Iron Regulation & Iron Panel

Heme Iron vs Non-Heme Iron

Heme Iron:

- Form that is better absorbed

- Found in meat

Non-Heme Iron:

- Plant iron that is not absorbed as well as heme

- Found in beans, cereal, dried fruit, nuts

Fe2+ vs Fe3+

- 2+: Ferrous Iron, absorbed

- 3+: Ferric Iron, absorbed less

Why is Fe2+ absorbed better than Fe3+?

- Fe2+ bc/ has higher solubility in the small intestine

Heme Iron: Derived from where? How Much is Absorbed?

- Hemoglobin/Myoglobin of animal food sources

- 15-35% absorbed

How is Heme Iron Absorbed?

- Enters enterocyte through HCP-1 transporter → heme portion is removed

Considering it was already in hemoglobin → Iron is already in Fe2+ state → easier absorption

Non-Heme Iron: Derived from what? How much is absorbed?

- Derived from plants/iron-fortified foods

- 2-10% absorbed

Non-Heme Iron: Does it need to be Fe2+ or Fe3+ to be absorbed?

- Fe2+

- Fe3+ can be reduced in stomach acid or by duodenal cytochrome B (ferric reductase enzyme) → Fe2+

How is Non-Heme Iron Absorbed?

- Must be converted from Fe3+ → Fe2+; then enters enterocyte through DMT-1 transporter

Ferroportin: Description/Location and Function

- D/L: Transmembrane protein found in intestinal, splenic, and hepatic cells

- Function: Transports iron ions from inside the cell to outside → bloodstream

HCP-1/DMT-1 let iron INTO cell while Ferroportin lets it OUT into bloodstream

What does Ferroportin ensure?

- By facilitating iron movement from the gut/spleen/liver → circulation, ensures that iron is available for other cells/tissues

- Especially important for erythroid cells to synthesize hemoglobin

Which cells is ferroportin expressed in?

- Enterocytes

- Macrophages

- Hepatocytes

- Placental cells

Ferroportin is essential for iron uptake and recycling

Hepcidin: Where is it synthesized?

- Peptide hormone produced in the liver

Hepcidin: Function

- Regulates iron levels by reducing dietary absorption and inhibiting iron release from cells

What causes an increase in hepcidin expression?

- ↑ Iron load

- Inflammation (mediated by IL-6)

What down-regulates hepcidin expression?

- Hypoxia

- Increased Erythropoietic demand (body needs more RBCs)

Both signal a demand for iron to construct new hemoglobin molecules

How does Hepcidin interact with ferroportin?

- Hepcidin binds to central cavity of ferroportin → causes ferroportin to be endocytosed and proteolysed (broken down)

Hepcidins interaction with ferroportin results in what?

- Iron retention w/in cell and ↓ iron export

What does over expression of Hepcidin result in?

- Leads to iron accumulation in cells and unusually low plasma [iron]

What does under expression of Hepcidin result in?

- Overloaded plasma [iron]

Which of the following best describes how excess iron is normally excreted from the body? (Pick one):

- Through active renal secretions into urine

- Through pancreatic secretions into intestine

- Through respiratory secretions in the lungs

- Through sloughing of intestinal cells and skin loss

- Through sloughing of intestinal cells and skin loss

Mechanisms of Iron Excretion

- Intestinal cell turnover

- Desquamation of skin

- Menstruation

- Hair loss

How does Intestinal cell turnover aid in iron excretion?

- Enterocytes constantly turn over, and they iron they contain is shed/excreted in the feces

How does the desquamation of skin aid in iron excretion?

- Dead skin cells, which contain some iron, are shed from the body and lost through exfoliation

How does menstruation aid in iron excretion?

- For women of reproductive age, menstrual bleeding is a source of iron loss

How does hair loss aid in iron excretion?

- Shedding of hair contributes a small amt to overall iron loss from the body

Iron levels in the body are primary controlled by what?

- Absorption

What occurs when body iron stores are high?

- Hepcidin levels ↑ → causes ferroportin to degrade → traps iron in enterocytes and prevents its release into bloodstream

Trapped iron is then excreted via enterocyte shedding

Which of the following proteins is responsible for the transport of iron in the bloodstream? (Pick one):

- Ferritin

- Ferroportin

- Hemoglobin

- Myoglobin

- Transferrin

- Transferrin

Mobilferrin: Function

- Involved in iron transport INSIDE the enterocyte cytoplasm

W/IN CELL

Transferrin: Function

- Involved in transport of iron through the plasma and delivery to cells

Ferritin: Function

- Involved in storage of iron w/in cells (bubbles full of iron)

Transferrin: Characteristics, what does it transport?

- Blood plasma glycoprotein

- Delivers ferric ions (Fe3+) to various tissues

Transferrin has a high affinity for what?

- Ferric Iron (Fe3+) and binds almost all iron in plasma

How does Transferrin interact with Free Fe3+?

- Fe3+ is insoluble at neutral pH → transferrin binds and it becomes soluble

Transferrin: Role in reactive oxygen species and toxic iron?

- Prevents formation of reactive oxygen species

- Chelates free toxic iron and acts as a protective scavenger

How does transferrin play a role in innate immunity?

- Binds iron and prevents bacteria from using

Does transferrin increase or decrease during periods of inflammation?

- Increases, serves as a marker for inflammation

Steps of Transferrin Delivering Iron to tissues

1. Transferrin binds 2x Fe3+ ions with/ high affinity → undergoes conformational change

2. For delivery, Iron-bound transferrin binds to cell surface transferrin receptors → endocytosis occurs and vesicle is internalized into cytoplasm

3. Proton pumps lower pH inside vesicles → Iron released from transferrin

4. Free iron in cell can then be used for storage or incorporation into hemoglobin

What happens to the transferrin molecule after releasing iron in the cell it delivered to?

- Can be either degraded or recycled

Which organelle is a major recipient of iron inside the cell? Why?

- Mitochondria

- Iron is involved in several redox centers of ETC // also essential for heme synthesis

Transferrin: Kiss and Run Steps

1. Transferrin+Iron is taken up via endocytosis and moved towards mitochondria in an endosome

2. Endosome connects briefly with/ mitochondria → transfers iron

3. Endosome then disconnects from mitochondria and transferrin is recycled

Which of the following describes a major function of ferritin? (Pick one):

- Exists only in hepatocytes

- Intracellular storage form of iron

- Regulator of iron release into bloodstream

- Transcription factor for transferrin

- Transport molecule for iron

- Intracellular storage form of iron

Ferritin: Structure

- Hollow protein made up of 24 subunits (alternating H/L isoforms)

- Stores iron

How is Iron stored w/in Ferritin? How many ions per ferritin complex?

- Fe2+ enters and is oxidized into Fe3+ → stored

- Can sequester ~4,500 Fe3+ ions

How is iron released from ferritin?

- By protein degradation in lysosomes

Where is ferritin found?

- Usually a cytosolic protein, but small quantities of ferritin are present in the bloodstream

Serum ferritin is an indirect marker of total amt of iron stored in the body

What occurs when macrophages phagocytose aged/damaged RBCs?

- Uses heme oxygenase to release iron from heme (accounts for 90% of body's daily iron needs)

What can happen to the iron after its been released from aged/damaged RBCs?

- Iron is released to transferrin (so it can be redistributed)

- In excess, stored in ferritin

Ferritinophagy

- Ferritin degraded via lysosomes to release stored iron

What needs to happen to the iron released from damaged/old RBCs prior to binding to transferrin for recycling to other tissues?

- Fe2+ is oxidized into Fe3+ by membrane bound oxioreductase → loaded to transferrin for transport

Serum Iron

- Measure of circulating iron

- Most of which is bound to transferrin

Serum Iron depends on what?

- Absorption

- Efficient recycling of iron through macrophages/bone marrow

Is Transferrin synthesis proportional or inversely proportional to body iron stores?

- Inversely; if stores are low → Transferrin production ↑↑ (wants to bind everything available)

Levels ↑ during iron deficiency

Total Iron Binding Capacity (TIBC)

- Reflects the available iron binding sites on transferrin

- TIBC and Transferrin are essentially different measures of the same parameter

Transferrin Saturation

- Ratio of serum iron to TIBC, actual amount of transferrin carrying iron

Serum Ferritin

- Serves as an important clinical marker of iron status

Causes of Iron Deficiency

- Diet (↓ intake or ↓ Vitamin C)

- ↓ Absorption (Gastritis, surgery)

- ↑ Needs (pregnancy, children)

- Blood loss/Hemolysis

- Inflammation (↑ Hepcidin)

Iron Deficiency Panel (Serum Iron, Ferritin, Transferrin, % Sat)

- ↓ Serum Iron

- ↓ Feritin

- ↑ Transferin

- ↓ % Sat

Why does % Sat decrease in the setting of iron deficiency?

- Iron levels are low, but transferrin ↑ to bind to any available iron