Vitamin B12 and Folic Acid Flashcards
Macrocytic Anemia
o MCV > 100 fl
Caused by: • Liver disease • Alcoholism • Reticulocytosis • Hypothyroidism • Primary marrow disorders (ex: myelodysplasia, aplastic anemia) • Drugs that block DNA synthesis • B12 and folate deficiency
Megaloblastic anemia
o Delayed nuclear maturation due to impaired DNA synthesis
o A subset of macrocytic anemia
Caused by:
• Myelodysplasia
• Drugs that block DNA synthesis (ex: chemotherapy drugs)
• B12 and folate deficiency
• Others causes: drugs (anticonvulsants, trimethoprim), arsenic, pesticides, other toxins, inherited metabolic disorders (rare), congenital dyserythropoietic anemia (rare)
Pathology:
• Large nucleus with finely dispersed chromatin; may have oval shape
• Giant bands in bone marrow
• Hypersegmentation of neutrophils in peripheral blood (6 or more lobes)
Causes of vitamin deficiency
Inadequate intake • Folic acid = alcoholics and institutionalized patients • B12 = vegans Malabsorption • Folic acid = in celiac disease, drug interactions • B12 = lack of intrinsic factor Increased utilization or loss • Pregnancy, hemolysis Drug inhibition • Folic acid = Methotrexate • B12 = Nitrous oxide inactivates cobalamin Genetic defects
Vitamin B12: role in body
Conversion of methylmalonyl CoA → (via adenosylcobalmin) succinyl CoA
Homocysteine → methionine
• Methylation reaction
• Requires methylcobalamin and N5-methltetrahydrofolate as methyl donor
Result: with B12 deficiency
• Get high homocysteine and methylmalonate
• Trapping of folate in MethylTH4 form = unavailable for thymidine synthesis → DNA synthesis
Vitamin B12: absorption
Dietary sources: meat, poultry, fish
• Typical intake 7-30 μg/day
• 2-3 μg absorbed
Stomach acid = enhances absorption
• Dietary B12 transferred to binding protein R-binder in stomach
• Intrinsic factor secreted from gastric parietal cells (facilitates absorption in ileum)
In duodenum = pancreatic enzymes degrade R-binders
• B12 transferred to intrinsic factor
In distal ileum = B12/IF complex binds cubulin receptor
• B12 absorbed; IF broken down
Absorbed vitamin bound to transcobalmin II
• Transported to liver and marrow
Most B-12 in blood bound to haptocorrin (transcobalmin I or R-binder)
• Not delivered to marrow
• Physiologic function of this pool of B-12 is unknown.
Normal body stores = 2000-3000 μg
• Biologic half-life = about 1 yr
Clinical disease when stores < 20% of normal
Vitamin B12: causes of deficiency
Insufficient intake (strict vegetarians/vegans)
Failure of absorption:
Lack of intrinsic factor:
1) Autoimmune (pernicious anemia)
o Antibodies to parietal cells (sensitive test)
o Antibodies to intrinsic factor (specific test)
o Permanent loss of B-12 absorption
o Achlorhydria; gastric atrophy (not corrected by B-12 replacement)
2) Gastrectomy
3) Inherited deficiency of IF (rare)
Pancreatic insufficiency (rare cause)
Lack of ileal absorption: Crohn’s, small bowel resection
Competition for vitamin by overgrowth of intestinal bacteria (eg “blind loop” syndrome) or tapeworm (Fish tapeworm)
Genetic lack of transcobalmin II (rare)
Destruction of B-12 by nitrous oxide
Vitamin B12: lab findings in deficiency
o Megaloblastic anemia
o WBC and platelets may be low (pancytopenia)
o Low serum B-12 level
o Increased methylmalonate and homocysteine
Marrow cellular
• Low G:E ratio (1:1)
• Megaloblastic changes in RBC and granulocyte series
o Reticulocyte count not increased (ineffective erythropoiesis)
o High LDH and bilirubin due to red cell breakdown in marrow (in advanced disease)
Vitamin B12 deficiency clinical consequences
Neurologic injury
• Especially loss of vibratory sense & proprioception = due to degeneration of posterior and lateral columns of spinal cord
• Advanced disease = spastic paralysis of lower extremities, loss of sphincter control, dementia
o Advanced disease may not be completely reversible o Giving folate may correct/prevent anemia, but make neurologic deficits worse o Neural tube defects (in pregnancy) o Glossitis (sore, smooth, red, glistening tongue due to lack of papillae)
Folic acid: role in body
o Needed for thymidine synthesis, amino acid metabolism, purine metabolism
o Function: transfers single carbon units
Folic acid: absorption
Small molecule = MW 400
Sources: Yeast, vegetables, dairy products, seafood
• But vitamin can be destroyed by cooking
Absorbed in jejunum (50-80% of dietary vitamin absorbed)
• Via passive diffusion and active transport
• Brush border deconjugase cleavage enhances absorption
Normal intake 200-250 mcg/day
• Requirement 100 mcg/day
Body stores 10-12 mg
Biologic half-life ~ one month
Folic acid: causes of deficiency
o Poor diet
o Celiac disease
o Pregnancy = increased utilization
o Increased RBC production (chronic hemolysis = increased utilization)
o Alcoholism (poor diet, poor absorption, poor storage if liver injured)
o Anticonvulsants (phenytoin) decrease absorption
Folic acid: lab findings in deficiency
o Megaloblastic anemia with ineffective erythropoiesis
• Typically less severe than advanced B-12 deficiency
o WBC and/or platelets may be low
o No neurologic injury
o Mild maternal deficiency → neural tube defects
o Low serum folate level
o RBC folate level does not provide additional useful information
o Increased serum homocysteine, normal methylmalonate
