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