1. Bile Salts Physiology and The Enterohepatic Circulation Paul James MD Msc Gastroenterology Block: Pancreas, Biliary and Nutrition September 22 nd, 2015

2. Objectives To convince you that bile salts are important! To describe the major components of bile To diagram the biliary tract To describe some regulators of bile secretion To explain how stool and urine colour are affected by biliary dysfunction To describe how to lower plasma cholesterol by interfering with bile salt recirculation

3. Objectives To discuss the role of the enterohepatic circulation of bile salts To define factors involved in gallstone formation To describe the consequences of cholestasis on gastrointestinal physiology

4. Bile is Important! 1. Essential for the digestion and reabsorption of dietary fat and fat soluble vitamins 2. Only excretory route for cholesterol 3. Main excretory route for: i) bilirubin (end product of blood breakdown) ii) detoxified hydrophobic endogenous metabolites and drugs

5. Bile is a Small Component of GI Secretions Secretions: Diet 1.5 L Saliva 1.5 L Gastric2.5 L Pancreas1.5 L Bile 0.5 L Intestine1.0 L

6. What are the components of bile? A. Bile acid salts: 1.Cholic acid 2.Deoxicholic acid 3.Chenodeoxicholic acid 4.Lithocholic acid B. Phospholipids Lecithin (main) C. Cholesterol

7. A Word About Bilirubin Product of heme catabolism (bili+Fe 2+ =heme) Bilirubin in its native state is toxic To reduce its toxicity and increase its solubility, bilirubin is covalently linked to glucuronic acid in a process called conjugation

8. Overview of Bilirubin Metabolism Provided by Dr. John Leddy See Note

11. How are bile acids synthesized?

12. Bile Acid Production-step 1 Not rate-limiting For Bile Salt Synthesis See Note in cholesterol synthesis

13. Bile Acid Production-step 2

14. Cholesterol is Excreted in Bile Hydrophobic Bile Salts and Lecithin aid in solubilizing cholesterol

15. Lecithin + - See Note

16. Cholesterol Solubility in Bile is Limited See Note

17. Cholesterol is dissolved in Micelles containing Lecithin and Bile salts

18. What is the Role of Bile Salts in Fat Digestion and Reabsorption?

19. Bile salts form micelles with dietary lipids that facilitate attack by lipases Micelles formed with MonoG and FFA facilitate lipid reabsorption Clinical relevance? See Note Completed by the Middle of the Jejunem

20. Enterohepatic Circulation The circulation of biliary acids, bilirubin, and other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. See Note

22. What Stimulates Gallbladder Contraction and flow of Bile into the Duodenum?

23. Answer Cholecystokinin, aka “CCK” Greek: chole (bile), cysto (sac), kinin (move) = move the bile sac Also relaxes the sphincter of Oddi

24. See Note

27. What is the role for CCK and Secretin in Bile Production? CCK: Gallbladder contraction Pancreatic acinar cells: release of pancreatic enzymes Secretin: Bile duct and pancreas: NaHCO 3 and H 2 O secretion

28. Secretin Stimulates Bile Duct NaHCO 3 and Water Secretion See Note

29. Schematic provided by Dr. John Leddy Modified by Dr. L. Peterson Bile Duct Fluid

30. Concentration of bile components in the liver ducts and the gallbladder Gallbladder can only store up to 60ml of fluid 50% of bile produced daily is stored in the gallbladder and concentrated up to 20x Electrolytes (NaCl) are absorbed from be gallbladder Gallbladder bile is acidic

31. Bile Is Concentrated in the Gallbladder See Note

33. Bile in ducts versus bile in stool… why?

34. Ileal Bile Salt Reabsorption See Note

35. 95% Efficient 99% Efficient

36. See Note Can use this pathway to pull cholesterol out of the body

37. Getting into a Bile Duct From Canniculus to the Extrahepatic Bile Duct

38. See Note

39. From Physiology to Pathology When Things Go Wrong…

40. Its Amazing More People Don’t Have Gallstones! Bile is concentrated 10-20 fold while in storage in the gallbladder Cholesterol solubility in bile depends the appropriate mixture of bile salts and lecithin- a very delicate balance Once a stone, always a stone?

41. Its Amazing More People Don’t Have Gallstones! Gallstones-cholelithiasis is the common cause of biliary tract disease in adults 130,000 admissions to Canadian Hospitals 80,000 cholecystectomies annually 1/5 of men and 1/3 women will have stones in their lifetime Takes 5-20 years for crystals to grow to obstructive size

42. Gallstones Where to they form? Anywhere in biliary system. Mainly gallbladder. Risk factors: 1.Age 2.Sex 3.Diet 4.Reduced biliary transit

43. See Note 5. Impaired gbladder contractility i.e progesterone may explain difference caused by sex

44. See Note Treatments Oral Bile acids Sound wave lithotripsy + bile acids Laprascopic or open surgical removal Endoscopic removal

45. See Note

46. Cholesterol Stones- Most Common See Note Ultrasound the first and best test

47. Cholestasis Condition in which the flow of bile from the liver to the duodenum is slowed or blocked Cause: –Mechanical –Motility –Systemic disease –Hepatic vs extrahepatic

48. Cholestasis It is a descriptive term 4 cardinal features Jaundice (yellow pigmentation–bilirubin) Pruritus (itching-associated with bile salts) Xanthomas (Cholesterol deposits) Steatorrhea (fat in stool)

49. Jaundice See Note Cholestasis is the most common cause of conjugated hyperbilirubinemia

50. Pruritus Mechanism unclear. Many propose that excess bile acids accumulates in body tissues and triggers the sensation of itch. Can lead to scratching, sometimes violent, resulting in excoriations and prurigo nodularis. This type of pruritus can lead to sleep deprivation, and in some patients, to suicidal ideations

51. What happens when bile salts do not reach the small intestine? Fat and fat-soluble vitamin malabsorption Steatorrhea Kidney stones Weight loss

53. What happens when bile salts are not reabsorbed? Bile Salts are toxic to colonic mucosa cells Bile salts stimulate Cl secretion (NaCl +water) and impair Na reabsorption = Secretory diarrhea Note: Giving a medication like cholestyramine will prevent the secretory diarrhea by binding the bile salts (but will not prevent steatorrhea from fat malabsorption)!

54. Review Are bile salts important? What are the major components of bile? Name two regulators of bile secretion? Why is stool brown and and urine yellow? How can cholestyramine hel lower plasma cholesterol?

55. Review What is enterohepatic circulation? Name 4 risk factors for gallstone formation Describe how cholestasis results in jaundice and pruritus?

56. Thank you! pjames@toh.on.ca

57. References Rose, S. Gastrointestinal and Hepatobiliary Pathophysiology, Fence Publishing Johnson, L. Gastrointestinal Physiology, Mosby Thompson and Shaffer, First Principles of Gastroenterology Costanzo, Physiology, 2 nd edition Berne, Levy, Koeppen, Stanton, Physiology 5th Boulpaep and Boron, Medical Physiology, 1 st edition