2. 2 Gastrointestinal Secretion 1. Regulatory substances 2. Salivary Secretion 3. Gastric Secretion 4. Pancreatic Secretion 5. Bile Secretion by the Liver 6. Secretions of the Small Intestine 7. Secretions of the Large Intestine

3. Regulatory substances in the GI tract GI Hormones Paracrines Neurocrines

4. GI Hormones Horm ones Site of Secretion Stimulus for SecretionInhibitorActions GastrinG cells of Stomach Distention of stomach Vagus (GRP) Small peptides and amino acids H+ in the stomach Somatostatin H+ secretion and stimulate gastric mucosa growth CCK I Cells of duodenum and jejunum Fatty acids small peptides and amino acid Somatostatin pancreatic enzyme and HCO 3 - Secretion Growth of exocrine pancreas/gallbladder inhibits gastric emptying SecretinS –cell of duodenum H+ in duoenum Fatty acids in duodenum Somatostatin pancreatic HCO 3 - Secretion Billiary HCO 3 - Secretion Gastric H+ secretion GIPDuodenu m and jejunum Fatty acids, amino acids and oral glucose Somastostatin insulin secretion Gastric H+ ecretion

5. Paracrines Site of Secretion InhibitorActions SomastostatinThroughout GI tract Vagal stimulation  inhibit s the release of all GI hormones  Inhibits gastric H+ secretion HistamineMast cells of the gastric mucosa Somatostatin  increased gastric H+ secretion directly  Also potentiate the effect of gastrin and vagal stimulation Paracrines are released from the endocrine cells in the GI mucosa and diffuse over short distances to act on the target cells located in the Gi tracts. The GI paracrines are:

6. Neurocrines NeurocrineSite of SecretionActions VIPNeurone in the mucosa and smooth muscle of GI tract  Relaxation of GI muscle and LES  Stimulate pancreatic HCO3 secretion and  Inhibit gastric H+ secretion GRP (bombesin) Vagus nerve that innervate G ccells Stimulate gastrin release from G cells Enkephalins Nerves in the mucosa and smooth muscle of the GI tract  Stimulate contraction of Gi smooth muscle, particularly the lower esophageal, pyloric and ileocecal sphincters  Inhibit intestinal secretion of fluid and electrolytes Neurocrines are synthesized in neurons of the GI tract, moved by axonal transport down the axon, and release by action potentials in the nerves. The released neurocrines then diffuse across the synaptic cleft to a target cell

7. 7 1. Salivary Secretion a. Structure of the salivary glands b. Formation of saliva c. Regulation of salivary secretion

8. 8 Typically around 1.0 L per day secreted into the mouth. Functions of saliva include: initial digestion of starch by a-amylase initial digestion of triglycerides by lingual lipase, lubrication of ingested food by mucus and protection of the mouth and esophagus by dilution and buffering of ingested foods. Salivary secretion

9. 9 a. Structure of the salivary glands serous mixed serous + mucous Three major salivary glands: Parotid glands Submandibular glands Sublingual glands

10. Salivary Glands Innervation Tongue Taste and tactile stimuli Parotic gland Sublingual gland Submandibular gland Glossophyregeal nerve Tractus solitarius Superior and inferior salivary nuclei Facial nerve Chorda tympani Submandibular ganglion Otic ganglion

11. 11 Unusual feature  : PSNS SNS both stimulate Saliva production Unusual feature  : unusual high blood flow, > 10 times the blood flow to exercising skeletal muscle (when corrected for organ size)

12. 12 b. Formation of saliva Step 1 - The acinar cells secrete the initial saliva. - The initial saliva is isotonic. - It has the same electrolyte composition as plasma. Step 2 - The ductal cells modify the initial saliva. - Absorption of Na +, CI - > secretion of K + and HCO 3 - - The final saliva is hypotonic.

13. 13 c. Regulation of salivary secretion Salivary secretion is exclusively under neural control. Both PSNS and SNS stimulate saliva production. PSNS is primary. Conditioning, food, thought, and nausea etc. also stimulate salivary secretion. Dehydration, fear, and sleep inhibit salivary secretion. PSNS: SNS: Primary controller of salivation, large amount of watery saliva containing enzymes Small volume of saliva, thick with mucus Because sympathetic stimulation accompanies frightening or stressful situations, the mouth may feel dry at such times.

14. 14 Saliva production is unique in that it is increased by both the parasympathetic and sympathetic activity. Parasympathetic activity is more important. PSNS – CN VII (Facial) and IX (Glossopharyngeal) – pterygopalatine, submandibular and otic ganglia – postganglionic fibers end at muscarinic synapses on target cells (IP3/Ca++ 2 nd messenger system). PSNS stimulation increases production of saliva by increasing the transport processes of the acinar and ductal cells and by causing vasodilation. Anticholinergic drugs (e.g., atropine) inhibit the production of saliva and cause dry mouth. c. Regulation of salivary secretion

15. 15 SNS – Preganglionic fibers from T1-T3 – Superior Cervical Ganglion = postganglionics end at  - and to a much lesser extent  - receptors.  -receptors are coupled to Gs (increased adenylyl cyclase activity and increaed cAMP). SNS stimulation promotes secretion of a low volume viscous saliva. Saliva production is increased (via activation of the parasympathetic nervous system) by food in the mouth, smells, conditioned reflexes, and nausea. Saliva production is decreased (via inhibition of the parasympathetic nervous system) by sleep, dehydration, fear, and anticholinergic drugs. c. Regulation of salivary secretion

16. Salivary Secretion First, the flow of saliva itself helps wash away pathogenic bacteria as well as food particles that provide their metabolic support. Second, saliva contains several factors that destroy bacteria. One of these is thorcyanate ions and another is several proteolytic enzymes—most important, lysozyme—that (a) attack the bacteria, (b) aid the thiocyante ions in entering the bacteria where these ions in turn become bactericidal, and (c) digest food particles, thus helping further to remove the bacterial metabolic support. Third, saliva often contains significant amounts of protein antibodies that can destroy oral bacteria, including some that cause dental caries. In the absence of salivation, oral tissues often become ulcerated and otherwise infected, and caries of the teeth can become rampant. 16

17. 17 lubrication Protection thiocyanate ions, proteolytic enzymes (lysozyme), IgA etc. α-amylase, lingual lipase Kallikrein cleaves kininogen to produce bradykinin (a strong vasodilator, accounts for high salivary blood flow) Summary of Salivary Secretion Characteristics of saliva secretion: high volume (approx. 1 L/day) high K + and HCO 3 - concentrations low Na + and Cl - concentrations hypotonicity The composition of saliva varies with flow rate. pH of 6.0 – 7.0 Functions of saliva: Inhibited By: Sleep Dehydration Atropine

18. 18 2. Gastric Secretion a. Structure and cell types of the gastric mucosa b. HCL secretion c. Pepsinogen secretion and activation d. Intrinsic factor secretion

19. Gastric Secretions Mucous cells AntrumMucus pepsinogen Vagal stimulation (ACh) Parietal Cell Body (fundus)HCL Intrinsic Factor Gastrin Vagal stimulation (ACh)) Histamine Chief cellsBody (fundus)Pepsinogen converted to pepsin at low pH Vagal stimulation (Ach) Cell Type Part of Stomach Secretion products Stimulus for Secretion G cells AntrumGastrinVagal stimulation (via GRP) Small peptides D cellsAntrumSomastostatinLow pH

20. Endocrine Control Secretin CCK Gastrin GIP Stomach GRP H+ Fat; CHO AA Duod i-cell Duod s-cell Duod k-cell Gall bladder Pancreas Fat; AA H+ Bile Relax Oddi Motility Distension CN - X G - cell Enzymes

21. Chief cells Parietal cell Mucous cells G cells Intrinsic factor Mucus pepsinogen Gastrin HCL Pepsinogen Stomach Secretions D-cellsSomastatin

22. 22 The stomach mucosa consists of pits and glands. The surface mucosa and the pits are lined by mucus cells. The oxyntic glands project downwards and are composed of oxyntic (parietal) cells which secrete HCl and intrinsic factor and peptic (chief) cells secreting pepsinogen. In pyloric glands the cell types are G-cells, secreting gastrin, D-cells secreting somatostatin, and mucus cells. Stomach Secretions

23. 23 histamine [ Enterochromaffin-like (ECL)]

24. 24 The inner surface of the stomach has deep wells called gastric pits. Each pit leads to gastric glands. Gastric pit

25. Stomach Secretions (cont) Between the pit and gland is a narrow neck region, consisting of mucus cells. A stem cell is also present in this area. When the stem cell divides, one of the daughter cells remains to become the next stem cell, the other goes on to divide many times, with cells migrating both upwards and downwards to differentiate into the different cell types present. This explains why gastric epithelium is able to rapidly regenerate following injuries that are restricted to the epithelial cell layer – a process called RESTITUTION.

26. 26 Parietal cell: resting and stimulated. In the resting, nonstimulated state, tubulovesicular membranes are presented in the apical portion of the parietal cell. Upon stimulation, cytoskeletal rearrangement causes the tubulovesicular membranes to fuse into the canalicular membrane. There is a substantial increase (50-100 fold) in the surface area of the apical membrane of the parietal cell, as well as the appearance of microvilli.

27. 27 b. HCI secretion Alkaline tide Omeprazole (-) Figure 8-7 Mechanism of HCl secretion by gastric parietal cells. ATP, Adenosine triphosphate. (in gastric venous blood) K+ channel

28. + H 2 CO 3 ATP Lumen Blood Vessel Gastric Parietal Cell H + ATP Na + K+K+ Cl - HCl K+K+ Carbonic anhydrase HCI secretion K+ channel CO 2 H 2 O HCO 3 - + Cl - Alkaline tide pH Cl pH

29. 29 Summary of HCI Secretion 1.Intracellular fluid: Carbonic anhydrase 2.Apical membrane H + -K + ATPase, inhibited by omeprazole CI - channel 3.Basolateral membrane Cl - —HCO 3 - exchanger alkline tide 4.Net secretion of HCl, net absorption of HCO 3 -

30. 30 secrete histamine

31. 31 a. Structure and cell types of the gastric mucosa Oxyntic glands-cardia, fundus and body(80%) surface epithelium mucous neck cells (mostly mucus but also pepsinogen) peptic or chief cells (pepsinogen) parietal or oxyntic cells (HCl and intrinsic factor) paracrine cells (histamine) Pyloric glands(20%) surface epithelium mucous cells (pepsinogen, mucus) G cells (gastrin)

32. 32 Cephalic (30% of total) Vagal ACh on parietal cells, vagal GRPergic effects on G-cells leading to gastrin release and subsequent H+ secretion. Gastric (60% of total) Distension of the stomach and presence of amino acids and small peptides: Vagal ACh and vagal GRP as above, stretch- receptor induced release of gastrin, peptide and amino acid-induced release of gastrin Intestinal (10% of total) Products of protein digestion mediate acid release. Phases of gastric H+ secretion:

33. 33 STIMULATION OF GASTRIC H + SECRETION 1.Vagal stimulation  Vagus nerve innervates G cells  gastrin  H + secretion   GRP is the neurotransmitter Direct path:  Vagus nerve innervates parietal cells  Ach is the neurotransmitter Indirect path: Atropine blocks ________ path. Vagotomy eliminates __________ pathway(s)

34. 34 3. Histamine is released in response to eating a meal. the second messenger for gastrin on the parietal cell is IP3/Ca2+ 2. Gastrin is released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuse to the nearby parietal cells. stimulates H + secretion by activating H 2 receptor on the parietal cell membrane. STIMULATION OF GASTRIC H + SECRETION H2 receptor-blocking drugs such as cimetidine (famotidine, ranitidine) inhibit H+ secretion by blocking the stimulatory effect of histamine.

35. 35 Potentiation occurs when the response to stimultaneous administration of two stimulants is greater than the sum of response to either agent given alone. Histamine potentiates the actions of Ach and gastrin; Ach potentiates the actions of histamine and gastrin. 4. Potentiating effects of Ach, histamine, and gastrin on H + secretion STIMULATION OF GASTRIC H + SECRETION

36. 36 Histamine potentiates the actions of ACh and gastrin in stimulating H+ secretion. Thus, H 2 receptor blockers (e.g., cimetidine) are effective because they block not only the action of histamine but also histamine's potentiating effects on ACh and gastrin. ACh potentiates the actions of histamine and gastrin in stimulating H+ secretion. Thus, muscarinic receptor blockers such as atropine not only block the action of ACh, but they also block the potentiating effects of ACh on histamine and gastrin. POTENTIATION OF GASTRIC H + SECRETION

37. 37 INHIBITION OF GASTRIC H + SECRETION 1.Low pH (< 3) in the stomach inhibits gastrin secretion by negative feedback, thus inhibits further H + secretion. 2. Somatostatin direct pathway: indirect pathway: 3. Prostaglandins via G i protein  cAMP  inhibit histamine release from ECL cells inhibit gastrin release from G cells

38. 38 c. Pepsinogen secretion and activation pepsinogenpepsin H+H+

39. 39 Vagus G-cells ECL cells Somatostatin Prostaglandins M 3 receptor CCK B receptor H 2 receptor ACh Gastrin Histamine GqGq IP 3 /Ca 2+ GsGs cAMP H +,K + -ATPase GiGi + + + - Control of H + secretion by gastric parietal cells Lumen H+H+ Atropine Cimetidine Omepraole GRP

40. 40 H+H+ Why doesn’t pepsin digest your stomach? alcohol, aspirin Helicobacter pylori ( H. pylori ) major causative factor of gastric ulcer Produce NH 4 +, damages mucosal barrier

41. 41

42. Infection with Helicobacter pylori (H. pylori) bacteria 42 Before After

43. GASTRIC AND PEPTIC ULCERS Peptic ulcers Erosions of the gastric and duodenal mucosa produced by action of HCl Results from – Excessive acid secretion (i.e., Zollinger-Ellison syndrome - ↑ secretion of gastrin) ↓ protective properties of the mucosal barrier (i.e., Helicobacter pylori - bacterium that resides in GI tract that liquefy and penetrate the barrier) Treatment: Antibiotics, proton pump inhibitors, inhibitors of gastric secretion, selective vagotomy Gastritis Bacterial infection of gastric mucosa Histamine released by tissue damage and inflammation stimulate further acid secretion Ingested irritant substances (i.e., alcohol, NSAID), smoking Cushing ulcer: Curling ulcer: Result from increase intra cranial pressure Result from burn injury

44. 44 d. Intrinsic factor secretion Intrinsic factor (IF): a mucoprotein, secreted by parietal cells along with HCl. Vitamin B 12 requires IF to be absorbed. IF combines with vitamin B 12 to form a complex that is absorbed in the terminal ileum. Vitamin B 12 is essential for maturation of red blood cells. The absence of IF prevent absorption of B 12 and leads to abnormal production of RBCs, which causes pernicioius anemia.. IF-B 12 The Schilling test is a clinical test for the presence of intrinsic factor.

45. 45 ~ 1.5 L is secreted per day, pH: 0.8 – 3.5 A Summary of Gastric Secretion Gastric juice: Thick alkaline mucus by surface epithelium Thin watery mucus by neck cells HCl by parietal cells Pepsinogen by chief cells Intrinsic factor by parietal cells Gastric mucosal epithelium is made entirely of secretary cells including exocrine, endocrine, and paracrine cells.

46. 46 Stomach Motility After A Meal 1. Fasting state 2. Meal enters stomach 3. Peristalsis begins 4. Antral systole Food bolus receptive relaxation accommodation retropulsion MMC (90 mins) Vago-vagal reflex ↑ gastric pressure

47. 47 1. Receptive relaxation to facilitate the entry of food into the stomach, regulated by a vagovagal reflex. Mechanism neither cholinergic or adrenergic 2. Accommodation in response to gastric filling without causing a rise in intragastric pressure. Vagovagal reflex, enteric nervous system mediated. 3. Slow Sustained contractions in proximal stomach designed to press food into distal stomach 4. Contractions of distal stomach serve to grind the food (trituration) and to mix it with gastric juice. Powerful propulsive contractile waves called “antral systole” at the rate of 3-4 per min. propel the luminal contents to the partially closed pylorus. No particle >2m.m leaves the stomach in the immediate postprandial period. 5. Retropulsion - Food is forcefully reflected back from pyloric sphincter into the stomach Gastric motility

48. 48 3. Pancreatic Secretion a. Structure of the pancreatic exocrine glands b. Formation of pancreatic secretion c. Regulation of pancreatic secretion Most chemical digestion and absorption occur in the small intestine- The secretions that initiate chemical digestion in the small intestine come from the exocrine (acinar) pancreas

49. 49 a. Structure of the pancreatic exocrine glands

50. 50 b. Formation of pancreatic secretion Exocrine pancreas Acinar cells Ductal cells enzymes Amylase Trypsinogen aqueous secretion (HCO 3 - ) Trypsin inhibitor is secreted by acini to prevent activation of trypsin. If the pancreas is damaged, large quantities of pancreatic secretion pools in the damaged areas, and trypsin inhibitor is overwhelmed. Pancreatic secretions can digest the pancreas, which is known as acute pancreatitis. lipases proteases procarboxypeptidase proelastase Chymotrypsinogen

51. 51 The exocrine pancreas produces two types of pancreatic juice: o enzyme-rich pancreatic juice (stimulated by CCK) o bicarbonate-rich pancreatic juice (stimulated by secretin) Exocrine pancreas secretions are delivered through the hepatopancreatic sphincter (a.k.a. sphincter of Oddi) into the duodenum via the pancreatic duct Exocrine pancreatic secretions include the following enzymes: o Proteases (a.k.a. proteolytic enzymes) o Amylase o Lipase Pancreatic proteases (in zymogenic or inactive form) include trypsinogen, chymotrypsinogen, procarboxypeptidase Enterokinase in the intestinal cell membranes, converts (activates) trypsinogen into trypsin Once produced, trypsin activates more trypsinogen in a positive feedback mechanism Duct cells secrete bicarbonate into the duodenum to neutralize acid from the stomach; this produces an optimal pH environment for pancreatic digestive enzymes to function in Phases of gastric H+ secretion

52. 52 Figure 8-21 Mechanism of pancreatic secretion. The enzymatic component is produced by acinar cells, and the aqueous component is produced by centroacinar and ductal cells. ATP, Adenosine triphosphate.

53. 53 The acinus and centroacinar cells Acinar cells secrete enzymes, while centroacinar cells produce a small volume of initial pancreatic juice, which is mostly Na+ and Cl-. Pancreatic amylase and lipase are secreted in the active forms, while the rest of pancreatic enzymes (proteases) are secreted as inactive pro-enzymes. Enzymes or proenzymes are produced on RER and stored in zymogen granules until a stimulus (CCK or PSNS) triggers release. Formation of pancreatic secretion

54. 54 Ductal cells modify the initial pancreatic juice by secreting HCO3- and absorbing Cl- via a Cl-/HCO3- exchange carrier in the luminal membrane of the ductal cells. Final pancreatic secretion has Na+ and K+ concentrations similar to plasma, but HCO3- and Cl- concentrations vary with flow rates. At lowest flow rates, HCO3- and Cl- concentrations are also similar to plasma, but as flow rate increases, the HCO3-/Cl- exchanger is stimulated and HCO3- rises as Cl- falls. Because the pancreatic ducts are permeable to water, H2O moves into the lumen to make the pancreatic juice isosmotic to plasma (increasing the volume). Ductal cells

55. 55 Enzymes often secreted in an inactive form, and activated near the wall of gastrointestinal tract - so food is broken down where it can be transported into the blood stream.

56. 56 Figure 8-23 Regulation of pancreatic secretion. ACh, Acetylcholine; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; IP3, inositol 1,4,5-triphosphate. c. Regulation of pancreatic secretion

57. 57 The Cl channel is encoded by the cystic fibrosis gene product CFTR. Thus patients with cystic fibrosis, who lack a functional Cl channel have defective duct transport. The ducts get clogged with precipitated enzymes and mucus and the pancreas undergoes a fibrosis (hence the name of the disease). The physiological significance of this model is twofold, first the HCO 3 delivered to the duodenal lumen neutralizes gastric acid and allows the digestive enzymes to operate at their pH optimum, close to neutral. Second, H+ which are produced in the duct cells when HCO is generated for secretion leave via Na-H exchange into the blood. The net effect is to neutralize the alkaline tide in the blood that was generated by gastric acid secretion.

58. 58 A Summary of Pancreatic Secretion HCO 3 - : neutralize the contents from the stomach Enzymes: digestion of protein, carbohydrate, and fats Pancreatic juice is characterized by: - high volume (1 L/day) - virtually the same Na + and K + concentrations as plasma - much higher HCO 3 - concentration than plasma - much lower Cl - concentration than plasma - isotonicity - pancreatic lipase, amylase, and proteases - pH of 8.0 – 8.3

59. 59 4. Bile Secretion a. Overview of the biliary system b. Composition and functions of bile c. Formation of bile and function of the gallbladder d. Regulation of bile excretion from the gallbladder e. Enterohepatic circulation of bile salts f. Clinical correlation

60. 60 Figure 8-24 Secretion and enterohepatic circulation of bile salts. Light blue arrows show the path of bile flow; yellow arrows show the movement of ions and water. CCK, Cholecystokinin. a. Overview of the biliary system

61. 61 Physiologic Anatomy of Biliary Secretion The hepatocytes, bile canaliculi, intrahepatic bile ducts, extrahepatic bile ducts, gall bladder and common bile ducts make up the biliary system. Bile is secreted by hepatocytes into bile canaliculi, passes through intrahepatic bile ducts to the right and left bile ducts, to the common hepatic duct, which joins the cystic duct to form the common bile duct. The CBD joins the main pancreatic duct (forming the hepatopancreatic duct) and empties into the 2 nd part of the duodenum at the hepatopancreatic ampulla / sphincter (of Oddi).

62. 62 Bile is secreted in two stages by the liver: (1) The initial portion is secreted by the principal functional cells of the liver, the hepatocytes; this initial secretion contains large amounts of bile acids, cholesterol, and other organic constituents. It is secreted into minute bile canaliculi that originate between the hepatic cells (2) Next, the bile flows in the canaliculi toward the interlobular septa, where the canaliculi empty into terminal bile ducts and then into progressively larger ducts, finally reaching the hepatic duct and common bile duct. From these the bile either empties directly into the duodenum or is diverted for minutes up to several hours through the cystic duct into the gallbladder, second portion of liver secretion is added to the initial bile. This additional secretion is a watery solution of sodium and bicarbonate ions secreted by secretory epithelial cells that line the ductules and ducts.

63. 63

64. 64 Hepatocytes secrete bile into the bile canaliculi and bile ductules. bile ductule

65. 65 Bile salts including bile acids (50%) Phospholipids (Lecithin, 40%) Bile pigments (2%): bilirubin Cholesterol (4%) Electrolytes (Na +, K +, Ca ++, Cl -, HCO 3 - ) Water emulsifying fat eliminating metabolic wastes Composition Functions aids in fat digestion aids in fat absorption b. Composition and functions of bile amphipathic molecules

66. Composition of bile Bile contains bile acids (50%), phospholipids (40%), cholesterol (4%), and bile pigments such as bilirubin(2%) in an aqueous solution containing electrolytes. Bile acids/salts are amphipathic molecules, having both hydrophilic and hydrophobic portions. In aqueous solution, bile salts orient themselves around droplets of lipid and keep the lipid dispersed in solution (emulsified), and aid in the intestinal digestion and absorption of lipids by emulsifying and solubilizing them in micelles. 66

67. Composition of bile Bilirubin is the yellow pigment in bile. Bilirubin is the product of RES degradation of hemoglobin (RBC turnover). Bilirubin is extracted from blood by hepatocytes and conjugated with glucuronide. The conjugated bilirubin is then secreted into bile. Bilirubin in the intestines has three fates: 1) reabsorption into blood (there is a normal circulating amount of conjugated bilirubin) 2) excretion in feces and 3) conversion by intestinal flora to urobilinogen Ions and water in bile are secreted by epithelial cells lining the bile ducts. 67

68. 68 c. Formation of bile and functions of the gallbladder Hepatocytes secrete:Bile ducts secrete: Organic constituents are highly concentrated (5 – 20 fold). Watery components are reabsorbed by the gallbladder mucosa. organic components (bile acids, cholesterol, bilirubin) watery solution, Na +, HCO 3 - Bile Gallbladder stores bile, concentrates bile, empties bile.

69. 69 Formation of bile Bile is produced continuously by hepatocytes, drains into the hepatic ducts and is stored in the gallbladder for release in response to a meal. Choleretic agents increase the formation of bile. The rate-limiting enzyme in bile acid synthesis is cholesterol 7-  -hydroxylase, which is inhibited by high levels of bile acids. Bile is formed by the following process: Primary bile acids (cholic acid and chenodeoxycholic acid) are synthesized by hepatocytes. In the intestine, bacteria convert a portion of each of the primary bile acids to secondary bile acids (deoxycholic acid and lithocholic acid).

70. 70 CCK is released in response to small peptides and fatty acids in the duodenum. tells the gallbladder that fats need to be emulsified and absorbed – in other words, bile is needed. causes contraction of the gallbladder smooth muscle. causes relaxation of the sphincter of Oddi. ACh also causes contraction of the gallbladder. d. Regulation of bile excretion from the gallbladder

71. 71 Figure 8-24 Secretion and enterohepatic circulation of bile salts. 94% active transport diffuse Na + -bile salt cotransporter Cholesterol 7α- hydroxylase (rate-limiting enzyme) e. Enterohepatic circulation of bile salts

72. Cholesterol Bile salt 1 Portal Circulation CCK 2 + + Ions and water GB Ions and water Bile salts Duodenum Ileum Liver Sphincter of oddi Bile duct Secretin 94% diffuse 3 4 active transport Na + -bile salt cotransporter Cholesterol 7α- hydroxylase (rate-limiting enzyme)

73. 73 f. Clinical correlation Gallstone formation: precipitated cholesterol high-fat diet, prone to the development of gallstones too much absorption of water from bile inflammation of epithelium Ileal resection IF-Vitamin B12 complex cannot be absorbed. Steatorrhea: recirculation of bile via enterohepatic circulation is reduced. Most secreted bile acids are lost in feces. Oil droplets in the stool. Diarrhea: bile acids  cAMP-dependent Cl - secretion in colonic epithelium, Na + and water follow Cl - into the lumen

74. GALLSTONES Mechanisms of stones formation  absorption of water in the gallbladder  absorption of bile acids (  solubility of cholesterol)  cholesterol concentration (fatty diet) Inflammation of the epithelium Mechanisms  the risk of stones formation Secretion of H+ by the mucosa (acidification of bile)   Ca 2+ precipitation Absorption of large amounts (about 50%) of Ca 2+ Release of the inhibitors of Ca2+ and cholesterol precipitation Secretion of water and electrolytes during digestion which intermittently dilute the gallbladder content Combination of cholesterol with lecithin and bile salts (micelles)   water solubility of cholesterol Contractions prevent accumulation of microcrystal 2 types of stones: Cholesterol stones Calcium bicarbonate stones

75. 75 Brunner’s glands Crypts of Lieberkühn 5. Secretions of the Small Intestine An extensive array of compound mucus glands Located in the wall of duodenum. Secrete mucus and HCO 3 - Located over the entire surface of the small intestine. Goblet cell: secrete mucus Enterocytes: secrete and absorb water and electrolytes

76. 76 The small intestine secretes watery mucus and hormones. Mucus, secreted by abundant epithelial goblet cells, protects the intestinal mucosa from auto-digestion by proteases and acid Intestinal glands or crypts (of Lieberkuhn) secrete water and electrolytes to combine with mucus to form intestinal juice Intestinal epithelial cells contain brush border enzymes in their microvilli cell membranes; these enzymes complete the chemical digestion of foodstuffs Secretions of the Small Intestine

77. 77 6. Secretions of the Large Intestine The large intestine has many crypts of Lieberkühn and secrets an alkline mucus solution containing bicarbonate and K +. The sole function of mucus is protection. It protects the large intestine wall from damage by acids formed in feces from attacking the intestinal wall. Acid and mechanical stimulation, mediated by both long and short reflexes, increase the secretion of mucus. the wall of the large intestine a mucus layer lining the wall Acid passage of feces Neural reflexes (long and short)  Mucus secretion

78. Case: Zollinger-Ellison Syndrome Description of Case: A 52-year-old man visits his physician complaining of abdominal pain, nausea, loss of appetite, frequent belching, and diarrhea. The man reports that his pain is worse at night and is sometimes relieved by eating food or taking antacids containing HCO3-. GI endoscopy reveals an ulcer in the duodenal bulb. Stool samples are positive for blood and fat. His serum gastrin level is measured and found to be markedly elevated. A CT scan reveals a 1.5 cm mass in the head of the pancreas. The man is referred to a surgeon. While awaiting surgery, the man is treated with the drug omeprazole, which inhibits H+ secretion by gastric parietal cells. During a laparotomy, a pancreatic tumor is located and excised. After surgery, the man’s symptoms diminish, and subsequent endoscopy shows that the duodenal ulcer has healed. Explanation of Case: All of the man’s symptoms and clinical manifestations are caused, directly or indirectly, by a gastrin-secreting tumor of the pancreas. In Zollinger- Ellison syndrome, the tumor secretes large amounts of gastrin into the circulation. The target cell for gastrin is the gastric parietal cell, where it stimulates H+ secretion. The physiologic source of gastrin, the gastric G cells, are under negative feedback control. Thus, normally, gastrin secretion and H+ secretion are inhibited when the gastric contents are acidified (i.e., when no more H+ is needed). In Zollinger-Ellison syndrome, however, this negative feedback control mechanism does not operate: gastrin secretion by the tumor is not inhibited when the gastric contents are acidified. Therefore, gastrin secretion continues unabated, as does H+ secretion by the parietal cells.

79. Case: Zollinger-Ellison Syndrome, explanation (cont.) The man’s diarrhea is caused by the large volume of fluid delivered from the stomach (stimulated by gastrin) to the small intestine; the volume is so great that it overwhelms the capacity of the intestine to absorb it. The presence of fat in the stool (steatorrhea) is abnormal, since mechanisms in the small intestine normally ensure that dietary fat is completely absorbed. Steatorrhea is present in Zollinger- Ellison syndrome for two reasons. 1) The first reason is that excess H+ is delivered from the stomach to the small intestine and overwhelms the buffering ability of HCO3--containing pancreatic juices. The duodenal contents remain at acidic pH rather than being neutralized, and the acidic pH inactivates pancreatic lipase. When pancreatic lipase is inactivated, it cannot digest dietary triglycerides to monoglycerides and fatty acids. Undigested triglycerides are not absorbed by intestinal epithelial cells, and thus, they are excreted in the stool. 2) The second reason for steatorrhea is that the acidity of the duodenal contents damages the intestinal mucosa (evidenced by the duodenal ulcer) and reduces the microvillar surface area for absorption. Treatment: While the man is awaiting surgery to remove the gastrin-secreting tumor, he is treated with omeprazole, which directly blocks the H+-K+-ATPase in the apical membrane of gastric parietal cells. This ATPase is responsible for gastric H+ secretion. The drug is expected to reduce H+ secretion and decrease the H+ load to the duodenum. Later, the gastrin-secreting tumor is surgically removed.

80. Case: Resection of the Ileum Description of Case: A 36-year-old woman has 75% of her ileum resected following a perforation caused by severe Crohn’s disease (chronic inflammatory disease of the intestine). Her postsurgical management included monthly injections of vitamin B12. After surgery, she experienced diarrhea and noted oil droplets in her stool. Her physician prescribed the drug cholestyramine to control her diarrhea, but she continues to have steatorrhea. Explanation of Case: The woman’s severe Crohn’s disease caused an intestinal perforation, which necessitated a subtotal ileectomy, removal of the terminal portion of the small intestine. Consequences of removing the ileum include decreased recirculation of bile acids to the liver and decreased reabsorption of the intrinsic factor-vitamin B12 complex. In normal persons with an intact ileum, 95% of the bile acids secreted in bile are returned to the liver, via the enterohepatic circulation, rather than being excreted in feces. This recirculation decreases the demand on the liver for the synthesis of new bile acids. In a patient who has had an ileectomy, most of the secreted bile acids are lost in feces, increasing the demand for synthesis of new bile acids. The liver is unable to keep pace with the demand, causing a decrease in the total bile acid pool. Because the pool is decreased, inadequate quantities of bile acids are secreted into the small intestine, and both emulsification of dietary lipids for digestion and micelle formation for absorption of lipids are compromised. As a result, dietary lipids are excreted in feces, seen as oil droplets in the stool (steatorrhea). This patient has lost another important function of the ileum, the absorption of vitamin B12. Normally, the ileum is the site of absorption of the intrinsic factor-vitamin B12 complex. Intrinsic factor is secreted by gastric parietal cells, forms a stable complex with dietary vitamin B12, and the complex then is absorbed in the ileum. The patient cannot absorb vitamin B12 and must receive monthly injections, bypassing the intestinal absorptive pathway. The woman’s diarrhea is caused, in part, by high concentrations of bile acids in the lumen of the colon (because they are not recirculated). Bile acids stimulate cAMP-dependent Cl- secretion in colonic epithelial cells. When Cl- secretion is stimulated, Na+ and water follow Cl- into the lumen, producing a secretory diarrhea (sometimes called bile acid diarrhea). Treatment: The drug cholestyramine, used to treat bile acid diarrhea, binds bile acids in the colon. In bound form, the bile acids do not stimulate Cl- secretion or cause secretory diarrhea. However, the woman will continue to have steatorrhea.

81. Contraction of the gallbladder is correctly described by which of the following statements? a. It is inhibited by a fat-rich meal b. It is inhibited by the presence of amino acids in the duodenum c. It is stimulated by atropine d. It occurs in response to cholecystokinin e. It occurs simultaneously with the contraction of the sphincter of Oddi The answer is D