Jaundice

Question 1

Liver Overview

Answer 1

• Receives all substances from the gut
• Source of proteins: albumin, complement, clotting factors.
• Storage organ for vitamins (A, D, E and K) and B12; and for minerals (Fe, Cu).
• Bile formation: ~1/2 liter daily. Bile acids are detergents: elimination of toxins (bilirubin).
• Drug and toxin metabolism and excretion: Cytochrome P-450 system

Question 2

Vascular anatomy

Answer 2

2 blood supplies
Blood leaves the liver via hepatic veins.
Blood enters liver via portal vein (80%), and hepatic arteries (20%).

Question 3

Portal triad

Answer 3

• Hepatic artery, portal vein and bile duct.
• Cholangiocytes line the bile duct.

Question 4

Zonal architecture

Answer 4

Zone 1, Zone 2, Zone 3. Blood goes from hepatic artery/portal vein toward the central vein.
Portal side: Zone 1.
Middle: Zone 2
Central vein: Zone 3

Question 5

Zone 1 Hepatocyte Function

Answer 5

• Fatty acid B oxidation
• Cholesterol Synthesis
• Gluconeogenesis
• these have the most O2

Question 6

Zone 2 Hepatocyte Function

Question 7

Zone 3 Hepatocyte Function

Answer 7

• Drug metabolism (overdose of Tylenol=zone 3 necrosis).
• Ketogenesis
• Bile acid synthesis
  -Glycolysis

Question 8

Phases of Metabolism/Detoxification

Answer 8

• Phase 0: Import from blood into the hepatocyte.
• Phase 1: Hydrolyzation in Smooth ER via Cytochrome P450s. CYP2D6. CUP3A4.
• Phase 2: Conjugation (made more water soluble) in SER or Cytosol: Sulfation, Glucuronidation, Glutathione. UGT1A1.
• Phase 3: Biliary export into bile.
• Phase 4: Sinusoidal Export back into portal blood.

Question 9

Bilirubin metabolism

Answer 9

• RBC-> Hgb molecule ->heme.
• unconjugated bilirubin (not water soluble) meets UGT1A1 –> conjugated bilirubin (water soluble).

Question 10

Bilirubin and bile acids are brought into the hepatocyte and then secreted into the bile duct via separate mechanisms

Answer 10

• Bile acids in blood are brought into hepatocyte via NTCP, then excreted into the canalicular space via BSEP (ABCB11).
• Unconjugated bilirubin in blood is bound to albumin, absorbed into hepatocyte via OATPs (SLCO1B1/3). Under goes conjugation via UGT1A1, then is secreted into canalicular space via MRP2 (ABCC2)

Question 11

Genetic causes of cholestasis

Answer 11

• PFIC2: BSEP (ABCB11).
• Dubin-Johnson: MRP2 (ABCC2).
• Gilbert’s disease/Rotor/Crigler Najjar I and II: UGT1A1.
• Prolonged indirect hyperbilirubinemia/Rotor: OATPs (SLC O1b1/3)

Question 12

Gilbert Syndrome

Answer 12

• Very Common: 5-10% of population
• High likelihood of +FHx
• Mild, episodic unconjugated hyperbilirubinemia (1.0-5.0).
• Found incidentally
• Presentation during adolescence
• Stress -> Gilbert’s presentation (fasting, illness, decreased sleep).
• Questionable clinical importance.
• Gene: UGT1A1 promoter mutation.

Question 13

elevated D bili

Answer 13

D bili >1.0.