Megaloblastic Anemia היגולוטמהל�סרוק �תימינפ�האופרל�אובמ–ד�הנש�' סשת"ו ד"�הדע�רברפדלוג
Diagnostic approach based on RBC’s indices MCV > 98 fl MCV < 80 fl 80 fl < MCV < 98 fl Microcytic Normocytic Macrocytic anemia anemia anemia
Macrocytic Anemia (MCV>100) Morphology Peripheral blood & Bone Marrow Megaloblastic Non-Megaloblastic Reticulocyte count Decreased/Normal Vit B12, Folate Increased deficiency Alcoholism Hemorrhage Liver Disease Hemolysis Hypothyroidism Cold agglutinins BM failure: MDS, Aplastic Anemia
DNA Synthesis DNA Methotrexate blocks here Thymidine monophosphate (dTMP) DHF Methyl B12 THF Methyl THF (plasma factor) 5,10 Methylene THF Deoxyuridine THF - tetrahydrofolate monophosphate DHF - dihydrofolate (dUMP)
B12/Folate deficiency affects all dividing cells 1. Ineffective Hematopoiesis Ineffective Erythropoiesis Anemia Ineffective Leukopoiesis Leukopenia Ineffective Thrombopoiesis Thrombocytopenia 2. RBC survival ↓ ↓ ↓ ↓
Normal Erythropoiesis (Bone Marrow)
Megaloblastic Erythropoiesis
Megaloblastosis (Giant Band Forms in Bone Marrow)
Megaloblastic Changes – Young Megakarocyte (Bone Marrow)
Peripheral Blood (2) Normal Megaloblastic Changes
Peripheral Blood Normal Megaloblastic Changes
Peripheral Blood Hypersegmentation (PMN)
Megaloblastic Anemia - Etiology •Vitamin B12 deficiency 95% •Folate deficiency • Antimetabolic drugs • Inborn errors of metabolism 5% • Refractory anemias • Erythroleukemia
Pernicious Anemia – Clinical Presentation “lemon yellow” pallor
Pernicious Anemia – Clinical Presentation Glossitis – “beefy tongue”
Pernicious Anemia – Clinical Presentation Neurological deficit: Subacute combined degeneration – gait disorders
Pernicious Anemia – Clinical Presentation Neurological deficit: Depression, dementia, behavioral changes (“megaloblastic madness”)
Pernicious Anemia – Clinical Presentation Vitiligo Associated autoimmune disorders: vitiligo, hyper/hypothyroidism etc.
Megaloblastic Anemias: Signs & Symptoms (1) Subjective: • Fatigue, weight loss,gastrointestinal complaints, sore tongue or mouth • Neurological complaints (may be irreversible !) : Paresthesias, difficulty walking(?)
Megaloblastic Anemias: Signs & Symptoms (2) Objective: • Pallor & jaundice (“lemon yellow”) • Loss of papillae of tongue (“beefy red”) • Neurological deficit (Only with B12 def) • ( ↓ position / ↓ vibration sense + romberg / spastic paraparesis) • Can also cause dementia & depression • Signs of associated conditions: vitiligo, thyroid disease etc.
Megaloblastic Anemia – Lab Results CBC : ↓ Hb/Hct, ↑ MCV, ↓ retics, ↑ RDW, ↓ WBC, ↓ Plts • • CAUTION: mixed deficiency or concurrent states (iron deficiency or thal+ megaloblastic anemia) MASKED SIGNS! Biochemistry : • ↑ Bilirubin, ↑ ↑ LDH, ↓ Vit B12 Autoantibodies : • anti-parietal cell, anti-thyroid etc. • Other associated: glucose, thyroid function etc.
Normal B12 Metabolism (1) B12 is a large, complex molecule with complex absorption 3 ACTIVE FORMS: CYANO, METHYL AND ADENOSYL
Normal B12 Metabolism (2) • B12 is present in foods of animal origin • Not in vegetables or plants!!!
Normal B12 Metabolism (3) • Minimum daily requirement is only 2 � g/day • Body stores total: 3-4000 � g (mainly hepatic) • Dietary deficiency: rare, in long term strict vegans
Normal B12 Absorption: a complex process involving 3 gastrointestinal organs: stomach, pancreas, terminal ileum
SCHILLING TEST
Common Etiologies of B12 def. • Lack of intrinsic factor – Pernicious anemia – Post-gastrectomy (partial / total / bypass) – Congenital • Biological competition a. Small-bowel bacterial overgrowth – Jejunal diverticuli – Blind loops stasis – Scleroderma, diabetes b. Fish tapewarm
Common Etiologies of B12 def .(cont) • Diseases of the ileum A. Surgical resections B. Crohn’s disease These are differentiated using the Schilling test !!!
B12 def - Treatment • Oral therapy – only if definitive dietary deficiency (rare) • Parenteral – injection of B12, 10 injections as a loading dose and then once a month for life • New!!! Sublingual/ Nasal Vit B12 therapy
B12 Def. – Response to Treatment Hb Retics g/dl % Platelets WBC x10 9 /L x103/L
Low B12 level is common • Since the introduction of commercial kits, the finding of a low B12 level is an all-too common finding in the workup of patients with anemia or other syndromes. • Even can be found in patients with LOW MCV
Low B12 is common in Israel • Reports say that low B12 level is common in Israel in all ethnic groups • Ashkenazi Jews: 22% (Gielchinsky, 2001) • Gaucher patients 40% (Gielchinsky, 2001) • Elderly living at home: 12-16% of (only 1- 2% of elderly living in institutions) (Figlin, 2003) • Israeli Olympic team: 1.7% (Eliakim, 2002)
Confirmation that low B12 level represents true deficiency HOW TO CONFIRM? Metabolic tests: • Methylmalonic acid (MMA) level • Homocysteine (HC) level
Association Between Folate, Vit B12 Biochemistry of B12 and Homocysteine Metabolism
Normal Folate Metabolism
Normal Folate Metabolism (2) • Folate is present in fruits, vegetables, human milk • Daily requirement: 50 � g/day • Well absorbed throughout the jejunum,ileum • Total body stores: 5 mg, only for several months
Etiologies of Folate Deficiency • Increased requirements (pregnancy, breastfeeding, hemolysis, exfoliative dermatitis) • Poor diet (longstanding) • Alcoholism, Parenteral feeding etc. • Poor absorption (diffuse intestinal diseases)
Folate Deficiency - Treatment • Oral folate (pills) for duration of state leading to deficiency
• Folate supplementation during pregnancy reduces significantly the risk for neural tube defects
Association Between Folate, Vit B12 and Homocysteine Metabolism
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