1. Metabolismo del Heme

4. Figure 7.3: Comparison of myoglobin and hemoglobin. © Irving Geis.

18. Compartamentalizacion de la Síntesis del Heme

19. PorphyriaEnzyme DefectPrimary Symptom Erythropoietic Class Congenital erythropoietic porphyriaCongenital erythropoietic porphyria, CEP Uroporphyrinogen III cosynthase Photosensitivity Erythropoietic protoporphyriaErythropoietic protoporphyria, EPPFerrochelatasePhotosensitivity Hepatic Class ALA dehydratase deficiency porphyriaALA dehydratase deficiency porphyria, ADP ALA dehydrataseNeurovisceral Acute intermittent porphyriaAcute intermittent porphyria, AIPPBG deaminaseNeurovisceral Hereditary coproporphyriaHereditary coproporphyria, HCPCoproporphyrinogen oxidase Neurovisceral, some photosensitivity Variegate porphyriaVariegate porphyria, VPProtoporphyrinogen oxidase Neurovisceral, some photosensitivity Porphyria cutanea tardaPorphyria cutanea tarda, PCT Uroporphyrinogen decarboxylase Photosensitivity Hepatoerythropoietic porphyriaHepatoerythropoietic porphyria, HEP Uroporphyrinogen decarboxylase Photosensitivity, some neurovisceral

20. Catabolismo del Heme

21. Extravascular Pathway for RBC Destruction (Liver, Bone marrow, & Spleen) Hemoglobin Globin Amino acids Amino acid pool Heme Bilirubin Fe 2+ Excreted Phagocytosis & Lysis

22. Regulation of iron metabolism

23. Handling of Free (Intravascular) Hemoglobin Purposes: 1. Scavenge iron 2. Prevent major iron losses 3. Complex free heme (very toxic) Haptoglobin: hemoglobin-haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss of iron in urine. Hemopexin: binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin. Methemalbumin: complex of oxidized heme and albumin.

28. DEGRADATION OF HEME TO BILIRUBIN P 450 cytochrome  75% is derived from RBCs  In normal adults this results in a daily load of 250-300 mg of bilirubin  Normal plasma concentrations are less then 1 mg/dL  Hydrophobic – transported by albumin to the liver for further metabolism prior to its excretion “unconjugated” bilirubin

29. NORMAL BILIRUBIN METABOLISM  Uptake of bilirubin by the liver is mediated by a carrier protein (receptor)  Uptake may be competitively inhibited by other organic anions  On the smooth ER, bilirubin is conjugated with glucoronic acid, xylose, or ribose  Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase  “Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi  Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut  Oxidized to stercobilin which is colored  Excreted in feces  Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney

30. Prehepatic (hemolytic) jaundice Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis Excess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease); or breakdown of extravasated blood High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

31. Intrahepatic jaundice Impaired uptake, conjugation, or secretion of bilirubin Reflects a generalized liver (hepatocyte) dysfunction In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

32. Posthepatic 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 stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin) In a complete obstruction, urobilin is absent from the urine

33. HYPERBILIRUBINEMIA  Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when there is an imbalance between its production and excretion  Recognized clinically as jaundice