Folic acid and vitamin B12 Flashcards
1
Q
Megaloblastic anemia
A
- Abnormal morphology of peripheral blood and BM precursor cells that reflects asynchrony btwn nuclear and cytoplasmic maturation
- Cells are enlarged, as opposed to microcytic anemia where cells are shrunken
- Results from impaired DNA synthesis (microcytic due to impaired Hb and RNA synthesis) and from misincorporation of deoxyuridylate in DNA for thymidylate
- Both folic acid and vit B12 (cobalamin) are required for DNA synthesis and may be the underlying cause
2
Q
Properties and reactions cobalamin
A
- 2 cobalamins found in the human body: methylcobalamin and adenosylcobalamin (Co must be Co+ to be active; Co2+ is inactive)
- Reactions: conversion of homocysteine to methionine via methionine synthase requires cobalamin
- Conversion of methylmalonyl CoA to succinyl CoA via methylmalonyl CoA mutase requires cobalamin
3
Q
Properties of folate
A
- General term for vitamins that act like folic acid
- Folic acid is reduced by dihydrofolate reductase to tetrahydrofolate, which acts as a carrier of a methyl-type group (methyl, methylene, or formyl) on the N5, N10, or both atoms (only carries 1 methyl group at a time)
- Participates in many reactions, the ones we are most interested in: formation of methionine from homocysteine and conversion of thymidylate from deoxyuridylate
4
Q
Synthesis of thymidylate
A
- To make many RBCs during erythropoiesis, the cells must have lots of DNA precursors including thymidylate
- Thymidylate is created by adding a methyl group from N5N10 methylene THF to deoxyuridylate, using thymidylate synthase
- During this reaction, N5N10 methylene THF is converted back to DHF, meaning it must be reduced back to THF by DHF reductase and must acquire a new methyl group (from carbonate) before it can be used again
5
Q
Synthesis of methionine
A
- Folic acid is brought into the cells as N5 methyl THF, and this form of folic acid remains TRAPPED unless there is cobalamin present to convert it back into THF
- The reaction uses the methyl group on N5 methyl THF and moves it to cobalamin forming methylcobalamin and THF (THF can then be converted to N5N10 methylene THF and used)
- Methylcobalamin is then used by methionine synthase, and the methyl group is moved from methylcobalamin to homocysteine to form methionine
- Methionine negatively feeds back to block the reaction of N5N10 methylene THF -> N5 methyl THF, since that rxn is only necessary if the cell is in need of methionine
6
Q
N5N10 methylene THF deficiency
A
- Can result from a number of factors
- Tissue folate deficiency (inadequate delivery of N5 methyl THF into cells)
- Tissue cobalamin deficiency (N5 methyl THF remains trapped in that form without cobalamin to convert it to THF)
- Cobalamin is also required to polyglutamate folic acid (it enters the cell in monoglutamate form, but will leak out unless polyglutamated)
- Thus a cobalamin deficiency results in folate leaking out of the cell
- Can also be due to DHF reductase deficiency, which prevents DHF from being converted to THF (and later N5N10 methylene THF), thus all the folic acid the cell receives eventually becomes trapped as DHF
7
Q
Absorption of cobalamin
A
- In food it is bound to proteins, and is liberated by peptic digestion and low pH in stomach
- Free cobalamin then binds to R protein in the stomach (favored by acidic environment)
- Once in the small intestine, trypsin from pancreatic juice degrades R proteins, and cobalamin binds to intrinsic factor (glycoprotein, resistant to trypsin)
- Normal absorption involves active transport across the brush border of the enterocytes of the terminal ileum
- The absorption process requires cobalamin to be attached to intrinsic factor, and presence of Ca ions, before the cells will endocytose the cobalamin complex
- Cobalamin bound to R protein will not be absorbed
- To exit GI epithelium and enter blood stream cobalamin must be in transcobalamin 2 (TC2) form
8
Q
Food intake and use of cobalamin vs folic acid
A
- Cobalamin: get it from animal products (incl dairy and eggs), can store 2-5 mg, use 1-2ug/day, intake 2-4 ug/day (2500:1 stores:daily requirement ratio), absorbed in ileum
- Folic acid: get it from vegetables, fruits, eggs, can store 5-10 mg, require 100-400 ug/day, daily intake varies (25-50:1 stores: daily requirement ratio), absorbed in jejunum
- Therefore it is much easier to become folate deficient than cobalamin deficient since you use more folate relative to stores, and intake is more variable
9
Q
Folate absorption
A
- Folate in foods is in polyglutamate form, and is hydrolyzed to monoglutamate form in small bowel by conjugases (found in bile, pancreatic juice, brush border of jejunal mucosa)
- No cofactor is needed for folate absorption, it is brought into the cell in an ATP-dependent manner within the jejunum brush border (folate receptor)
- Inside the epithelial cell, folate is converted to N5 methyl THF (monoglutamate), and is released into the blood in this form
- Folate is stored in the liver, and present in tissues (besides GI epithelia) as polyglutamate form (to keep from leaking out of the cell)
10
Q
Absorption sites
A
- Fe: duodenum
- Folate: jejunum
- Cobalamin: Ilium
- Not ingesting folate will cause megaloblastic anemia in about 5 months (common)
11
Q
Characteristics of megaloblastic hematopoiesis
A
- Pancytopenia (WBC, RBC, platelets all low) with low retic count
- Increased MCV, RDW (indicated DNA problem, not RNA/Hb)
- Hyperplastic BM w/ ineffective hematopoiesis, increased EPO
- Increased apoptosis of RBC precursor leads to increase in bilirubin, LDH
- In BM you can see hypersegmented PMNS, giant metamyelocytes (w/ parachromatin)
- Sequelae: GI tract atrophy/diseases (PA: pernicious anemia, can see large nuclei in small bowel epithelia), infertility, cadiopulmonary (2o to anemia), neuropsychiatric (only in cobalamin deficiency), neural tube defect (spinal bifida, only in folic acid deficiency)
12
Q
Etiology of megaloblastic anemia
A
- Cobalamin or folic acid deficiency
- Hereditary or acquired defects in cobalamin or folate transport/metabolism
- Drugs that interfere w/ DNA synthesis
- Acute leukemia/myelodysplasia
- Congenital dyserythropoietic anemia
13
Q
GI alterations in cobalamin or folate deficiency
A
- Atrophy of GI mucosa leading to further malabsorption
- Gluten enteropathy (celiac disease) or tropical sprue leads first to folate deficiency followed by cobalamin deficiency
- Pernicious anemia, characterized by autoimmunity to gastric proteins (leading to gastric atrophy)
14
Q
Degenerative changes in nervous system
A
- Only occurs in cobalamin deficiency
- Peripheral neuritis: numbness, burning, tingling of fingers/toes
- Posterior column damage: impaired sense of position and vibration, ataxia, positive Romberg sign (walking in space)
- Lateral column damage: spasticity, hyperactive deep reflexes, pathologic toe signs
- Disturbances of cerebration: memory impairment, mood changes
- These changes are independent from abnormal erythropoiesis/megaloblastic anemia
- N2O (nitrous oxide) given for surgery oxidizes cobalamin (inactivates) and inactivates methionine synthase. Low levels of cobalamin before surgery can lead to neurologic complications 2-6 weeks after surgery
15
Q
Cobalamin vs folate deficiency in megaloblastic anemia 1
A
- Use patient history and PE, but lab tests are required to differentiate the cause
- Low serum cobalamin and normal or elevated folate indicates cobalamin deficiency
- Low serum folate and normal serum cobalamin indicates folate deficiency
- Low folate and cobalamin serum levels means it is true deficiency of both, just folate deficiency (for some reason they also have reduced cobalamin), or just cobalamin (but recent diet has been deficient in folate)
