloblastic erythropoiesis with nuclear-cytoplasmic asynchrony
Final Diagnosis
Bone marrow with megaloblastic changes consistent with folate deficiency
Recommendations
Correlate with serum/RBC folate levels. Normal methylmalonic acid differentiates from B12 deficiency