1. David Hart Dec 13, 2006

2. HEME CH 3 -

3. Bonkovsky ASH Education Book December 2005

4. Hentze, Muckenthaler & Andrews Cell, Vol 117, 285-297, April 30, 2004 Hepcidin

5. Lecture Outline Heme function Heme synthesis and regulation Iron metabolism Porphyrias Heme degradation

6. Disorders of Heme Synthesis X-linked Sideroblastic Anemia Lead Poisoning Iron Deficiency Anemia The Porphyrias

7. Porphyrias Inherited defects in heme synthesis –Accumulation and excretion of porphyrins –Pattern depends on which enzyme affected –Decreased heme synthesis derepresses hepatic  ALAS Most are Autosomal Dominant Erythropoietic, Hepatic or Mixed Acute and Chronic –Acute: Neurovisceral attacks Porphyrin accumulation: Photosensitivity –Formation of reactive oxygen species –Damage tissues, Release lysosomal enzymes

8. Fuseli Three Witches Tate Gillray 1791 Weird Sisters Tate

9. Very Rare Recessive Porphyria Lead Poisoning ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

10. Acute Hepatic PBG and  ALA (Neurotoxic) Accumulate in Urine PBG in Urine: Diagnostic Screen Neurovisceral Attacks No Photosensitivity with AIP Hydroxymethylbilane Synthase Lead Poisoning X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia ALA-D Porphyria

11. Acute Porphyrias Clinically indistinguishable (Locus Heterogeneity) PBG in Urine: Diagnostic Screen Agents which induce cytochrome P450 –Drugs, Alcohol, Hormones Precipitated by fasting, treated with glucose After puberty; more in women Begin with minor behavioral changes Proceeds to autonomic and sensomotoric neuropathy; Convulsions Pain: Back, Extremities, Abdomen Hypertension and Tachycardia Arrhythmias; cardiac arrest

12. Acute Hepatic Erythropoietic RECESSIVE Porphyrin accumulation: Photosensitivity Porphyrins are Fluorescent compounds Formation of reactive oxygen species, Activate Complement Lead Poisoning Hydroxymethylbilane Synthase ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

13. Clin Med 2005:5 Dr. Meyer-Betz 1912

14. GM Murphy, Dermatologic Therapy, March 2003 CEP

15. NEJM 9/7/2006

17. mccaskey4.home.mindspring.com

18. Erythropoietic Acute Hepatic Chronic Lead Poisoning Hydroxymethylbilane Synthase ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

19. Porphyria Cutanea Tarda (PCT) Most common Porphyria –80% sporadic Hepatic and Erythropoietic Photosensitivity Uroporphyrin accumulates in Urine –Red-Brown in natural light Clinical expression in 4th - 5th decade Decrease in UROD activity by Iron-dependent mechanism –Alcohol, viruses, drugs, hormones –HFE Hemochromatosis Venesection, Chloroquine

20. Autosomal Dominant PCT (Hepatoerythropoietic Porphyria) Hepatic UROD activity < 50% during symptoms Additional decrease from reversible inactivation C282Y HFE causes earlier onset

21. PCT; www.Utah.edu

22. Erythropoietic Acute Hepatic Acute Hepatic Photosensitivity (Unlike AIP) Lead Poisoning Hydroxymethylbilane Synthase Chronic ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

23. medlib.med.utah.edu Normal Liver

24. www.med.niigata-u.ac.j Granular, Dark Reddish Brown Surface of Liver in Hemochromatosis

25. Lecha, Herrero, Ozalla, Dermatologic Therapy, March 2003 Hepatic Porphyria

26. Acute Hepatic Erythropoietic Acute Hepatic Acute Hepatic Photosensitivity Lead Poisoning Hydroxymethylbilane Synthase Chronic ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

27. Hair Analysis Lancet July 2005

28. Lancet July 23-29, 2005 King George III (1738-1820) Likely diagnosis of Variegate Porphyria –Proposed 1969 based on family tree Lock of hair showed high lead –Widespread use in his era Extremely high levels of arsenic –Likely secondary to medications

29. Lancet July 2005 Color of Urine “Alicante Wine”

30. http://www.aw-bc.com/mathews/GH/HEME.GIF Introduction of Fe 2+ into PPIX Occurs spontaneously, but Enhanced by FERROCHELATASE An enzyme which is inhibited by LEAD

31. http://www.photodermatologie.de Acute Hepatic Acute Hepatic Erythropoietic Acute Hepatic Erythropoietic Photosensitivity Lead Poisoning Hydroxymethylbilane Synthase Chronic ALA-D Porphyria X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia

32. Erythropoietic Protoporphyria Presentation in early childhood Burning, stinging pain with sunlight Subsequent skin changes Expression requires low-expression allele in trans –10% of population of France and UK –IVS3-48 alternative splice acceptor –With AD mutation FECH 35% of normal –Homozygosity does not cause disease Beta carotene: free radical scavenger

33. www.immunochemistry.com

34. GM Murphy, Dermatologic Therapy, March 2003 EPP

35. GM Murphy, Dermatologic Therapy, March 2003 EPP

36. www.goa-world.ne

37. Acute Hepatic Acute Hepatic Erythropoietic Acute Hepatic Erythropoietic Photosensitivity Lead Poisoning No Photosensitivity With Lead Lead Poisoning Hydroxymethylbilane Synthase Chronic X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia ALA-D Porphyria

38. http://www.photodermatologie.de Acute Hepatic Acute Hepatic Erythropoietic Acute Hepatic Erythropoietic Photosensitivity Iron Deficiency “Free” Erythrocyte PPIX accumulates in Lead Poisoning and Iron Deficiency Lead Poisoning Hydroxymethylbilane Synthase Chronic X-linked Sideroblastic Anemia X-linked Sideroblastic Anemia ALA-D Porphyria

39. Porphyrias: Genetics / Epigenetics 5 out of 7 are Low-penetrance Autosomal Dominant Most mutations are restricted to one family Rare Homozygotes very severe No dominant negative mutants described 50% residual activity is normally sufficient

40. Molecular basis of “low penetrance” Genotype/phenotype correlations Increased demand –Fasting (low Glucose) –Cell, August 26, 2005 Low expression allele in trans Iron / HFE hemochromatosis can directly inhibit enzymes Other epigenetic phenomena

41. Treatment Medical Support during acute attacks Treatment for pain and vomiting Glucose infusion until Hemin available Intravenous Hemin –Decreases synthesis of  ALAS Avoid Sunlight  -carotene, a free-radical scavenger Chronic transfusion for Erythropoietic

42. Degradation of Heme At end of their 120 day lifespan, red blood cells are taken up and degraded by the reticuloendothelial (RE) system (liver and spleen) 85% heme for degradation from RBC 15% immature RBC, cytochromes from extraerythroid tissues

43. N NHN HN H 3 C- -CH=CH 2 -CH 3 CH 2 COOH CH 2 COOH CH 3 Fe 2+ CH=CH 2 HEME

44. N NHN HN H 3 C- -CH=CH 2 -CH 3 CH 2 COOH CH 2 COOH CH 3 Fe 2+ CH=CH 2 MACROPHAGE takes up HEME Heme Oxygenase is Inducible by a variety of agents Inhibited by Tin Protoporphyrin

45. N NHN HN H 3 C- -CH=CH 2 -CH 3 CH 2 COOH CH 2 COOH CH 3 CH=CH 2 MACROPHAGE Heme Oxygenase Step 1 NADPH O 2 Fe 3+ OH

46. N NHN HN H 3 C- -CH=CH 2 -CH 3 CH 2 COOH CH 2 COOH CH 3 CH=CH 2 MACROPHAGE Heme Oxygenase Step 2 Fe 3+ CO Released OO BILIVERDIN HO also has Cytoprotective effects

47. J Cell Mol Med 2006

48. NHNH CH V M N PM NHNH MP NHNH O VM O BILIVERDIN

49. NHNH CH V M N PM NHNH MP NHNH O VM O NHNH V M NHNH CH 2 PM NHNH CH MP NHNH O VM O BILIVERDIN BILIVERDIN REDUCTASE + NADPH BILIRUBIN

51. ALBUMIN Low Albumin Anionic Drugs: Salicylates Sulfonamides BILIRUBINALBUMIN Unbound Bilirubin Can enter CNS Cause Kernicterus in Neonate Bilirubin Released from Macrophage, binds to Albumin in the Plasma

52. BILIRUBINALBUMIN LIVER BILIRUBIN LIGANDIN CONJUGATION with 2 Molecules Glucuronic Acid from UDP-glucuronic acid Bilirubin Glucuronyltransferase Bilirubin Diglucuronide BILE Active Transport

53. BILIRUBIN: Unconjugated (Indirect) LIVER CONJUGATION Bilirubin Glucuronyltransferase Bilirubin Diglucuronide: Conjugated (Direct) Bilirubin VAN DEN BERGH COLORMETRIC REACTION TOTAL BILIRUBIN: Soluble in Methanol Less Soluble in Aqueous Solution, reacts more slowly More Soluble, reacts more quickly

54. GALL BLADDER Active Transport Bilirubin Diglucuronide LIVER Bilirubin Diglucuronide UROBILINOGENSTERCOBILIN KIDNEY BILE INTESTINAL BACTERIA Urobilinogen Enterohepatic Circulation UROBILIN Bilirubin

55. GALL BLADDER Active Transport Bilirubin Diglucuronide LIVER Bilirubin Diglucuronide UROBILINOGENSTERCOBILIN KIDNEY BILE INTESTINAL BACTERIA Urobilinogen Enterohepatic Circulation UROBILIN BILIRUBIN HEMOLYSIS: Unconjugated (Indirect) Hyperbilirubinemia

56. GALL BLADDER Active Transport Bilirubin DG LIVER Bilirubin Diglucuronide UROBILINOGENSTERCOBILIN KIDNEY BILE INTESTINAL BACTERIA Urobilinogen Enterohepatic Circulation UROBILIN BILIRUBIN NEONATAL JAUNDICE: Unconjugated Hyperbilirubinemia

57. www.mtwthailand.org

58. home.hawaii.rr.com

59. GALL BLADDER Active Transport Bilirubin Diglucuronide LIVER KIDNEY BILE INTESTINAL BACTERIA UROBILIN Bilirubin OBSTRUCTIVE JAUNDICE Direct (Conjugated) Bilirubin

60. GALL BLADDER Active Transport Bilirubin DG LIVER Bilirubin Diglucuronide UROBILINOGEN STERCOBILIN KIDNEY BILE INTESTINAL BACTERIA Urobilinogen Dark Urine BILIRUBIN HEPATOCELLULAR JAUNDICE: Unconjugated Hyperbilirubinemia ENTEROHEPATIC CIRCULATION

61. www.privivka.ru

62. Carotenemia