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Clinical Medicine Lecture: _____ Topic: ____________________________________________________________ Date: ______________

Cobalamin (Vitamin B12) Deficiency Folate Deficiency Anemia


Daily requirement is 1-3 mcg and body stores 2-3 mg. Daily requirement is ~100 mcg and total body folate level is ~10 mg
Active absorption of Intrinsic Factor (IF)-cobalamin complex at ileum. Only ~50% gets absorbed by upper small intestine and enters portal
Stomach becomes barren wasteland (makes no IF). circulation as 5-MTHF when 1/3 bound to albumin and 2/3 unbound
Cobalamin deficiency Folate deficiency
o Nutritional rare, but considered mostly in unfortified Vegans o Dietary particularly in old age, poverty, alcoholism, chronic
o Malabsorption pernicious anemia invalids, and the psychiatrically disturbed (esp. anorexia nervosa)
Pernicious anemia is anemia due to B12 deficiency, due to severe o Malabsorption
lack of IF, due to gastric atrophy Major causes of deficiency tropical sprue, gluten-induced
Common in north Europeans at peak age of 60 enteropathy in children and adults
Serum IF antibodies (autoimmune disease) in 50% of patients Minor causes of deficiency extensive jejunal resection, Crohns
Etiology
with pernicious anemia that prevent complex of IF & cobalamin disease
(Pathophysiology):
(Type I) or prevents attachment of complex to ileum (Type II) o Excessive utilization or loss
Gastric effects from other anti-gastric antibodies and CD4 cells Physiologic pregnancy and lactation, prematurity
atrophy of all layers of fundus and body with absence of parietal Pathologic chronic hemolytic anemias, sick cell anemia,
and chief cells, which leads to a lack of IF thalassemia major, myelofibrosis, exfoliative dermatitis, active
production/release/function/B12 absorption liver disease, hemodialysis, peritoneal dialysis
o Gastric causes total or partial gastrectomy o Antifolate drugs esp. phenytoin and sulfasalazine
H2RAs and PPIs prevent B12 and IF binding
o Intestinal causes ileal resection and Crohns disease
Metformin decreases absorption at ileum
Cobalamin metabolism abnormalities
Usually few/mild, if any, anemia symptoms Usually few/mild, if any, anemia symptoms
Vague GI disturbances like anorexia and diarrhea Vague GI disturbances like anorexia and diarrhea
Glossitis Glossitis
Complex neurological syndrome NO neurological syndrome
Clinical o Loss of myelin and neuronal cell death Skin changes
Manifestations Least likely to improve with repletion therapy o Darkening of the skin and mucous membranes, particularly at the
(Signs and o First have paresthesias of peripheral nerves and then progression to dorsal surfaces of the fingers, toes, and creases of palms and soles
Symptoms): posterior columns of spinal cord (balance difficulties, proprioception o Patchy distribution
impairment, pallesthesia) followed by cerebrum (dementia, o Should gradually resolve after weeks or months of folate treatment
neuropsychiatric abnormalities) if severe Modest temperature elevation (< 102 F)
o Temperature typically falls within 24-48 hours of vitamin treatment
Neural tube defects in pregnant patients
1. CBC 1. CBC
o Hgb low o Hgb low
o Hct low o Hct low
o MCH. MCHC increased o MCH. MCHC increased
Diagnostic Studies:
o MCV usually elevated at 110-140 fL (can be normal) o MCV usually elevated at 110-140 fL (can be normal)
o WBC Leukopenia* o WBC Leukopenia*
o Platelets Thrombocytopenia* o Platelets Thrombocytopenia*
2. Peripheral Smear and Reticulocytes 2. Peripheral Smear and Reticulocytes
o RBC Appearance macrocytic, hyperchromic o RBC Appearance macrocytic, hyperchromic
See macro-ovalocytes and hypersegmented neutrophils (6 lobes See macro-ovalocytes and hypersegmented neutrophils (6 lobes
or mean lobe counts >4), anisopoikilocytosis on peripheral smear or mean lobe counts >4), anisopoikilocytosis on peripheral smear
In severe anemia, see Howell-Jolly bodies in RBCs, Cabot rings In severe anemia, will have basophilic stippling of the RBCs, but
in RBCs, and basophilic stippling of the RBCs NO Cabot rings in RBCs
o (Reticulocytes Too few: poor RBC production overall o (Reticulocytes Too few: poor RBC production overall
3. B12 and Folate Studies Iron Studies 3. B12 and Folate Studies Iron Studies
o Vitamin B12 (automated ELISA or competitive-binding o Vitamin B12 Assays normal
luminescence) assay decreased, <200 pg/mL (NL > 300 pg/mL) o Folate level (Normal: 2.5-20 ng/mL)
If borderline B12 assay (200-300 pg/mL) confirm dx with serum Cannot be used alone to establish diagnosis; only useful for ruling
methylmalonic acid level or homocysteine level out folate deficiency if > 5 ng/mL
o Folate level normal If < 5 ng/mL, serum homocysteine (reference range 5-16
4. IF antibodies (Types 1 and 2) Shilling test mmol/L) elevated in folate deficiency
o Specific for pernicious anemia (confirms dx) o RBC folate assay test of body folate stores
5. Bone marrow aspiration and biopsy Decreased (Normal range: 160-640 mcg/L of PRBCs) in folate
o If done find hypercellular megaloblasts, trilineage differentiation, deficiency and ~2/3 of patients with severe cobalamin deficiency
and erythroid precursors that are large and often oval 4. Bone marrow aspiration and biopsy
6. Other o If done find hypercellular megaloblasts, trilineage differentiation,
o Indirect hyperbilirubinemia (due to intramedullary hemolysis) and erythroid precursors that are large and often oval
o Serum lactate dehydrogenase (LDH) concentration markedly
increased
Eliminate cause of deficiency and treat with cobalamin Folic acid 1 mg PO daily usually continued x 4 months at least
o Parenteral vitamin B12 IM 1 mg QD x 1 week, weekly x 4 weeks, Prevention through proper diet or supplement PO (400-600 mcg dietary
then STOP or, if underlying disorder persists monthly for life folate equivalents as recommended daily allowance; max 1 mg)
o Oral and nasal vitamin B12 1-2 mg daily Response to treatment
Only use AFTER the patients vitamin B12 status has been o In 5-7 days, improved sense of well-being and reticulocytosis
normalized with parenteral treatment o In 2 months, total correction of hematological abnormalities (anemia
o Within first 1-2 days especially)
Serum iron, indirect bilirubin, and LDH fall rapidly
If anemic before treatment, reticulocytosis in 3-4 days, (peaking
Treatment (First & at 1 week, followed by a rise in hemoglobin and a fall in MCV)
Second Line): MCHC begins to rise within 10 days (normalizes in 8 weeks)
Hypersegmented neutrophils disappear at 10-14 days
Neurologic abnormalities improve over 3 months, with max
improvement attained at 6-12 months (the degree of improvement
is inversely related to the extent and duration of disease)
Blood transfusion for severe anemia (<6.5 g/dL?) or critically ill
patient/comorbid conditions (<8 g/dL?)
Lifestyle modifications diet and activity
Delayed treatment permits progression of anemia and permanent
neurological complications
Hematology and Neurology PRN Dietician
Referral:
Hematology PRN