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BIOC Heme-Onc II > Megoblastic Anemia > Flashcards

Megoblastic Anemia Flashcards

1
Q

what is seen on a blood smear in a person with megoblastic anemia?

A
  • erythrocytes that are either
    • normochromatic
    • and either
      • normal, or
      • VERY LARGE & misshapen (often oval)
  • PMNs with hyper-segmented nuclei
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2
Q

what is the general pathophysiology of megoblastic anemia?

A
  • impaired DNA synthesis → reduction of nuclear divisions during erythroblast maturation → abnormally large RBCs
    • DNA synthesis is impaired d/t a defect in the transfer of one carbon groups, which depends on the formation of a one carbon pool. an insufficient one carbon pool is usually d/t
      • folate deficiency
      • Vit B deficiency
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3
Q

what are the general steps / molecules required for the for the formation of the the carbon pool?

A
  • the one carbon pool consists of a tetrahydrofolate group (FH4) that carries a carbon unit in either a formyl, methylene, or methyl form.
    • FH4 comes from FH4 synthesis, which requires:
      • folate
      • dihydrofolate reductase
      • NADPH
    • the carbon unit is donated from either:
      • amino acids - glycine, serine, histidine
      • formaldehyde / formate
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4
Q

describe the structure of folate.

A

overall: pteridine ring + PABA (p-aminobenzoic acid) + glutamate(s)

  • two forms:
    • ingested form: has several glutamates
    • absorbed form: has single glutamate (mono-form)
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5
Q

tetrahydrofolate synthesis

  • requires what molecules?
  • involves what steps?
A
  • requires:
    • folate
    • DHFR (dihydrofolate reductase)
    • 2 NADPH
  • steps:
    • ingestion of folate
    • removal of extra glutamates in intestine
    • absorption of mono-form (pteridine ring+ PABA + single glutamate)
    • conversion of folate (F) → FH4
      • F reduced to FH2 by DHFR and NADPH
      • FH2 reduced to FH4 by DHFR and NADPH
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6
Q

what are the sources of one-carbon units that are carried by FH4 in the carbon pool?

A
  • glycine
  • serine
  • histidine
  • formaldehyde
  • formate
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7
Q

attachment of the one-carbon unit to FH4

  • requires what molecules?
  • involves what steps?
  • yields what forms of transferrable carbon?
A

three forms of carbon unit in carbon pool: formyl, methylene, methyl. they are synthesized in the following steps:

  • FH4 → N10-formyl-FH4: requires ATP
    • carbon attached in the form of a “formate” group to 10th nitrogen of FH4
  • N10-formyl-FH4 → N5,N10-methylene-FH4: requires NADPH
  • N5,N10-methylene-FH4 → N5-methyl-FH4: requires NADH
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8
Q

generation of what FH4-cabon product is the “least” reversible? why?

A
  • N5-methyl-FH4 (synthesized from N5,N10-methyelene-FH4 using NADH)
    • the “methyl” form of carbon is CH3, and is thus as reduced as possible.
    • thus, N5-methyl-FH4 must donate its methyl group or stay methylated)
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9
Q

what cellular processes require donation from the one-carbon pool? which form form of FH4 serves as the donor in each case?

A
  • purine biosynthesis - formyl form
  • dTMP synthesis - methylene form
  • SAM reactions - methyl form
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10
Q

purine biosynthesis requires carbon donation from what form of FH4?

A

formyl form: N10-formyl-FH4

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11
Q

SAM (S-adenosyl methionine) reactions require carbon donation from what form of FH4?

A

methyl form: N5-methyl-FH4

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12
Q

dTMP synthesis

A

methylene form: N5,N10-methyl-FH4

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13
Q

what are the roles of NADPH in one-carbon unit transfer?

A
  1. generation of FH4: used 2x by DHFR to reduce folate → FH2 → FH4
  2. generation of N5,N10-methylene-FH4 (used in dTMP synthesis) from N10-formyl-FH4
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14
Q

describe the structure of Vitamin B12.

A

= corrin ring + long chain + 3rd group

  • corrin ring
    • has cobalt in the center
    • resembles heme
  • 3rd group is one of the following:
    • methyl
    • adenosyl
    • cyanyl forms
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15
Q

outline the absorption of Vitamin B12

A

Vit B12 consumed in protein rich dietary sources, then moved into the blood by several steps:

  • Vit B12-protein carrier complex enters stomach
  • here, the protein carrier is denatured, after which Vit B12 immediately becomes bound by other carriers:
    • initially - bound by R-binders made by gastric mucosa
      • this is brief, as R-binders are quickly degraded by acid
    • next - bound by intrinsic factor made by parietal cells
  • Vit-B-intrinsic factor complex travels all the way to the ileum, where it:
    • is absorbed into the blood through ileal enterocytes, then
    • attached to transcobalamin-II, which transports it to
      • liver for storage
      • other tissues for use
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16
Q

what is the role of intrinsic factor in the absorption of Vit B12?

A
  • made by parietal cells
  • are attached to Vit B12 in the stomach (after R-binders are degraded) then transport it to the ileum
17
Q

what is the role of transcobalamin II in the absorption of Vit B12?

A
  • receives Vit B12 from intrinsic factor once the complex has entered the blood, then transports Vit B12 to
    • liver for storage
    • tissues for use
18
Q

what issues could disrupt cellular processes dependent on Vitamin B12?

A
  • inadequate consumption of Vit B12
  • decreased Vit B12 absorption, due to
    • gastric surgery
      • dec # of parietal cells → dec intrinsic factor production
    • aging
      • decreases HCl production → inhibited denaturing of dietary protein carrier → less free Vit B12
19
Q

what cellular processes require Vit B12?

A

only two reactions (but they are major)

  1. regeneration of SAM (S-adenysoylmethionine)
  2. conversion of metabolic products into succinyl CoA for entry into TCA cycle
20
Q

what is the role of Vit B12 in regeneration of SAM?

A
  • Vit B joins N5-methyl-THF to form methyl-cobalamin, a group which can donate the methyl group to homocysteine to produce methionine + THF
    • methionine → SAM → methylation of various molecules
21
Q

what is the role of Vit B12 in the conversion of metabolic products into succinyl CoA? why is this important?

A
  • Vit B joins methymalonyl CoA - a by product of 1. ketogenic metabolism and 2. odd-chain FA metobolism - allowing its conversion to succinyl-CoA
    • thus, allowing its entry into the TCA cycle
22
Q

SAM

  • what molecules / steps are necessary for the generation of SAM?
  • what is this importance of the SAM pathway?
A
  • SAM synthesis
    • requires
      • N5-methyl-FH4
      • Vit B12
    • steps
      • N5-methyl-FH4 bound by Vit B12
      • this enables N5-methyl-FH4 to donate its methyl group to homocysteine, forming → methionine + THF
        • THF: recycled into carbon pool for re-use
        • methionine: converted to S-adenosyl methionine (SAM) by ATP
  • importance of SAM pathway:
    • SAM methylatation is required for the production of several molecules, such as:
      • EPI
      • creatinine
      • methylated nucleotides
      • phosphatidyl choline
      • melatonin
    • serves to regenerate THF
23
Q

what does homocysteine come from?

how is homocysteine metabolized?

A
  • homocysteine comes from a SAM molecule that has donated its methyl group
  • homocysteine then processed in one of two ways:
    • converted into methionine for regeneration of SAM. requires
      • N5-methyl-THF
      • Vit B12
    • converted ty cystathionine → cysteine. requires
      • Vit B6
24
Q

what leads to hyper-homocysteinemia? explain.

A
  • accumulation of homocysteine, due to either
    • impaired conversion to methionine
      • folate deficiency
      • Vit B12 deficiency
    • impaired conversion to cystathionine
      • Vit B6 deficiency
25
Q

clinical presentation of hyper-homocysteinemia?

A

several neurological + CV effects

26
Q

what is the “alternative pathway to methionine”? what is required for this pathway?

A
  • a pathway (in the liver) that can partially mitigate hyper-homocysteinemia by converting homocysteine to methionine
  • requires: choline
    • choline → betaine
    • betaine donates a methyl group to homocysteine, restoring methionine
27
Q

what biochemical pathways can somewhat mitigate hyper-homocysteinemia due to Vit B12 deficiency? what is the caveat of each?

A
  • conversion of homocysteine → cystathione
    • this works temporarily, eventually cysteine accumulates & inhibits cystathione generation by neg feedback
  • conversion of homocysteine → methionine by betaine (choline)
    • this only pathway only works in the liver. it does NOT stop the neurological affects of hyper-homocysteinemia
28
Q

what is the clinical presentation of hyper-homocysteinemia?

A

several neurological + CV effects

29
Q

what is the methyl trap hypothesis?

A

the idea that Vit B12 deficiency - by slowing conversion of homocysteine to methionine, leads to accumulation of

  • homocysteine
  • Methyl-FH4

this leads to

  • neurological sx
  • impaired folate recycling → inhibition of processes that require one carbon pool (purine synthesis, dTMP synthesis, ect)
30
Q

explain the features of erythrocytes in megoblastic anemia

A

seen in both folate & Vit B12 deficiency:

  • abnormally large RBCs:
    • impaired DNA synthesis → fewer divisions → larger RBCs
      • impaired DNA synthesis d/t insufficient FH4 b/c of:
        • insufficient folate - no FH4 production
        • insufficient Vit B12 - no FH4 recycling
  • normochromic RBCs
    • hemoglobin production normal
31
Q

what clinical features would help dx folate-deficient megoblastic anemia (vs Vit B12 megoblastic anemia?)

A
  • presentation
    • folate deficiency, during pregnancy, can also lead to several fetal defects:
      • neural tube defects
      • spina bifida
      • anencephaly
  • dx
    • increased FIGLU levels (histidine metabolite)
32
Q

what clinical features would help dx Vit B12-deficient megoblastic anemia (vs folate deficient megoblastic anemia?)

A
  • presentation
    • several neurological sx (likely d/t hyper-homocysteine)
      • paresthesia - symmetrical, in hands & feet
      • spastic gate - d/t position sense deficits
      • irritability
      • vision / taste disturbances
  • diagnosis
    • elevated methylmalonic acid
33
Q

methotrexate

  • what is its role?
  • how does it work?
A
  • used in tx of cancer
  • inhibits dTMP synthesis by interfering with one-carbon transfer:
    • blocks DHFR → no conversion of FH2 to FH4 → no N5,N10=methylene-FH4
34
Q

5-FU

  • what is its role?
  • how does it work?
A

used in the tx of cancer

  • used in the tx of cancer
  • inhibits synthesis of dTMP
    • by serving as an analog of uracil (F-dUMP) blocking dUMP → dTMP

BIOC Heme-Onc II (3 decks)

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