Bilirubin Metabolism and Excretion

Question 1

how are bile salts recycled?

Answer 1

through the enterohepatic circulation

95% recycled through the terminal ileum

Question 2

describe steps of heme conversion to bilirubin

Answer 2

1) heme recycled in RES from senescent RBCs, myoglobin, P450 from muscle/liver
2) heme -> (heme oxygenase) -> biliverdin + CO
3) biliverdin -> (biliverdin reductase) -> bilirubin

Question 3

bilirubin - properties

Answer 3

lipid
transported by bilirubin binding protein (BBP) within blood
bilirubin+BBP too large to come out of circulation, but toxic
hepatocytes selectively transport bilirubin+BBP

Question 4

describe process of bilirubin conjugation

Answer 4

1) bilirubin+BBP complex selectively transported into hepatocytes
2) bilirubin conjugated + 1-2 UDP-glucuronate/UDP-glucuronic acid -> (UDP-glucuronyl transferase) -> bilirubin mono/diglucuronate
product is water soluble, no carrier protein, cannot be reabsorbed from intestinal lumen

Question 5

describe process of bilirubin excretion

Answer 5

1) bilirubin mono/diglucuronate put into bile
2) bilirubin mono/diglucuronate -> (gut flora) -> urobilinogen
3) urobilinogen leaks into blood, excreted in urine; most remains in colon
4) urobilinogen + O2 -> urobilin (yellow), excreted in urine
5) urobilinogen + e- (from gut flora) -> stercobilinogen
6) stercobilinogen + O2 -> stercobilin (dark brown), excreted in feces

Question 6

normal blood bilirubin values

Answer 6

conjugated (direct): <0.2 mg/dL

Question 7

hyperbilirubinemia - causes, effects

Answer 7

bilirubin >1.2 mg/dL

cholestasis: impaired bile flow, increased blood [bilirubin], [bile acids] and [cholesterol]

jaundice/icterus: bilirubin >2.5 mg/dL; yellow coloration of skin, sclera

kernicterus: bilirubin > 15-20 mg/dL; enters CNS (BBB not fully formed, not enough BBP to bind); mental retardation, motor dysfunction, brain damage, cerebral palsy
treatment: immediate blood transfusion; phototherapy (trans -> cis bilirubin, cis more water soluble)

Question 8

unrelated enzymatic/cofactor causes of hyperbilirubinemia

Answer 8

1) G6PD deficiency: non-immune hemolytic anemia; massive hemolysis, liver cannot handle
2) pyruvate kinase deficiency: second most common cause of enzyme-deficient hemolytic anemia
3) vitamin K toxicity: required in liver for synthesis of 4 coagulation factors; high doses may lead to certain types of anemia or liver damage

Question 9

Crigler-Najjar syndrome - cause, effects

Answer 9

UDP-glucuronyl transferase gene mutation
cannot conjugate bilirubin
severe congenital jaundice
indirect bilirubin 30-50 mg/dL in blood
increased urine [bilirubin]
death in 6 months-1 year

Question 10

Gilbert syndrome - cause, effects

Answer 10

UDP-glucuronyl transferase gene point mutation
sub-optimal enzyme performance
indirect bilirubin 2-3 mg/dL
increased urine [bilirubin]
6-8% of population affected, no sx

Question 11

Dubin-Johnson syndrome - cause, effects

Answer 11

direct hyperbilirubinemia
defective canalicular transport of bile
chronic, benign
black liver (biopsy)
brown urine
moderate jaundice
otherwise normal

Question 12

Rotor syndrome - cause, effects

Answer 12

direct hyperbilirubinemia
multiple defects in hepatocellular uptake and excretion of bilirubin
bilirubin storage issue -> leaks into blood
liver normal
moderate jaundice
otherwise normal

Question 13

prehepatic causes of jaundice

Answer 13

excessive bilirubin presented to liver for metabolism
overcomes ability of liver to clear
usually cause is hemolytic process
increased serum [unconjugated bilirubin]
negative urine bilirubin
negative urine urobilinogen

Question 14

hepatitis - effects

Answer 14

decreased conjugation/excretion of bilirubin
increased serum [direct bilirubin] and [indirect bilirubin]
total bilirubin 5-10 mg/dL

Question 15

posthepatic causes of jaundice

Answer 15

mechanical obstruction of bile flow into intestines (ex. gallstones, tumors)
increased serum and urine [direct bilirubin]
decreased urobilin/stercobilin
no urinary urobilinogen