Plasma Iron Section 3 - PDF

Plasma iron (section 3) By: Dr. Moshtaghie  Plasma Iron 1. The Iron concentration changes during daytime 2. The serum iron is higher in the morning 3. At menstrual cycle the serum iron is lower than prior to that 4. During this cycle women loses 104 to 3.4 mg iron per day 5. 5...

Plasma iron (section 3) By: Dr. Moshtaghie  Plasma Iron 1. The Iron concentration changes during daytime 2. The serum iron is higher in the morning 3. At menstrual cycle the serum iron is lower than prior to that 4. During this cycle women loses 104 to 3.4 mg iron per day 5. 50 percent loses 1.4 mg/day 6. 25 percent loses 1.7 mg per day 25 percent loses 3.2 mg per day 7. Elevated level of iron in the plasma of pregnant women should be occur  Plasma Iron Transferrin=mg/dl=0.7 X TIBC µg/dl TIBC=1.43 X Transferrin mg/dl Transferrin saturation=100 x serum iron /TIBC TIBC=Total iron binding capacity  Iron Storage - Ferritin Iron store in the liver and nearly all other cells. MW 460,000. Outer shell: apoferritin, consists of 22 protein subunits Iron-phosphate-hydroxide core. 20% iron by weight, binding up 4,500 atoms of iron per molecule. Small fraction found in circulation (contains less than 1% of serum iron). Stores iron and releases it in a controlled fashion.  Plasma Ferritin This is a storage iron protein It contains iron and apo-ferritin Apo-ferritin contain 24 subunit Ferritin has 4000 atom of iron per molecule Measurement of this protein is very important in Low level plasma iron patient Those who have anemia due to infection Those who have high level of plasma iron  Ferritin - Measurement A routine blood test – reflects iron stores Low serum levels – Indicate Iron deficiency (high specificity) High serum levels – Iron overload Other - Ferritin may be increased in serum by: – Tissue release (hepatitis, leukaemia, lymphoma) – Acute phase response (tissue damage, infection, cancer) Interpretation – Low levels always indicate Fe deficiency. – Other factors may mask deficiency  Iron Release from cells Ferroportin present on cell surface to release iron Found on gut cells, liver cells and macrophages Requires cofactor to oxidise iron to allow for binding to transferrin – Hephaestin in gut – Caeruloplasmin in other cells Hepcidin blocks iron release from all cells A possible mechanism for anaemia of chronic disease  Iron uptake by cells Fe-Transferrin binds to receptors (hepatocytes and erythrocytes) Fe-transferrin-receptor complex endocytosed to the cell Transferrin donates iron to the mitochondria Iron will be used for heme synthesis Iron will be inserted to apoferritin Ferritin loses iron for enzyme and other iron containing protein synthesis The receptor will be exocytosed from the cell  Transferrin Receptors Collects iron from transferrin for uptake into cells – Recognises and binds transferrin – Receptor + transferrin endocytosed – Iron released into cell via Iron transporter (DMT1) – Receptor + transferrin return to cell surface – Transferrin released  Soluble Transferrin Receptors Truncated form of cell surface receptors Found in the circulation High levels with iron deficiency Low levels with iron overload Possible role in diagnosis of iron deficiency compared in setting of inflammation Not currently routinely available  Intracellular movement of iron Fe-apotransferrin(tf) binds to transferrin receptor at cell membrane Transferrin +Receptor →Tf-receptor [Tf-receptor] Ka= [transferrin] [Receptor] Ka=binding constant=10-7 Internalization Cycle of transferrin 1. Transferrin bind to the receptor 2. Transferrin internalize to the cell 3. Iron release from transferrin 4. Transferrin-apotransferrin exocytosis from the cell and return to the plasma 5. Apotransferrin release from receptor and return to the intestine site to bring another atoms of iron 6. transferrin itself may release from receptor and directly take its iron to the mitochondria for heme synthesis 7. Some iron may go to ferritin as storage protein  Hepcidin 25 aa peptide Identified 2000 Antimicrobial activity Hepatic bacteriocidal protein Master iron regulatory hormone Inactivates ferroportein – Stops iron getting out of gut cells – Iron lost in stool when gut cells shed Leads to decreased gut iron absorption  Heme Synthesis Glycine + Succinc CoA→ Aminolevlinic acid 2ALA →Porphobilinogen 4 Porphoblinogen →Uropophyrinogen III Uroporphyrinoge III→ Coproporphyrinogen III CoproporphyrinogeIII → Porphyrinogen IX Porphyrinogen IX→ Protoporphrin IX Protoporphyrin IX + Fe →Heme  Related publications Moshtaghie et al: Study of Skillen and Moshtaghie. the relationship between The effect of aluminum on aluminum toxicity and heme the interaction between synthesis. IJMS:15:46 transferrin and its receptors (1990) on placenta membrane. in: Moshtaghie and Taher. Aluminum in renal disease. Identification of transferrin pp85(1986) in mitochondria isolated from rat liver. Biochem Soc Trans 15:67s(1990)  Related articles to heme synthesis Ani and Moshtaghie. Chromium interaction with iron metabolism. IJMS.15:43(l990) Moshtaghie, Ani and Taher. Identification of transferrin in mitochondria isolated from rat liver. Biochem. Soc. Trans. 15:67S(1990) Moshtaghie. How aluminum is taken up by red blood cells. Med. J.IRI. 7:87(1993) Interference of metal ions with heme synthesis (anemia) Aluminum interferes with iron uptake by Hepatocytes and erythrocytes causing anemia Cadmium interferes with iron uptake by hepatocytes Pb causes disturbances to heme synthesis Chromium as well as Zn toxicity causes Anemia  Hemoglobins structure site Type of hemoglobins α2β2 97 to 98% Hb-A1 α2∂2 2 to 3% Hb-A2 α2ð2 Up to 6 month Hb-F  Hemoglobins (con) Hb-O Hb-Co Met-Hb S-Hb Hematine Myoglobin haptoglobin  Iron Scavenging Intravascular haemolysis Breakdown of red cells in the circulation – Free haemoglobin binds haptoglobins -> taken up by liver – Free haem binds haemopexin -> taken up by liver – Haem passing through kidney resorbed – Three mechanisms to conserve iron in pathological situations Historically iron deficiency is the disease we have evolved to avoid.  Iron re-use Old cells broken down in macrophages in spleen and other organs Iron transported to liver and other storage sites Red cell iron recovered from old red cells Very little iron lost in routine metabolism  Bilirubin Hb→ Fe+ Protoporpherin Protoporpherin → Biliverdin Biliverdin → Bilirubin Bilirubin + Albumin →Alb-Bilirubin Alb-Bilirubin Liver Bilirubin Bilirubin+ glucoronic acid→ bil-glucoronate bil-glucoronate Bile duct esterco-bilin+ esrcobilinogene  Iron deficiency It can be due to the following reasons: 1. Iron deficiency 2. Malabsorption 3. Lost of iron therefore the biochemical parameters are: 1. High level of TIBC 2. Low level of Ferritin 3. Low level of plasma iron  Iron Deficiency Extremely common Due to reduced intake, increased loss or increased demands Stores reduced before deficiency seen Iron deficiency is not a diagnosis – A cause needs to be identified! – Eg obstetric causes, low intake, malabsorption, bowel cancer, haemorrhoids, inflammatory bowel disease  Iron Deficiency Laboratory changes: – Low iron (poor specificity) – Low ferritin (excellent specificity) – Elevated Transferrin (TIBC) – Low transferrin saturation – Hypochromia, microcytosis – Anaemia Stages – Reduced iron stores – Iron deficient erythropoiesis – Iron deficient anaemia  Iron overload This can be due to: 1. High level of plasma iron due to consumption 2. intraperitoneal injection 3. Hemochromatosis Therefore plasma iron is very high and transferrin saturation is 100% and plasma ferritin is very high  Hemochromatosis 1. It is rare disease 2. High iron absorption 3. Appearance of hemosiderine in the skin 4. Liver serosis 5. Pancreatic dysfunction 6. Diabetic 7. Heart infarction  Genetic haemochromatosis Iron overload disease Caused by increased iron absorption Known since 1700s May affect liver, pancreas, skin, heart, joints, endocrine organs (bronze diabetes) Gradual accumulation of iron over the life of the person (positive iron balance) – Iron overload detectable in teens and 20s – Organ overload in 30s – Organ damage in 40s and 50s Cirrhosis and liver disease main cause of increased mortality  Genetic Haemochromatosis >95% defect in HFE gene (C282Y) Associated with low hepcidin Leads to overactivity of ferroportin – Increased gut absorption of iron Also other mechanisms – Increased DMT1 and DcytB activity – Not related to hepcidin Limited penetrance (1 – 50%) – May require other genes to be involved  Genetic Haemochromatosis HFE-Related Type 1 – HFE defects Non HFE Related Type 2a – Haemojuvelin defects Type 2b – Hepcidin defects Type 3 – Transferrin receptor defects Type 4 – Ferroportin defects  Anaemia of chronic disease Infection, inflammation, malignancy Low iron absorption Low serum iron Stainable iron stores in RE cells Hepcidin is an acute phase protein Increased hepcidin – blocks iron in gut cells – Traps iron in macrophages and liver cells Produces a functional iron deficiency – Not responsive to iron therapy  Anaemia of chronic disease Hard to separate from iron deficiency anaemia May co-exist Ferritin: low with pure iron deficiency but increased with acute phase response Iron: low in both conditions Transferrin: high in pure iron deficiency but decreased with acute phase response  Other tests related to iron status Haemoglobin – Low with iron deficiency, anaemia of chronic disease Mean Cell Volume – Low with iron deficiency, thallassaemia Liver iron – High with iron overload – Better marker for GH when corrected for age – (Hepatic iron index) Bone marrow iron – Low with iron deficiency  Future possibilities Treatment with hepcidin for iron overload Blocking of hepcidin for anaemia of chronic disease Diagnostic tests based on hepcidin  Conclusions Iron related diseases are common and clinically important Recent advances have changed our understanding Groups of tests “Iron studies” are the best first line investigation New tests and therapies will follow the new understandings.