Heme Degradation and Jaundice

Question 1

describe jaundice

Answer 1

• yellowish discoloratino of the skin, mucus membranes, sclera and nail beds
• characterized by binding of bilirubin (bile pigment) to the connective tissue
• occurs when serum bilirubin levels >2 mg/dL

Question 2

describe heme degradation

Answer 2

• RBCs contain hemoglobin that is broken down to heme and globin (amino acids enter amino acid pool)
• heme containing proteins like myoglobin and cytochromes also release heme on degradation that also forms bilirubin

Question 3

describe the formation of bilirubin in macrophages/reticular endothelial system

Answer 3

• heme oxygenase
  
  • Fe2+ is released
  • porphyrin ring is cleaved
  • CO is formed in the rxn
  • biliverdin is a green pigment
• biliverdin reductase
  
  • bilirubin formed has an orange-yellow color

Question 4

describe the transport of bilirubin in the blood to the liver

Answer 4

• bilirubin formed in macrophages is not water soluble
  
  • this bilirubin is unconjugated bilirubin
• it binds in blood to albumin for transport
  
  • prevents it from being excreted in urine
  • drugs can displace bilirubin from albumin (salicylates, sulfonamides)
    
    • administratino of these drugs can displace bilirubin from albumin and free uncojugated bilirubin can cross the BBB to cause kernicterus in children

Question 5

describe the uptake of unconjugated bilirubin by the liver

Answer 5

• unconjugated bilirubin is taken up by the liver by specific transporters on the the hepatocytes
• within the hepatocyte, bilirubin is bound to ligandin (intracellular protein)

Question 6

describe the conjugation of bilirubin in the liver

Answer 6

• bilirubin is converted to conjugated biliruin (more water soluble) by the addition of 2 molecules of glucuronic acid
  
  • this is done my microsomal UDP-glucuronyl transferase
  • the donor of glucuronic acid is UDP-glucuronic acid

Question 7

describe the secretion of conjugated bilirubin into bile

Answer 7

• conjugated bilirubin is actively transported into the bile canaliculus against a concentration gradient by a specific ABC transporter
• conjugated bilirubin is a component of bile and is released into the 2nd part of duodenum via the common bile duct

Question 8

describe the formation of urobilinogen and then stercobilin in the large intestine

Answer 8

• conjugated bilirubin is acted upon by bacterial flora in the large intestine
• conjugated bilirubin undergoes deconjugation and is next converted to urobilinogen (colorless)
  
  • ​lost in urine as urobilin (10%) (light yellow color)
• bacterial action on urobilinogen forms stercobilin that is lost in the feces and gives the feces a characteristic brown color

Question 9

give an overview of heme degradation

Answer 9

Question 10

describe the Van den Berg reaction

Answer 10

• conjugated bilirubin (direct reacting) is water soluble and reacts rapidly with the reagent
• unconjugated biliruin (indirect reacting) is water insoluble and reacts in the presence of methanol
• total bilirubin - direct (conjugated) bilirubin = indirect (unconjugated) bilirubin

Question 11

describe the 3 types of jaundice

Answer 11

• prehepatic (hemolytic): increased breakdown of RBCs
• hepatic: decreased conjugation capacity of liver and decreased excretion of bilirubin
• posthepatic (obstructive/cholestatic): decreased excretion of bilirubin via bile

Question 12

describe prehepatic/hemolytic jaundice

Answer 12

Question 13

describe the lab findings in prehepatic/hemolytic jaundice

Answer 13

Question 14

describe hepatic jaundice

Answer 14

Question 15

describe the lab findings of hepatic jaundice

Answer 15

• serum conjugated bilirubin is elevated since the capacity to excrete conjugated biliruin into the biliary canaliculus is reduced; conjugated bilirubin regurgitates into the plasma (cannot be excreted into the bile)
• serum unconjugated bilirubin is elevated as hepatocellular damage results in lower uptake of unconjugated bilirubin into liver
  
  • also liver damage reduces the conjugating capacity of liver

Question 16

describe posthepatic/obstructive/cholestatic jaundice

Answer 16

Question 17

describe lab findings of posthepatic/obstructive/cholestatic jaundice

Answer 17

Question 18

describe jaundice in newborn and phototherapy

Answer 18

• unconjugated bilirubin crosses the blood brain barrier (since it is lipid soluble and not well developed) and deposits in the basal ganglia of the brain resulting in kernicterus
• phototherapy: light converts bilirubin to more polar, water soluble isomers that can be excreted in bile without conjugation

Question 19

describe Crigler-Najjar syndrome I, II and Gilbert’s syndrome

Answer 19

all caused by lowered activity of bilirubin glucuronyl transferase

• Crigler-Najjar syndrome I
  
  • most severe
• Crigler-Najjar syndrome II
  
  • lowered activity of enzyme
  • children respond to phenobarbital (induces the enzyme)
• Gilbert’s syndrome
  
  • mild jaundice
  • 50% of normal enzyme activity

Question 20

describe Dubin-Johnson syndrome

Answer 20

• inherited deficiency of the ABC transporter that transports conjugated bilirubin from the hepatocyte into the biliary canaliculus
• typically presents in young adults
• characterized by elevated levels of conjugated (direct) bilirubin in circulation