Topic 2&3: Iron Metabolism

Question 1

what two states does iron exist in?

Answer 1

reduced ferrous (Fe+2) state

oxidized ferric (Fe+3) state

Question 2

how is iron both good and bad?

Answer 2

iron can be combined with enzymes for reduction-oxidation (redox) reactions that generate energy or neutralize drugs

BUT

as a solo catalyst iron can generate free radicals that destroy cellular components

Question 3

What is the difference between ferrous and ferric iron?

Answer 3

Reduced ferrous iron is missing two electrons whereas oxidized ferric iron is missing three electrons. This means that ferrous iron has one more electron than ferric iron.

Question 4

what’s the main dietary source of ferrous iron?

Answer 4

meat

exists in a heme-bound form

Fe+2

Question 5

what’s the main dietary source of ferric iron?

Answer 5

vegetables

exists in a non-heme-bound form

Fe+3

Question 6

how is ferrous iron imported into the body?

Answer 6

heme-bound ferrous iron is imported directly into duodenal enterocytes by heme carrier protein-1 (HCP1)

once inside, the surrounding heme structure is degraded to release the ferrous iron.

Question 7

how does ferric iron enter the enterocytes?

Answer 7

trick question: iron does not enter the enterocyte in the ferric state!!

Non-heme-bound ferric iron must first be reduced to ferrous iron by the intestinal brush border enzyme ferroreductase before it is imported into the enterocyte by divalent metal transporter 1 (DMT-1)

Question 8

what happens to iron once it’s absorbed into the enterocyte?

Answer 8

not immediately transported to the blood

it remains within the enterocyte bound to the protein ferritin

Question 9

what does ferritin do?

Answer 9

iron remains within the enterocyte bound to the protein ferritin

ferritin acts as both a catalyst neutralizer to prevent iron from producing pesky free radicals and as a storage reservoir to pack iron within the cell.

Question 10

what two signal molecules regulate iron influx into the bloodstream from the enterocyte?

Answer 10

hepcidin and erythropoetin

Question 11

what does hepcidin do?

Answer 11

it’s secreted by hepatocytes in response to adequate iron concentrations

as long as there are adequate iron levels, hepcidin prompts the internalization and degradation of ferroportin

hepcidin essentially prevents iron influx into the blood by blocking ferroportin from shuttling iron across the cell membrane so iron remains sequestered in the enterocytes

Question 12

what is ferroportin?

Answer 12

transports iron across the cell membrane into the bloodstream

Question 13

what does erythropoietin do?

Answer 13

when iron concentrations are low, erythropoietin down-regulates the synthesis of hepcidin in hepatocytes

the suppression of hepcidin by erythropoietin, allows iron to be transported into the bloodstream via ferroportin

Question 14

What is the effect of hepcidin on enterocytes?

Answer 14

Hepcidin leads to the internalization and degradation of ferroportin, preventing iron transport into the bloodstream

Question 15

what happens to Fe+2 once it’s in the blood?

Answer 15

Once in the blood, ferrous iron is converted into ferric iron by hephaestin, an enzyme present in the basolateral membrane of the enterocyte

Fe+3 is then bound to transferrin for transport in the bloodstream

Question 16

how does transferring reflect the body’s current iron requirement?

Answer 16

concentration of transferrin is inversely proportional to the concentration of iron in the bone marrow

high transferrin correlates to low bone marrow iron, thereby indicating insufficient iron stores

low transferrin correlates to high bone marrow iron, thereby indicating overabundant iron stores

Question 17

what do increased transferrin levels cause?

Answer 17

creates a chemical gradient that facilitates an influx of iron into the bloodstream for subsequent delivery to the bone marrow

Question 18

what do decreased transferrin levels cause?

Answer 18

create a chemical gradient that limits the influx of iron into the bloodstream, thereby preventing overload

influx of iron can come from enterocyte absorption, mentioned above, or macrophage mobilization, discussed below

Question 19

what does transferrin saturation tell you?

Answer 19

if transferrin levels best reflect the body’s current iron requirement, then the transferrin saturation best reflects the body’s ability to meet that requirement

transferrin saturation is the percent of transferrin binding sites currently occupied by iron (two binding sites per one transferrin molecule)

when the body is not meeting its iron requirement, transferrin saturation is low

Question 20

in what diseases is transferrin saturation low?

Answer 20

during iron deficiency anemia and anemia of chronic disease

the body is not meeting its iron requirement

Question 21

when is transferrin saturation low?

Answer 21

when the body is not meeting its iron requirement

this occurs during iron deficiency anemia and anemia of chronic disease

Question 22

when is transferrin saturation high?

Answer 22

when the body is exceeding its iron requirement

Question 23

how do you calculate transferrin saturation?

Answer 23

Transferrin saturation is calculated by dividing the serum iron by the total iron binding capacity (TICB), which is basically a fancy way of saying the total amount of transferrin available to carry iron.

Question 24

in iron deficiency does the liver make more or less transferrin?

Answer 24

the liver makes extra transferrin to create a favorable gradient for iron influx into the blood

TCIB is high!

Question 25

what happens to the TICB during anemia?

Answer 25

the body actually sequesters iron in storage sites to hide it from scavenging pathogens, thus it does not make extra transferrin

TICB is correspondingly low

Question 26

where is iron normally stored?

Answer 26

within liver and spleen macrophages

Question 27

how does iron enter the liver and spleen?

Answer 27

when the iron-transferrin complex reaches the liver and spleen macrophages, the complex is detected by transferrin receptor-1 and then undergoes receptor-mediated endocytosis

Question 28

what happens to iron once its inside the liver and spleen?

Answer 28

once inside, iron is released from transferrin and then transferrin is recycled back into the bloodstream

the remaining iron is stored within the macrophage again bound to ferritin

Question 29

how does ferritin act as a storage reservoir for iron?

Answer 29

iron is stored within the liver and spleen macrophage bound to ferritin

by acting as a storage reservoir it buffers against iron deficiency or overload

in times of deficiency, ferritin can release some of its iron; conversely, in times of overload, ferritin can sequester more iron within cells

Question 30

on an iron panel, what do ferritin levels best reflect?

Answer 30

total body iron storage

Question 31

what do low ferritin levels indicate?

Answer 31

meaning low iron stores

used to diagnose iron deficiency anemia

Question 32

what do high ferritin levels mean?

Answer 32

high iron stores

used to diagnose anemia of chronic disease

Question 33

what is mobilization of iron? what’s it controlled by?

Answer 33

the release of iron from macrophages

whether or not Fe remains within the macrophage is regulated by hepcidin

mobilization is controlled in conjunction with iron serum levels

Question 34

What two physiological conditions promote the synthesis of hepcidin by hepatocytes?

Answer 34

1. increased inflammatory cytokines in bloodstream

2. increased iron serum levels

Question 35

why does increased inflammatory cytokines in bloodstream decrease hepcidin synthesis?

Answer 35

iron is just as valuable to pathogens as it is to humans!

as a protective response, the body has hijacked its iron storage mechanism to also hide iron from scavenging pathogens

unfortunately this means that under prolonged inflammatory conditions like during chronic infections, the blood doesn’t deliver enough iron to bone marrow to make new RBCs

Question 36

what causes anemia of chronic disease?

Answer 36

iron is just as valuable to pathogens as it is to humans!

as a protective response, the body has hijacked its iron storage mechanism to also hide iron from scavenging pathogens

unfortunately this means that under prolonged inflammatory conditions like during chronic infections, the blood doesn’t deliver enough iron to bone marrow to make new RBCs

this culminates in anemia of chronic disease

Question 37

what are the two functions of iron?

Answer 37

1. when bound to the relevant proteins, the redox properties of iron aid in the generation of energy and metabolism of harmful substances
2. when bound to heme, the positive charge of iron aids in the transportation of oxygen

Question 38

what are the two purposes of redox reactions?

Answer 38

1. generate energy through ETC

2. metabolism of harmful substances

Question 39

how do redox reactions of Fe generate energy through the ETC?

Answer 39

As a part of the proteins involved in the ETC, iron can accept electrons from carrier molecules

By accepting the electrons iron becomes reduced (ferrous iron = Fe+2) while the carrier molecules become oxidized

From here iron can donate the electrons to lower energy complexes that also usually contain an iron core - here the donating iron atom becomes oxidized to Fe+3 and the accepting iron atom becomes reduced to Fe+2

passing down e- releases energy to fuel a hydrogen gradient that can be used to generate adenosine triphosphate (ATP)

Question 40

how does iron metabolize harmful substances through redox reactions?

Answer 40

accomplished through the cytochrome P450 system in hepatocytes

cytochrome enzymes use iron to preform redox reactions on harmful substances, like drugs or toxins we ingest, ultimately converting them into water-soluble byproducts ready for excretion

Question 41

what oxidation state is iron in the heme core of Hb?

Answer 41

ferrous Fe+2

there is sufficient positive charge on ferrous iron to gently hold the dense valence electron cloud of oxygen (O2) during transport, but then release oxygen (O2) during delivery to the tissues

Question 42

why isn’t Fe+3 used in heme to transport O2?

Answer 42

ferric iron has too strong of a positive charge causing it to bind oxygen (O2) so tightly that it cannot easily release it upon delivery to the tissues = methemoglobinemia

Question 43

how is oxygen stored in muscle cells?

Answer 43

Fe+3

iron is also used to store oxygen (O2) in muscles cells on the related protein myoglobin

Question 44

how does the body control the serum concentration of iron?

Answer 44

the ONLY way the body can control the serum concentration of iron is by regulating its absorption from enterocytes or its mobilization from macrophages

there is no true regulated mechanism for the excretion of iron!!

Question 45

what is hereditary hemochromatosis?

Answer 45

a substitution of cysteine for tyrosine at the amino acid 282 in the HFE gene controlling hepcidin

hepcidin controls both iron absorption from enterocytes and its mobilization from macrophages

mutated hepcidin is malformed and cannot down-regulate iron absorption

over decades, the extra iron gradually deposits in the heart, liver, pancreas, and skin

Question 46

is iron excretion regulation?

Answer 46

No

iron excretion is not regulated. Iron can only be excreted via the regular sloughing off on intestinal enterocytes

Question 47

what is the Fenton Reaction?

Answer 47

when not bound to an enzyme iron can act as a solo catalyst performing redox reactions on hydrogen peroxide (H2O2) which is called the Fenton Reaction

mobile valence electron on reduced iron attacks the valence electrons on hydrogen peroxide (H2O2). This causes iron to become oxidized and hydrogen peroxide (H2O2) to break down into a hydroxide ion and a hydroxyl radical (OH )

Fe+2 + H2O2 –> Fe+3 + Oh- + OH(radical)

Question 48

how does iron cause cellular damage?

Answer 48

Iron can cause damage through the Fenton reaction. In this reaction iron catalyzes redox reactions on hydrogen peroxide (H2O2)

This reaction generates damaging hydroxyl free radicals (OH ).

Question 49

Inside enterocytes or macrophages, ferric iron (Fe+3) is bound to which one of the following storage proteins?

Answer 49

ferritin

Question 50

The synthesis of transferrin is prompted by what?

Answer 50

Low levels of iron in the bone marrow

The synthesis of transferrin is controlled in coordination with the concentration of iron in the bone marrow. Low iron levels in the bone marrow prompt increased transferrin synthesis whereas high iron levels in the bone marrow prompt decreased transferrin synthesis

transferrin synthesis does not change in response to serum iron levels!!

Question 51

what is the mechanism by which dysfunctional hepcidin causes hemochromatosis?

Answer 51

Decreased hepcidin leads to increased iron absorption