Iron Metabolism

Iron Metabolism

Reactions
1. redox
  1. accept e-
    1. ferrous (Fe2+)
  2. donate e-
    1. ferric (Fe3+)
  3. physiology
    1. electron transport
      1. Fe-S clusters, cytochromes
        respiratory chain
  4. pathophys
    1. free Fe
      1. lipid peroxidation
        PUFAs
        atherogenesis
2. Fenton
  1. free radical formation
    1. ROS
      1. H2O2
  2. free iron
    1. injured tissue
    2. breakdown of heme
Distribution
1. major
  1. hemoglobin
    1. RBC
      1. 1800 mg
2. minor
  1. muscle fibers
    1. 300 mg
  2. liver
    1. 1000 mg
  3. macrophages
    1. 600 mg
Transport/Storage
1. plasma
  1. transferrin
    1. 30% saturated
2. cell storage
  1. ferritin
    1. interact w/ ceruloplasmin or hephaestin
      1. binds transferrin
        transported
3. other binders
  1. neutrophils
    1. lactoferrrin
  2. tissue injury
    1. hemosiderin
  3. mitochondrial storage protein
    1. frataxin
Steps of Metabolism
1. 1) intestinal absorption of ferrous
  1. stomach
    1. low pH
      1. reduce iron (III) --> (II)
  2. intestines
    1. alkaline environment
      1. heme
        direct absorption
        mucosal cells
        iron dissociates
        free iron
        oxidized
        (II)-->(III)
        reduced again
        taken up by mucosal
  3. transport across epithelium
    1. apical
      1. DMT1
    2. basolateral
      1. ferroportin
        requires hepaestin
  4. regulation
    1. dietary regulator
      1. short term
      2. decrease DMT1
    2. stores regulator
      1. hepcidin
        responds to total body iron
        25 aa peptide
        regulate export
        intestinal cells
        macrphages
        hepatocytes
        inactivates ferroportin
        induces internalization
        lysosomal degradation
        synthesis regulation
        activates
        inflammation
        inhibits
        iron deficiency
        increased erythropoiesis
        hypoxia
    3. erythropoietic regulator
      1. modulate reabsorption based on erythropoiesis requirements
        no reponse to iron
2. 3) cellular uptake and storage in ferritin and frataxin
  1. transferrin receptor
    1. uptake at PM
      1. di-ferric transferrin internalized
        endocytosis
  2. regulation
    1. IRP-1
      1. cytosolic aconitase
        RNA binding protein
        cells iron depleted
        cell ironreplet
      2. senses iron depletion/oxidative stress
      3. activation
        binds 2 mRNAs
        ferritin IRE
        5' untranslatable regioon
        inhibits translation
        transferrin receptor
        3' untranslatable region
        increases translation
        overall effect
        decrease ferritin synthesis
        increase transferrin receptor synthesis
        increase cellular uptake
3. 2) plasma transport by transferrin
  1. Fe (III) delivered to apo-transferrin
    1. transport to diff tissues
      1. binds 2 Fe (III) atoms
    2. from bone marrow
Nutrition
1. dietary sources
  1. liver, red meat, eggs, whole grain, dried fruit, beans, drinking water, iron cooking pots
    1. SPINACH
2. absorption
  1. enhanced
    1. ascorbic acid, dietary protein, erythropoiesis, hypoxia, low stores
  2. inhibited
    1. oxalic acid, coffee, tea, bran, egg yolk, soybean products, calcium, polyphenols, excess metals, inflammation, achlorydria
3. excretion
  1. limited capacity
    1. transferrin bound
      1. not excreted in kidney
    2. chelators
      1. excretable
  2. hemorrhage
Disease
1. deficiency
  1. anemia
  2. impaired immune resonse
  3. initial
    1. no symptoms
  4. diagnosis
    1. < 20% transferrin sat
  5. treatment
    1. ferrous sulfate
    2. packed RBCs
2. iron overload
  1. acute iron poisoning
    1. hypotension
    2. metablolic acidosis
    3. coma
  2. chronic iron overload
    1. patients who receive transfusions
      1. congenital anemias
  3. ineffective erythropoiesis
    1. increased iron absorption
      1. certain anemias
        destroy erythrocytes in bone marrow
        signal erythroid regulator
        increased iron absorption
    2. conditions
      1. thalassemias
      2. sideroblastic anemias
3. Hereditary Hemochromatosis HH)
  1. iron overload
  2. mutation
    1. HFE gene
      1. caucasian
        carrier = 1/10
    2. TFR2
    3. HJV
  3. absorb/store too efficiently
  4. symptoms
    1. iron accumulation
      1. oxidative damage in these tissues
        liver
        cirrhosis
        heart
        cardiomyopathy
        pancreas
        DM
        skin
        pigmentation
        joints
        polyarthropathy
        gonads
        hypogonadotrophic hypogonadism
  5. treatment
    1. phlebotomy
      1. chelators
    2. before organ damage
4. Anemia of chronic disease (ACD)
  1. impaired utilization of iron
    1. no deficiency/excess
  2. defect
    1. blockage
      1. stores --> erythroid precursors
  3. treatment
    1. underlying cause
  4. disease leads to ACD
    1. chronic infections
    2. inflammatory bowel disease
    3. neoplasia
    4. autoimmune disease
    5. mechanism
      1. inflammatory cytokines
        IL6
        Hepcidin upregulated

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