Bilirubin Metabolism

Question 1

what are bilirubin and biliverden?

Answer 1

• endogenously derived substances
• they are generated during enzymatic degradation of heme

Question 2

bilirubin is a product of…

Answer 2

• hemoglobin
• it circulates in plasma prior to undergoing hepatic conjugation and biliary excretion

Question 3

senescent RBC’s are taken up by

Answer 3

• phagocytic cells of the spleen
• also kupffer cells (macrophages of the liver)
• these cells degrade hemoglobin into heme and globin
• the heme gets broken down into iron and bilirubin
• bilirubin formed in tissues circulates in the serum before undergoing hepatic conjugation

Question 4

where does bilirubin go after it forms in the tissues (liver and spleen)

Answer 4

• it is released in the blood
• in the blood, it binds to albumin
• this is unconjugated bilirubin, which means it is not water soluble

Question 5

describe bilirubin conjugation

Answer 5

• unconjugated bilirubin is not water soluble
• gets taken up by hepatocytes and conjugated by adding one or two glucuronic acid residues
• the enzyme UDPGT does this
• this creates water soluble, conjugated bilirubin

Question 6

what happens to bilirubin after it has been conjugated?

Answer 6

• some conjugated bilirubin is excreted in bile. this way it will participate in fat digestion in the intestine, but cannot be absorbed in the si
• some will be converted back to unconjugated bilirubin by bacteria in the terminal ileum and colon. this will then be further converted into colorless urobilinogen

Question 7

what happens to urobilinogen

Answer 7

• a little bit gets absorbed in the colon and re-circulated and re-excreted by the liver and kidneys
• if it enters the plasma and gets filtered by the kidney, it gets oxidized to urobilin, which gives urine the yellow color
• if it stays in the colon, it will be converted to stercobilin, which makes poop brown
• relate this back to chart on slide 60!

Question 8

what happens to urobilinogen in the presence of liver disease?

Answer 8

• liver dysfunction is associated with a rise in urinary urobilinogen
• hepatic fraction (conjugating bilirubin) decreases
• urinary fraction increases (urobilinogen to urobilin)

Question 9

define jaundice/icterus

Answer 9

• both unconjugated and conjugated bilirubin bind to connective tissue and stain it yellow
• they also stain mucous membranes and skin
• when bilirubin builds up, this is what happens

Question 10

hyperbilirubinemia

Answer 10

• unconjugated: prehepatic origin
• conjugated: posthepatic obstruction
• too much of both unconjucated and conjugated: hepatic origin

Question 11

normal process of bilirubin metabolism

Answer 11

• hemolysis of erythrocytes occurs, resulting in unconjugated bilirubin in the blood
• goes to liver cells, gets conjugated
• conjugated bilirubin gets released from the liver as bile
• goes to the intestine
• if not used in the intestine, can get converted back into unconjugated and then urobilinogen in the colon
• urobilinogen can get converted to urobilin in the kidney and get excreted in urine, or can get converted to stercobilin in the colon and get excreted in feces

Question 12

prehepatic (or hemolytic) jaundice

Answer 12

• this happens with hemolytic anemia
• excessive hemolysis leads to increased unconjugated bilirubin in the blood
• normal liver cannot process excessive amounts of bilirubin
• feces are normal or darker

Question 13

intraheptic jaundice

Answer 13

• this happens with hepatitis
• hemolysis of rbc’s is normal
• hepatocellular damage prevents conjugation and excretion
• results in increased conjugated (not properly excreted in bile) and unconjugated (not properly conjugated) bilirubin in blood
• note that liver inflammation obstructs flow of the bile duct, which is why excretion is impaired
• feces are variable

Question 14

posthepatic or obstructive jaundice

Answer 14

• this can happen with gallstones
• hemolysis is normal and so is hepatic conjugation of bilirubin
• obstructed flow to intestine causes conjugated bilirubin to back up to liver and blood
• feces are a light color. this is because conjugated bilirubin doesn’t get to si in bile, so never gets converted to urobilinogen and stercobilin, which is the pigment in feces

Question 15

important point about jaundice/icterus

Answer 15

• this is the manifestation of hyperbilirubinemia
• hyperbilirubinemia can be cellular or ductal!

Question 16

what can cause prehepatic origin hyperbilirubinemia?

Answer 16

excessive hemolysis

Question 17

what can cause hyperbilirubinemia of hepatic origin?

Answer 17

• viral hepatitis
• drugs
• cirrhosis
• tumors

Question 18

what can cause posthepatic hyperbilirubinemia?

Answer 18

• gallstones
• cancer of bile ducts

Question 19

gilbert syndrome

Answer 19

• unconjugated hyperbilirubinemia (so prehepatic origin)
• caused by a mutation in UGT1A1 gene
• autosomal recessive
• occurs worldwide, 3-7% of americans affected
• mild because about 30% of the UGT enzyme function is normal
• impairment in this enzyme messes up conjugation of bilirubin b/c this is the enzyme that does the conjugation

Question 20

how does this process affect the neonate?

Answer 20

• neonate is particularly sensitive to free unconjugated bilirubin
• it can diffuse into the brain and cause a type of encephalopathy called kernicterus
• put baby under blue light, which converts bilirubin back into biliverdin, which is soluble

Question 21

what happens when there is complete obstruction to bile flow or intestinal obstruction above the colonic level?

Answer 21

urinary urobilinogen falls to zero because no bilirubin reaches the colon

Question 22

why does urinary urobilinogen increase with liver dystunction?

Answer 22

because the urobilinogen does not get re-circulated and re-excreted by the liver
- this means it will just go to the systemic circulation and get filtered and excreted by the kidneys