Iron metabolism

• Fe metabolism

  intake= 10-20mg/day

  absorpted=1-2mg/day
• Absorption

  takes place in the duodenum and upper jejunum via two pathways; heme and non-heme
• Fe balance


  achieved via control of aborption

  intake = loss

  higer aborption in deficiency and low absorption in overload states
• Heme pathway

  Heme is directly and independently taken up into the enteroctyes by heme transporters.
• Non-heme pathway

  1.in the intestinal lumen, Fe3+ is converted to Fe2+ by DcytB reductase ( ferriductase).

  2. Fe2+ enters the enterocyte via the DMT-1.

  3. it is stored as ferritin or taken up into the bloodstream via ferroportin 1.

  4. Fe2+ is again converted to Fe3+ in the blood stream by a ferroxidase (Hephaestin)

  5. Fe3+ is taken to the bone marrow by transferrin(bound) for erythropoiesis and some is taken up by macrophages in the reticuloendothelial system as a storage pool.
• Regulation

  major regulator is Hepcidin produced by the liver.

  1. it binds to ferroportin degrading it hence prventing Fe from leaving the cell and getting into the bloodstream.
  2. it inhibits DMT-1 reducing Fe aborption.
• Importance of regulation

  excess Fe can lead to formation of ROS.

  optimize Fe absorption and distribution.
• Hepcidin

  low Fe levels= low hepcidin

  high He levels= high hepcidin, Hepcidin also acts as a gatekeeper
• Transferrin

  important in Fe transport; when not bound=apotransferrin

  33% normally and the concentrations vary based on pathologic and physiologic states.

  e.g; high transferrin= Fe deficiency & low transferrin= Fe overload
• Iron storage

  mainly as ferritin and haemosiderin
• Ferritin

  water soluble

  found in all body cells and tissue fluids.

  high ferritin=Fe overload & low ferritin=Fe deficiency
• Haemosiderin

  not water soluble and found mainly in macrophages.

  formed from ferritin aggregates.

  may pathologically accumulate in tissues.
• FBC in deficiency

  low Hb, HCT/PCV, MCHC; MCV<76fl & MCH<26pg
• Biochemical tests in deficiency

  low serum Fe, ferritin, transferrin saturation

  high TIBC, RBC porphyrins, serum transferrin
• Other lab tests

  PBF

  BMA-not necessary unless in complicated IDA; absent Fe stores.
• Iron metabolism


  Iron is vital for living organisms, essential for many cellular functions such as oxygen transport, cell division, and electron transport
• Iron in tissues


  • Usually incorporated into various proteins: heme, iron flavoproteins, heterogonous groups
  • Nearly half of enzymes & co-factors of krebs cycle contain iron or need its presence

  
• Body iron compartments


  • Hb (67%, 2.5 - 3g)
  • Stores (30%, 0.8 - 1g)
  • Myoglobin (3%, 0.1g)
  • Tissue iron (6 - 8mg)

  
• Total body iron approx 4g (3.5 - 4.5) in adult male, less in female
• Iron requirements


  • 1-2 mg/day
  • Higher requirements in growth periods, pregnancy, lactation, females of reproductive ages
• Sources of iron


  • Heme iron (meats, poultry, fish, 10 - 15% of Fe in diet)
  • Non haem iron (cereals, vegetables, fruits, roots, 70% of dietary Fe, mostly ferric form)
• Dietary iron


  Variable, 10-30mg in "well balanced", 5 - 10 % absorbed (0.6 - 1 mg), heme iron better absorbed and it enhances absorption of non-haem iron, reducing agents in HCL in gastric juice enhance non-haem iron absorption
• Dietary substances that enhance or inhibit dietary non-haem iron absorption

  • Enhancers: ascorbic acid, heme, organic acids, amino acids, simple sugars, cysteine
  • Inhibitors: phytates, phosphates, polyphenols, tanin, calcium, zinc, soil clay, cadmium
• Iron loss is 1 mg/day through desquamation of epithelial cells (GIT, GU, skin, etc)
• Iron balance


  Intake = loss, balance achieved via control of absorption, iron content in mucosal cells affects absorption, absorption increased in iron deficient states, reduced in overload states
• Iron absorption


  1. Absorption takes place in the duodenum and upper jejenum

  2. Haem pathway: haem absorbed into enterocyte by independent pathway as intact metalloprotein through specific receptor

  3. Non-haem pathways: ferric iron (3+) converted to ferrous by ferrireductase, ferrous iron (2+) uses the divalent metal transporter-1 (DMT-1) to enter the enterocyte, HCL in gastric juice facilitates the conversion of ferric iron to ferrous iron

  
• Although essential, iron in excess can promote the formation of highly toxic reactive oxygen species (ROS), which can damage DNA, protein, and lipid membrane, leading to organ dysfunction
• Hepcidin


  Key factor in iron regulation, a hormone (25 aa) produced by liver cells, major hormonal regulator of iron homeostasis, inhibits the activity of iron exporter, ferroportin-1 (FPN-1), inhibits iron release from macrophages, intestinal cells

  
• Hepcidin regulation


  1. Decreased production in iron deficiency, hypoxia, ineffective erythropoiesis

  2. Increased production in inflammation, infection when iron stores are full, causes reduced intestinal iron absorption and increased iron retention in macrophages, protects organism from infection with siderophilic and gram-negative bacteria

  
• Internal iron cycle


  1. Absorption

  2. Circulating erythrocytes

  3. Macrophages: storage pool

  4. Plasma

  5. Marrow erythroblasts

  
• Transferrin


  MWt 80,000 Daltons, glycoprotein synthesized in liver, many genetic variants, when not compounded to iron - apotransferrin, normally 33% saturated with iron, concentration varies in physiologic and pathologic conditions

  
• Ferritin


  Water soluble, compound of ferric hydroxide and apoferritin, found in all body cells and tissue fluids, plasma content closely correlates with body stores
• Haemosiderin


  Mainly in macrophage system (marrow, kupffer cells in liver, spleen), water insoluble, may pathologically accumulate in tissue, formed from aggregates of ferritin, Perl's stain (Prussian blue reaction) used to show iron stores

  
• Laboratory tests for deranged iron metabolism

  • Full blood counts (Hb, HCT/PCV, MCV, MCH, MCHC, WBC, PLTs)
  • Peripheral blood film examination (microcytic hypochromic cells in deficiency state)
  • Biochemical features (serum Fe, serum ferritin, transferrin saturation, TIBC, red cell porphyrin)
  • Bone marrow aspiration (not necessary in uncomplicated IDA)