GIT 2: Liver, Gallbladder and Pancreas PDF

PHYSIO-LEC: LE 4 | TRANS 2 GIT 2: Liver, Gallbladder and Pancreas RALPH BAUTISTA, M.D. & MARIA THERESA G. CACAS, MD, MPH, FPPS, FPSNbM | 01/13/2025 OUTLINE NICE TO...

PHYSIO-LEC: LE 4 | TRANS 2 GIT 2: Liver, Gallbladder and Pancreas RALPH BAUTISTA, M.D. & MARIA THERESA G. CACAS, MD, MPH, FPPS, FPSNbM | 01/13/2025 OUTLINE NICE TO KNOW INFORMATION I.​ Liver A.​ Anatomy of the III.​ Exocrine Pancreas Statistics on the Causes of GIT Diseases That Liver A.​ Overview Cause Death[Synchronous Lecture] B.​ Functions of the B.​ Digestive Enzyme Liver C.​ Mechanism of II.​ Gallbladder Enzyme Secretion A.​ General D.​ Other Components Formatting of Acinar Fluid B.​ Figure E.​ Summary C.​ Tables IV.​ Review Questions D.​ Important/Nice To V.​ References Know Information SUMMARY OF ABBREVIATIONS ABST Apical Sodium-dependent Bile Acid Transporter Ach Acetylcholine ALT Alanine aminotransferase AST Aspartate aminotransferase Figure 1. Specific Causes of GIT Diseases That Cause Death 📣 CCK Cholecystokinin [Synchronous Lecture] CCK-RP Cholecystokinin-releasing peptide ​ Even if it’s not one of the Top 10 causes of death CFTR Cystic Fibrosis Transmembrane conductance and disability, GIT diseases have an impact on our Regulator health because it also ends up with some form of GRP Gastrin-Releasing Peptide disability or morbidity, or worse, mortality. MRP-2 Multidrug Resistance Protein 2 UGT Uridine Glucuronosyltransferase VIP Vasoactive intestinal polypeptide I. LIVER A. ANATOMY OF THE LIVER ❗️ Must know 📣 Lecturer 📖 Book 📋 Previous Trans LEARNING OBJECTIVES ​ 📖 GROSS ANATOMY OF THE LIVER Largest organ in the body, contributing about 2% of body weight in the average adult human ✔​ Discuss the physiological processes in the ​ Peritoneal organ positioned in the right upper quadrant of hepatobiliary system. the abdomen underneath the diaphragm o​ Discuss the functions of the liver and ​ General shape: prism or wedge, with the base located at gallbladder. the right and apex located at the left o​ Describe the function, composition, and formation of bile. o​ Trace the enterohepatic circulation of bile acids. ✔​ Discuss the functions of the pancreas in digestion and describe the phases of pancreatic secretion. Figure 2. Anatomy of the liver.[Asynchronous Video Lecture] Space intentionally left blank ​ Falciform ligament: divides the liver into a larger right lobe and smaller left lobe anteriorly ​ Dual blood supply: →​25% of blood flow to the liver is from the hepatic artery, a branch of the celiac trunk from the abdominal aorta ▪​ Blood is well-oxygenated but nutrient-poor →​75% of hepatic blood volume is delivered from the portal vein, which carries blood from the spleen, stomach, pancreas, and intestines LE 4 TRANS 2 VER 2 TG B17-18: B. Madrazo, N. Magalang, D. Magallanes, S. TE: D. Magallanes, N. AVPAA: C. Eduardo Page 1 of 21 Magbata, N. Magnaye, Y. Magpantay, R. Magpayo*, J. Magnaye, C. Mangubat, T. Magsakay, M. Mangalindan*, C. Mangubat, J. Mañibo, L. Manuel Manlutac, A. Mantilla, T. Manuel, D. Manzon  ▪​ Blood is rich in nutrients (absorbed from the gut) but relatively poor in oxygen content Figure 6. Classic Lobule.[Asynchronous Video Lecture] ​ Liver Acinus →​Overlaps two classical lobules →​Regarded as the true functional unit of the liver →​The acinus is diamond or oval-shaped; involves approximately two adjacent portal triads and two central veins →​Blood still flows from the portal triad to the central vein ▪​ However, within the shape of the liver acinus, the flow Figure 3. Typical blood flow through the splanchnic circulation in is from the center to the periphery a fasting adult human.[Berne and Levy Physiology, 7th ed.] →​Bile flows in opposite directions: from periphery to the ​ Blood filtration and bile production takes place within the center hepatic lobule, where terminal branches of the afferent and efferent blood vessels meet ​ Central vein: located at the center of the lobule; this collects blood from the lobule and conveys it to the hepatic veins Figure 7. Liver Acinus. [Asynchronous Video Lecture] →​Within the liver acinus, there are “functional zones” based on oxygen tension and nutrient content ▪​ Zone 1: closest to the arteriole, where cells receive most of the oxygen and nutrients available −​ Cells in Zone 1 are most active in detoxification ▪​ Zone 2: transitional or intermediate zone between Zones 1 and 3 Figure 4. Portal triad.[Asynchronous Video Lecture] ▪​ Zone 3: farthest from the arteriole but closest to the ​ Portal triad: portal vein, hepatic artery, and bile duct central vein, therefore receives lowest concentrations →​located at the periphery of the lobule of oxygen and nutrients →​Portal vein and hepatic artery: supply blood to the liver −​ Cells in Zone 3 are thought to be most active in bile acid synthesis Figure 5. Cross-sectional view of the lobule.[Asynchronous Video Lecture] VIEWS OF THE LIVER ORGANIZATION Figure 8. Functional zones of the Liver Acinus.[Asynchronous Video Lecture] ​ Classic Lobule →​Six portal triads surround a single central vein →​Blood flows from portal triads to central vein, while bile flows in opposite direction PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 2 of 21  HISTOLOGICAL CHARACTERISTICS OF THE LIVER →​Capable of producing connective tissue matrix 📣 (collagen) →​ Formation of collagen in the space of Disse usually occurs in fibrosis, conditions in fatty liver disease, 📣 cirrhosis →​ Liver is unable to function well B. FUNCTIONS OF THE LIVER ​ Metabolic ​ Protective ​ Excretory ​ Storage ​ Synthetic Figure 9. Basic structure of a liver lobule. [Guyton and Hall, 14th ed.] ​ Secretory ​ The lobule is composed mainly of hepatocytes arranged in ​ Detoxification anastomosing cords that form the liver cell plates ​ Hepatocytes are arranged in two columns which enclose a METABOLIC bile canaliculus in its center ​ Carbohydrate Metabolism ​ The bile canaliculus collects bile from hepatocytes and →​Generates glucose from non-carbohydrate substrates drains into biliary ductules, which are lined by (Gluconeogenesis) cholangiocytes →​Converts glucose to glycogen for storage ​ Review: liver receives dual blood supply from hepatic (Glycogenesis) artery and portal vein →​Releases the stored glucose into the bloodstream when →​Blood from these vessels percolates around the needed (Glycogenolysis) hepatocytes via the sinusoids before draining into the →​Serves as a buffer for blood glucose concentration since central vein it can either consume glucose in the blood or synthesize ▪​ These sinusoids (or capillaries) are lined by glucose fenestrated endothelium, permitting passage of large →​Aside from the endocrine pancreas, the liver is molecules (e.g. albumin) especially important for maintaining normal blood ▪​ In addition to endothelial cells, these sinusoids also glucose concentration contain Kupffer cells, the organ’s resident ​ Lipid Metabolism macrophages →​Site of beta-oxidation of fatty acids →​Space of Disse: between the endothelium and the →​Synthesizes: hepatocytes, which contains interstitial fluid ▪​ Cholesterol & phospholipids from unused free fatty ▪​ Also contains the stellate cell, which is another acids important liver cell type ▪​ Lipoproteins (HDL, LDL, VLDL, and chylomicrons) ▪​ Fatty acids and triglycerides from non-lipid sources ▪​ Ketone bodies for export into the blood especially when the blood glucose is low →​Converts portion of cholesterol into bile acids, which participate in digestion and absorption of lipids ​ Protein Metabolism →​Main site for synthesis of the non-essential amino acids →​Causes deamination of amino acids so they may enter biosynthetic pathways for carbohydrates Figure 10. Stellate cells in a normal and injured liver.[Asynchronous Video →​Serves as a primary site for urea cycle by converting Lecture] ammonia into urea →​Under normal conditions (or quiescent state), stellate PROTECTIVE cell serves as a major storage site for vitamin A and is ​ The liver also has important detoxification and immune also a source of key growth factors for hepatocytes functions: →​In cases of liver cell injury, however, stellate cells are →​Protects the body from potentially toxic substances that activated to become transitional cells which are capable are absorbed from the GI tract of synthesizing large quantities of collagen that ▪​ Phagocytosis of bacteria and foreign bodies by orchestrate liver fibrosis 📣 DIFFERENT CELLS IN THE LIVER ​ Hepatocytes: appears as plaque Kupffer cells →​Modifies endogenous and exogenous toxins through a “first pass metabolism” to ensure that little or none of →​Most numerous; 75 - 80% of cells in the liver these substances make it into the systemic circulation, →​Apical side made up of bile canaliculus which generally occurs in two phases: →​Each hepatocyte is linked through tight junction ​ Sinusoidal Endothelium cells: Fenestrated and do not have a basement membrane →​Doesn’t serve as a barrier to the big molecules (proteins) ​ Kupffer cells: Arise from the macrophage lineage →​Plays role in host defense Figure 11. Detoxification function of the liver.[Asynchronous Video Lecture] ​ Stellate cells: Located in Space of Disse →​Stores wide variety of lipids PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 3 of 21  ▪​ First phase: cytochrome P-450 (CYP enzymes) ▪​ All cell types within the liver can store iron, but converts the parent drug or substance into polar majority is stored within the hepatocytes active metabolites →​Copper ▪​ Second phase: conjugation to generate products ▪​ The hepatocytes are also responsible for the uptake and storage of copper, as well as its regulation of that are more soluble for excretion excretion in the bile −​ This involves the addition of glucuronide, sulfate, or glutathione to the parent molecule SYNTHETIC −​ The substrate is then transported either into the ​ This refers to the synthesis of serum proteins bile or the blood to allow subsequent urinary ​ Except immunoglobulins, the liver synthesizes almost all excretion the proteins present in the plasma: EXCRETORY →​Albumin (most important) ▪​ Most abundant protein in the blood and principally ​ The liver is the main site for converting ammonia to urea determines the plasma oncotic pressure →​Ammonia is a byproduct of protein catabolism and is ▪​ Its synthesis occurs exclusively in the liver derived from two major sources: kidneys and colon →​Hormone-binding proteins (e.g. thyroid binding ▪​ A small amount of ammonia is also generated from globulin, sex hormone-binding globulin) metabolic processes in the muscles and from the →​All the clotting factors (except Factor VIII) breakdown of old red blood cells ▪​ Factor VIII is synthesized in endothelial cells →​Ammonia is freely permeable across the blood-brain barrier, so even a slight elevation in its plasma SECRETORY concentration is potentially toxic to the CNS ​ The digestive function of the liver is related to its secretion ▪​ Thus, its levels in the blood must be carefully of bile, which plays a very important role in lipid digestion controlled by converting it into an excretable form ​ Main functions of bile: which is urea →​facilitates absorption and digestion of lipids through →​The liver is the only organ in the body that has a emulsification complete urea cycle ▪​ The bile salts break down large fat globules into smaller droplets, thereby increasing the surface area for digestive enzymes, particularly lipase ▪​ Since more lipid is available for digestion at any given time, the lipase enzyme can quickly degrade the fat into fatty acids and glycerol →​helps eliminate waste products from the body ▪​ Excessive amounts of cholesterol will be converted into bile acids, to allow the body to maintain cholesterol homeostasis Figure 12. Ammonia homeostasis in health. [Berne and Levy,7th ed.] ​ Urea Cycle →​Consists of biochemical reactions that converts ammonia into urea Figure 13. Composition of bile.[Asynchronous Video Lecture] →​Body’s way of disposing excess nitrogen →​After a series of biochemical reactions in the liver, the ​ Bile consists of 95% water, while its organic constituents or newly formed urea is transported to the systemic solutes make up about 5% circulation; majority of which will be filtered and excreted ​ The solute consists of bile acids (primary solute), by the kidneys phospholipids, cholesterol (aids bile salts in micelle →​On the other hand, urea excreted in the intestine will be formation), pigment such as bilirubin, and protein cleaved by the urease-containing bacteria to form ammonia; which will either be reabsorbed in the portal circulation or converted to ammonium for fecal BILE ACID BIOSYNTHESIS elimination ​ Bile acid is synthesized from the parent compound ​ Aside from ammonia, the liver is also involved in the cholesterol excretion of exogenous dyes such as: →​Bromsulphthalein: used in tests for liver function →​Rose Bengal: used in diagnosing tear film disorders STORAGE ​ The liver stores: →​Glycogen (e.g. postprandial period) →​Fat-soluble vitamins (Vitamins A, D, E, K) →​Vitamin B12 →​Iron ▪​ Most iron within the cells is stored in ferritin, a protein produced by the liver Figure 14. Biochemical pathways of bile acid.[Asynchronous Video Lecture] PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 4 of 21  ​ Biochemical pathways: ​ Enterohepatic Circulation →​Classical pathway: direct conversion of cholesterol to →​Movement of bile acid molecules from the liver to the cholic acid via the enzyme cholesterol 7α-hydroxylase small bowel (and then back to the liver) →​Second or alternative pathway: involves an additional →​95% of bile salts released in the duodenum are step which favors the synthesis of chenodeoxycholic reabsorbed into the blood acid →​5% of the remaining bile salts will escape reabsorption ​ Before secretion into the bile canaliculus, both the cholic and will be eliminated in the feces and chenodeoxycholic acids are conjugated with amino ▪​ Review: Reabsorption of most bile salts takes place acids, glycine or taurine in the distal ileum. →​Ensures the pool of bile acids are sufficient and can be used repeatedly during digestion of a single or multiple meals throughout the day Figure 15. Bile salts.[Asynchronous Video Lecture] ​ This conjugation process is extremely efficient, so virtually all the biliary bile acids are in this conjugated form ​ Conjugation is essential to maintain high concentrations of bile acids throughout the length of the small bowel →​Once secreted in the intestine, the bile salts function as surfactants to solubilize dietary fats →​As they pass down the intestinal tract, they are metabolized by bacterial flora, so some of them are converted into deoxycholic acid and lithocholic acid (collectively called Secondary bile acids) Figure 18. Apical Sodium-Dependent Bile Acid Transporter (ASBT) [Asynchronous Video Lecture] ​ Apical Sodium-dependent Bile Acid Transporter (ABST) →​Apical membrane of the enterocytes express the apical sodium-dependent bile acid transporter →​Mediates the reabsorption of bile acids from the ileum Figure 16. Secondary bile acids.[Asynchronous Video Lecture] ​ The bile acids are absorbed from the small intestine via two pathways: →​(1) Passive absorption down the length of the small bowel →​(2) Taken up at the distal ileum via an active transport system, → reabsorbed to transport bile salts back to the liver → re-conjugated and re-secreted to the bile Figure 19. Reabsorption of Bile Acids.[Asynchronous Video Lecture] ​ Reabsorption of Acids →​Liver extracts the bile salts from the portal blood and adds them to bile acid pool →​Bile acids will induce flow of bile and the secretion of biliary lipids (i.e. phospholipids and cholesterol) by generating an osmotic water flow as it moves into the bile canaliculus Figure 17. Enterohepatic Circulation.[Asynchronous Video Lecture] PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 5 of 21  Bilirubin Production (refer to Figure 21) →​Enzyme heme oxygenase catalyzes the oxidation of heme moiety to biliverdin, which has a characteristic green color →​Biliverdin is quickly broken down to yellow bilirubin, which is the end product of heme metabolism →​Bilirubin is released from the macrophages and binds to albumin in the plasma ▪​ This protein-bound form of bilirubin is referred to as unconjugated, free, or indirect bilirubin (B1) →​The unconjugated bilirubin is carried to the liver where it is taken up by hepatocytes Figure 20. Enterohepatic Circulation.[Asynchronous Video Lecture] →​Cholesterol 7⍺-hydroxylase ▪​ Inhibited by bile salts ▪​ Rate-limiting enzyme in bile acid synthesis →​When large quantities of bile salts are recirculated to the liver, it will shut off bile acid synthesis →​When there are few bile salts in the portal circulation, there will be an increased demand for bile acid secretion →​Bile flow from liver to duodenum depends on a balance between the production and demand for bile →​The total pool of bile salts in the body is ~2-4 grams ▪​ Includes the bile salts in the liver, bile ducts, gallbladder, and the intestine →​While significant amounts of bile acids are secreted into Figure 22. Intrahepatic processing of Bilirubin.[Asynchronous Video Lecture] the GIT every day, only small quantities of it are lost ▪​ The liver replaces only a small percentage of bile salt →​At the cell surface (commensurate to what was excreted in the feces) ▪​ Bilirubin dissociates from albumin and is selectively transported in the hepatocyte towards the endoplasmic reticulum. →​Inside the endoplasmic reticulum ▪​ Bilirubin undergoes conjugation with glucuronic acid through the action of Uridine Glucuronosyltransferase (UGT) ▪​ The newly conjugated bilirubin is transported into the bile canaliculus by the Multidrug Resistance Protein 2 (MRP-2) Figure 21. Bilirubin Production and Excretion.[Asynchronous Video Lecture] Bilirubin → Major pigment in the bile → Breakdown product of hemoglobin ❗ Figure 23. Bilirubin Excretion.[Asynchronous Video Lecture] Bile Pigment Elimination Pathway ​ Conjugated bilirubin is called direct bilirubin (B2) → Responsible for the normal color of urine and feces ​ Two pathways for elimination (Refer to Figure 23) PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 6 of 21  →​(1) A portion is excreted in the urine be transported to the kidneys in the form of →​(2) Other portion travels down the intestine, where it is urobilinogen. deconjugated and converted into the colorless ​ Any problem encountered at any point in the pathway will molecule, urobilinogen produce jaundice. ▪​ ~20% of intestinal urobilinogen enters the →​Example: enterohepatic circulation and is delivered back to the ▪​ ↑ senescent cells = hemolytic disease = ↑ heme liver ▪​ Hypoalbuminemia = ↓ binding with unconjugated ▪​ ~80% passes to the colon, where it is metabolized by bilirubin bacteria into urobilin and stercobilin, which are ▪​ Any factor that can separate bilirubin from albumin: responsible for the brown color of feces acidosis, hypoglycemia, hypoxia, drugs = ↑ ▪​ Some enters the systemic blood circulation and is unconjugated bilirubin excreted in the urine as the yellow pigment, urobilin ​ The liver needs to conjugate bilirubin because it is toxic. ​ Bile pigments do not have an established digestive ▪​ Unconjugated bilirubin can gain entry into different function membranes (e.g., blood-brain barrier) since it is lipid BILIRUBIN FORMATION & EXCRETION BY THE LIVER soluble. ▪​ Unconjugated bilirubin permeability to blood-brain barrier: Kernicterus (bilirubin encephalopathy) ​ Possible problems with conjugation in the liver: →​Lack of enzymes to conjugate bilirubin →​Obstruction LIVER FUNCTION TESTS ​ To assess whether: →​Hepatocytes have been injured or are dysfunctional: ▪​ Alanine aminotransferase (ALT) & Aspartate aminotransferase (AST) −​📣 −​ Formerly called SGOT & SGPT ALT is more sensitive →​To determine whether bile excretion has been interrupted ▪​ Alkaline phosphatase is expressed in the canalicular membrane, and elevations of this enzyme in plasma suggest localized obstruction to bile flow. →​To evaluate whether cholangiocytes have been injured or are dysfunctional ▪​ Increased levels of GGT are seen when there is damage to cholangiocytes. →​To monitor responses to therapy or rejection reactions after liver transplantation OTHER TESTS ​ Bilirubin ​ Serum albumin Figure 24. Bilirubin Formation & Excretion. [Synchronous Video Lec] ​ Blood clotting parameter ( PT) ​ Blood glucose ​ The majority will be coming from the heme released when ​ Ammonia RBCs become old, hemolyse, or if the patient has ​ Imaging test hemolytic disease. ​ Histological exam of biopsy specimen (percutaneous liver ​ Heme will be acted upon by heme oxygenase to form the biopsy) biliverdin. →​Biliverdin: green pigment; circulates in the blood as II. GALLBLADDER unconjugated bilirubin ​ Blind outpouching beneath the liver ▪​ Biliverdin will be reduced to bilirubin ​ Divided into three sections: fundus, body, and neck, ​ Bilirubin reductase will act on biliverdin to form the which connects to the biliary tree via the cystic duct unconjugated bilirubin ​ In the system, the unconjugated bilirubin is transported along with albumin to the liver for the conjugation to occur. ​📣 ​ Has a storage capacity of about 20-50 mL We can survive without a gallbladder →​Because the liver produces bile, and its release is ​ Conjugation will yield substances such as urobilinogen, regulated based on the meals consumed and stercobilin within the intestinal lumen, producing the color of the stools. ​ In the colon, there are organisms that can produce enzymes that can deconjugate a previously conjugated bilirubin. →​Review: When bilirubin becomes unconjugated, it becomes lipid-soluble. It can then now be transported through the membranes and go back to the portal circulation (liver) and peripheral blood. Eventually, it will Figure 25. Structure of Gallbladder. [Synchronous Lecture] PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 7 of 21  ​ The flow of bile is primarily regulated by hormonal and neural signals that affect the actions of both gallbladder and the Sphincter of Oddi Cholecystokinin (CCK) ❗ →​A critical mediator of this response is the hormone, ▪​ Released in response to products of lipid and protein digestion ▪​ Released into the bloodstream by the I cells of the intestine ▪​ Directly causes the contraction of the gallbladder ▪​ Can bind to vagal afferents −​ Causes the relaxation of the Sphincter of Oddi −​ Contribute to gallbladder contractility →​The net result is the ejection of bile into the duodenal lumen Figure 26. Pathway of Gallbladder.[Asynchronous Video Lecture] ​ Functions of the gallbladder →​Filling or storage of bile →​Concentration ❗ →​Ejection of the bile into the lumen of the small bowel ❗ →​ As the gallbladder stores bile, it concentrates it →​ When does the bile get stored in the gallbladder? ▪​ In between meals ​ Biliary Ductules →​Drain into larger bile ducts that coalesce into right and left hepatic ducts →​Both ducts together form the common hepatic duct, from which bile can flow either into the gallbladder (via the cystic duct) or into the small intestine →​The common bile duct is joined by the pancreatic duct to open into the duodenum via the Ampulla of Vater ▪​ Guarded by a thickening of smooth muscles called the Sphincter of Oddi ​ Functions of the Sphincter of Oddi →​Regulates the flow of bile and pancreatic juices into the duodenum Figure 28. Neurohormonal control of Gallbladder contraction and Biliary secretion.[Asynchronous Video Lecture] →​Prevents the reflux of duodenal contents into the bile duct and pancreas →​Promotes the filling of the gallbladder with hepatic bile INTERDIGESTIVE (FASTING) PERIOD ​ The gallbladder is dilated (or relaxed) and the Sphincter of Oddi is contracted ​ Bile moves down the biliary tract, but it cannot pass through the closed sphincter →​Redirected to the gallbladder where it is concentrated and stored ​ To concentrate the bile, the epithelial cells of the gallbladder will absorb water and ions (i.e. sodium and chloride), but NOT the organic components (i.e. bile salts, cholesterol and phospholipids) →​Normally, bile is concentrated to about 5 times but it can be concentrated up to a maximum of 20-fold →​The more concentrated the bile, the more effective it is for promoting fat digestion Figure 27. Illustration of Gallbladder.[Asynchronous Video Lecture] PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 8 of 21  OVERVIEW OF THE HEPATOBILIARY SYSTEM Figure 31. Overview of Hepatobiliary System[Asynchronous Video Lecture] ​ Refer to Figure 31 →​Hepatocytes synthesize and secrete the constituents of bile →​Composition of bile can be modified further as it flows through the biliary ductules and upon storage in the Figure 29. Illustration of Gallbladder.[Asynchronous Video Lecture] gallbladder where it is concentrated due to the active transport of sodium, water, chloride, and most other POSTPRANDIAL (FED) PERIOD diffusible constituents ​ During feeding, beginning with the cephalic phase, there →​Release of cholecystokinin from the I cells triggers the will be gradual rhythmic gallbladder contractions mediated contraction of the gallbladder and the relaxation of the by cholinergic pathways Sphincter of Oddi ​ In response to a meal, the S cells and the I cells actively ▪​ Thus, causing the stored bile to flow into the release the hormones secretin and CCK respectively duodenum →​Secretin stimulates cholangiocytes to provide additional →​In the small bowel, the bile salts will emulsify and bicarbonate into the bile solubilize dietary lipids →​CCK mediates simultaneous contraction of the ▪​ When the absorption of lipids has been completed, gallbladder and relaxation of the Sphincter of Oddi, the bile salts are transported back to the liver via the allowing the bile and pancreatic secretions to be enterohepatic circulation released into the duodenum →​Bile salts will be extracted from the portal blood by the ▪​ Ejection of bile from the gallbladder usually begins hepatocytes to recycle and conserve the pool of bile within 30 minutes after ingestion of food acids available for digestion throughout the day BILIARY SYSTEM Figure 30. Postprandial Period[Asynchronous Video Lecture] ​ 📣 Figure 32. Biliary system[Synchronous Lecture] Right and left hepatic duct (from the liver) → forms the common hepatic duct → joined by the cystic duct (from the gallbladder) → makes up the common bile duct → enters the intestine through the sphincter of Oddi, while PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 9 of 21  the pancreatic duct merges with common bile duct (this is ​ Physical examination: why the secretion of the pancreas combines with the bile) → emaciated with mild jaundice ​ At a functional level, the biliary system can be divided into → abdomen was soft and scaphoid four components: → firm liver edge was palpable 3 cm below the 1.​ Canaliculi: Form the initial biliary secretion right subcostal margin 2.​ Biliary ductules: Made up of columnar epithelial → soft, nontender, tennis ball-sized lump in her cells (cholangiocytes), and both absorb and secrete right upper quadrant; (+) Courvoisier sign various substances into and out of the bile (palpable gallbladder and painless jaundice) ▪​ Perfused by a capillary network arising from the ​ Cholestatic jaundice related to conjugated hepatic artery (rather than from the sinusoids) hyperbilirubinemia ▪​ Majority of this periductular capillary plexus drains →​(+) Jaundice into the sinusoids ▪​ Ictericia: yellowish or greenish pigmentation of the 3.​ Larger bile ductules: Dilute and alkalize the bile skin and sclera due to high bilirubin levels and add mucus ▪​ Big liver: compresses/adds pressure to the tubes 4.​ Gallbladder: For storage →​(+) Pale / Clay-colored feces ▪​ Abnormal: Gray, cream BILE ▪​ Normal: Yellow to brown ▪​ Lack of pigment due to the obstruction to the flow of bile ▪​ Accumulation of conjugated bilirubin →​(+) Dark-colored Urine ▪​ Conjugated bilirubin: water soluble and can be excreted in urine, giving it a dark color →​(+) Pruritus *Note: See appendix for UpToDate® tables shown during the synchronous lecture Figure 33. Biliary system[Synchronous Lecture] 📣 ​ Main secretion of the liver →​ Liver fulfills its excretory function by producing this substance ​ Yellow, brownish or olive-green liquid secreted by hepatocyte (0.5L/day) ​ pH of 7.6-8.6 Figure 34. CT Scan of the Abdomen[Synchronous Lecture] ​ ​ 📣 ​ Stored and concentrated in the gallbladder 📣 Lipid-rich Components: bile acids, phosphatidylcholine, ​ Figure 34 shows a fatty liver and dilated intrahepatic ducts (black arrow) →​When a patient has a palpable mass, the first ​📣cholesterol Primary bile acids enter the distal small intestine or colon where they are acted upon by bacteria, which imaging procedure is likely an ultrasound ▪​ Ultrasound can differentiate between a cyst and a solid mass, but a CT scan provides more produces enzymes that leads to the production of specificity secondary bile acids. ​ Primary Bile Acids →​Chenodeoxycholic acid →​Cholic acid ​ Secondary Bile Acids →​Litocholic →​Deoxycholic acid →​3rd secondary bile acids: *Ursodeoxycholic acid Case 1: Conjugated Hyperbilirubinemia [Synchronous Lecture] 85 year old woman with 2-month history of generalized weakness, malaise, nausea, decreased appetite and 9 kg weight loss, (+) generalized pruritus of 2 weeks duration, (-) abdominal pain, vomiting or abnormal bowel Figure 35. CT Scan of the Abdomen[Synchronous Lecture] movements, (+) darker urine color ​ Figure 35 shows the dilated pancreatic duct (white ​ Vital signs: BP: 120/80 mmHg HR= 87 RR 18/min arrowhead), dilated common bile duct (white arrow), T= 37 C and enlarged gallbladder (black arrow) PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 10 of 21  →​Why is everything dilated? →​Its main duct (pancreatic duct) forms a merger with the ▪​ Probably because something is obstructing the common bile duct, which then opens in the duodenum flow through the major papilla (Ampulla of Vater) Figure 36. CT Scan of the Abdomen[Synchronous Lecture] Figure 38. Network of Ducts of the Pancreas[Asynchronous Video Lecture] ​ Figure 36 shows an enlarged gallbladder (black arrow), and an inhomogeneous head of pancreas ​ Divided into three regions: head, body, and tail with a small soft-tissue density (white arrow) Figure 39. Regions of the Pancreas[Asynchronous Video Lecture] FUNCTION OF THE PANCREAS ​ Classified as a mixed gland as it has both endocrine and exocrine functions ​ Endocrine Function Figure 37. Probable location of the mass (red circle) [Synchronous →​Secretes hormones responsible for the maintenance of Lecture] glucose homeostasis, including insulin and glucagon ​ Elderly patients presenting with jaundice and an ​ Exocrine Function enlarged, palpable gallbladder →​Secretes digestive enzymes responsible for normal →​There is an obstruction that is causing the digestion, absorption, and assimilation of nutrients enlargement →​Most enzymes required for digestion of macromolecules ​ Significant weight loss →​Findings: 9 kg weight loss within a period of 2 are from the pancreas months →​Also secretes an alkaline fluid, which functions to ​ Possibility: neutralize the acidic chyme from the stomach →​Neoplastic process involving the head of pancreas or →​Majority of the pancreatic cell population is the ampulla of Vater exocrine in nature →​Figure 37 describes the probable location of the ▪​ Arranged in several lobules, each of which contains mass which explains all the dilation of all the ducts clusters of secretory cells called acinar cells and the gallbladder →​It is possible that this is the mass seen in Figure (last ▪​ Secretion of these cells are then released into the CT scan) ducts, which then open into the main pancreatic duct ▪​ Scattered throughout the pancreatic lobules are III. EXOCRINE PANCREAS discrete islets called islets of Langerhans (this A. OVERVIEW OF THE PANCREAS actually comprises the endocrine portion) ​ Pear-shaped organ located in the retroperitoneal compartment ​ Lies directly behind the stomach and is surrounded by the following: proximal small bowel, liver, and gallbladder ​ Plays an important role in digestion by secreting digestive enzymes via a network of ducts PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 11 of 21  ​ Epithelial Cells of the Pancreatic Duct or Ductular cells →​Primary function: to produce a bicarbonate-rich aqueous secretion ▪​ Alkalinizes whatever is secreted by acinar cells 📣 ▪​ When stimulated, these transport bicarbonate ions into the pancreatic juice −​ Dilutes the pancreatic juice = makes it more alkaline Figure 40. Organization of the Pancreas[Asynchronous Video Lecture] Figure 43. Pancreatic Ductular Cells [Synchronous Lecture] 📣 [Synchronous Lecture] Figure 41. Structure of the Pancreas ​ The acinar cells secrete digestive enzymes into the pancreatic duct which eventually joins the common bile ​ 📣 Structural divisions: duct as it enters the duodenum →​Head →​Neck →​Body ​ 📣 →​Tail Functional divisions: →​Endocrine pancreas →​Exocrine pancreas CELL TYPES OF EXOCRINE PANCREAS ​ Pancreatic acinus or Acinar cell →​Regarded as the functional unit →​Main role: to synthesize and secrete the digestive 📣 enzymes →​ source of the majority of pancreatic juice Figure 44. Schematic of pancreatic structure[Asynchronous Video Lecture] B. DIGESTIVE ENZYMES OF THE PANCREATIC ACINAR SECRETION ​ Produced in minute volumes and functions to digest proteins, carbohydrates, fats, and nucleic acids Table 1. Products of Pancreatic Acinar Cells Precursors of Proteases Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase A Procarboxypeptidase B Starch-Digesting Enzymes Amylase Lipid-Digesting Enzymes or Precursors Figure 42. Pancreatic Acinar Cells [Synchronous Lecture] Lipase →​Basolateral membrane Nonspecific esterase ▪​ Contains receptors for neurotransmitters (e.g., CCK) Prophospholipase A2 ▪​ Leads to production of Ca2+ intracellularly ⇒ results Nucleases in discharge of granules in the apical side Deoxyribonuclease −​ These granules contain the inactive forms of Ribonuclease enzymes Regulatory Factors →​Apical membrane Procolipase ▪​ Where these granules are liberated and will now be Trypsin inhibitors secreted in the ductular cells Monitor peptide PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 12 of 21  📣 Theoretically, majority of the products are proteases ​ All are inactive precursors of their specific enzymes →​Pancreatic proteases are packaged and stored in the pancreas as inactive to prevent auto-digestion ​ Most abundant: Trypsinogen PRECURSORS OF PROTEASES ​ Precursors of Proteases →​Enzymes that break down dietary proteins →​Secreted as inactive forms (called precursors or zymogens) ❗️ →​Become active upon its secretion in the duodenal lumen →​ Premature activation of these zymogens will damage the cells and trigger inflammation in the pancreas ▪​ The inactive forms of these enzymes is one of the protective mechanisms that prevent the pancreas from digesting itself Figure 45. Enzyme synthesis, condensation, and storage [Asynchronous Video Lecture] ▪​ Other enzymes on the table above are already secreted as their active forms 4. The granules then move closer to and fuse with the plasma ​ Starch-Digesting Enzymes membrane at the apical region upon stimulation of the acinar →​Pancreatic Amylase cell by the following secretagogues: ▪​ Digests starch →​Acetylcholine (Ach) ▪​ Also used as a primary marker for the secretion of ▪​ From the vagal pathways (vagal nerve) acinar cells, and as a diagnostic tool for screening →​Cholecystokinin (CCK) acute pancreatitis ​ Lipid-Digesting Enzymes or Precursors ❗️ ▪​ Hormone →​ In some textbooks, Ach and CCK are considered the main stimuli or pathways for pancreatic enzyme →​Pancreatic Lipase ▪​ Digests lipids secretion ​ Nucleases →​Gastrin-Releasing Peptide (GRP) →​Helps digest DNAs and RNAs present in our diet ▪​ From the enteric nervous neurons in the stomach and intestines ​ Regulatory Factors (miscellaneous products) →​Procolipase ▪​ Digestion of intestinal fat →​Trypsin inhibitors ▪​ Prevent the activation of trypsin while inside the pancreas, thus serve as an internal blocker of proteolytic enzymes →​Monitor Peptide ▪​ Plays a role in the release of cholecystokinin C. MECHANISM OF ENZYME SECRETION ​ By pancreatic acinar cells; the main pathway for the synthesis and secretion of pancreatic digestive enzymes. 1. Enzymes are synthesized in the rough endoplasmic reticulum 2. Transferred to the Golgi complex 3. Transferred to condensing vacuole, where they are concentrated and stored in zymogen granules Figure 46. Acinar cell stimulation by secretagogues[Asynchronous Video Lecture] 5. These three act by mobilizing intracellular calcium 6. This leads to the phosphorylation of cytosolic proteins 7. Move the granules towards the apical membrane for exocytosis of these zymogens and enzymes into the acinar lumen Space intentionally left blank PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 13 of 21  Figure 47. Mobilization, phosphorylation & exocytosis of zymogens Figure 49. Contents of pancreatic acinar & duct cell and enzymes[Asynchronous Video Lecture] secretion[Asynchronous Video Lecture] E. TRANSPORT PROCESSES IN THE DUCTAL SECRETIN AND VIP EPITHELIAL CELL ​ Other hormones such as secretin and vasoactive intestinal polypeptide (VIP) also stimulate enzyme secretion via the cyclic AMP-dependent signaling pathways Figure 50. Mechanism of Pancreatic Duct Cell Secretion[Asynchronous Video Lecture] ​ Polar sides of the cell have different channels/transporters →​Basolateral side/membrane: ▪​ Na-H Exchanger Figure 48. Secretin and VIP stimulation of enzyme secretion[Video ▪​ Na-K ATPase Lecture] →​Apical membrane ▪​ Chloride-bicarbonate exchanger D. OTHER COMPONENTS OF THE ACINAR FLUID ▪​ CFTR (Cystic Fibrosis Transmembrane conductance ​ Contents of pancreatic acinar secretion: Regulator) Chloride channel →​Digestive enzymes ​ Ductal cells →​Water →​Primary source of bicarbonate in the pancreas →​Sodium, Potassium, Chloride, and Bicarbonate →​Achieved by the coordinated actions of ion transport ▪​ The ionic composition of this “primary secretion” is pathways similar to plasma in terms of concentration MECHANISM FOR SECRETION OF AQUEOUS ​ The primary secretion (pancreatic acinar secretion) is then COMPONENTS modified by the epithelial cells of the pancreatic ducts ​ Bicarbonate can be generated intracellularly from CO2 and which secrete the aqueous component of the pancreatic water via the enzyme carbonic anhydrase juice →​This is secreted through an exchange mechanism with ​ Contents of pancreatic duct cell secretion (pancreatic chloride on the apical membrane juice): ​ Chloride is transported into the lumen through the CFTR →​Water channel and it will be recycled by anion exchanger →​Sodium, and (rich in) bicarbonate (Chloride-bicarbonate exchanger) to secrete bicarbonate ▪​ Bicarbonate serves to neutralize the acid from the →​Cystic fibrosis stomach ▪​ Caused by a mutation in the CFTR gene that leads to →​Secretion of the pancreatic duct cells accounts for a defective chloride channel approximately 75% of the pancreatic fluid ▪​ This affects the function of a variety of epithelial organs—lungs, intestine, biliary system, and pancreas PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 14 of 21  ▪​ There is an impaired ability to hydrate and alkalinize ​ ↑ increase in flow rate = ↑ concentration of bicarbonate in the luminal contents of the gut the pancreatic juice ​ On the other hand, Na-H exchanger on the basolateral ​ ↑ increase in flow rate = ↓ concentration of chloride membrane acts as an extruder of protons →​because Chloride is absorbed in lumen →​By removing excess hydrogen in the cell, it promotes the formation of bicarbonate from carbonic acid ​ This modified secretion is mainly comprised of sodium, ​ In addition, through the actions of Na-K ATPase, together bicarbonate, and water with the basolateral potassium channels, the cell is able to ​ Similar to saliva, electrolyte composition of the pancreatic maintain its negative membrane potential fluid is dependent on its secretory rate →​This provides a driving force for the secretion of anions G. PHASES OF PANCREATIC SECRETION across the luminal membrane ​ The net effect of these transport processes is the net secretion of bicarbonate into the pancreatic juice ​ After the transport of bicarbonate into the ductal lumen, sodium and water are also secreted to counter the electrical and osmotic forces resulting from bicarbonate secretion F. MODIFICATION OF PRIMARY SECRETION ALONG THE PANCREATIC DUCTS Figure 53. Typical Pattern of Enzyme (e.g. Trypsin) Secretion during Fasting and Fed State[Asynchronous Video Lecture] ​ Two distinct patterns of secretion which correspond to two physiologic states →​Fasting State (or Interdigestive Period) →​Fed State (or Digestive Period) FASTING STATE Figure 51. Relationship between Ionic Composition of Pancreatic Juice and the Pancreatic Flow Rate[Asynchronous Video Lecture] ​ Concentration of sodium and potassium remain constant regardless of the flow Figure 54. Typical Pattern of Trypsin Secretion during the Fasting ​ Concentration of bicarbonate and chloride varies, and State[Asynchronous Video Lecture] has a reciprocal relationship because of the ​ The pancreas (like other organs in upper GIT) chloride-bicarbonate anion exchanger in the ductal cells demonstrates a basal enzyme release during fasting ​ During unstimulated state (flow rate is basal), electrolyte →​Its rate of secretion varies with the changes in small composition of the pancreatic juice resembles the plasma bowel motility ​ The colored vertical bands correspond to phases I, II, and III of the migrating motor complex of the small bowel (as discussed in the lower GI lecture) ​ The cyclical pattern of secretion during fasting is predominantly under parasympathetic control ​ Conversely, sympathetics will inhibit the secretion, but they are only a minor influence →​Phase I (Intestinal Quiescence): Minimal Secretion →​Phase III: Reaches peak ​ However, this maximal secretion during fasting is still relatively low compared to the rate of secretion when food is being digested FED STATE ​ During digestion (fed state), pancreatic secretion increases Figure 52. Plasma contents[Video Lecture] significantly to about ten-folds of the basal rate ​ Three phases of pancreatic secretion during digestion: ​ Upon stimulation, ductal cells secrete greater amounts of Cephalic Phase, Gastric Phase, and Intestinal Phase isotonic solution →​Follows the progression of a meal along the GI tract PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 15 of 21  →​Physiological concentrations of gastrin can stimulate the acinar cells to induce digestive enzyme secretion, although its mechanism is still unclear ​ However, this phase contributes only about 5-10% of pancreatic enzymes because of the continued lack of significant fluid secretion INTESTINAL PHASE Figure 55. Phases of Pancreatic Secretion [Synchronous Lecture] CEPHALIC PHASE Figure 58. Intestinal Phase[Asynchronous Video Lecture] ​ Most important physiologically →​Because most pancreatic secretions and activity occur in this phase ​ Acidic chyme enters the duodenum →​In response, the pancreas secretes bicarbonate ▪​ Bicarbonate is used to restore the neutral pH of the lumen ​ Hormone secretin is released when pH falls below approximately 4.5 Figure 56. Cephalic Phase[Asynchronous Video Lecture] →​Released by S Cells (found in small intestinal epithelia) ​ Initiated by sight, smell, or taste of the food (during SECRETIN mastication) and other conditioned reflexes (ex. thought MECHANISM and hearing about food) ​ Mediated by the same neural pathways that cause secretions in the stomach ​ The efferent signal travels along the vagus nerve to stimulate the muscarinic receptors of the acinar as well as the ductal cells →​This secretory activity is inhibited by adrenergic stimuli ​ Produces mainly an enzymatic secretion and generates only modest amounts of fluid and electrolytes ​ Altogether, this accounts for up to 25% of pancreatic secretion GASTRIC PHASE Figure 59. Secretin binding to corresponding Pancreatic Duct Cell ​ 📣 Receptor[Asynchronous Video Lecture] To which pancreatic ducts respond →​Also released by the duodenum ​ From the S Cells, secretin diffuses into the bloodstream →​Ultimately, binding to pancreatic duct cells (on the basolateral membranes) ▪​ Triggers copious secretion of pancreatic fluid rich in bicarbonate Figure 57. Gastric Phase[Asynchronous Video Lecture] ​ Binding of secretin to pancreatic duct cell receptors involves the action of the following secondary messengers ​ Initiated by distension of the stomach with food by as secondary effectors: stimulating the local neural pathways, specifically the →​Cyclic AMP gastropancreatic reflex (vagovagal reflex) →​Protein Kinase A ​ Presence of specific peptides or amino acids stimulates ​ Phosphorylation of serine activates CFTR chloride the release of gastrin from the G-cells of the stomach, channels which target the CCK2 receptors of the acinar cells PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 16 of 21  →​Causes outflow of Cl- ions into the pancreatic duct CCK lumen ▪​ Chlorine outflow secondarily drives the activity of an adjacent chloride-bicarbonate anion exchanger −​ Exchanges chlorine ions to bicarbonate Figure 62. Role of CCK [Synchronous Lecture] Figure 60. Role of Secretin [Synchronous Lecture] ​ 📣 Role: acinar secretion of pancreas ⇒ leads to release of all these enzymes ACTION →​Also plays role in gallbladder ⇒ allows it to contract ​ MAINLY stimulates the secretion of bicarbonate-rich →​Synergistically relaxes the sphincter of Oddi so that all pancreatic juice from pancreatic duct cells these can happen for digestion →​Results in the buffering action (acidic chyme →​Main receptor of role of CCK: acinar cells neutralization) that is important in: ▪​ Protecting intestinal mucosa REGULATION ▪​ Ensuring pancreatic lipase, which is inactive at low ​📣 pH, remains active upon secretion Considered to function as a “pH meter” →​Able to sense the acidity of the luminal contents ​ It also has a direct effect on acinar cells and digestive enzyme secretion →​Amino acids, small peptides, and fatty acids in chyme stimulate CCK hormone release (Figure 63. CCK Regulation) ▪​ CCK is released by the I cells of the intestinal mucosa REGULATION ​ The increase of luminal pH signals the termination of secretin release from S cells (Negative Feedback Loop) ​ The effect of secretin is potentiated by: Figure 63. CCK regulation[Asynchronous Video Lecture] →​Acetylcholine ​ CCK release is stimulated and regulated by two releasing →​CCK factors: →​CCK-releasing peptide (CCK-RP) ▪​ From intestinal epithelial cells ▪​ Also secreted in response to amino acid and fatty acid digestion in the intestinal lumen →​Monitor peptide ▪​ From pancreatic acinar cells ▪​ Contained within pancreatic juice −​ This is why, unless pancreatic secretion is already underway, CCK stimulation will not be stimulated readily ​ Secretion of both factors can be initiated by neural inputs →​Especially during the cephalic and gastric phases ▪​ Done to prepare the system for digestion once the Figure 61. Action & Regulation of Secretin[Asynchronous Video Lecture] food arrives in the duodenum Space intentionally left blank Space intentionally left blank PHYSIOLOGY GIT 2: Liver, Gallbladder and Pancreas Page 17 of 21  MECHANISM OF RELEASE SUMMARY ​ CCK secretion is a response to protein and fat digestion products in the intestinal lumen ​ The main effect of CCK in the pancreas is its stimulation of digestive enzyme release from acinar cells ​ Regulation is done by two releasing factors →​CCK-RP from the small bowel →​Monitor peptides from the pancreas ​ Take note of the important pancreatic enzymes secreted once food arrives in the duodenum (as seen in Table 2) G. MYTHS AND REALITIES ABOUT ALCOHOL AND SMOKING IN CHRONIC PANCREATITIS ​ Myth #1: Chronic Pancreatitis patients are ALL Figure 64. Role of proteins in CCK regulation[Asynchronous Video Lecture] alcoholics ​📣 Produced by the duodenum ​ Both the CCK-releasing peptide and monitor peptide →​Reality: Pancreatitis is a multifactorial disease. Alcohol is the most commonly identifiable risk factor for chronic pancreatitis, but many cases of chronic pancreatitis may stimulate the I cells to release CCK occur independently of any alcohol. ​ Both releasing factors being peptides, they are subjected ​ Myth #2: Alcohol causes pancreatitis to proteolytic degradation →​Reality: Alcohol does not cause pancreatitis directly. →​Degradation is done by pancreatic proteases such as Heavy alcohol consumption has a variety of effects on trypsin the pancreas, brain, and the immune system. These ▪​ Results in low CCK secretion effects sensitize the pancreas to injury and promote ​ However, protein may “compete” with the two factors for disease progression after initiation of pancreatic injury. degradation by trypsin ​ Myth #3: Most people who drink heavily develop →​When protein is ingested, the lumen will have: pancreatitis ▪​ Protein >>> releasing factors →​Reality: Clinical pancreatitis develops in 5% of →​The presence of protein in the proximal bowel will individuals who drink heavily. Consumption of greater protect both releasing factors from being broken down than or equal to 4-5 drinks per day increases the risk of by trypsin, making them available for the stimulation of developing pancreatitis. Regular consumption of alcohol CCK release at lower levels is likely a co-factor in disease →​Once the meal has been digested and absorbed, the development. Safe limit of alcohol consumption for releasing factors will start to get degraded incident pancreatitis is currently not established. Alcohol ▪​ Eventually shutting off the signals for CCK secretion consumption affects the clinical presentation of the FUNCTION IN THE PANCREAS disease. ​ Main function is to evoke the secretion of pancreatic ​ Myth #4: The risk of pancreatitis is lower with beer (or digestive enzymes, which may occur through two wine) drinking pathways →​Reality: The role of beverage type on the risk of →​First Pathway pancreatitis needs further study. The amount of alcohol ▪​ CCK will travel through the bloodstream to reach the consumed likely has a far greater impact in the risk of CCK-1 receptors of pancreatic acinar cells pancreatitis than beverage type. ▪​ Aside from releasing digestive enzymes, acinar cells ​ Myth #5: Patients with alcoholic acute pancreatitis also secrete small amounts of isotonic fluid either have or will progress to chronic pancreatitis →​Second Pathway →​Reality: Progression to chronic pancreatitis after an ▪​ CCK binds to receptors in vagal afferent nerve episode of alcohol pancreatitis occurs in a subset of endings in small bowel and pancreas patients. The risk of disease progression is directly −​ Indirectly stimulates acinar cell secretion through linked to the continuation of alcohol consumption (and the cholinergic pathway smoking). o​ Secretion may also be stimulated by H. SUMMARY secretagogues: GRP, Secretin, VIP ​ Hormones CCK and Secretin mainly control the secretions during the intestinal phase of pancreatic secretion →​Net effect is the stimulation of enzymatic and aqueous secretions in response to acid and partially digested