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
What is ascending cholangitis?
(presentation)
- as a result of reduced bile outflow from the biliary tree, enteric bacteria is able to ascend inside the biliary tract (which it normally is unable to do due to bile flow) and cause infection
- can progress to casue spesis -> suppurative cholangitis
Charcot’s triad (ascending cholangitis):
-jaundice
- RUQ pain
- fever
Reynold’s pentad (acute suppurative cholangitis):
- Charcot’s tirad plus signs of sepsis
- hypotension
- confusion
How does sepsis cause cholestasis?
- intrahepatic infection -> impaired function
- ischemia
- response to circulating microbial products
What is primary hepatolithiasis?
(populations and complications)
intrahepatic gallstone formation that is most common is common in east Asia
-pigmented gallstones
Complications:
- recurrent ascending cholangitis
- inflammation
- biliary neoplasia
What is the most common cause of cholestasis in neonates?
-biliary atresia
What is biliary atresia?
What is special about it?
-obstruction of the extrahepatic biliary lumen that occurs within first 3 months of life
-fatal without surgical correction
- causes 1/3 of cholestasis in infants
- most common cause of death in early childhood due to liver disease
- majority of liver transplantations in childhood
What surgical procedure (aside from transplantation) is used to correct biliary atresia?
only possible if obstruction does not occur proximally to the porta hepatis
Kasai procedure:
- small intestine is severed distal to duodenum
- distal portion is attached to liver at porta hepatis allowing bile to drain into the SI
- proximal portion of SI is attached to side of distal portion, allowing food to enter into the SI
What should raise suspicion of biliary atresia in a neonate/infant?
Why?
jaundice beyond the first two weeks of life
anything before two weeks has a decent probability of being physiologic neonatal jaundice due to its high prevalence; it typically resolved after 2 weeks which is why other causes should be evaluated at that time
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Liver Tests12
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General Features of Liver Disease30
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Infectious Liver Disease22
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Drug, Alcohol, and Metabolic Liver Disease42
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Cholestasis22
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Autoimmune Hepatitis/Cholangiopathies7
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Structural and Circulatory Disorders20
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Hepatic Complications in Pregnancy10
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Liver Nodules and Tumors28
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Gallbladder23
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Pancreas34
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Viral Hepatitis Pharm40
