Hepatic Secretions Flashcards
Anatomy of liver
. Hepatocytes bordered by sinusoids and space of Disse (lymph) and bile canniculi on other side
. Tight junctions btw individual hepatocytes separate sinusoidal and lymphoid contents from canaliculi content
. Substances secreted into bile canaliculi or sinusoid and composition of each compartment kept separate
Major components of bile
. Smile salts . Phospholipids . Cholesterol . Bile pigments (bilirubin) . Inorganic ions . Detoxified chemicals . Water
Bile salts
. Amphipathic
. Hydrophobic regions interact w/ other hydrophobic molecules and hydrophilic region interacts w/ water causing micelle formation
Micelle function
. Important in fat digestion and absorption in SI lumen and in conc. Of bile in gallbladder lumen
Major bile salts synthesized in hepatocytes
. Cholyglycine and cholytaurine (from cholic acid)
. Chenodeoxycholglycine/taurine (from chenodeoxycholic acid)
. Hepatocytes synthesize primary bile salts using cholesterol 7alpha-hydroxylase and oxysterol 7alpha-hydroxylase
Major bile salts synthesized in lumen of colon
. Deoxycholic acid
. Lithocholic acid
Secondary bile salts
. Formed y action of bacterial enzymes in lumen of colon that deconjugate primary bile salts
. More lipid-soluble
. Bacterial enzymes can also deconjugate primary and secondary bile salts making them more lipophilic
Bile secretion
. Liver secretes bile continuously
. Rate of secretion based on amt of bile salts returned to liver by circulation
. Conc. Bile salts in portal blood depends on amt of bile salts absorbed from intestines
. Conc. In intestinal lumens depends on digestive state of person
. Eating: most salts in lumen, fasting: most slats in gallbladder
. Btw meals most bile is stored in gallbladder w/ only small amt secreted into duodenal lumen during phase 3 of MMC
. During meal, gallbladder continuously secretes bile into duodenal lumen and total amt of bile salts in body is secreted 2-3 times
Enterohepatic circulation
. Circulation of bile salts from the liver, to the gallbladder, to the duodenum, to the ileum or colon, into the portal vein and back to the liver
Bile reabsorption
. 90% reabsorbed by active transport in terminal ileum
. Secondary bile salts reabsorbed by diffusion from colon (5%)
. 5% is excreted in feces
Amount of new bile salts synthesizes is ______ related to the amount of bile salts returned to liver by enterohepatic circulation
. Inversely
. Fasting: synthesis high
. Eating: synthesis low
Does bile acid synthesis increase if total cholesterol is too high?
No it is too regulated
. HMG-CoA reductase dec. de novo cholesterol synthesis when plasma cholesterol is high
Passive transport of bile salts
. Simple diffusion of secondary bile salts in colon through enterocytes into mucosal capillaries
. Prox small intestine: passive absorption of lipid-soluble bile salts through SI enterocytes into mucosal capillaries
Carrier-mediated transport of bile sals in ileum
. Active absorption of H2O=soluble bile salts into ileal enterocytes
. Apical Na-dependent bile salt transporter (ASBT) mediates uptake into enterocytes
. Major mechanism of bile salt absorption
Carrier mediated transport of bile salts in liver
. Bile salts are removed from portal blood into hepatocyte by Na-dependent transport proteins (NTCP) or by Na-independence organic anion transport (OAT) proteins
. Monovalent bile salts are secreted into the canaliculi by hepatocytes using ATP-dependent bile salt export pump (BSEP)
. Sulfates or glucuronidated bile salts are secreted into canaliculi by hepatocytes using multidrug resistance-assoc. protein 2 (MRP2)
Defects in bile salt formation
. Depletion of bile salt pool via excretion
. Loss of bile-salt dependent hepatic bile flow
. Reduced intestinal absorption of cholesterol
. Accumulation of cytotoxic intermediates of bile salt synthesis
Categories of enterohepatic circulation disorders
. Defects in bile salt formation: synthesis and conjugation
. Defects in membrane transport of bile salts: uptake and secretion
. Disturbances involving bacteria: deconjugation (too much bacteria depletes salts)
. Disturbances in movement through or between organs: bile salt circulation
Types Disturbances in movement through or btw organs for bile salts
. Bile duct obstruction
. Ileal resection
. Bile salt malabsorption from crohn’s or celiac
Source of bilirubin
. When RBCs die it is released into plasma and binds to albumin
. Mostly bound to albumin (unconjugated/free bilirubin)
Hepatic metabolism of bilirubin
. Uptake via transporter using ATP
. Bilirubin conjugated w/ 2 glucuronic acid molecules using enzyme UGT1A1
. Excretion: rate-limiting step, bilirubin glucuronides (direct bilirubin) are secreted into bile via active transport
Intestinal phase of bilirubin metabolism
. In colon direct bilirubin is converted to urobilinogen by bacteria
. Some urobilinogen is absorbed and is excreted in urine or secreted in bile
. Urobilin (oxidized form) gives urine yellow color
. Majority of urobilinogen is converted to stercobilin that makes poo brown
Jaundice
. Accumulation of bilirubin in blood causes yellow pigmentation of plasma
. Imbalance btw production and elimination of bilirubin
What is likely the issue is indirect bilirubin is high (unconjugated hyperbilirubinemia)
. Inc. bilirubin production by excessive breakdown of RBCs (hemolysis)
. Impaired conjugation (neonatal jaundice, Gilbert’s syndrome)
. Impaired hepatic uptake of bilirubin (prolonged fasting, sepsis)
What is likely the issue if direct bilirubin is high?
. Defect in transport of conjugated bilirubin into canaliculi (hepatocellular disease, alcohol liver disease)
. Defect in biliary excretion into duct (intra or extraheptic obstruction)
