Megaloblastic Anemia

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Diagnostic approach based on RBCs indices

MCV < 80 fl

80 fl < MCV < 98 fl

MCV > 98 fl

Microcytic anemia

Normocytic anemia

Macrocytic anemia

Macrocytic Anemia (MCV>100)

Morphology
Peripheral blood & Bone Marrow

Megaloblastic

Non-Megaloblastic
Reticulocyte count

Vit B12, Folate deficiency

Increased
Hemorrhage Hemolysis Cold agglutinins

Decreased/Normal
Alcoholism Liver Disease Hypothyroidism BM failure: MDS, Aplastic Anemia

DNA Synthesis
DNA
Methotrexate blocks here Thymidine monophosphate (dTMP)

DHF
Methyl B12

Methyl THF (plasma factor)

THF
5,10 Methylene THF

THF - tetrahydrofolate DHF - dihydrofolate

Deoxyuridine monophosphate (dUMP)

B12/Folate deficiency affects all dividing cells

1. Ineffective Hematopoiesis
Ineffective Erythropoiesis Ineffective Leukopoiesis Ineffective Thrombopoiesis Anemia Leukopenia 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 Folate deficiency

Antimetabolic drugs Inborn errors of metabolism Refractory anemias Erythroleukemia

95%

5%

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 2g/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. Crohns 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 g/dl

Retics %

Platelets x109/L

WBC 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 12% 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: 50g/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