1. Metabolism of heme Alice Skoumalová

2. Heme structure:  a porphyrin ring coordinated with an atom of iron  side chains: methyl, vinyl, propionyl Heme is complexed with proteins to form: Hemoglobin, myoglobin and cytochromes

3. Mitochondria Cytosol

4. Disease stateGeneticsTissueOrgan pathology Acute intermittent porphyria dominantLiverNervous system Hereditary coproporphyria dominantLiverNervous system, skin Variegate porphyriadominantLiverNervous system, skin Porphyria cutanea tardadominantLiverSkin, induced by liver dis. Erythropoietic protoporphyria dominantMarrowGall stones, liver dis., skin Congenital erythropoietic porphyria recessiveMarrowSkin, RES Lead poisoningAll tissuesNervous system, blood, others Derangements in porphyrin metabolism:

5. Synthesis of δ-aminolevulinic acid: induced by: drugs (barbiturates), oral contraceptive pills Pyridoxal phosphate (vit. B 6 )

6. inhibited by lead Formation of porphobilinogen:

7. Degradation of heme:

8. Conversion of heme to bilirubin: ER enzyme system the major source is Hg Cytoprotective role: CO biliverdin

9. Formation of bilirubin diglucuronide: increase the water solubility of bilirubin

10. Hyperbilirubinemia  Elevated bilirubin levels in the blood (>10 mg/l); bilirubin may diffuse into peripheral tissues, giving them a yellow color (jaundice)  Cause: 1. Pre-hepatic: excessive formation of bilirubin by increased degradation of erythrocytes (icterus neonatus, hemolytic anemia) 2. Hepatic: insufficient processing of bilirubin as a result of liver defects (hepatitis, liver toxic damage, cirrhosis, hepatic failure) 3. Post-hepatic: by impaired excretion of gall (obstructive jaundice due to gallstones, inflammation of biliary tract)  Unconjugated bilirubin can cross the blood-brain barrier, leading to brain damage  Jaundice in neonates (increased bilirubin degradation+immaturity of the conjugation enzymes): phototerapy – isomerization of bilirubin to more soluble pigments

11. TypeCauseExampleFrequence PrehepaticHemolysisAutoimmune Haemoglobinopathy Rare According to the region HepaticInfection Damage Genetics Autoimmune Newborn Hepatitis A,B,C Alcohol, drugs Gilbert´s syndrome Wilson´s disease α 1 -Antitrypsin deficiency Chronic hepatitis Physiologic Very common Common 1 in 20 1 in 200 000 1 in 1000 Rare Very common PosthepaticIntrahepatic bile ducts Extrahepatic bile ducts Drugs Primary biliary cirrhosis Cholangitis Gallstones Pancreatic cancer Common Rare Common Very common Rare

12. Bilirubin blood urine deriv. in feces Urobilinogen blood urine Prehepatic ↑↑ (UC) N ↑ ↑ ↑ Intrahepatic ↑↑ (both) ↑ N ↑↑ ↑↑ Posthepatic ↑↑ (C) ↑ ↓ ↓ ↓

13. Summary: Synthesis of heme:  from glycine and succinate  induction by drugs and ↓ glucose; inhibition by lead  intermediates → porphyrinogens (porphyrins)  porphyrias Degradation of heme  to bilirubin (hydrophobic)  conjugation in liver  conversion to urobilinogen in intestine  hyperbilirubinemia (differential diagnosis)

14. Pictures used in the presentation: Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks) Principles of Biochemistry, 2008, (Voet D, Voet J.G., and Pratt C.W)