1. Porphyrins & Bile Pigments

2. Objectives After studying this chapter, you should be able to: Know the relationship between porphyrins and heme Be familiar with how heme is synthesized Understand the causes and general clinical pictures of the various porphyrias Know how bilirubin is derived from heme and how it is handled in the body Understand the nature of jaundice and appreciate how to approach determining its cause in a patient.

3. Hemoproteins Heme Porphyrias (Inherited) Catabolism of the heme Jaundice (causes of)

4. Some important hemoproteins

5. The porphyrins The porphin nucleus – Methenyl bridges – Pyrrole ring Side chains

6. The porphin molecule

7. Arrangement of the substituents – Side chains Asymmetric substitution – Type III porphyrin » More abundant Symmetric arrangement – Type I porphyrin

10. Synthesis of Heme

11. ALA Synthase Is the Key Regulatory Enzyme in Hepatic Biosynthesis of Heme – ALAS1 – ALAS2 Heme – Repression-derepression mechanism – Translation of the enzyme – Its transfer from the cytosol to the mitochondrion Drugs – Cytochrome P450 Utilization of heme

12. Glucose Hematin (ALAS2) – Not induced by the drugs – Does not undergo feedback regulation by heme

13. Biosynthesis of porphobilinogen

14. Conversion of porphobilinogen to uroporphyrinogens

16. Decarboxylation of uroporphyrinogens

17. Addition of iron to protoporphyrin

19. Absorption spectrum of hematoporphyrin

21. The porphyrias 85% of heme synthesis occurs in erythroid precursor cells in the bone marrow and the majority of the remainder in hepatocytes Erythropoietic or Hepatic

22. THE PORPHYRIAS ARE GENETIC DISORDERS OF HEME METABOLISM Genetic or acquired Diagnosis – Assay of the activity eg, red blood cells – Use of appropriate gene probes Prenatal diagnosis

23. The Porphyrias are Genetic Disorders of Heme Metabolism The signs and symptoms of porphyria result from – Deficiency of metabolic products Deficiency of heme – Accumulation of metabolites behind the block Prior to the formation of porphyrinogens – ALA and PBG will accumulate Abdominal pain and neuropsychiatric symptoms Later in the pathway – Accumulation of the porphyrinogens

24. Major findings in the porphyrias

26. Porphyrias Treatment – Avoid drugs that cause induction of cytochrome P450 – Repress ALAS1 Glucose loading Hematin – β-carotene Lessen production of free radicals – Sunscreens

27. Catabolism of heme produces bilirubin Hemoglobin – Globin – Iron – Porphyrin Hemoglobin Ineffective erythropoiesis other heme proteins – Cytochrome P450 Reticuloendothelial cells

29. Structure of bilirubin diglucuronide

30. Conjugation of bilirubin

32. Hyperbilirubinemia – Bilirubin in the blood exceeds 1 mg/dL – Overproduction – Failure of a damaged liver to excrete bilirubin Jaundice or icterus – 2–2.5 mg/dL Direct reacting – React without the addition of methanol Indirect-reacting

33. Kernicterus – Unconjugated bilirubin can cross the blood-brain barrier

34. Elevated Unconjugated Bilirubin in Blood HEMOLYTIC ANEMIAS – Usually only slight (< 4 mg/dL) NEONATAL “PHYSIOLOGIC JAUNDICE” – Accelerated hemolysis – Immature hepatic system CRIGLER-NAJJAR SYNDROME – TYPE I Serum bilirubin usually exceeds 20 mg/dL Mutations in the gene encoding bilirubin-UGT

35. Elevated Unconjugated Bilirubin in Blood TYPE II – Some activity of the enzyme is retained – Usually do not exceed 20 mg/dL GILBERT SYNDROME – Mutations in the gene encoding bilirubin-UGT – 30% of the enzyme’s activity is preserved – Harmless

36. Elevated Unconjugated Bilirubin in Blood TOXIC HYPERBILIRUBINEMIA – Acquired disorders – Liver dysfunction – Impairs conjugation

37. Conjugated Hyperbilirubinemia OBSTRUCTION OF THE BILIARY TREE DUBIN-JOHNSON SYNDROME ROTOR SYNDROME

38. OBSTRUCTION OF THE BILIARY TREE Due to – Gallstone – Cancer of the head of the pancreas Cholestatic jaundice – Include All cases of extrahepatic obstructive jaundice Micro-obstruction of intrahepatic biliary ductules

39. DUBIN-JOHNSON SYNDROME Benign autosomal recessive Mutations in the gene encoding MRP-2 – Secretion of conjugated bilirubin into bile

40. ROTOR SYNDROME Rare Benign A chronic conjugated hyperbilirubinemia Normal liver histology

41. Delta bilirubin – Longer half-life

42. Laboratory results in normal patients and patients with three different causes of jaundice. Hepatitis – Damage to parenchymal cells – Micro-obstruction to bile ductules

43. Causes of jaundice Prehepatic Hepatic Posthepatic Distinction – Measurement of prothrombin time – Electrophoresis of proteins – Activities of the enzymes ALT,AST, and alkaline phosphatase

44. Causes of jaundice Measurements of plasma – Total and Nonconjugated bilirubin Urinary – Urobilinogen and bilirubin