Megaloblastic Anemia

קורס להמטולוגיה

' שנה ד–מבוא לרפואה פנימית

ו"תשס

גולדפרבר עדה "ד

Diagnostic approach based on RBC’sindices

MCV < 80 fl 80 fl < MCV < 98 fl MCV > 98 fl

Microcyticanemia

Normocyticanemia

Macrocyticanemia

Macrocytic Anemia (MCV>100)

MorphologyPeripheral blood & Bone Marrow

Megaloblastic

Vit B12, Folatedeficiency

Non-Megaloblastic

Reticulocyte count

Increased

Hemorrhage

Hemolysis

Cold agglutinins

Decreased/Normal

Alcoholism

Liver Disease

Hypothyroidism

BM failure:

MDS, Aplastic Anemia

DNA SynthesisDNA

THF

5,10 Methylene THF

DHF

Deoxyuridinemonophosphate

(dUMP)

Thymidinemonophosphate

(dTMP)

Methyl B12

Methyl THF (plasma factor)

THF - tetrahydrofolate

DHF - dihydrofolate

Methotrexate blocks here

B12/Folate deficiency affects all dividing cells

1. Ineffective HematopoiesisIneffective 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 2µg/day• Body stores total: 3-4000 µg (mainly

hepatic)

• Dietary deficiency: rare, in long term strict vegans

Normal B12 Metabolism (3)

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 competitiona. Small-bowel bacterial overgrowth

– Jejunal diverticuli– Blind loops– Scleroderma, diabetesb. Fish tapewarm

stasis

Common Etiologies of B12 def.(cont)

• Diseases of the ileumA. Surgical resectionsB. 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%

Hbg/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 B12Association Between Folate, Vit B12 and Homocysteine Metabolism

Normal Folate Metabolism

Normal Folate Metabolism (2)

• Folate is present in fruits, vegetables, human milk

• Daily requirement: 50µg/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, exfoliativedermatitis)

• 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