Heme metabolism

heme metabolism

1. Heme metabolism Dr. Mohamed Badr

2. Heme synthesis: A.Location : a. Intracellular location: Mitochondria,cytosol and then mitochondria again. b. Organ location: Liver and bone marrow. B. Steps: 1) The two starting molecules are succinyl CoA (derived from citric acid cycle) and Glycine. The reaction occur in mitochondria and needs aminolevulonic acid (ALA) synthase enzyme and pyridoxal phosphate as activator for glycine

3. Ferrochelatase

4. B. Types of hemoglobin: Several different types of haemoglobin are normally found in human. They vary in the primary structure of the peptide chains of globin. 1- Hemoglobin A:  It is the major Hemoglobin in adults (97%).  Its globin comprises 4 polypeptide chains: 2 alpha and 2 Beta chains. 2- Hemoglobin A2:  It is minor in adults (2%).  Its globin comprises 4 polypeptide chains: 2 alpha and 2 Delta chains. 3- Fetal hemoglobin ( HbF ):  It is present in fetus during intrauterine fetal life.  It is 1 % of adult human hemoglobin.  Its globin comprises 4 polypeptide chains: 2 Alpha and 2 gamma chains. 4- Hemoglobin A1c ( Glycated hemoglobin):  Hemoglobin A reacts non-enzymatically with glucose to form glycated hemoglobin (HbA1c). It is normal Value: 5 – 6.5 %.  In diabetes mellitus the concentration of HbA1c may reach 12 % or more  The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months.  The HbA1c is used in monitoring Diabetes Mellitus.

5. Abnormal derivatives of haemoglobin 1- Methemoglobin (Met- Hb ):  It is oxidized hemoglobin (Fe++ oxidized to Fe+++).  Oxidation may occur by some drugs, hydrogen peroxides, and free radicals.  Met- Hb binds oxygen irreversibly thus cannot act as oxygen carrier. 2- Carboxyhemoglobin ( COHb ):  It is hemoglobin combined with carbon monoxide.  Carbon monoxide has 200 time greater affinity to Hb than oxygen.  Increase in COHb more than 40% results in unconsciousness and may be fatal. 3- Sulfhemoglobin (S- Hb ):  It is hemoglobin combined with sulfur.  It is caused by exposure of hemoglobin to toxic effect of certain drugs as sulfonamides.  S- Hb produce anoxia & cyanosis because it cannot act as oxygen carrier. 4- Hematin :  It is hemoglobin without iron (i.e. protoporphyrin combined with globin).  It may be formed following intravascular hemolysis

6. Porphyrias : A.These are a group of diseases resulting from a deficiency of one of the enzymes needed for heme synthesis. Effect of porphyraris : porphyrias lead to disturbance in heme synthesis and causes: Anemia : due to decrease production of heme . Abdominal pain and neuropsychiatric symptoms due to toxic effect of accumulated porphyrin intermediates. Photosensitivity : Some porphyrin derivatives when exposed to light react with molecular oxygen to form oxygen radicals which cause skin damage. B. Porphyrias are either hereditary or acquired.

7. Hemoglobin Catabolism  The average life span of red blood cells is 120 days .  At the end of that time, they are removed from the circulation by the cells of reticuloendothelial system mostly present in liver, spleen and bone marrow, where they are hemolysed and hemoglobin comes out giving globin and heme molecules .  Globin molecule is hydrolyzed into amino acids.  Heme gives iron and bilirubin.

8. Types of Hyperbilirubinemia A. Neonatal (Physiological) Jaundice :  Common, particularly in premature infants.  Transient (resolves in the first 10 days).  Due to immaturity of the enzymes involved in bilirubin conjugation.  High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus.  If bilirubin levels are judged to be too high, then phototherapy with UV light as bilirubin is broken down in light.  Jaundice within the first 24 hrs. of life or which takes longer than 10 days to resolve is usually pathological and needs to be further investigated.

9. Pathological Hyperbilirubinemia 1. Prehepatic ( haemolytic ) Jaundice  Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis.  Excess RBC lysis is commonly the results of autoimmune diseases; hemolytic disease of the newborn; structurally abnormal RBC’s (sickle cell disease ).  High plasma concentrations of unconjugated bilirubin (normal concentration 0.5 mg/dl)

10. Post hepatic Jaundice  Caused by an obstruction of the biliary tree  Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma.  Characterized by pale colored stool (absence of fecal bilirubin or urobilin ), and dark urine (increased conjugated bilirubin).  In a complete obstruction, urobilin is absent from the urine.

11. Type Cause Age Characters Gilbert's disease Mild deficiency of UDP- glucuronyl transferase enzyme At any age Male more than female Bilirubin concentration less than 3 mg/dl Crigler-Najjar syndrome Marked reduction of UDP-glucuronyl transferase enzyme Neonates leading to kernicterus → early death bilirubin concentration exceeds 20 mg/dl Dubin-Johnson syndrome (conjugated non cholestatic) defect in hepatic secretion of conjugated bilirubin into bile adult life ↑ conjugated bilirubin Normal bile acid level (exclude cholestasis) Bilirubin present in urine Prognosis is excellent No treatment needed. Congenital hyperbilirubinemia:

12. Gilbert's syndrome Crigler-Najjar syndrome Due to defect in uptake of bilirubin by liver &low activity of UDPG transferase . Due to deficiency of UDPG transferase Attacks bet.10 -20 years old Presents at birth plasma level of IB =1.2-2.5 mg/dl plasma level of IB exceeds the protein binding capacity   No kernicterus kernicterus present Harmless condition Serious condition Confusion with hepatitis & hemolysis