Uploaded byDr Ramesh Krishnan
Pophyria
This document discusses heme metabolism and porphyrias. It begins by outlining heme biosynthesis and degradation, then focuses on porphyrias. Porphyrias were once thought to be the basis for vampire legends due to symptoms like sunlight sensitivity and anemia, but this idea has been discarded. The document discusses different types of porphyrias caused by defects in various enzymes in the heme biosynthesis pathway. It also discusses heme degradation and the causes of jaundice related to increased bilirubin levels.
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Pophyria
- 1. Heme Metabolism •Heme biosynthesisand Porphyrias •Heme degradation: Jaundice
- 2. Heme Biosynthesis: Porphyrias •Cruelly referred to as a Vampire’s disease. Thought to be a cause of the madness of King George III. • Can be caused by lead poisoning: The fall of the Roman Empire!
- 3. Not a ‘vampire’s’disease Some symptoms of porphyrias have lead people to believe that these diseases provide some basis for vampire legends: •Extreme sensitivity to sunlight •Anemia This idea has been discarded both for scientific reasons: •Porphyrias do not cause a craving for blood. •Drinking blood would not help a victim of porphyria. And for compasionate reasons:Porphyria is a rare, but frightening condition: hard to diagnose and there is no cure.
- 4. The Madness ofInbreeding George III : Severe abdominal pain, mental confusion, dark urine.
- 5. PORPHYRIAS GLYCINE + SuccinylCoA δ-aminolevulinicacid(ALA) Porphobilinogen(PBG) hydroxymethylbilane uroporphyrinogen III coprophyrinogene III Protoporphyrinogene IX protoporphyrin IX Heme ALA synthase ALA dehydratase PBG deaminase Uroporphyrinogen III cosynthase Uroporphyrinogen decarboxylase Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferrochelatase ALA-dehydratase Deficiency porphyria Acute intermittent porphyria Congenital erythropoietic porphyria Prophyria cutanea tarda Herediatary coproporphyria Variegate porphyria Erythropoietic protoporphyria Mitochondria 9q34 11q23 10q26 1q34 9 1q14 18q21.3 3p21/Xp11.21 Agent Orange
- 6. COORDINATED REGULATION OFHEME AND GLOBIN SYNTHESIS: Heme: Inhibition of the synthase and stimulation of globin synthesis are the most important aspects in balancing hemoglobin production. diminishes the transport of δ-ALA synthase from cytoplasm to mitochondria after synthesis of the enzyme. represses the production of δ-ALA synthase by regulating gene transcription. inhibits activity of pre-existing δ-ALA synthase stimulates globin synthesis to ensure that levels of free heme remain low in concentration.
- 7. Heme Catabolism Heme Degradation HEME BILIVERDIN O2 Fe+3 NADPH NADP+ (opensthe porphyrin ring) BILIRUBIN NADPH NADP+ BILIRUBIN diglucuronide BILE
- 9. Jaundice Hyperbilirubinemia: Two forms: Direct bilirubin:Conjugated with glucoronic acid Indirect bilirubin: unconjugated, insoluble in water.
- 10. What’s the causeof jaundice? 1- Increased production of bilirubin by hemolysis or blood disease: •Increase in blood indirect bilirubin •Called pre-hepatic jaundice •Stool color remains normal. 2- Abnormal uptake or conjugation of bilirubin: •Leads to non-hemolytic unconjugated hyperbilirubinemia •Increased indirect bilirubin. •Stool color turns gray. •Caused by liver damage or disease.
- 11. What’s the causeof jaundice? 3- Cholestasis = Problems with bile flow. a:Intrahepatic cholestasis: hyper conjugated bilirubinemia •Increase in blood indirect and direct bilirubin •Caused by liver damage or disease: eg cirrhosis, hepatitis •Can also occur in pregnancy: b:Extrahepatic cholestasis: •Blockage of bilirubin transport in the bilary tract. •Increased direct bilirubin. •Stool color turns gray. •Caused by: Tumors or gall stones.
- 12. CLINICAL PREMISE Newborns oftenhave a yellowish tint to their skin. This condition is known as jaundice and results from the infant ridding itself of "fetal" hemoglobin which will be replaced by "adult" hemoglobin. As you will learn in this lecture, catabolic products from hemoglobin are removed by the liver. However, the infant's liver is often too immature to handle the excessive breakdown products. Instead they accumulate giving the yellowish tint. Exposure to mild UV light from the sun is usually sufficient to destroy these compounds, although in very severe cases blood dialysis may become necessary as these byproducts can be toxic.
- 13. Table 1- Theporphyrias. You are responsible for the enzyme defects in red Type Enzyme Involved Major Symptoms Laboratory tests Acute intermittent porphyria Uroporphyrinogen synthase Abdominal pain Neuropsychiatric urinary porphobilinogen ⇑ Congenital erythropoietic porphyria Uroporphyrinogen cosynthase Photosensitivity urinary uroporphyrin ⇑ porphobilinogen ⇔ Porphyria cutanea tarda Decarboxylase Photosensitivity urinary uroporphyrin ⇑ porphobilinogen ⇔ Variegate porphyria Oxidase Photosensitivity Abdominal pain Neuropsychiatric urinary uroporphyrin ⇑ fecal coproporphyrin ⇑ fecal protoporphyrin ⇑ Erythropoietic protoporphyria Ferrochelatase Photosensitivity fecal protoporphyrin ⇑ red cell protoporphyrin ⇑
- 14. BLOOD CELLS LIVER Bilirubin diglucuronide (water-soluble) 2 UDP-glucuronicacid via bile duct to intestines Stercobilin excreted in feces Urobilinogen formed by bacteria KIDNEY Urobilin excreted in urine CO Biliverdin IXα Heme oxygenase O2 Bilirubin (water-insoluble) NADP+ NADPH Biliverdin reductase Heme Globin Hemoglobin reabsorbed into blood Bilirubin (water-insoluble) via blood to the liver INTESTINE Figure 2. Catabolism of hemoglobin
- 15. A. Hemolytic anemia excess hemolysis unconjugated bilirubin (in blood) conjugated bilirubin (released to bile duct) B. Hepatitis unconjugated bilirubin (in blood) conjugated bilirubin (in blood) C. Biliary duct stone unconjugated bilirubin (in blood) conjugated bilirubin (in blood) Figure 3. Examples of hyperbilirubinemia
- 16. Table 2- GeneticDisorders of Bilirubin Metabolism Condition Defect Bilirubin Clinical Findings Crigler-Najjar syndrome severely defective UDP-glucuronyltransferase Unconjugated bilirubin ⇑⇑⇑ Profound jaundice Gilberts syndrome reduced activity of UDP-glucuronyltransferase Unconjugated bilirubin ⇑ Very mild jaundice during illnesses Dubin-Johnson syndrome abnormal transport of conjugated bilirubin into the biliary system Conjugated bilirubin ⇑⇑ Moderate jaundice
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- 18. Cyclization to theporphyrin
- 19. Cyclization to theporphyrin