Bile and Bile Salts Flashcards
80% of bilirubin comes from ____
red cells –> heme –> iron, CO, biliverdin –> bilirubin
Unconjugated bilirubin is polar/nonpolar
polar –> but insoluble b/c polar groups are hidden in tertiary structure
How is insoluble unconjugated bilirubin transported?
by hydrogen bonding to albumin –>separates at the hepatocyte membrane in the space of disse
Where in the cell does bilirubin become conjugated?
in endoplasmic reticulum –> e.g. if pt has elevated unconjugated bilirubin, we know the defect is at the conjugation step or after
What is the rate limiting step in bilirubin production?
ATP mediated pumping into canaliculus against a large concentration gradient
Most bilirubin is secreted as a ______
diglucoronide, few as monoglucoronide, <1% unconjugated
Is conjugated bilirubin water soluble?
yes –> glucuronidation opens up the molecule and exposes hydrophilic moieties
Where in the body is conjugated bilirubin normally found?
bile but not blood
Where in the body is unconjugated bilirubin normally found?
bile and blood
Mechanisms body employs to protect against neurotoxicity of unconjugated bilirubin
binding to albumin, blood brain barrier, conjugation, excretion
T/F all the body’s protective mechanisms against unconjugated bilirubin may be somewhat defective in the newborn.
T
What is delta bilirubin and when does it show up?
conjugated bilirubin COVALENTLY bonded to albumin (vs. H bonds in unconjugated bilirubin) –> serum of pts with long-standing hyperbilirubinemia
Why does it take a while for bilirubin levels to normalize after treatment?
delta bilirubin bound to albumin is too big to pass into urine and takes a while to get cleared
Bacteria convert bilirubin to colorless water soluble _____
urobilinogen –> some is absorbed, some reaches urine via serum
What are pyrroles?
bacteria act on urobilinogen to produce pyrroles to give stool its color
Unconjugated hyperbilirubinemia results in direct/indirect jaundice and conjugated hyperbilirubinemia results in direct/indirect jaundice.
indirect and direct
How does unconjugated hyperbilirubinemia lead to jaundice?
H bonds to albumin make molecules too large to pass into urine
How does conjugated hyperbilirubinemia lead to jaundice?
conjugated bilirubin is actually mixed –> conjugated part is water soluble and passes into urine, unconjugated part and delta part get stuck in circulation
What are the urine color differences in (un)conjugated bilirubin?
tea/red color = conjugated == + on dipstick
3 causes of unconjugated hyperbilirubinemia
overproduction, reduced uptake, defects in conjugation
2 etiologies of reduced hepatic uptake resulting in unconjugated jaundice
- altered circulation (portal shunting, right heart failure)
- effect of drugs (rifamycin)
Name a few etiologies of overproduction of bilirubin leading to unconjugated jaundice
hemolysis, extravasation/bruising, ineffective erythropoeisis/pernicious anemia
Lab findings in overproduction of bilirubin leading to unconjugated jaundice
normal liver histology/tests, serum bilirubin < 3X b/c of effective liver clearance AKA really high bilirubin is probably not due to overproduction
Name a few etiologies of conjugation defects leading to unconjugated jaundice
inherited: crigler najjar I and II (rare) and gilberts (benign, common)
acquired: testosterone, novobiocin, wilson’s/chronic heptatitis, hyperthyroidism, jaundice of newborn
What kind of crigler najjar is more dangerous?
type I
What is kernicterus?
bilirubin mediated injury to CNS –> phototherapy to prevent in jaundice of newborn
MOA of phototherapy
exposure of unconjugated bliirubin to UV breaks H bonds and makes it water soluble
Gilbert’s syndrome
benign, common, defect in promoter gene for G-transferase, slightly elevated serum unconjugated bilirubin
How does bilirubin change during fasting?
increases slightly –> increases greatly in Gilbert’s/fasting can cause jaundice
Gilbert’s: Is there bilirubin in the urine?
no –> remember, it’s mostly unconjugated
Gilbert’s: liver chemistries
normal
How do we normally get conjugated bilirubin in the blood?
injury to cell or biliary obstruction leads to reflux (even during severe liver disease, conjugation continues) –> most of the serum bilirubin is conjugated and only some of it is unconjugated
What two rare syndromes are inherited secretory defects leading to conjugated hyperbilirubinemia?
Dubin-Johnson (black pigment in liver) and Rotor (no black pigment) –> both have normal liver enzymes and normal excretion of bile salts
PBC is intra/extrahepatic
intrahepatic –> no dilated ducts
PSC is intra/extrahepatic
intra but also extrahepatic –> dilated biliary duct obstruction
Cholestasis: liver chemistries
alkphos >3X (could also be bone disease), GGT increase, increase in conjugated bilirubin
Symptoms of cholestasis
pruritis (opiates, bile salt resin irritation), jaundice, fatigue, anorexia, xanthelasma (cholesterol deposit near eye)
Tx of pruritis
cholestyramine
Malabsorptions in cholestasis
Vit A: night blindness
Vit D: osteomalacia/osteopenia
Vit K: prothrombin impairment
Vit E: cerebellar and peripheral nerves
Tx of PBC
ursodeoxycholic acid –> protects against hydrophobic bile salts –> can be used in many kinds of cholestasis
Liver chemistries: acute biliary obstruction
early elevation in transaminases, after passage of stone, delayed increase in bilirubin, alkphos
Gallstones- 3 predisposing factors
cholesterol or bilirubin precipitation –> supersaturation, stasis, nucleation factors
Detection of gallstones
ultrasound
What is the difference between (un)pigmented stones?
unpigmented = cholesterol pigmented = unconjugated bilirubin (black form in gallbladder, brown form in bile ducts)
Risk factors for cholesterol gallstones
females, >30, multiparity, obesity, lack of exercise, rapid weight loss, genetic (native americans), estrogens, TPN, western diet
What kind of gallstones show on xray?
cholesterol in gallbladder
What kind of gallstones show on xray?
all
