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Hematology and Oncology > EXAM #1: IRON HEMOSTASIS & PORPHYRIN METABOLISM > Flashcards

EXAM #1: IRON HEMOSTASIS & PORPHYRIN METABOLISM Flashcards

1
Q

What is the typical daily iron requirement from the diet?

A

10-20mg

*****Note that this comes from heme in animal products, and non-heme (Fe+++) from vegetables.

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2
Q

What patient populations have an increased iron need?

A

1) Menstruating women
2) Pregnant women
3) Growing children

**Note that there may be increased need in vegetarians b/c non-heme iron is not easily absorbed*

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3
Q

Why is iron complexed with proteins and biomolecules in the body?

A

Free Fe++ and Fe+++ would generate damaging ROS

Note that Fe+++ is NOT biologically useful and is reduced by RBCs back to Fe++. Oxidation of Fe++ to Fe+++ produces hydroxide radical and superoxide anion

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4
Q

What are the functional forms of iron?

A

1) Hb
2) Myoglobin
3) Cytochromes
4) Other iron containing enzymes

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5
Q

What are the two storage forms of iron?

A

Ferritin

Hemosiderin

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6
Q

What is Ferritin?

A

Storage molecule from which iron is released on demand

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7
Q

What is hemosiderin?

A

Degenerated iron/protein complex that cannot be metabolized

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8
Q

Clinically, what is hemosiderin in tissues an indication of?

A

Iron overload

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9
Q

What cells in the body take-up iron?

A

Enterocytes in the proximal duodenum

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10
Q

What is the role of transferrin in the body?

A

Binds iron in the plasma for transport

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11
Q

Once iron is in the plasma, what happens to it?

A

Travels to the bone marrow and is incorporated into RBCs

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12
Q

When is iron stored as ferretin?

A

Once it has been phagoctosed by splenic macrophages

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13
Q

When iron is released from macrophages on demand, how is it transported?

A

As transferrin in plasma

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14
Q

What organ stores ferretin iron aside from splenic macrophages?

A

Liver stores ferretin

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15
Q

How is iron homeostasis regulated?

A

Iron UPTAKE is regulated at the level of the ENTEROCYTES

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16
Q

Can iron be excreted from the body?

A

NO

Iron only leaves the body from bleeding or sloughing off of duodenal enterocytes

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17
Q

How is heme iron taken up into the body via enterocytes?

A

Heme Carrier Protein 1

i.e. HCP-1

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18
Q

How is non-heme (Fe+++) iron absorbed?

A

1) Reduction by enterocyte cytochromep450

2) Uptake by divalent metal transporter (DMT-1)

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19
Q

What is the function of ferroportin?

A

Transporter that releases Fe++ iron from the enterocytes into the plasma

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20
Q

What regulates whether iron stays in the enterocyte or is transported into the plasma?

A

Hepcidin from the liver

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21
Q

What is the role of Hepcidin?

A

Prevents iron transport through ferroportin

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22
Q

Why does the liver want to diminish iron concentrations?

A

Infectious organisms need iron to grow; this is a strategy to combat infection

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23
Q

Outline the process of transferrin-bound iron uptake into cells.

A

1) Transferrin-bound iron binds transferrin receptor
2) Clathrin mediated endocytosis into endosome
3) ATPase acidifies the endosome
4) Change in transferrin conformation to release iron as Fe+++
5) Fe+++ is reduced to Fe++
6) DMT-1 transports Fe++ into the cytoplasm

Transferrin receptor is recycled back to the surface of the cell.

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24
Q

Once in the cytoplasm, how is iron stored?

A

As ferretin

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25
Q

What are the three anatomical locations with the highest concentrations of ferretin-bound iron?

A

1) Liver
2) Spleen
3) Bone marrow

26
Q

When RBCs are destroyed in splenic macrophages, what happens to the iron? What happens to that iron when it is needed?

A
  • Stored as ferretin in splenic macrophages

- On demand, iron is transported via ferroportin into the circulation

27
Q

What organ produces hepcidin?

A

Liver

28
Q

What is the function of hepcidin?

A

1) Blocks ferroportin in ENTEROCYTES

2) Blocks ferroportin in SPLENIC MACROPHAGES

29
Q

At what level is ferretin regulated?

A

Post-transcriptional level via the “Iron Response Element” in the 5’ UTR of the mRNA

30
Q

Describe how ferretin mRNA responds to free iron in the blood.

A
  • Ferretin mRNA contains the IRE bound to Iron Regulatory Proteins (IRPs)
  • Bound IRPs BLOCK translation
  • Free iron binds IRPs, allowing for the translation of ferretin mRNA
31
Q

What is alpha-ALA synthase?

A

Enzyme that produces heme

32
Q

What is the effect of free iron on alpha-ALA synthase?

A
  • Free iron increases alpha-ALA synthase

- Thus, free iron increases heme synthesis

33
Q

What is the effect of free iron on the transferrin receptor?

A

Free iron binds IRPs, which STABILIZES mRNA to PREVENT translation

Thus, free iron DECREASES the synthesis of transferrin receptors

34
Q

What is the clinical utility of a serum iron concentration?

A

Determining iron overload or iron poisoning

35
Q

What is the “Total Iron Binding Capacity?” What is normal?

A

A measure of transferrin saturation

~30% is normal

36
Q

What does a TIBC below 15% indicate?

A

Iron deficiency

37
Q

What is the clinical utility of serum ferretin concentrations?

A

Best measure of body iron stores

38
Q

What is red cell protoporphyrin?

A

The iron-free precursor of heme

39
Q

What is an elevated red cell protoprophyrin an indication of?

A

Iron deficiency–not enough iron to complete heme synthesis

40
Q

What are the five most common causes of iron deficiency anemia?

A

1) Blood loss
2) Chronic disease (inflammatory marks induce hepcidin)
3) Poor dietary intake
4) Intestinal parasite
5) Malabsorptive syndrome

41
Q

What are the three stages of iron deficiency anemia?

A

1) Iron depletion
2) Deficient erythropoesis w/ normal Hb concentration
3) Iron deficiency anemia i.e. Hb production is inadequate

42
Q

What are the common causes of iron overload?

A

1) Chronic blood transfusions
2) Inappropriate parenteral nutrition
3) Ineffective hematopoiesis
4) Hereditary uptake disorder e.g. Hemochromatosis

43
Q

What is Hemochromatosis?

A
  • Mutation of HFE gene that codes for Hepcidin

- Increased iron release

44
Q

Where does heme synthesis occur in the cell?

A

Mitochondria

45
Q

What is the committed, regulated step of heme synthesis?

A

ALA synthase

Succinyl-CoA + glycine= aminolevulinc acid (ALA)

46
Q

What happens to ALA after it is synthesized in the mitochondria?

A

1) Transport into the cytosol

2) 2x molecules of ALA are joined by prophobilinogen synthase to form PBG

47
Q

What happens after PBG is formed in heme synthesis?

A

4x PBG are joined to make uroporphyrinogen by uroporphyrinogen synthase

48
Q

What happens to Uroporphyrinogen in heme synthesis?

A

Modifications are made in the cytoplasm and mitochondria to make

  • coprophyrinogen
  • protoporphyrinogen
49
Q

What is the final step of heme synthesis? Where does it occur?

A

Mitochondira

Ferrochetolase inserts Fe++ into heme

50
Q

What activates ALA synthase?

A

Iron

51
Q

What inhibits ALA synthase?

A
  • Heme
  • Fe+++ heme
  • Hemin
52
Q

What is X-Linked Sideroblastic anemia?

A
  • X-linked disorder that causes bone marrow to produce ringed sideroblasts vs. healthy RBCs
  • Unable to produce sufficient heme
53
Q

What is the gene mutation associated with sideroblastic anemia?

A
  • Mutant ALA synthase encoded by the ALAS2 gene on the X-Chromosome

Results in reticuloytes that are unable to produce sufficient heme and accumulate iron, forming “siderblasts.”

54
Q

What are “porphyrias?”

A

Diseases of heme synthesis

55
Q

What is the enzymatic defect in Acute Intermittent Porphyria (AIP)?

A

Porphobilinogen deaminase deficiency

56
Q

What products of heme synthesis accumulate in AIP?

A

ALA
PBG

Note that these products give the urine a dark red color.

57
Q

What are the symptoms of AIP?

A
  • Confusion

- Abdominal pain

58
Q

What is the deficiency in Porphyria Cutanea Tarda (PCT)?

A

Uroporphyrinogen decarboyxlase

59
Q

What is the hallmark of PCT when examining the urine?

A

Under UV light, urine will be pink flourescent

60
Q

What product of heme synthesis builds up in Prophyria Cutanea Tarda?

A

Prophyrins

61
Q

What is the hallmark symptom of PCT?

A

Photosensitivity of the skin leading to blistering

Porphyrins do NOT absorb visible and UV light; rather, this energy is dissipated into the skin of forms damaging ROS.

62
Q

How does lead inhibit heme synthesis?

A

Inhibits 3 key enzymes:

1) Prophobilinogen synthase
2) Ferrochetalase

Hematology and Oncology (38 decks)

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