Cholestasis Flashcards
What is cholestasis?
decreased bile flow due to:
- impaired secretion by hepatocytes
- or-
- obstruction of intra/extrahepatic bile ducts
What histologic features are characteristic of cholestasis?
- accumulation of bile pigment in liver parenchyma
- dilation of bile canaliculi (intrahepatic) w/ bile plugs
- Kupffer cells containing phagocytosed bile pigments
-hepatocytes with intracellular bile pigments -> “feathery degeneration“/apoptosis
How is bile made?
7α-hydroxylase in hepatocytes:
cholesterol -> 7α-hydroxycholesterol -> -> -> bile salts
What is the function of bile?
emulsification of dietary fat allowing for absorption
excretion of non-water (or insufficiently) soluble substances:
- bilirubin
- excess cholesterol
- trace metals
How is bilirubin made and excreted?
Hemolysis/recycling of RBCs releases heme
Macrophages:
- degrade heme (heme oxygnease) -> biliverdin
- biliverdin (biliverdin reductase) -> unconjugated bilirubin (released into blood)
Blood:
-unconjugated bilirubin binds albumin (unconjugated bilirubin is not water soluble hence albmin carrier)
Liver:
-glucuronidation of unconjugated bilirubin (UGT1A1) -> conjugated bilirubin (conjugated bilirubin is water soluble)
Excretion into bile:
- metabolized by gut bacteria to urobilinogen either…
- oxidized by bacteria to stercobilin and excreted (gives stool brown color)
- or-
- reabsorbed in gut to be reexcreted by liver
- or-
- excreted by kidneys where it is oxidized to urobilin (gives urine yellow color)
What symptoms are associated with elevated bilirubin?
- jaundice
- icterus
- deposition in skin -> pruritis
- xanthomas (acumulation of cholesterol)
- inability to digest dietary fat -> intestinal malabsorption -> failure to absorb fat soluble vitamins (A, D, E, and K)
What are the main inherited hyperbilirubinemias?
Unconjugated hyperbilirubinemia:
- Crigler Najjar syndrome
- Gilbert syndrome
Conjugated hyperbilirubinemia:
- Dubin-Johnson syndrome
- Rotor syndrome
What is Crigler-Najjar syndrome?
Mutation in UGT1A1 gene responsible for conjugation of bilirubin -> unconjugated hyperbilirubinemia
Type 1:
absence of UGT1A1 activity -> fatal in neonatal period
Type 2:
-decreased activity of UGT1A1 -> mildly symptomatic; occasional kernicterus
What is Gilbert syndrome?
Mutation in UGT1A1 gene responsible for conjugation of bilirubin -> unconjugated hyperbilirubinemia
-decreased activity of UGT1A1 -> asymptomatic/innocuous; jaundice during physiologic stress
What is Dubin-Johnson syndrome?
Mutation in multidrug resistance protein 2 (MRP2) gene responsible for excretion of conjugated bilirubin (and other substances) into bile duct -> conjugated hyperbilirubinemia
-impaired bilirubin excretion -> asymptomatic/innocuous
**liver has gross black pigmentation due to imparied excretion of pigmented epinephrine metabolites
What is Rotor syndrome?
defective bilirubin transport protein -> conjugated hyperbilirubinemia
asymptomatic/innocuous
What is phsyiologic neonatal jaundice?
jaundice occuring in newborns due to transiently low UGT1A1 activity -> unconjugated hyperbilirubinemia
-usually resolves spontaneously in 1-2 weeks as UGT1A1 activity increases
How is phsyiologic neonatal jaundice treated?
phototherapy; converts non-water soluble unconjugated bilirubin into its more soluble isomer, allowing for excretion
What are the most common causes of cholestasis in adults?
- cholelithiasis
- tumors
- strictures related to previous surgeries
- sepsis
- primary hepatolithiasis
*most causes in adults are obstructive
What complications occur with obstructive cholestasis?
cholestatic changes are reversible originally, but can become presistent and lead to fibrosis if not resolved -> secondary biliary cirrhosis
-obstruction increases risk of ascending cholangitis
