Term
| Robbins Figure 14-19 (FH4, methionine synthase, and thymidylate synthetase) |
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Definition
Methylcobalamin (B12) serves as an essential cofactor in the conversion of homocysteine to methionine by methionine synthase
Methylcobalamin yields a methyl group that is recovered from N5-methyl FH4, the principal form of folic acid in plasma.
N5-methyl FH4 is converted to (FH4).
FH4 is crucial, since it is required (through its derivative N5,10-methylene FH4) for the conversion of dUMP to dTMP, an immediate precursor of DNA |
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Term
| Explain the relationship b/t folate and DNA synthesis, specifically the nucleotides |
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Definition
| N5-methyl FH4 is the principal form of folate in plasma. It is converted to FH4 by methionine synthase (also requires B12), which is the DNA precursor |
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Term
| Review the proposed biochemical metabolism of B12 (cobalamin) and folate deficiency by describing their roles in the synthesis of DNA And the role of B12 in fatty acid metabolism |
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Definition
The fundamental cause of the impaired DNA synthesis in vitamin B12 synthesis is the reduced availability of FH4, most of which is "trapped" as N5-methyl FH4.
FH4 deficit may be exacerbated by folate deficiency
lack of folate is the proximate cause of anemia in vit B12 deficiency |
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Term
| Explain the role biochemical reactions of homocysteine to methionine and the succinyl pathway has to B12 metabolism |
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Definition
vitamin B12 facilitates the transfer of methyl groups from FH4 to homocysteine to form methionine
Vit B12 is the cofactor for methylmalonyl CoA mutase, which catalyzes the rearrangement of methylmalonyl coA to succinyl CoA (this is the rxn coupled to methyl5FT4 to FT4) |
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Term
| Define nuclear-cytoplasmic asynchronism/nuclear-cytoplasmic dissociation, specifically for megaloblastic maturation |
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Definition
B12/folate deficiency -> bad DNA
Cytoplasm develops at a faster rate than the nucleus |
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Term
| Contrast normoblastic maturation and megaloblastic maturation of erythroid cells |
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Definition
unlike normal cells, the majority of megaloblastic cells aren't resting but are trying to double their DNA, with frequent arrest in S phase and lesser arrest in other phases
as a result, an i/c % of these cells have DNA values b/t 2N and 4N b/c of delayed cell division |
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Term
| Describe the peripheral blood features (on CBC and peripheral blood smear) of megaloblastic anemia (either B12 or folate) |
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Definition
Defect in DNA synthesis, with lesser alterations in protein and RNA synthesis, leads to a state of unbalanced cell growth and impaired cell division
larger than normal "immature" nuclei with finely particulate chromatin, whereas the relatively unimpaired RNA protein synthesis results in larger cells with greater "mature" cytoplasm and cell volume
erythroid precursors and red cells are abnormally large
HYPERSEGMENTED NEUTROPHILS
macrocytic (high MCV), oval
thrombocytopenia
retic count usually *d/c* |
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Term
| Describe the bone marrow features in megaloblastic anemia (either B12 or folate) |
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Definition
nuclei in megaloblasts are not pyknotic
granulocytic precursors are large, have abnormally immature chromatin |
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Term
| List increased metabolic products as a result of impaired pathways dependent upon B12 |
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Definition
5-methyl-FT4
homocysteine
methylmalonyl CoA |
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Term
| Explain the mechanism of anemia in megaloblastic anemia (2 explanations) |
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Definition
-not enough B12 or folate in the diet
-atrophic gastritis/pernicious anemia (impaired intrinsic factor) |
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Term
Define ineffective erythropoiesis
in megaloblastic anemia |
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Definition
premature destruction of RBC
The derangement in DNA synthesis in megaloblastic anemia causes most precursors to undergo apoptosis in the marrow, leads to pancytopenia |
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Term
| Describe the physiologic effects the following have on B12 absorption: gastric pH, release of intrinsic factor, and pancreatic enzymes |
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Definition
| B12 absorption requires intrinsic factor |
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Term
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Definition
B12 deficiency
a specific form of megaloblastic anemia caused by atrophic gastritis and attendant failure of intrinsic factor production |
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