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megaloblastic anemia
- 1. CLINICAL CASE DISCUSSION Dr. Neha.Newadkar Guide : Dr.Aditya.Nesargi
- 2. A 35 year old female who is strict vegetarian and has only small amounts of dairy products in diet ,came with unsteady gait since 15 days , dyspnoea since two months. On questioning gives history of tingling numbness in both feet .
- 3. ON EXAMINATION • Glossitis++,pallor++,lemon coloured complexion. • Pulse was 90/min • P/A – soft , liver spleen not palpable • CVS- Haemic murmur, heart sounds normal • RS-NAD
- 4. • CNS – • Pressure ,vibration and touch sensation reduced in B/L lower limbs • Plantars are extensors
- 5. POSITIVE FINDINGS • Dietary history : Strict vegetarian • General examination : Pallor , glossitis , lemon coloured complexion • RS : Haemic murmur, dyspnoea
- 6. PALLOR Pale appearance of the skin and mucous membranes • CAUSES : • Anemia • Myxodema • Nephritis • Collapse and shock • Sheehan’s Syndrome • WHERE TO SEE ?? • Lower palpebral conjunctiva • Tongue(tip and dorsum) • Nail beds • Palms ,soles
- 7. GLOSSITIS • Inflammation with red sore tongue • Red swollen ,painful • Also known as red beefy tongue • B12 and folic acid deficiency • Iron deficiency anemia (Bald tongue) • Cirrhosis of liver • Riboflavin deficiency
- 8. DYSPNOEA • Cardiac cause : • Congestive Cardiac failure • Pericardial Effusion • Acute Myocardial infarction • Respiratory cause : • Bronchial asthma • Acute Bronchitis • Pneumonia • Chronic obstructive lung disease • Metabolic cause : • Diabetic Ketoacidosis • Uremia • Hypokalemia • Hematological cause : • Severe anemia
- 9. TINGLING NUMBNESS• Peripheral Neuropathy: • Vit B12 deficiency, • Diabetes • Isoniazid, phenytoin, lead exposure • Renal failure, hypothyroidism • Small cell carcinoma of lung • Guillain barre syndrome • Shingles (post herpetic neuralgia) • Charcot marie tooth disease • Lumbar canal stenosis • Tumours • Past history of trauma • Compressive lesions
- 10. LEMON COLOURED COMPLEXION • Severe anemia + Mild jaundice = lemon coloured complexion • Due to severe anemia • Pregnancy • Thyrotoxicosis HAEMIC MURMUR
- 12. PRIMARY INVESTIGATIONS • CBC with Peripheral blood smear • Reticulocyte count • LFT
- 13. COMPLETE BLOOD COUNT • Hb - 5.1 g/dL ( 12-15 ) • RBC -4.5 ×106/µL (4.5- 5.5) • HCT- 18% ( 35- 45) • MCV- 128 fL (80- 100) • MCH- 40 pg (27- • Plateletes- 1,00,000• WBC – 3×103/µL • Neutrophil - 72% • Lymphocyte- 24% • Eosinophils-02% • Monocytes – 02%
- 14. PERIPHERAL BLOOD SMEAR Hypersegmented Neutrophil Megaloblastic anemia Iron deficiency Myeloproliferative disorder Chronic renal failure
- 15. Oval Macrocytes
- 16. CAUSES OF MACROCYTIC ANEMIA Oval Macrocytosis • Deficiency of folate or Vit B12 • Drugs : Methoterxate ( folate antagonists) Hydroxyurea Cyclophosphamide Trimethoprim OC pills Round macrocytosis • Alcoholoism • Liver disease • Hypothyroidism • Myelodysplastic syndrome • Post splenectomy
- 17. Basophilic stippling Megaloblastic anemia Thalassemia Heavy metal poisoning Liver disease Hemogobinopathies
- 18. Megaloblastic anemia Thalassemia Hemolytic anemia Post splenectomy
- 19. • RBC morphology: • Anipoikilocytosis ++, Macrocytic ++, macro ovalocytes+, Few Normblastic Normochromic, few nRBCs • Also noted : Howel Jolly bodies, Basophilic stipplling • WBC : Leucopenia with hyper segmented neutrophils • Platelets : reduced to 1,00,000.
- 20. APPROACH TO MACROCYTIC ANEMIA (MCV>100) Reticulocyte count • Increased Normal /low • Hemolytic anemia, h/o liver disease ,drugs , Acute blood loss hypothyroidism NO YES Bone marrow examination Normoblastic Megaloblastic Myelodysplastic Hypocelllular Liver disease vit B12 /folate Myelodysplastic Aplastic Hypothyroidism deficiency syndrome Anemia
- 21. RETICULOCYTE COUNT • 2.5% (0.5-2.5%) • Total Bilirubin : 1.8 ml/dl (0.2-1.2) • Serum conjugated bilirubin : 0.2 mg/dl (0-0.2) • Serum unconjugated bilirubin : 1.6mg/dl (0.2-1.0) • LDH 2225 IU/L (225-450) • SGOT 40 LIVER FUNCTION TESTS
- 22. TESTS FOR B 12 AND FOLATE DEFICIENCY • Serum B12 : 90 ng/L ( 160-900ng/L) • Serum folate : 3 ng/mL (5-16 ng/mL) • RBC folate :110 ng /mL (>150 ng/mL) To rule out co existing iron deficiency ,Serum iron : increased(170µg/dl)
- 23. BONE MARROW • Cellularity : hypercellular • M:E ratio 1:1 • Erythroid series : shows hyperplasia with megaloblastic maturation with maturation arrest • Myeloid series : normal progressive maturation with giant metamyelocytes with fine nuclear chromatin , eosinophilic precursors are increased. • Megakaryocytes : large with multiple nuclear lobes and paucity of cytoplasmic granules. • Iron stores : grade III
- 29. MEGALOBLASTIC ANEMIA Characterized by defective synthesis of DNA in all proliferating cells most commonly resulting from lack of folic acid or vit B12
- 30. VITAMIN B12 / COBALAMIN• Sources : • Liver , dairy products ,seafish • It is exclusively synthesized by microorganism • Daily requirement 2-5 µg/dl • Stored in LIVER as adenosylcobalamin (2 to 5mg ) • Excreted in bile and shedding
- 31. • Vit B12 in food stomach R binder • B12 R binder complex duodenum Intrinsic factor IF- B12 complex + freed R binder • Receptor-IF B12 Degradation IF • B12-TCII • Circulation Receptor TC II Terminal ileum epithelial cell
- 32. TRANSPORT OF VITAMIN B12 • Transcobalamin I • Synthesized by granulocytes • Acts as storage protein • Transcobalamin III • Binds only small quantities of B12 in circulation • Transcobalamin II • Synthesized by liver cells,macrophages, hematopoetic cells • Major transport protein • Congenital absence causes megaloblastic anemia
- 33. FUNCTIONS OF VITAMIN B12 Homocysteine Methionine Dietary folates Intestinal cell Methyl FH4 FH4 Dihydrofolate reductase dUMP dTMP DNA synthesis FH2 Methylene FH4 Methyl cobalamin
- 34. Adenosyl cobalamin Methyl malonyl Co A Succinyl Co A methymalonyl Co A mutase FUNCTIONS OF VITAMIN B 12
- 35. Adenosyl cobalamin • Methyl malonyl Co A Succinyl Co A methymalonyl Co A mutase Methyl malonate and propionate Abnormal myelin lipids Myelin degeneration Neurological abnormalities
- 36. • Diffuse and irregular degeneration of the white matter of the central nervous system (CNS) characteristically involves the posterior and lateral columns of the spinal cord (subacute combined degeneration) . • Subacute combined degeneration of posterior column presents as: • Symmetrical sensations of “pins and needles” of the distal extremities • Numbness and tingling • Loss of position sensation (difficulty with balance and gait) • Loss of vibratory sensation (the most constant sign)
- 37. • Lateral column involvement presents as weakness, spasticity and increased deep tendon reflexes. • The brain may be affected, and the patient shows irritability, emotional instability, or a change in personality : Megaloblastic madness • Neuropsychiatric disordersmay be associated with cobalamin deficiency even without accompanying hematologic manifestations
- 38. Mechanism Disorder Seen in Decreased dietary intake Nutritional B12 deficiency Vegans Impaired absorption Gastric causes Atrophic gastritis Proton pump inhibitors Pernicious anemia Gastrectomy Intestinal Causes Pancreatic insufficency Zollinger Ellison syndrome Consupmtion of luminal B12 Blind loop syndrome Fish tapeworm infestation Diverticulosis Diminished IF cobalamin receptors Ileal bypass,ileal resection Crohns disease Disorders of transport Congenital TC II deficiency Disorder of cellular B 12 metabolism Inborn enzyme errors Nitrous oxide inhalation
- 39. TESTS FOR VITAMIN B12 • CBC • PBS • RETICULOCYTE COUNT • LFT • Bone marrow aspiration and biopsy
- 40. SPECIAL TESTS • Serum Vitamin B12 assay -late biomarker, lacks sensitivity and specificity • Holotranscobalamin -( active B12)- earliest laboratary marker( <23pmol/L, normal : 23- 100pmol/L) • Methylmalonic acid – functional marker, increases when B12 stores depleted (0-0.4micromol/L) • Homocysteine – increased , also increased in folate deficiency (4-15micromol/L) • Therapeutic trial- 10µg/day, increase in retic count after 4-7 days
- 41. Test Rationale and Advantage Disadvantage IF antibodies specific for pernicious anemia 70% sensitivity Pepsinogen Mirrors gastric function Low speficity Parietal cell antibodies Maybe + in pernicious anemia Very low specificity Cobasorb Functional test, measures increase in holotranscobalamin Needs further evaluation Schilling’s test Gold standard as a functional test for B12 absorption False positive in with reduced renal function
- 42. PERNICIOUS ANEMIA • Failure of secretion of Intrinsic factor by stomach resulting in cobalamin deficiency • Autoimmmune factors : gastric parietal cell auto antibodies (90%) and intrinsic factor antibodies (50-70%) • Hypochlorhydria • Increased serum gastrin levels • Complete absence of chief cells and parietal cells • Frequently seen in females and associted with other autoimmune diseases like Grave’s disease and Hashimoto’s thyroiditis • Increased risk of gastric adenocarcinoma and gastric carcinoids
- 43. DIAGNOSIS OF PERNICIOUS ANEMIA • Blood picture : low Hb, elevated MCV,thrombocytopenia, leucopenia with hypersegmented neutrophils • Bone marrow : hypercellular, megaloblastic with nuclear cytoplasmic asynchrony • Serum vitamin B12 assay : Low,essential pre requisite for diagnosis • Anti IF antibody (75%), anti parietal cell antibody ( 90%) • Radioactive vit B12 absorption test (Schilling’s test) • Serum gastrin levels : Raised
- 44. SCHILLING’S TEST • PART 1 : radiolabelled Vit B 12 ( 0.5 to 1µg) given orally ,after 2 hours IM dose of unlabelled Vit B12 (1000µg) • Measure radioactivity in 24 hour urine sample • RESULT : Normallly : >7% of oral dose • Abnormal : less than 7%, seen in defective absorption in small intestine • Part 2 : along with oral dose IF factor is also given • RESULT : If Abnormality in part 1 corrected then – PERNICIOUS ANEMIA, gastrectomy • If not corrected then – Malabsorption in small intestine , Ileal disease
- 45. • Sources : Green leafy vegetables, fruits and liver ; easily destroyed by boiling, cooking and canning • Adult daily requirement : 200µg • Absorbed in proximal jejunum and duodenum • Transport : released in portal circulation as 5-Methyl Tetrahydrofolate • Storage : Liver (5-20mg) FOLATE
- 46. FUNCTIONS OF FOLATE • Synthesis of thymidylate to uridylate mediated by folate : required in DNA synthesis • Synthesis of methionine from homocysteine • Synthesis of purines • Histidine catabolism ( Formiminoglutamic acid –FIGlu)
- 47. CAUSES OF FOLATE DEFICIENCY • Decreased intake • Impaired Absorption • Increased demand • Drugs Nutritional deficiency Coeliac disease Tropical sprue Pregnancy, lactation Hemolytic anemias , thalassemias Sidroblastic anemia Leukemia ,Lymphoma Hyperthyroidism Methotrexate, phenytoin,barbiturates,OC pills
- 48. SEQUENCE OF EVENTS IN FOLATE DEFICIENCY • Reduction in serum folate • Neutrophil hypersegmentation • High excretion of FIGlu Reduction in Red cell folate • Appearance of megaloblastic anemia • 2 weeks • 7 weeks • 14 weeks • 17weeks • 20weeks
- 49. TESTS FOR FOLATE DEFICIENCY • Serum Folate Assay (5-21µg/L) Microbiological and radio-isotope methods, levels below 3µg/l suggest clinically significant folate deficiency • Red cell Folate Assay (150-600µg/L of RBC) More reliable indicator of tissue folates than serum folates • Urinary FIGlu excretion increased
- 50. TREATMENT • VIT B 12- given 1000µg IM dose once daily for a week , then once in 3 months • Oral doses are equally effective • Folate given orally 1-2 mg, duration depends on cause • Feeling of well being in 24 hours and return of normal erthrypoesis in case of parentral dose • Retic starts to rise in 3 days ,peaks on 5-6th day and comes to normal by the end of 3 weeks • Hematocrit rises and normalises in 1-2 months • Hypokalemia EFFECT OF TREATMENT SIDE EFFECT OF TREATMENT
- 51. MEGALOBLASTIC ANEMIAS NOT DUE TO B12 AND FOLATE DEFICIENCY • Myelodysplastic Syndromes • Orotic Aciduria • Erythroleukemia • Thiamine responsive megaloblastic Anemia • Antineoplastic drugs :hydroxyurea,cytaranibe