Iron - Nutrition + Metabolism

What time of element is iron?

transition metal

What are the two forms of Iron

Fe2+ and Fe3+

Fe2+

ferrous reduced

Fe3+

ferric oxidized

What pH does Fe2+ precipitate out

2

What pH does Fe3+ precipitate out?

3

Which Iron form is most soluble in duodenum?

ferrous

Why is ferrous iron more bioavailable

It is more soluble in duodenum due to precipitation point of it being 6

Iron storage

2.3g in women, 3.8g in men

Where is the majority of Iron stored?

in hemoglobin, ~65%

hemoglobin

binding and transport of O2

Iron Storage

65% - hemoglobin

10% - myoglobin

2% - heme enzymes (cytochromes)

1% - nonheme enzymes ( succinate dehydrogenase)

1% - intracellular labile iron

0.001% - transferrin

compare hemoglobin and myoglobin

both function to bind and transport O2

myoglobin has 1 subunit and found in your muscle

Transferrin

allows for transport of iron; very little amount of iron is begin transported at any given time

Structure of hemoglobin

Hemoglobin has 4 subunits each with a molecule of heme (heme is like a ring with Fe locked into the center)

Iron RDA

18mg

How much Iron do you absorb if you were to ingest 18mg

1-2mg

How much Iron travels to the bone marrow in a given day?

24mg (most of which coming from recycling of macrophages)

Heme Fe

Fe is contained in a protoporphyrin ring

Found in meat in hemoglobin, myoglobin, and cytochromes

highly bioavailable

Non-heme Fe

can be organic chelates (e.g. ferric citrate, ferrous fumarate)

can be constituents of biological molecules (e.g.) iron-sulfur enzymes, ferritin

found in plants

relatively poor bioavailable

Nutrients that enhance iron uptake

ascorbic acid

dietary protein (Cys, His)

Iron chelation (e.g., heme)

“Meat Factor”

Endogenous factors the enhance Fe uptake

Enhanced erythropoiesis (high altitude → inc. Hgb production)

Low iron stores

Hemochromatosis

inc. HCl (stomach acid) (makes it more soluble)

Nutrients that inhibit iron uptake

phytic acid (in dietary fiber)

oxalic acid

polyphenols (in coffee + tea)

Endogenous factors that inhibit iron uptake

High iron stores

Infection

Inflammation

Lack of stomach acid

What are the two main proteins for Fe absorption?

ferroportin and DMT1

What are the 2 accessory proteins for Fe absorption?

hephaestin and Dcytb

DMT1

divalent metal transporter 1

transport into intestinal cell through lumen.

up-regulated with iron deficiency

1st discovered in rodents w/ anemia

Dcytb

duodenal cytochrome b

works with DMT1

up-regulated by iron deficiency

utilizes ascorbate to providing reducing equivalents

located at lumen for absorption into enterocyte

Ferroportin

export iron from intestinal cells

induced by iron deficiency

****main regulated point of entry for iron into the body

Hephaestin

ferroxidase

oxidizes Fe2+ into Fe3+ so it can bind to transferrin

Bone Marrow

site of RBC synthesis (erythropoiesis) major consumer of iron in the body

acquires iron from transferrin via the transferring receptor

RBC production

in bone marrow

2.3 million cells per second

3 billion per day

3 billion RBS require

25 mg of Fe

Macrophages

found in tissues of spleen/liver/bone marrow (reticuloendothelial system)

eat damaged RBCs by “popping the membrane to allow recycling of heme and iron

export iron into plasma

reticuloendothelial system

RES

macrophages - cells that eat RBCS and recycle iron

serves as large storage reserve for iron

Ferritin

iron storage protein

MW: 450,000 k Da

consists of 24 subunits

Basically a large soccer ball, where iron can be stored inside

4300-4500 atoms of iron

mRNA contains and IRE in it 5’ UTR

Where is Fe mainly stored

liver → also regulates iron status by producing hepcidin

Hepcidin

iron-regulatory peptide hormone produced by liver

secreted into the circulation

induced by iron

production shuts off during iron deficiency

How can iron be taken up to hepatocyte?

transferrin receptor 1 (TFR1) - transferrin bound form

ZIP14 - non-transferrin bound (iron overload conditions)

Where is iron metabolism regulated

at site of absorption (no way to actively get rid of iron)

How does the body know how much iron to absorb?

hepcidin

As iron stores increase hepcidin production ____

increases and vice versa

How does hepcidin function

brakes of iron absorption

Hepcidin pathway

travels to enterocyte → binds to ferroportin —> internalizes complex + ferroportin degrades —> dec iron transport into plasma from enterocytes + dec. transport by macrophages into plasma

What form of iron is available for uptake by cells?

transferrin bound to be stored in ferritin in cell

IRE

iron responsive element

UTR

untranslated region

IRP

iron regulatory protein

under low iron conditions

blocks transcription → no ferritin made

no affect on transferring receptor mRNA so it keeps being made but stabilization prevents degradation

under high iron conditions: no IRP

ferritin made but transferrin receptor not made because stabilization is removed

How to inhibit IRP binding to mRNA in UTR

High iron allows for Fe to be bound to IRP preventing its binding to mRNA

What other proteins have IRE/IRP regulatory system

DMT1, ferroportin, eALAS

Redox capacity of iron is exploted by

dioxygen transport

oxidative and reductive transformations (cytochrome P450s)

electron transfer

cytochrome oxidase

complex IV

contains 2 heme groups

catalyzes the final step in the electron transport chain

transfer electrons from oxygen to yield water

Clinical Assessment

hemoglobin (12-15g/dL) → 1st screen

plasma iron/transferrin saturation - how much iron is available to go to bone marrow (~35%)

plasma ferritin - measure stores (>12ng/mL)

Hemoglobin (Hb)

routinely measured

Low Hb = anemia

<12 g/dL for women

<13.5 g/dL for men

not iron specific

Transferrin Saturation

roughly 1/3 of iron its being transported at a given time

anything <335 is signaling a deficiency

Plasma Ferritin

specific indicator

low plasma ferritin = iron deficiency

high plasma ferritin = iron overload or inflammation

cutoff values for iron deficiency

ferritin <20ng/L

not routinely measured - you have to ask

Iron deficiency vs iron deficiency anemia

iron deficiency is no mobilizable iron stores

iron deficiency anemia - no mobilizable iron stores and anemia

world prevalence of anemia

~40% of children and 30% of women of reproductive age

in 2019, there were 1.8 billion cases of anemia

50-70% of anemia cases are due to iron deficiency

cases of iron deficiency

broadly: increased iron requirements or inadequate iron absorption

inc. iron requirements

menstruation

GI tract

• food sensitivity

• hookworms

Genitourinary tract

respiratory tract

Blood donation

growth

pregnancy

inadequate iron absorption

diet low in bioavailable iron

impaired absorption

• intestinal malabsorption

• gastric surgery

• hypochlorhydria

consequences of iron deficiency

• poor cognitive perforamnce

• diminished immune function

• reduced exercise and endurance capacity

• anemia

• growth retardation in children

• poor pregnancy outcomes