Megaloblastic Anemia

Introduction

These are disorders caused by impaired DNA synthesis in the erythroid lineage due to the deficiency of vitamin B12 or folic acid which gives rise to anemia and macro-ovalocytic RBC (MCV >100fL) and bone marrow shows intense erythroid hyperplasia and megaloblastic changes.

Here, DNA maturation lags behind.

Absorption of Vitamin B12

Common causes of vitamin B12 deficiency in India 

• Nutritional deficiencies 

• Malabsorption 

• Defective absorption from food (gastric achlorhydria, partial gastrectomy, drugs blocking gastric secretion)

• Inadequate intrinsic factor production

• Disorders of terminal ileum (tropical/coeliac sprues, intestinal resection, granulomatous diseases)

• Competition for cobalamin by bacteria (blind loop syndrome)

• Drugs like colchicine and neomycin 

Uncommon causes of vitamin B12 deficiency in India 

• Pernicious anemia

• Absence or abnormalities in intrinsic factor

• Crohn's disease 

• Selective B12 malabsorption (Imerslund - Grasbeck syndrome)

• Fish tapeworm ingestion 

• Transcobalamin deficiency 

Common causes of folic acid deficiency in India 

• Nutritional deficiencies 

• Increased requirement (infants, children, pregnancy, hemodialysis, malignancy, chronic hemolytic anemia, chronic exfoliative dermatitis)

• Malabsorption 

• Impaired metabolism (inhibitors of dihydrofolate reductase)

• Methotrexate, pyrimethamine 

• Alcohol 

Uncommon causes of folic acid deficiency in India 

• Rare enzyme defect (dihydrofolate reductase)

• Drugs that impair DNA synthesis 

• purine antagonists: 6 mercaptopurine, azathioprine

• pyrimidine antagonists: 5 fluorouracil, cytosine arabinoside

• others: hydroxyurea, procarbazine, zidovudine, acyclovir

• Metabolic disorders (Lesch Nyhan Syndrome, hereditary orotic aciduria)

• Megaloblastic anemia of unknown etiology 

• Refractory megaloblastic anemia in myelodysplastic syndrome

Diagnosis 

Blood picture:

• Decreased hemoglobin 

• Increased MCV 

• Normal MCHC

• Increased MCH

• Macrocytic RBC: macro-ovalocytes, and Howell - Jolly bodies are seen

• Decreased RBC with an increase in hypersegmented neutrophils

• Normal or reduced platelet count 

Bone marrow:

• Hypercellularity

• Hyperactive erythropoiesis and megaloblastic changes are seen in all stages of development 

• Megaloblasts are larger than erythroblasts with increased cytoplasm and nuclear size

• Chromatin is more open being arranged in a fine reticular fashion giving a stopped appearance 

• Predominant cells are pro-megaloblasts and basophilic megaloblasts indicating maturation arrest

• Active granulopoiesis showing giant metamyelocytes

• Normal megakaryocytes

Biochemistry:

• Serum vitamin B12

• Red Cell folate assay

• Microbial assay of vitamin B12 using Lactobacillus leichmannii

Treatment

Goal:

• Reversal of hematologic manifestation

• Replacement of body stores

• Prevention/ resolution of neurologic manifestations

Dietary intake:

• Animal rich food

• Green leafy vegetables 

• Milk and milk-based products

Medications:

• Oral administration of vitamin B12 (1-10 micrograms/ day)

• Parenteral administration (100-1000 micrograms deep i.m)

Pernicious Anemia 

Vitamin B12 deficiency anemia due to lack of intrinsic factor due to atrophic gastritis or antibodies against intrinsic factor

Blood and bone marrow pictures are similar to megaloblastic anemia.

Clinical features:

• Paresthesia of hand and feet

• Spinal cord - Posterior or lateral column defect 

• Dementia 

• Neuropsychiatric features

• Optic nerve involvement 

• Atrophic glossitis - red beefy tongue

• Angular cheilitis

• Intestinal-type gastric adenocarcinoma 

• Gastric carcinoid type 1

Diagnosis:

• Schilling’s test

• Antiparietal cell antibody type 3 - most sensitive 

• Anti-intrinsic factor antibody type 1 / 2 - most specific 

Treatment - cyanocobalamin/ hydroxycobalamin

• 1000 micrograms i.v. daily for a week

• Followed by once a week for a month

• Followed by once a month for 6-8 months

• If symptoms are not improved - Lifelong cyanocobalamin/ hydroxycobalamin treatment.