Lecture 19: Hepatobiliary Function Flashcards
What are the main functions of the liver?
-bile, billirubin, metabolism of carbs/lipids/proteins, detoxification
What are the metabolic functions of the liver?
carbohydrate metabolism (make/release glucose storing clycogen) protein metabolism (AA and plasma protein synthesis and modification, ammonia conversion) lipid metabolism (FA oxidation, lipid synthesis)
If protein metabolism is impaired due to liver dysfunction, what happens?
Hypoalbuminemia > loss of oncotic pressure in capillary so fluid leaks out > edema/ascites
Describe the blood flow system serving the liver
2 capillary beds connected by hepatic portal system:
Abdominal/pelvic bed > hepatic portal vein (all GI blood passes through liver sinusoidal bed
Hepatic artery feeds liver with oxygenated blood
How can liver dysfunction cause bruising?
-lack of coagulation factors synthesized by liver
What is cirrhosis and how does it happen
-liver cells are damaged & replaced with fibrotic tissue
major cause is alcohol > fat accumulation in hepatocytes > fatty liver > steatohepatitis (fat + inflammation) > scarring
What is portal hypertension and what causes it?
-hepatocytes are dysfunctional and can’t drain the venous blood well > turbulence at HPV > blood is shunted to other veins causing them to distend
Clinical manifestations of Portal HTN
esophageal varices - swollen vessels at inferior esophagus
caput medusae - swollen vessels by umbilicus
What is hepatic encephalopathy and what causes it?
- alteration of brain function due to NH3+ buildup
- impaired urea cycle in liver > NH3+ accumulates and is able to cross the BBB
What is the importance of bile?
basically “opens” lipid cluster so enzymes can digest it
Be able to draw the synthesis of bile (also from Zaidi’s lecture)
Ok
Where are primary bile acids synthesized?
Where are secondary bile acids generated?
Where is bile conjugated?
liver
Small intestine
liver
What are the relative amounts of the four bile acids in the body?
cholic > chenodeoxycholic > deoxycholic > lithocholic
What happens to bile at these locations?
duodenum
jejunum
ileum
- bile emulsifies
- bile aggregates and forms micelles and recruit lipases to break down lipids
- bile and b12 reabsorbed/recycled
What is the mechanism of bile secretion and absorption?
- canalicular bile formed @ liver (isotonic to plasma)
- some of the final bile formed from secretions of HCO3, Na and H2O by secretin
- storage @ gallbladder and release in bile duct
- Sphincter of Oddi opens in response to CKK > bile released to duodenum
- bile salts and b12 reabsorbed in ileum
- return to canaliculi via portal circulation
How much bile does the liver produce?
As much as it lost/excreted
What happens at the biliary system during these periods of digestion?
Interdigestive
Eating
- ) Bile fills gallbladder (relaxed), sphincter of Oddi is closed contracted
- ) CCK stimulates = signals food, gallbladder contracts, Sphincter of Oddi opens and relaxes to release the bile
What are two transport mechanisms for recycled bile to return to the hepatocyte?
Na dependent: Na taurocholate cotransporting polypeptide
Na independent: organic anion transport proteins
-both located on the basolateral side of the hepatocyte
What transporters allow bile to enter the canaliculi from the hepatocyte?
BSEP and MRP2 (active transport)
*located on the canalicular membrane
What transporters allow bile to be reabsorbed at the ileum?
What transporters allow bile to travel from the enterocyte in the ileum back to portal circulation?
ASBT (with reabsorbed Na)
OSTa/B
What type of transport is utilized by bile at these regions?
Jejunum
Ileum
Colon
- passive
- active and passive, absorbs most bile
- passive
Is the bile that makes it to the ileum conjugated or unconjugated?
Conjugated, so needs to be actively reabsorbed at the ileum
-unconjugated bile passively diffuses proximal to the ileum
What happens to bile synthesis during ….
ileal resection
bile acid feeding
- ileum gone so most bile isn’t reabsorbed > increase in bile synthesis
- lots of bile secreted so lots of bile coming back from the ileum > decrease in bile synthesis
How is bile synthesis inhibited?
returning bile feedbacks and inhibits 7a hydroxylase > inhibits bile synthesis, not secretion
*secretion is triggered by food
Draw the pathway of bilirubin excretion including locations in the GI tract
Ok
Jaundice
How would you determine if jaundice is unconjugated or conjugated?
defect @ pathway up to liver > unconjugated jaundice
after liver > conjugated jaundice
Hemolytic anemia
Physiological neonatal jaundice
- RBC destruction > unconjugated bili buildup
- UDPGT activity not up to speed at birth > unconjugated bili from fetal Hgb breakdown builds up, treat with phototherapy to avoid brain damage
Crigler Najjar syndrome
Cause
Clinical
-UDPGT enzyme mutations, Type 1 (complete absence) more sever than Type 2 (decreased activity)
-Type 1: manifests in infancy, leads to kernicterus
Type 2: later onset, less likely to lead to kernicterus, less than 20% activity of UDPGT
Gilbert syndrome:
- UDPGT mutation > UGT1A1 activity 30% of normal
- usually asymptomatic
Kernicterus
Cause
clinical
- unconjugated bilirubin buildup in brain (yellow brain
- cerebral palsy, gaze abnormalities, sensorineural hearing loss
Treatment for Crigler-Najjar syndrome
phototherapy blood transfusion phenobarbitol (type 2 only) liver transplant (type 1) oral phosphate and carbonate
Dubin Johnson syndrome
cause
clinical
- MRP2 transporter mutation > can’t transport conjugated bilirubin into bile
- black liver (due to melanin buildup), mild jaundice
Rotor syndrome
cause
clinical
- OSTPB1/B3 mutations that transport bilirubin from ileum to portal circulation
- conjugated bilirubin buildup, non-pigmented liver
How does phototherapy work?
- converts trans bilirubin to soluble cis bilirubin
- used to treat infants with > 21 mg//dL bilirubin
Cholelithiasis:
-caused by cholesterol buildup in bile, too much absorption of bile acids from bile or epithelium inflammation
Cholecystitis
Choledocholithiasis
Cholangitis
- cystic duct obstruction by stone > gallbladder inflammation
- common bile duct occlusion > jaundice or conjugated hyperbilirubinemia
- bile duct infection
What do biochemical tests evaluate?
Examples?
test liver enzyme function
-ALT, AST: elevated in hepatocyte injury
Alkalinephosphatase: elevated in bile duct injury
If albumin is reduced, what does this mean about liver function?
If PT is elevated, what does this mean about liver function?
- albumin is made in the liver, so if it is reduced there is something wrong with hepatic function
- longer clotting time means liver isn’t producing enough clotting proteins, synthetic ability is impaired
