Hepatic Secretions

Question 1

Anatomy of liver

Answer 1

. 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

Question 2

Major components of bile

Answer 2

. Smile salts 
. Phospholipids 
. Cholesterol 
. Bile pigments (bilirubin) 
. Inorganic ions
. Detoxified chemicals 
. Water

Question 3

Bile salts

Answer 3

. Amphipathic
. Hydrophobic regions interact w/ other hydrophobic molecules and hydrophilic region interacts w/ water causing micelle formation

Question 4

Micelle function

Answer 4

. Important in fat digestion and absorption in SI lumen and in conc. Of bile in gallbladder lumen

Question 5

Major bile salts synthesized in hepatocytes

Answer 5

. Cholyglycine and cholytaurine (from cholic acid)
. Chenodeoxycholglycine/taurine (from chenodeoxycholic acid)
. Hepatocytes synthesize primary bile salts using cholesterol 7alpha-hydroxylase and oxysterol 7alpha-hydroxylase

Question 6

Major bile salts synthesized in lumen of colon

Answer 6

. Deoxycholic acid

. Lithocholic acid

Question 7

Secondary bile salts

Answer 7

. 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

Question 8

Bile secretion

Answer 8

. 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

Question 9

Enterohepatic circulation

Answer 9

. 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

Question 10

Bile reabsorption

Answer 10

. 90% reabsorbed by active transport in terminal ileum
. Secondary bile salts reabsorbed by diffusion from colon (5%)
. 5% is excreted in feces

Question 11

Amount of new bile salts synthesizes is ______ related to the amount of bile salts returned to liver by enterohepatic circulation

Answer 11

. Inversely
. Fasting: synthesis high
. Eating: synthesis low

Question 12

Does bile acid synthesis increase if total cholesterol is too high?

Answer 12

No it is too regulated

. HMG-CoA reductase dec. de novo cholesterol synthesis when plasma cholesterol is high

Question 13

Passive transport of bile salts

Answer 13

. 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

Question 14

Carrier-mediated transport of bile sals in ileum

Answer 14

. 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

Question 15

Carrier mediated transport of bile salts in liver

Answer 15

. 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)

Question 16

Defects in bile salt formation

Answer 16

. 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

Question 17

Categories of enterohepatic circulation disorders

Answer 17

. 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

Question 18

Types Disturbances in movement through or btw organs for bile salts

Answer 18

. Bile duct obstruction
. Ileal resection
. Bile salt malabsorption from crohn’s or celiac

Question 19

Source of bilirubin

Answer 19

. When RBCs die it is released into plasma and binds to albumin
. Mostly bound to albumin (unconjugated/free bilirubin)

Question 20

Hepatic metabolism of bilirubin

Answer 20

. 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

Question 21

Intestinal phase of bilirubin metabolism

Answer 21

. 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

Question 22

Jaundice

Answer 22

. Accumulation of bilirubin in blood causes yellow pigmentation of plasma
. Imbalance btw production and elimination of bilirubin

Question 23

What is likely the issue is indirect bilirubin is high (unconjugated hyperbilirubinemia)

Answer 23

. Inc. bilirubin production by excessive breakdown of RBCs (hemolysis)
. Impaired conjugation (neonatal jaundice, Gilbert’s syndrome)
. Impaired hepatic uptake of bilirubin (prolonged fasting, sepsis)

Question 24

What is likely the issue if direct bilirubin is high?

Answer 24

. Defect in transport of conjugated bilirubin into canaliculi (hepatocellular disease, alcohol liver disease)
. Defect in biliary excretion into duct (intra or extraheptic obstruction)

Question 25

Does renal excretion go bilirubin occur in a normal person?

Answer 25

No

Question 26

If a person is jaundice but does not have bilirubin in urine what does this mean?

Answer 26

. Supports unconjugated hyperbilirubinemia (it is bound to protein when unconjugated and cannot be filtered by kidney)

Question 27

If a person is jaundice and there is bilirubin in their urine what does this mean?

Answer 27

. Supports conjugated hyperbilirubinemia

. Urine will have color of black tea

Question 28

What does it mean if a person is jaundice and have urinary urobilinogen above the normal range?

Answer 28

. Hepatic uptake and canaliculi Ramirez secretion omg urobilinogen is impaired (hepatocellular disease)
. Production of bilirubin is greatly inc.

Question 29

If a person is jaundice and plasma and urinary urobilinogen are dec. or not detected it means ____

Answer 29

. Extrahepatic biliary obstruction (compression of biliary duct by tumor)
. Intrahepatic biliary obstruction (gall stones)

Question 30

T/F patient w/ liver disease usually has defects in all steps of bilirubin metabolism

Answer 30

T
. Usually the excretion by hepatocytes is the most impaired since it is the rate limiting step and conjugated bilirubin predominates in serum

Question 31

Components of hepatic water and electrolyte secretion

Answer 31

. Bile salt-dependent secretion produced in bile canaliculi, major substance actively secreted into canaliculi setting up osmotic gradient for water flux into the canaliculi accompanied by solvent drag of electrolytes
. Bile salt-independent secretion produced by bicarbonate secretion by bile duct epithelial cells, inc. by secretin

Question 32

Bile will flow into either duodenal lumen or gallbladder depending on ____

Answer 32

. Resistance to filling of the gallbladder smooth m.

. Resistance fo entering duodenal lumen provided by sphincter of Oddi (hepatopancreatic sphincter)

Question 33

Sphincter of oddi and gallbladder smooth m. Tone during fasting

Answer 33

. Sphincter Mostly closed
. Tone of gallbladder smooth m. Low
. Bile flows into gallbladder where it is stored and concentrated (5-20x conc.)

Question 34

Process of bile concentration

Answer 34

. Na absorption by gallbladder epithelial cells via Na/K ATPase creates electrochemical gradient
. Cl or HCO3 accompanies Na to maintain electroneutrality
. Bile salts, phospholipids and cholesterol form micelles to dec. osmotic driving force for H2O retention in lumen
. Passive H2O flux dertermined by Na absorption (in) and micelle formation (out)
. Total solute conc. Of bile salts inc. to twice what it is in plasma
. Final secretion is isotonic

Question 35

Most bile secretion from gallbladder into duodenal lumen occurs during ______

Answer 35

Digestion of meals

Question 36

Vagus nerve effect on bile

Answer 36

. Stimulation inc. bile flow
. Contraction of gallbladder smooth m.
. Relaxation of sphincter of Oddi

Question 37

CCK effect on bile

Answer 37

. When CCK secretion inc., CCK-1 receptors on vagal afferent nn. Are activated
. Causes vagal efferent n. Induced contraction of gallbladder and relaxation of sphincter of Oddi
. Bile flows into the duodenal lumen
. Opposite when CCK secretion dec.

Question 38

Gallstones

Answer 38

. Types: cholesterol, mixed, and pigment
. Diagnosed via ultrasound
. Causes: bile supersaturation w/ cholesterol, nucleation of cholesterol (mucin causes cholesterol to glom together), abnormal gallbladder motor function (delayed emptying and stasis)