Physiology - GI - L4 - Bile

the synthesis and secretion of bile

• electrolytes
• bile salts (50%)
• phospholipids (30-40%)
• cholesterol (4%)
• bile pigments (2%)

• the gall bladder
• standing osmotic gradient
• recycling through the enterohepatic circulation

efficiently absorbs bile salts in the terminal ileum and returns them to the liver where they are absorbed by specialized transporters on the basolateral membrane

• the cytosol of the hepatocyte
• reprocessing

the feces

cholesterol -> primary bile acid -> conjugated acid/salt -> secondary bile acid -> conjugated acid/salt

• Primary: cholic acid, chenodeoxycholic acid
• Secondary: deoxycholic acid, lithocholic acid

• low return -> high synthesis, low secretion
• high return -> low synthesis, high return

• steroid nucleus is hydrophobic
• the other end hydroxyl/carboxyl - hydrophilic

for micelle, emulsify lipid

the lowest concentration at which the bile salt/acid can be secreted and form micelle

• CKK: induced by fatty acids and AA in I cells, small intestine -> basolateral CCK-A receptor -> strong contraction, relax Sphincter of Oddi
• gastrin: much weaker

• ACh: weak contraction
• VIP: released secondary to CCK; inhibits gall bladder contraction and fluid and electrolyte transport; relax Sphincter of Oddi

Sympathetic: inhibit contraction, relax gall bladder and sphincter

• Na/K ATPase moves Na out to the lateral space
• Cl flows out
• H2O flows out osmotically
• lateral space dilates and hydrostatic pressure increases
• Push the isotonic fluid out to capillary

• Liver vs. gallbladder
• Osmolarity: =; isotonic
• pH: weak base vs weak acid
• [Na]: ~plasma level vs >plasma level
• [Ca]: <
• bile salts: <

• bile acid conjugated in liver
• secreted in bile acids/salts form
• bile acids absorbed all along small intestine passively
• bile salts absorbed actively by ASBT at terminal ileum
• primary bile salts deconjugated and deoxylated by bacteria to form secondary bile acid, absorbed passively or moved down to colon

phospholipid, esp lecithin, mix with bile salts to form micelle, increase the solubility of lipid

cholesterol mix in micelle

Jaundice: bilirubin excessive, enters blood, cause discoloration. Obstructive: no way to go; hemolytic: too much; hepatitis and cirrhosis: most common; physiologic: immature glucoronidation pathway; congenital enzyme absence for bilirubin conjugation

• Gall stone: 80% cholesterol stone when lecithin:cholesterol is unbalanced, bile supersaturated w/ cholesterol -> crystal
• Pigment stone: unconjugated billirubin precipitates with Ca++, often accompanied by bacterial infection.

choleretic: sustained secretion of bile induced by high return rate

cholecystectomy: removing gall bladder for treating gall stone

cholelithiasis: gallstone

cholestasis: no bile or bile flow into digestive tract is obstructed.

• - 50% bile salts/acids - digestive function – emulsify fats
• - bile pigments – bilirubin and biliverdin
• - synthesized from cholesterol
• - lipids- cholesterol, phospholipids, lecithins, fatty acids, triglycerides

• - water
• - ions of plasma
• - high HCO3- - alkaline, supplement pancreatic juice in neutralizing gastric juice

Cholesterol -> primary bile acids [in liver; 7-a hydrolase - rate limiting step]

• primary bile acids: mainly cholic acid and chenodeoxycholic acid
• from liver
• steroid nucleus with attached carboxyl and hydroxyl groups
• nonionized and poorly water soluble at duodenom pH
• amphipathic molecule - enables micelle formation; critical micellar concentration

• Secondary bile acids: produced by bacteria in testine from primary bile acids
• deoxycholic and lithocholic acids

• all bile acids link with glycine or taurine to form conjugated acid
• have negative charges at duodenom pH
• more soluble
• can bind with bile acid-binding proteins at low concentration inside liver, to prevent toxicity if backflow into blood or forming micelle.
• the negatively charged end attracts cations and form salts - bile salts, the main component of bile.

• Bile-acid dependent fraction
• - bile salt bound to protein
• - diffuse to apical (canalicular) membrane
• - 4 types ATP-dependent bile salt export pumps
• - produce large osmotic gradient
• - water follows ions and bile (bile salts establish the gradient, water follows osmostically; hence bile-acid dependent fraction)

merging of canaliculi

Bile-acid independent

• - ions transported, water follows
• - membrane exchangers and channels similar to pancreas
• - HCO3–/Cl– exchanger: HCO3– secreted
• - multiple types of apical Cl channels (eg. CFTR): recycling Cl
• - secretin & VIP: basolateral receptors; stimulate insertion apical aquaporins for water outflow
• - overall: increases volume, alkalinity and Cl–

- total bile flow = flow from hepatocytes plus addition from duct

• - Liver continually secretes bile
• - total bile pool: about 2-4 grams
• - single meal requires: 12-36 gram
• - Recycling required for digestion
• - Enterohepatic Circulation: liver -> gallbladder -> intestine -> ileum resporption -> portal vein -> liver
• - recycles pool 2-5 times per meal
• - recycling saves the energy to synthesize more

Bile released immediately and directly to duodenum

- Sphincter of Oddi - relaxes

- released at critical micellar concentration

- fat digestion begins - allows nutrient absorption throughout small intestine

• - Bile resorption - across intestinal epithelium
• - passive absorption – all along small intestine
• - active transport - specialized transporters; terminal ileum
• - returned to liver – portal blood
• - reabsorbed by liver and resecreted

• sphincter of Oddi constricted
• gall bladder relaxed
• Bile diverted to gallbladder
• Concentrated and Stored in gallbladder - gallbladder bile

• - high epithelium - enough lateral space; important
• - basolateral Na/K pump: high density; essential for producing osmotic gradient; blocked pumps (atropine) stops bile concentration
• - Cl: follows Na; through basolateral Cl channels
• - water: hypertonic solution in lateral space; water osmosis; increased hydrostatic pressure, dilation of lateral spaces
• - fluid in lateral space becomes isotonic eventually, then enters capillaries, pushed by the hydrostatic pressure

- hepatic bile - slightly alkaline (pH 7.5)

• - gallbladder bile pH 6 - 6.5
• - apical Na/H exchanger
• - acidity increases Ca solubility -> discourages gall stone formation

• - always isotonic
• - [Na+] and bile acid anions increase to 300 mM; overall osmolarity is 300mM, don't dissociate
• - [Cl] and [HCO3] decrease to 0
• - hepatic: Na>Cl>HCO3>Bile acids
• - gallbladder: Na=Bile acids >> Cl = HCO3 = 0
• - organic components all more concentrated

• - CCK
• - released from I-cells by fatty acids and amino acids
• - most important regulator
• - basolateral CCK-A receptor
• - causes the strongest contraction of gallbladder smooth muscle
• - relaxes sphincter of Oddi (smooth muscle)
• - indirectly activates vago-vagal pathway

• - gastrin
• - much weaker even though structurally similar

– lesser importance

• ACh
• - weak contraction

• VIP
• - released secondary to stimulation by CCK
• - inhibits gall bladder contractions and fluid and electrolyte transport
• - relaxes sphincter of Oddi

• Sympathetics
• – inhibit contraction, relax gall bladder and sphincter

• Epithelial Absorption
• - Pathway #1 - Passive (diffusion) Absorption - all along intestine - minor pathway
• - Pathway #2 - Active Carrier Mediated Absorption - most important
• - Pathway #3 - Deconjugation -> unconjugated primary bile acid is passively absorbed in ileum
• - Pathway #4 - cholic acid -> deoxycholic acid (by bacteria) -> passively absorbed
• - Final Pathway - Plasma Transport to liver

• - primary route for liphophilic and secondary bile acids
• - bacteria form new bile acids - ileum and colon (Pathway #3)
• - cholic acid -> deoxycholic acid - passively absorbed (Pathway #4)
• - chenodeoxycholic acid -> lithocholic acid – lost in feces
• - deconjugation and dehydroxylation - increase lipid solubility; higher micellar concentration - less incorporation into micelle

• - most important
• - bile salts, acids ionized - cannot diffuse across membrane

• - Apical Sodium-Dependent Bile Salt Transporter (ASBT) at terminal ileum
• - secondary active cotransporter
• - prefers negatively charged, conjugated polar acids

- ileal resection – decreases lipid absorption; steatorrhea

• - Plasma Transport to liver
• - protein bound (albumen)
• - portal transport - high density lipoprotein
• - returned to liver

• Absorption
• - specialized transepithelial (the layer is only one cell thick) transporters for all types bile acids and salts
•   - Na-dependent
•   - Na-independent
•   - passive absorption – unconjugated acids

Liver Reprocessing: conjugation, hydroxylation, recycling, before resecretion.

• - secretes 20-30 gm (600 -1200 mls)
• - recycles 6-10 times
• - 5-20% excreted (lost from body)

concentration and rate of bile return to liver

• low return rate:
• - between meals or terminal ileum removal
• - synthesis stimulated and secretion inhibited
• - controlling enzyme
• - replace lost bile fractions
• - Terminal Ileum - removal increases synthesis

• high return:
• - recycling through enterohepatic circulation during meals
• - choleretic effect = high return stimulates secretion; inhibits synthesis; sustained till hours after eating
• - inhibits 7α hydrolase - negative feedback
• - replaces lost bile fractions

• - Phospholipids – (40%) - second largest component
•   - Lecithins (phosphatidyl choline) - aid solubilization lipids (cholesterol) in the micelle when lecithins are incorporated into the micelle w/ bile salts; more soluble than bile salts alone

• - Cholesterol
•   - 4% of total
•   - Secreted by active transport, incorporated into micelle
•   - bile primary excretory route for regulating of body stores (in feces)

• - Bile Pigments
•   - 2% of solids
•   - water insoluble waste products
•   - from old red blood cells degraded by reticuloendothelial system
•   - toxic to central nervous system
•   - bile is the major pathway for excretion

• - from old red blood cells degraded by reticuloendothelial system
• - toxic to central nervous system - bile major pathway for excretion
• - Bilirubin
•   - primary bile pigment - albumen bound
•       - toxic to CNS
• - conjugated with glucuronic acid in liver - increases solubility; not incorporated into micelle, not readily absorbed
• - deconjuated by bacteria in colon and eliminated
•   - urobilinogens - give excretory products color
•       - stercobilin - give its color to feces
•       - urobilin - urine

cholelithiasis

• cholesterol stones - 80%
• - lecithin and cholesterol ratios unbalanced
• - bile supersaturated with cholesterol (aggregates as crystals, grows and increases and forms stones)

• pigment stones
• - bilirubin not conjugated with glucuronic acid
• - unconjugated bilirubin precipitates with Ca2+
• - often accompanied by bacterial infections

treatment - cholecystectomy – gall bladder removal

• icterus
• - high serum bilirubin
• - symptom – yellow skin and sclera of eye
• - several types

• obstructive jaundice
• hepatitis and cirrhosis
• hemolytic jaundice
• physiologic jaundice

• – bile duct obstruction (stone or tumor), liver damage
• - elevated bilirubin forced into blood

• - most common
• - liver inflammation <- alcoholism
• - scarring and loss hepatocytes

• - premature rupture of red blood cells
• - excessive bilirubin; hepatocytes can't absorb and conjugate all
• - unconjugated bilirubin crosses blood brain barrier and produces neurologic damage - kerinicterus
• Causes
• - mismatched transfusions
• - Rh factor – neonate
• - snake bites

• - new born infants
• - immature glucuronidation pathways
• - congenital enzyme absence for bilirubin conjugation