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Biochemistry Exam #3 > Megaloblastic Anemia > Flashcards

Megaloblastic Anemia Flashcards

1
Q

What is the underlying issue with anemia resulting from underproduction of RBCs? What about with destruction of RBCs?

A
  • Defective precursor cells (underproduction)

- Defective function/structure of RBCs (destruction)

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2
Q

What is the difference between underproduction anemia and destruction anemia in terms of reticulocyte levels? (hint: both increase the demand for RBCs)

A
  • Underproduction causes bone marrow to work harder, BUT because of a problem with RBC production, there is no change (or even a decrease) in the reticulocyte levels
  • Destruction causes bone marrow to work harder, leading to an increase in reticulocyte levels
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3
Q

What exactly causes megaloblastic anemia in terms of DNA synthesis and what is this a result of?

A

Megaloblastic anemia occurs when there is impaired DNA synthesis due to lack of DNA precursors (no nucleotides)

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4
Q

Decreased nucleotide synthesis combined with what leads to megaloblastic cells? Describe why this happens

A

Nucleotide synthesis is impaired, but protein synthesis continues at a normal rate
- Cells that produce protein are unable to divide and this causes protein accumulation, leading to cell enlargement

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5
Q

Why is there a decrease in precursor cells (2)?

A
  • Decreased division of precursor cells

- Increased destruction of precursor cells in bone marrow

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6
Q

What are the two specific markers of megaloblastic anemia found in the results of a peripheral blood smear?

A
  • Oval-shaped RBCs

- Hyper-segmented neutrophils (>5 lobes)

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7
Q

What are the three results of a blood analysis shown with megaloblastic anemia?

A
  • Low RBC count (and therefore, low Hb concentration)
  • Low/normal reticulocyte count (underproduction anemia)
  • Proliferation of precursor cells of other lineages will also be decreased (like WBCs and platelets so pancytopenia)
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8
Q

What are the three results of a bone marrow sample shown with megaloblastic anemia?

A
  • Enlarged precursor cells of RBCs (megaloblasts)
  • Diffuse nuclear condensation (i.e. salami)
  • Asynchronized nuclear and cytoplasmic maturation
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9
Q

What is the typical MCV result value found with megaloblastic anemia?

A

MCV > 110 fL (typically 110-160 but can be up to 160 fL)

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10
Q

What are the two most common causes of Megaloblastic Anemia?

A
  • Folate (Folic Acid) deficiency

- Vitamin B12 deficiency

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11
Q

What is the most common cause of Folate deficiency? What are three other causes?

A

Most common cause of Folate deficiency is inadequate dietary intake (lack of green, leafy vegetables, legumes, cereal grains, nuts)

  • Drugs (Methotrexate)
  • Malabsorption
  • Increased requirements (pregnancy)
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12
Q

What is a common cause of Vitamin B12 deficiency? In what three populations is this deficiency often found?

A

A common cause of Vitamin B12 deficiency is malabsorption

  • Vegans
  • Neglected elderly
  • Alcoholics
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13
Q

What are three common clinical presentations of Folate Deficiency and Vitamin B12 deficiency? What is a large clinical difference between these two deficiencies?

A
  • Glossitis (tongue inflammation)
  • Stomatitis (mouth inflammation/sores)
  • Angular cheilitis (inflammation of corners of mouth)

Vitamin B12 deficiency can result in irreversible peripheral neuropathy (damages myelin, which demyelinates neurons)

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14
Q

What are the two main functions of Folate?

A
  • Synthesis of nucleotides

- Synthesis of SAM

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15
Q

What step is required for the continual production of nucleotides (starting substrate and end product)? What two nucleotides is the end product used to produce and by what conversion?

A

Methyl THF > THF (THF is required for production of dTMP and purines)

  • dTMP produced when Methylene-THF > DHF
  • Purines produced when Formyl-THF > THF
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16
Q

What is the major methyl donor in many methylation reactions, and what is it produced from?

A

SAM is the major methyl donor used in many methylation reactions (second most widely used following ATP)
- Methionine > SAM (methionine comes from homocysteine via the Homocysteine Methyltransferase reaction)

17
Q

What is the ultimate consequence of a Folate deficiency? Describe why this occurs in 6 steps

A

Folate deficiency leads to decreased nucleotide synthesis, causing Megaloblastic Anemia

  1. Low Folate levels
  2. Low DHF and THF levels
  3. Low formyl-THF and methylene-THF levels (= low nucleotides)
  4. Low methyl-THF levels
  5. Even lower regeneration levels of THF from low methyl-THF, AND low production of SAM (from low methionine levels)
  6. Low nucleotide synthesis
18
Q

What is the Folate Trap Hypothesis?

A

If there is a deficiency in Vitamin B12, Homocysteine Methyltransferase will not function properly (Vitamin B12 is a cofactor), and therefore methyl-THF will accumulate, unable to convert back into methylene-THF (irreversible reaction) or convert to THF (no enzyme)

19
Q

What two enzymes is B12 a cofactor of, and what is each enzyme used to convert (starting substrate and end product)?

A
  • Homocysteine Methyltransferase: converts Methyl-THF > THF and Homocysteine > Methionine
  • Methyl Malonyl CoA Mutase: converts Methylmalonyl CoA > Succinyl CoA (used in TCA Cycle)
20
Q

What are the two ultimate consequences of a Vitamin B12 deficiency (hint: think of enzymes)? Describe why these occur (4 steps for each)

A

Vitamin B12 leads to decreased nucleotide synthesis, causing Megaloblastic Anemia

  1. Low Vitamin B12 levels
  2. Decreased activity of Homocysteine Methyltransferase (Vitamin B12 is a cofactor)
  3. Methyl-THF not converted to THF AND homocysteine not converted to methionine
  4. Low nucleotide synthesis

Vitamin B12 also leads to increased production of Methylmalonic Acid

  1. Low Vitamin B12 levels
  2. Decreased activity of Methyl Malonyl CoA Mutase (Vitamin B12 is a cofactor)
  3. Buildup of Methylmalonyl CoA
  4. Increased production of Methylmalonic acid (Methylmalonyl CoA used to convert to Methylmalonic acid)
21
Q

What is the gold standard test to differentiate between Folate deficiency and Vitamin B12 deficiency? Why?

A

Methylmalonic Acid because this will be unchanged with a Folate deficiency, but elevated with a Vitamin B12 deficiency

22
Q

What medication can cause a Folate deficiency (and ultimately Megaloblastic Anemia as a side effect)?

A

Methotrexate (MTX)

23
Q

What enzyme does Methotrexate (MTX) inhibit and what two conversions is this enzyme involved in?

A

MTX is an inhibitor of DHFR which converts:

  • Folate > DHF
  • DHF > THF
24
Q

What two health issues is this medication typically used to treat? How does this work?

A

MTX is used to treat cancer and autoimmune disorders

- Prevents DNA synthesis in rapidly-dividing cells (cancer cells or autoimmune cells)

25
Q

With regards to Vitamin B12 absorption, what two molecules play a role in the mouth?

A
  • Vitamin B12

- R-binder

26
Q

With regards to Vitamin B12 absorption, what two molecules play a role in the stomach?

A
  • Vitamin B12

- Intrinsic factor

27
Q

With regards to Vitamin B12 absorption, what one molecule plays a role in the duodenum?

A
  • B12-Intrinsic Factor complex
28
Q

With regards to Vitamin B12 absorption, what two molecules play a role in the ileum?

A
  • B12-Intrinsic Factor complex

- B12-Intrinsic Factor complex receptor

29
Q

With regards to Vitamin B12 absorption, what molecule plays a role in the blood? In the tissues?

A
  • Blood: B12-transcobalamin II

- Tissues: B12-transcobalamin II receptor

30
Q

What is the significance of R-binder proteins in Vitamin B12 absorption? Where are they produced and degraded?

A

R-binders bind to Vitamin B12 in the stomach

- They are produced in the mouth (saliva) and degraded in the duodenum

31
Q

What is the significance of Intrinsic Factor (IF) proteins in Vitamin B12 absorption? Where are they produced and absorbed?

A

IF bind to Vitamin B12 in the duodenum

- They are produced in the stomach (gastric parietal cells) and absorbed in the ileum

32
Q

What is the significance of Intrinsic Factor (IF) receptors in Vitamin B12 absorption? Where are they located?

A

IF receptors bind to the B12-Intrinsic Factor complex to promote endocytosis and absorption
- They are located on the apical membrane of ileal cells

33
Q

What is the significance of Transcobalamin II protein in Vitamin B12 absorption?

A

Transcobalamin II binds to Vitamin B12 in circulation to transport B12 to the tissues (using B12-transcobalamin II receptors)

34
Q

What is the step by step process of Vitamin B12 absorption (6 steps, hint: separate by location)?

A
  1. In mouth: Vitamin B12 is taken in with dietary protein; R-binders are secreted by salivary glands
  2. In stomach: acidic pH causes Vitamin B12 to be released from protein (via pepsin), and the Vitamin B12 binds to R-binder; IF is produced by gastric parietal cells
  3. In duodenum: pancreatic proteases degrade R-binders, releasing Vitamin B12 which then binds to IF
  4. In ileum: Vitamin B12-IF complex binds to receptors on the apical surface of ileal cells and complex is endocytosed - Vitamin B12 is released into circulation
  5. In blood, Vitamin B12 binds to Transcobalamin II
  6. In tissues, Vitamin B12-Transcobalamin II complex binds to tissue receptors and is endocytosed
35
Q

What is the mechanism (2) behind Pernicious Anemia (PA)?

A

PA is autoimmune destruction of parietal cells, resulting in Vitamin B12 malabsorption

  • Impaired production of IF
  • Leakage of IF from damaged parietal cells into bloodstream (instead of in stomach)
36
Q

What is the primary consequence of leakage of IF from damaged parietal cells into bloodstream? What does this interfere with?

A

Antibodies against IF are produced in the blood, interfering with:

  • Vitamin B12 binding to IF (antibodies bind instead)
  • Vitamin B12-IF complex binding to receptors on surface of ileal cells
37
Q

What condition does PA essentially mirror symptomatically?

A

PA is characterized by all of the symptoms typical of Vitamin B12 deficiency, including Megaloblastic Anemia

38
Q

Evaluation of what can be used to rule out PA clinically?

A

Achlorhydria (decreased HCl content in stomach) can rule out PA
- If you have decreased levels of HCl in the stomach, then this means parietal cells are not functioning properly to release H+ (pH is more basic) = you have PA

Biochemistry Exam #3 (8 decks)

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