1 / 44

Porphyrins & Bile Pigments

Porphyrins & Bile Pigments. 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

margieelkins
Télécharger la présentation

Porphyrins & Bile Pigments

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

  8. Synthesis of Heme

  9. 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

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

  11. Biosynthesis of porphobilinogen

  12. Conversion of porphobilinogen to uroporphyrinogens

  13. Decarboxylation of uroporphyrinogens

  14. Addition of iron to protoporphyrin

  15. Absorption spectrum of hematoporphyrin

  16. 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

  17. THE PORPHYRIAS ARE GENETICDISORDERS OF HEME METABOLISM • Genetic or acquired • Diagnosis • Assay of the activity • eg, red blood cells • Use of appropriate gene probes • Prenatal diagnosis

  18. The Porphyrias are GeneticDisorders 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

  19. Major findings in the porphyrias

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

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

  22. Structure of bilirubin diglucuronide

  23. Conjugation of bilirubin

  24. 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

  25. Kernicterus • Unconjugated bilirubin can cross the blood-brain barrier

  26. Elevated UnconjugatedBilirubin 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

  27. Elevated UnconjugatedBilirubin 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

  28. Elevated UnconjugatedBilirubin in Blood • TOXIC HYPERBILIRUBINEMIA • Acquired disorders • Liver dysfunction • Impairs conjugation

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

  30. 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

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

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

  33. Delta bilirubin • Longer half-life

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

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

  36. Causes of jaundice • Measurements of plasma • Total and Nonconjugated bilirubin • Urinary • Urobilinogen and bilirubin

More Related