porphyrin metab

Question 1

describe the synthesis of heme

Answer 1

• Aminolevulinic acid synthase synthesizes ALA from succinyl-CoA and glycine
• 2 Molecules of ALA are joined to form porphobilinogen (PBG)
• Four molecules of PBG are joined to form Uroporphyrinogen
• Modifactions of side-chains generate coporphyrinogen and protoporphyrinogen
• Ferrochelatase INSERTES a Fe2+ into the molecule to yield heme

Question 2

describe the regulation points of HEME synethesis

Answer 2

• Low HEME concentration ACTIVATES ALA synthase
  
  • Increased demand for heme Increases, ALA synthase restocks the heme
    
    • negative feedback loop
• Synthesis of Heme-containing cytochrome p450 enzymes consumes Heme
  
  • induction of p450 enzymes (EtOH, Barbituates) induces HEME SYNTHESIS

Question 3

describe Lead affect on Heme production

Answer 3

inhibits heme at 2 sites

• Lead inhibits PBG synthase (ALA dehydratase)
  
  • leads to accumulation of Aminolevulinic acid (ALA)
• leads inhibits Ferrochelatase
  
  • leads to build up protoprophyrinogen IX in the mitochondrion
• SYMPTOMS are similary to porphyrias (mental symptoms, light sensitivity, abdominal pain etc)

Question 4

Acute intermittent porphyria (AIP)

Answer 4

• Caused by ALPHA deficiency in porphobilinogen deaminase (PBGD)
• ALA and PBG Accumulate in the circualtion and in URINE, giving the urine a DARK RED COLOR
• AIP can be life-threatening and causes episodes of confusion and sharp abdominal pain
• drinking alcohol can trigger this disorder

Question 5

Porphyria cutanea tarda (PCT)

Answer 5

• Results from a deficiency of UROPORPHYRINOGEN DECARBOXYLASE
• leads to a buildup of porphyrins (can be detected in the urine)
• Porphyrins are able to absorb visible and UV light
• (LIGHT SENSITIVITY)
  
  • blistering of the skin
  • urine held under UV light will glow pink

Question 6

describe Bilirubin formation and conjugation

Answer 6

1. Heme –Heme oxgenase–> Biliverdin
2. Biliverdin –biliverdin reductase–> bilirubin (electron acceptor, can protect from oxidative stress)
3. Bilirubin –conjugated in liver by UGT–> bilirubin diglucuronide which is excreted in bile
   
   1. also called direct bilirubin
   2. direct bilirubin is conjugated and more water soluble

Question 7

overview of bilirubin metabolism

Answer 7

1. Bilirubin in splenic macrophages –> blood where it binds to albumin and transported to liver
2. Bilirubin becomes conjugated to glucuronic acid to form bilirubin-DG
3. transported into gut where it is broken down by bacteria to bilirubin and urobilinogen
   
   1. can be reabsorbed into the liver where it goes to blood ad through kidneys
   2. OR it can continue into the gut and excreted through feces

BILIRUBIN IN THE URINE is ABNORMAL

Question 8

Jaundice

Answer 8

• yellow pigment accumlation in the skin (bilirubin)
  
  • defect in the process of bilirubin metabolism and excretion
• 3 types
  
  • pre-hepatic jaundic
  • hepatic jaundice
  • post-hepatic jaundice

Question 9

Prehepatic Jaundice

Answer 9

• TOO MUCH UNCONJUGATED BILIRUBIN PRODUCED
  
  • often caused by hemolysis–> newborn jaundice
  • So much it NO LONGER BINDS TO ALBUMIN therefore unconjugated bilirubin starts to accumulate in other tissues and BRAIN
• liver is still conjugated bilirubin and functioning normally
  
  • urine and feces appear normal (normal levels)

Question 10

Hepatic jaundice

Answer 10

• Liver does not produce enough conjugated bilirubin
  
  • lots of unconjugated bilirubin in body (found in tissues, including brain)
  • bilirubin conc in serum is normal or slightly elevated (high in membranes)
• Since liver doesn’t produce conjugated bilirubin
  
  • Pale urine and Pale feces (no pigment –> no bilirubin)
• occurs in acetaminophen poisoning, hepatitis impair bilirubin conjugation/excretion

Question 11

POST-hepatic jaundice

Answer 11

• Occluded digestive tract leads to lots of conjugated bilirubin going through the kidneys –> DEEP ORANGE color of urine and PALE FECES
• Unconjugated bilirubin and conjugated bilirubin found in other tissues including brain
• occurs in gallstones, cancer, cirrhosis close gall duct

Question 12

describe the lab values associated with prehepatic jaundice

Answer 12

• bilirubin usually only slightly elevated
• no bilirubin in urine
• blood anaylsis shows hemolysis
• hemoglobin is low

Question 13

describe lab values of hepatic juanidce

Answer 13

• elevated bilirbuin
• bilirubin in urine (indicative of cholestasis)
• markers of liver disease up (ALT and AST)

Question 14

lab alues of post-hepatic jaundice

Answer 14

• bilirubin may be highly elevated (MOSTLY CONJUGATED)
• bilirubin in urine (conjugated)
• markers of cholestasis are up (alkaline phosphatase)