Megaloblastic Anemia - - PowerPoint PPT Presentation

Megaloblastic Anemia

היגולוטמהלסרוק תימינפהאופרלאובמ–דהנש' סשת"ו

ד"הדערברפדלוג

Diagnostic approach based on RBC’s 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 Vit B12, Folate deficiency Non-Megaloblastic

Reticulocyte count Increased

Hemorrhage Hemolysis Cold agglutinins

Decreased/Normal

Alcoholism Liver Disease Hypothyroidism BM failure: MDS, Aplastic Anemia

DNA Synthesis

DNA THF

5,10 Methylene THF DHF

Deoxyuridine monophosphate (dUMP) Thymidine monophosphate (dTMP) Methyl B12

Methyl THF (plasma factor) THF - tetrahydrofolate DHF - dihydrofolate

Methotrexate blocks here

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)

Normal Megaloblastic Changes Peripheral Blood (2)

Normal Megaloblastic Changes Peripheral Blood

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.

B12 is a large, complex molecule with complex absorption

3 ACTIVE FORMS: CYANO, METHYL AND ADENOSYL

Normal B12 Metabolism (1)

Normal B12 Metabolism (2)

• B12 is present in foods of animal origin
• Not in vegetables or plants!!!

• 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 Metabolism (3)

Normal B12 Absorption:

a complex process involving 3 gastrointestinal

• rgans:

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 – Scleroderma, diabetes

• b. Fish tapewarm

stasis

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

Retics % Hb g/dl Platelets x109/L WBC x103/L

B12 Def. – Response to Treatment

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

Biochemistry of B12

Association Between Folate, Vit 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