Week 5: Jaundice and bilirubin

Question 1

Overview of bilirubin metabolism

Answer 1

1. breakdown of RBCs to heme in reticuloendothelial cells (Macs)
2. converted to biliverdin then to bilirubin, which is reversibly bound to albumin and circulates to liver
   LIVER
3. bilirubin transported across sinusoids via OATP
4. binding to glutathione S-trasnferases (GSTs or ligandins)
5. Moves to ER, converted to glucuronides by transfer of glucuronic acid by UGT
6. Transport across canalicular membrane by ATP dependent transport, MRP2 (ABCC2). Some transported by ABCC3 back into sinusoidal to be taken by neighboring hepatocytes via OATP1B1 and OATP1B3

Question 2

Systemic and enterohepatic circulation of bilirubin and metabolites

Answer 2

• ~250 mg/day conjugated bilirubin (CB) secreted into intestines
• converted to urobilinogen by bacteria. 127 mg/day excreted in stool and rest recycled
• some urobilinogen filtered and excreted by the kidney, 0-4 mg/day.
• If there are significant amounts of urinary urobilinogen, then patient doesn’t have complete obstruction of biliary tree.

Question 3

unconjugated hyperbilirubinemia vs. conjugated or mixed hyperbilirubinemia

Answer 3

• For unconjugated hyperbili, means virtually all of the bill measured is in unconjugated form
• if more than 20-30% of total bill is CB, then it is a mixed hyperbilirubinemia. or if CB> 2

Question 4

Ddx of unconjugated hyperbilirubinemia

Answer 4

1. Increased bilirubin load
   - hemolysis
   - sequestration of blood, e.g. hematoma
   - ineffective erythropoiesis
2. Decreased hepatic uptake of bilirubin
   - Drugs, e.g. rifambin
3. Decreased UDP-glucuronosyltransferase activity (UGT 1).
   - Crigler-Naijjar Syndrome: Type I and II
   - Gilbert’s syndrome

Question 5

Criger-najjar Syndrome

Answer 5

TYPE I
-absent UGT-1. Rare. Severe hyperbilirubinemia. Autosomal recessive
-serum levels of UCB 15-45 mg/dL
-normal liver panel. Kernicterus is common. Non responsive to phenobarbital. Need Liver transplant.
TYPE II
-decreased UGT-1. More common. Moderate hyperbili. Autosomal dom. most likely.
-Serum UCB 8-25 mg/dL.
-normal liver panel
-neuro complications less common.
-phenobarbital therapy reduces serum bilirubin.

Question 6

Kernicterus

Answer 6

• high levels of circulating UCB are lipid soluble and can cross BBB
• basal ganglia is most vulnerable
• occurs at serum UBC> 25-30 mg/dL
• clinical findings: opisthotonos, extensor rigidity, tremors, ataxic gait, oculomotor paralysis, hearing loss (most sensitive finding)

Question 7

Gilbert’s syndrome

Answer 7

• common cause of mild, non hemolytic unconjugated hyperbilirubinemia
• adolescents/adults
• at least 50% reduction in UGT-1 activity, may be due to group of mutations in promotor region of UGT-1 gene
• may be related to Crigler-Najjar syndrome type II
• benign disorder that requires no treatment
• jaundice appears when stressed

Question 8

Physiologic jaundice in neonate

Answer 8

• newborns have increased bilirubin level.
• they have increased bilirubin production (large RBC mass and decreased RBC survival)
• decreased binding of bili to albumin
• decreased binding to GSTs
• decreased UGT activity
• increased enterohepatic circulation of bilirubin
• normally: rapid rise in UCB around day 3, followed by decline. Falls to adult levels by day 14. If have elevated CB at 2 weeks, consider other problems.
• up to 3% have sustained levels of > 13 mg/dL

Question 9

Breast milk jaundice

Answer 9

• very common, onset during first 3 days of life
• late onset is uncommon. Treat by discontinuing breast feeding for 24-48 hours.
• Possible etiologies: increased FFAs in breast milk. breast milk may increase enterohepatic circulation of bili, or inhibit UGT activity.

Question 10

Phototherapy for neonatal hyper bilirubinemia

Answer 10

• induces formation of isomers of UCB
• the isomeric forms are more water soluble, and can be transported through the liver and excreted faster
• also decreases among of UCB that crosses BBB

Question 11

Dubin-Johnson syndrome

Answer 11

• Mutations of MRP2 (ABCC2)- recessive disorder involving loss of CB transport across the canalicular hepatocyte
• CB hyperbilirubinemia
• normal synthetic function of liver
• liver is dark color
• usually asymptomatic

Question 12

Rotor’s syndrome

Answer 12

• conjugated hyperbilirubinemia with alterations in urinary excretion of coproporphyrin isomers
• mutations in SLCO1B1 and SLCO1B3, genes that code for OATP transport proteins for uptake of bilirubin into hepatocytes
• Differens in coproporphyrin isomer excretion: In dubin johnson’s, 88.9% is excreted as coproporphyrin I, in Rotor’s, 42%.