EXAM #1: IRON HEMOSTASIS & PORPHYRIN METABOLISM

Question 1

What is the typical daily iron requirement from the diet?

Answer 1

10-20mg

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

Question 2

What patient populations have an increased iron need?

Answer 2

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*

Question 3

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

Answer 3

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

Question 4

What are the functional forms of iron?

Answer 4

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

Question 5

What are the two storage forms of iron?

Answer 5

Ferritin

Hemosiderin

Question 6

What is Ferritin?

Answer 6

Storage molecule from which iron is released on demand

Question 7

What is hemosiderin?

Answer 7

Degenerated iron/protein complex that cannot be metabolized

Question 8

Clinically, what is hemosiderin in tissues an indication of?

Answer 8

Iron overload

Question 9

What cells in the body take-up iron?

Answer 9

Enterocytes in the proximal duodenum

Question 10

What is the role of transferrin in the body?

Answer 10

Binds iron in the plasma for transport

Question 11

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

Answer 11

Travels to the bone marrow and is incorporated into RBCs

Question 12

When is iron stored as ferretin?

Answer 12

Once it has been phagoctosed by splenic macrophages

Question 13

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

Answer 13

As transferrin in plasma

Question 14

What organ stores ferretin iron aside from splenic macrophages?

Answer 14

Liver stores ferretin

Question 15

How is iron homeostasis regulated?

Answer 15

Iron UPTAKE is regulated at the level of the ENTEROCYTES

Question 16

Can iron be excreted from the body?

Answer 16

NO

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

Question 17

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

Answer 17

Heme Carrier Protein 1

i.e. HCP-1

Question 18

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

Answer 18

1) Reduction by enterocyte cytochromep450

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

Question 19

What is the function of ferroportin?

Answer 19

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

Question 20

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

Answer 20

Hepcidin from the liver

Question 21

What is the role of Hepcidin?

Answer 21

Prevents iron transport through ferroportin

Question 22

Why does the liver want to diminish iron concentrations?

Answer 22

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

Question 23

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

Answer 23

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.

Question 24

Once in the cytoplasm, how is iron stored?

Answer 24

As ferretin

Question 25

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

Answer 25

1) Liver 2) Spleen 3) Bone marrow

Question 26

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

Answer 26

- Stored as ferretin in splenic macrophages | - On demand, iron is transported via ferroportin into the circulation

Question 27

What organ produces hepcidin?

Answer 27

Liver

Question 28

What is the function of hepcidin?

Answer 28

1) Blocks ferroportin in ENTEROCYTES | 2) Blocks ferroportin in SPLENIC MACROPHAGES

Question 29

At what level is ferretin regulated?

Answer 29

Post-transcriptional level via the "Iron Response Element" in the 5' UTR of the mRNA

Question 30

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

Answer 30

- 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

Question 31

What is alpha-ALA synthase?

Answer 31

Enzyme that produces heme

Question 32

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

Answer 32

- Free iron increases alpha-ALA synthase | - Thus, free iron increases heme synthesis

Question 33

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

Answer 33

Free iron binds IRPs, which STABILIZES mRNA to PREVENT translation Thus, free iron DECREASES the synthesis of transferrin receptors

Question 34

What is the clinical utility of a serum iron concentration?

Answer 34

Determining iron overload or iron poisoning

Question 35

What is the "Total Iron Binding Capacity?" What is normal?

Answer 35

A measure of transferrin saturation ~30% is normal

Question 36

What does a TIBC below 15% indicate?

Answer 36

Iron deficiency

Question 37

What is the clinical utility of serum ferretin concentrations?

Answer 37

Best measure of body iron stores

Question 38

What is red cell protoporphyrin?

Answer 38

The iron-free precursor of heme

Question 39

What is an elevated red cell protoprophyrin an indication of?

Answer 39

Iron deficiency--not enough iron to complete heme synthesis

Question 40

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

Answer 40

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

Question 41

What are the three stages of iron deficiency anemia?

Answer 41

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

Question 42

What are the common causes of iron overload?

Answer 42

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

Question 43

What is Hemochromatosis?

Answer 43

- Mutation of HFE gene that codes for Hepcidin | - Increased iron release

Question 44

Where does heme synthesis occur in the cell?

Answer 44

Mitochondria

Question 45

What is the committed, regulated step of heme synthesis?

Answer 45

ALA synthase Succinyl-CoA + glycine= aminolevulinc acid (ALA)

Question 46

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

Answer 46

1) Transport into the cytosol | 2) 2x molecules of ALA are joined by prophobilinogen synthase to form PBG

Question 47

What happens after PBG is formed in heme synthesis?

Answer 47

4x PBG are joined to make uroporphyrinogen by uroporphyrinogen synthase

Question 48

What happens to Uroporphyrinogen in heme synthesis?

Answer 48

Modifications are made in the cytoplasm and mitochondria to make - coprophyrinogen - protoporphyrinogen

Question 49

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

Answer 49

Mitochondira Ferrochetolase inserts Fe++ into heme

Question 50

What activates ALA synthase?

Answer 50

Iron

Question 51

What inhibits ALA synthase?

Answer 51

- Heme - Fe+++ heme - Hemin

Question 52

What is X-Linked Sideroblastic anemia?

Answer 52

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

Question 53

What is the gene mutation associated with sideroblastic anemia?

Answer 53

- 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."

Question 54

What are "porphyrias?"

Answer 54

Diseases of heme synthesis

Question 55

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

Answer 55

Porphobilinogen deaminase deficiency

Question 56

What products of heme synthesis accumulate in AIP?

Answer 56

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

Question 57

What are the symptoms of AIP?

Answer 57

- Confusion | - Abdominal pain

Question 58

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

Answer 58

Uroporphyrinogen decarboyxlase

Question 59

What is the hallmark of PCT when examining the urine?

Answer 59

Under UV light, urine will be pink flourescent

Question 60

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

Answer 60

Prophyrins

Question 61

What is the hallmark symptom of PCT?

Answer 61

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.

Question 62

How does lead inhibit heme synthesis?

Answer 62

Inhibits 3 key enzymes: 1) Prophobilinogen synthase 2) Ferrochetalase