Iron Metabolism

Lecture Objectives


IL Objectives

Identify the biochemical functions of iron and iron proteins.

  • Iron is essential for life
  • cofactor in ribonucleotide reductase (makes deoxyribose)
  • central role in cytochromes of the ETC :. ATP production
  • bind O2 in hemoglobin
  • There are two iron proteins: transferrin and ferritin
    • Transferrin: bilobular serum protein transport iron between tissues. Such as from the site of hemoglobin destruction (liver, spleen) to site of RBC formation (bone marrow)
    • Ferritin: cellular protein that acts as reservoir for storing iron in tissues (mainly spleen and liver)

Identify and describe tests used to measure iron deficiency and iron overload.

  • Serum Fe
    • These are all bound to transferrin
    • Normal: 10-30 umol Fe /L
  • Total iron binding capacity
    • Amount of iron capable of being bound if every Tf molecule had both sites occupied
    • Normal: 45-75 umol Fe /L
  • Transferrin saturation
    • How much of the available iron binding sites are actually occupied with iron (%)
    • Serum Fe / TIBC
    • best measure of Fe delivery to the erythron
  • Serum ferritin
    • leakage of very small amount of ferritin from cells
    • inconsequential for metabolism of Fe, but important for clinical marker of iron stores
    • usually 1% of total ferritin
    • measure amount of iron available in stores
  • Hemosiderin
    • complex of denatured ferritin
    • visual estimate by Prussian blue stain of liver/bone marrow

Explain steps of iron absorption and metabolism.

FeAbs.jpg
  • Two pathways - Heme and Non-heme
  • Common at first: absorbed by enterocytes in the duodenum. These cells are "polar" - one side face lumen, other face interstitium
  • Heme:
    • taken up by heme carrier protein (HCP) into an intestinal intracellular vesicle
    • Acted on by heme oxygenase to release iron
  • Non-heme:
    • Fe3+ reduced to Fe2+ by duodenyl cytochrome B (DCYTB) in the intestinal lumen
    • taken up by divalent metal transporter (DMT1)
  • Once uptaken, both can be stored as ferritin or absorbed viz the basolateral membrane of the transporter ferroportin 1 to circulation.
    • Haphaestin is a ferrioxidase. It is also required for basolateral iron transport
    • hepcidin (secreted by liver) inhibit iron absorption at this step by promoting ferrioportin destruction

Absorption Regulation

  • bleeding
      • important source of Fe loss (normally or not). Lose ~1mg for women, and 1.5 for men
    • absorption from food
      • When iron stores drop, absorption increases to correct the deficit. Vice versa
      • MoA Unknown. Affect both types of iron absorption

Compare between heme-Fe and nonheme-Fe and absorption of each.

  • Heme Iron: present in hemoglobin and cytochromes. Iron is bound tightly to heme. High amounts are present in meat, especially red meat
    • Better absorbed because surrounded by the porphyrin ring and not subjected to luminal factors that affect solubility of non-heme iron
  • Non-heme Iron: All other iron forms not described above. Including Iron in ferritin, inorganic iron in foods, medications, etc. Non-heme iron can exist as Fe2+ (more soluble), or Fe3+ (tendency to oxidize into this, but less soluble)
    • Not well absorbed and less soluble because will bind to many food items (e.g. organic acids and fibres)
    • Stomach acid is important in releasing and solubilizing non-heme iron from food
    • Vit C is important in solubilizing non-heme iron and improves absorption

Describe key features of iron homeostasis.

  • Body homeostasis of iron is controlled by its intestinal absorption.
  • Loss of blood can cause significant Fe loss from the body.

Describe features of iron toxicity, primary and secondary iron overload.

  • Free ionic iron will induce free radicals.
  • Free radicals cause cellular damage and carcinogensis
  • Acute poisoning: The first indication of iron poisoning by ingestion is a pain in the stomach, as the stomach lining becomes ulcerated. This is accompanied by nausea and vomiting. The pain then abates for 24 hours as the iron passes deeper into the body and damages internal organs, particularly the brain and the liver, and metabolic acidosis develops. The body goes into shock and death from liver failure.
  • Chronic overload/toxicity: Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands. Cirrhosis of the liver; Diabetes due to pancreatic islet cell failure; Cardiomyopathy; Arthritis (iron deposition in joints); Testicular failure; Tanning of the skin
  • Primary iron overload
    • from non-regulated iron absorption
    • Can be due to genetic hemochromatosis (HC)
  • secondary iron overload
    • from a disease or treatment
      • Transfusion
      • Liver failure
      • Hemolysis

Describe and compare the key features of hemochromatosis and hemoglobinopathies.

  • Patients with hemoglobinopathies cannot synthesize adequate hemoglobin and this must be provided by blood transfusions.
  • Patients who receive blood transfusions regularly will require Fe-chelation treatment to avoid iron toxicity and morbidity.

Genetic hemochromatosis (HC)

  • the hemochromatosis gene (HFE) cannot make functional (or present) products, so iron sensing is defective in intesting crypt cells. Expression of hepcidin is also lowered
  • a silent disease - accumlation over many years without symptoms until storage limit reached and increasing free iron cause tissue damage
  • expressed more in men because women lose iron during menstruation
  • autosomal recessive
  • frequently missed as a diagnosis even though disease incidence is 0.3%
  • Phlebotomy is the treatment of choice for patients with genetic hemochromatosis.

Sickle Cell

  • beta 6th AA glutamic acid -> valine
  • Deoxy Hb stick to each other
  • cell sickle and precipitate
  • get stuck in small vessels

Thalassemia

  • not enough a or b globin
  • may require chronic transfusions (the alpha thalassemia)

Sideroblastic

  • Impaired heme synthesis
  • iron cannot be incorporated into heme
  • Could be due to lack of B6

Describe the relationship between iron and bacterial growth.

  • bacteria need iron to grow
  • Siderophores (very high iron affinity) bind iron and transport back
  • As a result, bacteremia always a concern during iron supplementation or overload, because of the increase in unbound, available iron

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