Biliary Secretion and the Enterohepatic Circulation of Bile

Question 1

Why is bile important?

Answer 1

• Lipid digestion and absorption
• Cholesterol homeostasis
• Excretion of lipid soluble xenobiotics / drug metabolites / heavy metals

Question 2

what is bile?

Answer 2

• Complex lipid-rich micellar solution (water, inorganic electrolytes, and organic solutes – bile acids, phospholipids, cholesterol, bile pigments)
• Isosmotic with plasma
• 500-600mls per day
• Formation depends on the hepatic SYNTHESIS and cannalicular SECRETION of bile acids (=major organic anion in bile)
• Maintenance of hepatic bile formation is essential for normal liver function
• Most bile acids (95%) secreted by hepatocyte have been previously secreted into intestine (enterohepatic circulation)

Question 3

Bile acids

Answer 3

• Synthesised from cholesterol in pericentral hepatocytes of the acini
• Cholesterol (lipophilic) – cholic acid (CA) and chenodeoxycholic acid (CDCA) (water soluble) (primary bile acids)
• CA and CDCA are conjugated (N-acyl amidated with glycine or taurine) before secretion into the bile canaliculus
• Conjugation enhances the hydrophilicity and acidic strength of the side chain (pKa = 5.0 unconjugated; pKa = 3.9 glycine conjugate; pKa 2.0 taurine conjugate
• Conjugation decreases passive diffusion of bile acids across cell membranes during transit through EHC (ie keeps intraluminal)
• Amphipathic (hydrophilic and hydrophobic parts) – reduce surface tension and aid emulsification

Question 4

emulsification

Answer 4

• Fat (TG) is insoluble in water
• Emulsification increases surface area for lipolysis. Stable emulsion important for the close apposition of lipase and TG
• Lipases act at surface of emulsified droplets and liberate FA from the glycerol backbone of TG (lipolysis)

Question 5

function of bile acids

Answer 5

• Induce bile flow (osmotic effect) & secretion of biliary lipids (PL and cholesterol)
• Digestion of dietary fats – by solubilising lipids and lipid digestion products as mixed micelles facilitating aqueous diffusion across intestinal mucosa
• Facilitates protein absorption – accelerating hydrolysis by pancreatic proteases
• Cholesterol homeostasis – facilitates dietary absorption / elimination as BA are water-soluble end-products of cholesterol catabolism. Induce bile flow and solubilise cholesterol – enabling movement from hepatocyte to intestinal lumen
• Antimicrobial (physicochemical + inducing anti-microbial genes)
• Prevents calcium gallstones and oxalate renal stones

Question 6

Enterohepatic circulation 1

Answer 6

• FASTED – bile acids travel down biliary tract to GB (concn x10)
• FED – CCK (cholecystokinin) released from duodenal mucosa
• CCK – relaxes SO and contracts GB releasing concentrated solution of mixed micelles (BA, PL, cholesterol)
• Bile acids (conjugated) remain intraluminal
• Actively transported (reabsorbed) via the apical sodium bile acid transporter (ASBT)
• Re-enters liver via portal circulation
• Bile acids taken up by hepatocyte and (re-conjugated) secreted into biliary canaliculi
• Usually 2-3 cycles per meal
• Bile acid feedback mechanism – inhibition of CYP7A1 (cytochrome P450 7A1) = cholesterol 7𝛼 hydroxylase

Question 7

Enterohepatic circulation

Answer 7

• Rare inherited defects in bile acid synthesis
• Deconjugation of bile acids (small bowel bacterial overgrowth)
• Cholecystectomy (5% diarrhoea) – daily bile acid secretion is not altered much. Bile is ‘stored’ in proximal small intestine – likely big ‘shift’ to distal small intestine ‘overwhelms’ transport mechanism or feedback mechanism
• Ileal resection or disease – unabsorbed bile acids enter colon where inhibit water absorption / induce secretion resulting in ‘bile salt diarrhoea’
• Biliary obstruction – CBD stone, pancreatic carcinoma – intestinal malabsorption of fat soluble vitamins and fat resulting in steatorrhoea and develop jaundice