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IHO Week 1 > Iron Metabolism > Flashcards

Iron Metabolism Flashcards

1
Q

Why is iron a “double-edged sword”?

A

It’s essential for all living organisms, but it can be dangerous because it’s a pro-oxidant that can form ROS

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2
Q

Through what reaction can iron form a ROS?

A

THe fenton reaction takes hydrogen peroxide and Fe2+ to yield Fe3+, hydroxide ion and a hydroxyl radical (which can cause a lot of damage)

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3
Q

What is the main physiologic pathway for excreting excess iron?

A

TRICK QUESTION: there isn’t one - that’s why the system has to be so tightly regulated; we usually absorb exactly as much iron as we lose so we are in homeostasis

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4
Q

What are the two forms of dietary iron and what foods are they in?

A 
heme iron (Fe2+)  (beef, chicken, fish, etc)
non-heme iron (Fe3+) (cereals and veggies)
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5
Q

Which is absorbed more easily - heme iron or non-heme iron?

A

heme iron is more readily absorbed

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6
Q

Where in the GI tract is the majority of iron absorbed?

A

proximal small bowel (duodenum)

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7
Q

How does gastric acid enhance iron absorption?

A

It can reduce Fe3+ to Fe2+, which is easier to absorb

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8
Q

How is heme iron absorbed?

A

we actually don’t really understand it yet - we assume it somehow crosses the brush border in the duodenum…probably via a carrier protein

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9
Q

How is non-heme iron absorbed?

A

non-heme iron is usually Fe3+ ferric
It’s converted to Fe2+ in two ways: stomach acid and by duodenal cytochrome b reductase
the Fe2+ is then brought into the enterocyte via the divalent metal transporter 1 (DMT1)

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10
Q

What are some promoters of non-heme iron absoption?

A

ascorbic acid, some spices, beta carotene, and alcohol

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11
Q

What are some inhibitors of non-heme iron absorption?

A

phytic acid, polyphenols, tannins, calcium

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12
Q

How does iron leave the enterocyte and enter the plasma?

A

Through a transporter called ferroportin

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13
Q

What form does iron have to be in for ferroportin to export it? How does it get in this form? What does it remain bound to during transport?

A

It has to be Fe3+
Remember that it’s abosrbed into the enterocyte as Fe2+, so there is another enzyme at the brush border HAEPHESTIN which will convert it back to Fe3+ for export
In the enterocyte, it’s bound to its carrier protein called ferritin

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14
Q

What is the haephestin homologue in non-enterocyte cells?

A

ceruloplasmin

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15
Q

If Haephestin is inactive, what happens to the iron

A

It remains bound to ferritin inside the enterocyte and is eventually lost when the enterocyte is sloughed off with a senescent cell

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16
Q

What is the iron transporter (carrier protein) in the PLASMA?

A

transferrin

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17
Q

How man Fe3+ molecules can transferrin carry at one time?

A

one or two (usually monoferric under normal conditions)

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18
Q

What does transferrin binding of Fe3+ depend on ?

A

pH of the plasma

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19
Q

How is iron then deposited where it needs to be from transferrin in the plasma?

A

Transferrin-bound iron can bind to the transferring receptor

  1. the bound receptor is then internalized via clathrin coated vesicles
  2. the endosome of whatever cell it entered is then acidified so the iron is released
  3. the transferrin - receptor complex is then recycled
  4. Fe3+ is reduced back to Fe2+ within the cell
  5. Fe2+ is moved across the endosomal membrane into the cytoplasm by DMT1
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20
Q

In erythroid progenitors, the Fe is predominantly used to produce H. What enzyme incorporates the iron into heme?

A

ferrochelatase incorporates iron into protoporphyrin to form heme

21
Q

What reticuloendothelial cells phagocytize the old RBCs in the spleen? In the liver?

A

spleen - macrophages, liver - Kupffer cells

22
Q

Where does most of the 20-24 mg iron needed daily for Hb production come from?

A

just from recycling of the iron picked up by breakdown in the macrophages

23
Q

What is the longterm storage form for iron (more like storage for iron-bound ferritin)?

A

hemosiderin

24
Q

What cell is the master regulator of iron production? Via what enzyme?

A

the hepatocyte - by hepcidin

25
Q

What does hepcidin do? In response to what?

A

It’s produced in response to inflammation and increased iron stores

It binds to ferroportin and triggers it internalization and degradation in lysosomes

essentially, this traps the iron inside cells, so it never is absorbed

26
Q

What does hepcidin deficiency cause?

A

iron overload, because there’s no switch to turn off iron absorption when iron stores are high

27
Q

What gene generates hepcidin and how is it related to inflammation? Iron stores?

A

inflammation causes release of cytokines which act as transcription factors to increase expression of the HAMP gene, of which hepcidin is a product

Increased iron stores increases transferrin saturation, which signals to the hepatocytes to increase expression via HFE and TfR2 dependent manner

28
Q

What three types of cells do most of the iron storage in the body?

A

liver cells, macrophages, and bone marrow (the latter two store recycled O2)

29
Q

Evolutionarily, why is it a good idea to keep iron bound to ferritin intracellularly?

A

It means the iron can’t undergo a fenton reaction in the cell whenever it feels like it

30
Q

What is the major mechanism of iron release from ferritin?

A

proteolysis

31
Q

Describe HIF-1alpha’s role in iron storage regulation.

A

During times of normal iron levels, HIF1a is hydroxylated, targeting it for degradation

DUring time of low O2 pressure and low iron concentration, HIF1a forms a heterodimer with HIF1b to bind to hypoxia response elements and induce transcription of genes like the EPO gene

32
Q

Describe the post transcriptional regulation of iron metabolism proteins.

A
  1. Iron response elements contain hairpin structures that can bind the 3’ and 5’ UTR of mRNAs encoding proteins involved in iron or oxidative metabolism
  2. Iron response proteins can bind to the IREs with high affinity in iron depleted cells to either suppress translation of the mRNA (bind the 5’ UTR) or enhance mRNA stability against nuclease attack (bind the 3’ UTR)
33
Q

Specifically for ferritin/transferring receptor, what will the IRPs do in times of low iron?

A

Just remember, the goal is to enhance iron absorption and decrease iron storage (because it needs to be used), so…

  1. IRP will bind 3” UTR for the transferrin receptor (to enhance absorption)
  2. IRP will bind 5’ UTR for ferritin (to decrease storage)
34
Q

What are the indirect indicators of Fe status you can do for labs?

A
  1. serum iron concentration
  2. serum transferring concentration or total binding capacity (2x transferring basically)
  3. transferring saturation
  4. serum ferritin
35
Q

How would you directly measure Fe stores? (not usually done, and definitely not by a family practice doc)

A
  1. bone marrow aspirate and stain with prussian blue to see iron in the marrow
  2. Liver biopsy and prussian blue to see iron in the liver
  3. MRI-T2 star of the liver to visualize iron without biopsy
36
Q

Why do you have to take the ferritin levels with a grain of salt on labs?

A

because it’s an acute phase reactant that will increase in iron overload, but also inflammation/malignancy

37
Q

If labs show low serum iron and low transferrin saturation with increased transferrin concentration and transferrin receptor, what is the slam dunk diagnosis?

A

iron deficiency anemia

38
Q

What are the 3 general reasons you would have an iron deficiency anemia?

A
  1. blood loss
  2. increased physiologic requirements (pregnancy, infants)
  3. reduced iron absorption
    (and then nutrition issues in general)
39
Q

If you have a patient in his or her 50s-60s and they present with an acute iron deficiency anemia after having no history of that, what is the first thing you should rule out?

A

GI bleed from colon cancer, so get a colonoscopy/endoscopy

this is often how a colon cancer presents

40
Q

How does an anemia of chronic disease occur?

A

It’s a hyperproliferative anemia secondary to inflammation

  1. cytokines (esp IL6) induce hepcidin production and inhibit EPO production
  2. This alters iron metabolism such that you have REDUCED serum iron concentrations and INCREASED macrophage iron stores
  3. Since all the iron is stuck in macrophages, you don’t have enough iron to keep up with demands of erythropoiesis
  4. This shortens the lifespan of the RBCs and they lyse prematurely, causing a hemolytic anemia
41
Q

What are some symptoms of iron overload?

A

weakness, fatigue, abdominal pain
liver: increased ALT, fibrosis, cirrhosis
Heart: CHF, arrhythmia
arthritis
diabetes, secondary amenorrhea, impotence
hyperpigmentation
susceptibility to infection

42
Q

What is hereditary hemachromatosis?

A

It’s a group of iron overload disorders, affecting the hepcidin/ferroportin access

43
Q

What causes Type 1 hemachromatosis?

A

It’s an HFE gene mutation resulting in a cysteine-to-tyrosine substitution at AA 282

44
Q

What is the HFE gene responsible for? And why do deficits cause hemachromatosis?

A

HFE is a MHC class 1 transmemebrane protein expressed in high levels in the liver

It regulates hepcidin expression through interactions with the transferrin receptor.

THe mutation means you don’t get an interaction between HFE and transferrin receptor 2. Because of this, you have decreased hepcidin expression

the decreased hepcidin expression means you don’t have a brake on iron absorption an dyou just taking iron in constantly

45
Q

What will you see on labs in hemachromatosis? What is the gold standard for diagnosis?

A
  1. increased serum iron
  2. increased transferrin saturation

Gold standard for diagnosis is a liver biopsy with Perl’s stain (you can also do quantitative phlebotomy and an MRI T2 star)

46
Q

What does death typically occur from with hemachromatosis/

A

cirrhosis, hepatocellular carcinoma or CHF

47
Q

What is the treatment for hemachromatosis?

A

phlebotomy

48
Q

Why do you really want to catch hemachromatosis early?

A

you want to catch it early, because once the iron is stores in hemosiderin instead of just ferritin, it’s very resistant to phlebotomy and chelation

Life expectancy is normal if you can catch it and start phlebotomy before cirrhosis or DM develop

IHO Week 1 (11 decks)

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