Iron

Iron Dietary sources

Animal

• Liver

• Beef

Seafood

• Clams

• Oysters

Vegetables

• Spinich

• Peas

Grains

• Pasta

What is the best dietary source of iron?

Animal

Iron forms

Plant sources

• Non-heme

• Ferric Fe 3+

• Ferrous Fe 2+

Animal sources

• Heme

• Hemoglobin

• Myoglobin

Iron is always ____

protein bound

Protein bound iron prevents ___

oxidative damage

Free iron

Initiates oxidative damage

Hydroxyl radical

Hydrogen peroxide (H2O2) is produced ____

in metabolism

Iron Digestion

Digestion needed to free them

Different pathways for non-heme and heme iron

Fe 3+

Non-heme iron absorption

Very low

Maximal 3% of Fe 3+

Enhancer elevate this to 8% through conversion to Fe 2+

Where does iron get absorbed in the body?

Jejunum of the SI

Non-heme iron uptake on the _____

brush border membrane

Non-heme absorption

mostly reduced iron (Fe2+) is absorbed through DMT1 (Divalent metal transporter 1)

DMT1 is unregulated by":

Low iron status

Hypoxia

• Low blood oxygen

Ferric Iron (Fe3+)

May or may not be absorbed

Pathway not known

Heme Iron Uptake on Brush Border Membrane

Through Heme Carrier Protein 1 (HCP1)

15 - 35% of heme iron is absorbed

Heme Iron: Intracellular Handling

Heme oxygenate interacts with heme to create protoporphyrin and release of Fe2+

Iron binding proteins in the enterocyte

Poly (rC)-binding protein 2 (PCBP2)

Directs iron to the functional sites

Ferritin

Mostly intracellular storage

Cellular Export of Iron

Basolateral pole of enterocyte by ferroportin

Hephaestin

• Oxidizes Fe2+ to Fe3+

Fe3+ gets transferred to transferrin

Iron bioavailability

Low

Heme

• 15 - 35%

Non-heme iron

• 2 - 10%

Iron bioavailability depends on __

iron status

Iron Normal status vs Deficiency

Normal

• 10%

Deficiency

• Up to 35%

Iron Distribution

Transferrin

• Does not release iron in the plasma

How does Iron Cellular Uptake through the blood stream differ from enterocyte?

Receptor mediated endocytosis

Iron Cellular Uptake from the blood stream

1. Transferrin binds to transferrin receptor

2. Transferrin-transferrin receptor complex is endocytosed

3. Transferrin-TfR complex is “digested”

4. Iron is released and reduced

5. DMT1 exports iron from the endosome

6. Iron into the cytosol

7. Binds to ferritin and integrated in functional proteins

Iron Homeostasis and Turnover

Storage and regulation by liver

Regulation of iron status

Liver hepatocytes recognize iron status

• Extracellular recognition

• Intracellular recognition

What is the key protein in iron regulation?

Hepcidin

Hepcidin

Controls absorption, storage and distribution of iron

Inhibits ferroportin

Released from the liver when iron status is good

Binds to ferroportin in effector cells

• e.g. enterocyte and macrophages

Causes ferroportin degradation

Extracellular recognition of iron status

Transferrin levels in the blood are recognized

1. Transferrin receptors bind transferrin

2. Intracellular signalling enhance hepcidin expression

Intracellular recognition of iron status

Intracellular iron levels in some hepatic cells of the liver are recognized

1. BMP6 is secreted (Bone morphogenetic protein 6) and binds to receptor complex

2. Induces hepcidin expression

Where is the most iron?

Key cells

• Erythrocytes (RBCs)

  • 70% of your body’s iron is in hemoglobin

• Myocytes (Muscle cells)

  • Myoglobin

Iron storage

60% in liver hepatocytes

40% in spleen and bone marrow

Iron “Recycling”

Iron is highly retained

Old erythrocytes are degraded in macrophages

Macrophages can release iron via ferroprotin

Iron excretion

No mechanism

Iron elimination

Loss through sloughed cells and bleeding

What are the functions of iron?

Oxygen transport

Electron transport

Iron containing enzymes

Function: Oxygen Transport

Hemeproteins for oxygen delivery

• Hemoglobin and Myoglobin

Cytochromes

Pathology: Oxygen Transport

Anemia

Function: Electron transport

Cytochromes

• e.g. ETC

Pathology: Electron transport

Decreased energy metabolism

Function: Iron containing enzymes

Metallo-enzymes

Oxidoreductases

• Catalase

  • Antioxidant enzyme

  • Detoxifies hydrogen peroxide

• Detoxification of aldehydes/alcohols

• Pro-oxidant enzymes

  • Myeloeproxidase

Myeloperoxidase

Hypochlorous acid to destroy bacteria

In neutrophiles and macrophages

Pathology

• Bacteria are not cleared

Function: Glucose Metabloism

Carb/Glucose oxidation

Glycolysis

Gluconeogenesis

Function: Lipid metabolism

Steroid hormones synthesis

Lipophilic drug metabolism

Iron Deficiency

Complex etiology

Anemia

• Microcytic (small erythrocytes)

• Hypochromic (no color)

Iron Deficiency Symptoms

Pale

Behavior changes

Impaired cognitive tasks

Impaired learning

Short attention span

How long does it take to restore iron status to adequate levels?

2 weeks of hemoglobin counts

• Stores up to a year

Iron and Supplements

Supplements may have adverse effects

• GI disturbance

Iron Acute and Chronic

Acute

• Overdose on supplements causes tissue damage leads to excessive bleeding

Chronic

• Slow overload

  • Hemochromatosis

    • Excessive iron supplementation

    • Hereditary

    • 10% caucasian are carriers

One cause of hemochromatosis

Decreased hepcidin synthesis

• Leads to continued ferroportin activity

Iron absorption is not ____

down regulated Hemoc

Hemochromatosis symptoms

Organ damage

Skin discooloration

Fatiuge and weakness

Liver disease

• Cirrhosis

Join pain and arthritis

Diabetes

• iron buildup in pancreas

Hemochromatosis Treatment

Bleeding

What are the “enhancers” used for digestion of non-heme iron?

Sugars

Acids

Acidic pH

Mucin

Meat, fish and poultry factors