47: Pancreatic/Biliary Function Flashcards
List the stimuli that release secretin and CCK and explain the route by which these regulatory peptides stimulate the pancreas.
Vagal stimulation is via ACh. CCK, ACh, and gastrin increase intracellular calcium. Secretin and VIP increase cAMP. Secretin and CCK act synergistically, i.e. their effect when both are present is greater than the sum of their effects when either is acting alone.
VIP is a neurotransmitter in the gut normally not important in pancreatic secretion, but it becomes important in certain pancreatic tumors known as vipomas, which result in a watery diarrhea.
Note that secretin and CCK potentiate each others actions both on pancreatic enzyme secretion and stimulate pancreatic aqueous secretion described later.
Secretin, using a cMP 2nd messenger activates the CFTR Cl- channel, thereby replenishing lumenal Cl- needed for Cl-/HCO3- exchange.
CCK acts via PLC to increase the intracellular calcium concentration. This potentiates the action of Secretin by priming the Na/K ATPase.
Describe the role of CFTR in the pancreatic ductal secretion, and predict the consequences of cystic fibrosis on the GI system.
Both ACh and CCK stimulate Cl- (NaCl) secretion.
Bicarbonate accumulates inside the pancreatic duct cell and exits across the apical membrane via a Cl-/HCO3- exchanger. The rate at which this exchanger cycles depends on the availability of substrate, including luminal chloride, which in turn depends on the opening of an apical Cl- channel.
This chloride channel is the CFTR (Cystic Fibrosis Transmembrane Regulator) channel, which is activated by the hormone secretin, utilizing cAMP as its second messenger to open the chloride channel. (The channel only opens when its R domain is phosphorylated by PKA.) The basolateral membrane contains the ubiquitous Na+/K+ pump which provides much of the driving force for the Na+/H+ exchanger.
Cystic fibrosis. If the CFTR chloride channel is blocked or defective, the pancreatic ducts become filled with a thick viscous secretion of enzymes which clog the pancreatic ducts which interferes with digestion. Pulmonary mucous is also thick & viscous causing dypsnea & death. Salty baby.
Describe the mechanism by which bicarbonate is taken up or generated by the pancreatic ductal cells.
Exocrine Pancreas produces bicarb.
The aqueous secretion originates in the centro-acinar cells and epithelial cells of intercalary ducts. The acid chyme in the stomach is less than pH 2 and must be neutralized to permit the pancreatic enzymes to function.
The fundamental secretory unit is composed of an acinus and an intercalated duct. Intercalated ducts merge to form intralobular ducts, which, in turn, merge to form interlobular ducts, and then the main pancreatic duct.
The secretion of enzymes originates in pancreatic acinar cells. Enzymes formed on ribosomes accumulate in rough surfaced cisternae. Smooth-surfaced vesicles containing enzymes bud off, coalesce to form zymogen granules that usually contain pro-enzymes. Mature zymogen granules fuse with apical membrane and contents are discharged into lumen of acinus during secretion.
The zymogen granule protects the pancreas from auto-digestion. In pancreatitis, enzymes are released into the cell instead of being packaged in granules.
Model for Na+ and HCO3- secretion by pancreatic duct cells:
The initial step in bicarbonate secretion by the duct cell is diffusion of CO2 from the blood across the basolateral membrane into the duct cell. It is immediately hydrated by carbonic anhydrase (CA) to carbonic acid, which rapidly dissociates to form H+ and HCO3-. The proton moves across the basolateral membrane either by a Na+/H+ exchanger or an electrogenic proton pump. Note that this pump is different from the H+/K+ pump of the parietal cell (it is not affected by omeprazole). Bicarbonate accumulates inside the duct cell and exits across the apical membrane via a Cl-/HCO3- exchanger. The rate at which this exchanger cycles depends on the availability of substrate, including luminal chloride, which in turn depends on the opening of an apical Cl- channel.
This chloride channel is the CFTR (Cystic Fibrosis Transmembrane Regulator) channel, which is activated by the hormone secretin, utilizing cAMP as its second messenger to open the chloride channel. (The channel only opens when its R domain is phosphorylated by PKA.) The basolateral membrane contains the ubiquitous Na+/K+ pump which provides much of the driving force for the Na+/H+ exchanger.
Also in the basolateral membrane is a Ca++-activated K+ channel. Cholecystokinin (CCK), which utilizes Ca++ as its second messenger, serves to potentiate the action of secretin. The K+ which leaves the cell via this channel is thought to help prime the Na+/K+ pump, thereby increasing the rate of secretion by the duct cell. One consequence of anion diffusion into the lumen, and cation diffusion into the interstitial fluid across the duct cell, is the generation of a luminal negative transmembrane PD. This PD provides a driving force to move Na+ and K+ ions into the lumen via the cation-selective paracellular pathway.
When the pancreatic flow rate changes, the Na+ and K+ concentrations in pancreatic juice remain constant, whereas the HCO - and Cl- change. If the rate of secretion is rapid, the secretion will be high in bicarbonate. If the rate of secretion is slow, the bicarbonate and chloride concentrations will resemble those of plasma and extracellular fluid due to exchange. The ‘exchange hypothesis’ accounts for the increase in bicarbonate with increased secretory rate.
Explain the effect of the autonomic innervation of the pancreas and the vago- vagal reflexes on pancreatic secretion.
3 stages of pancreatic secretions:
1) cephalic phase: vagal stimulation has greater effect on enzyme secretion from acini than on ductal aqueous secretion.
2) gastric phase: distension of body of stomach induces pancreatic enzyme secretion by vago-vagal reflex. Antral distension release gastrin which stimulates acinar cells to secrete enzymes (and the oxyntic parietal cells to secrete HCl).
3) Intestinal phase: Secretin and Cholecystokinin (CCK) released into the blood from intestinal cells in response to products of digestion.
Secretin (nature’s antacid) - hormone released into blood from duodenal mucosa in response to acid in the duodenum, elicits an aqueous secretion by duct cells. Pancreatic aqueous secretion is:
(a) high in volume
(b) high in HCO3- concentration
(c) low in enzyme content
(d) stimulates pepsinogen secretion
Cholecystokinin (CCK) - hormone released into blood from duodenal mucosa in response to either protein digestion products or fatty acids in the duodenum; elicits enzyme secretion by acinar cells. Pancreatic enzyme secretion is:
(a) high in enzyme content
(b) low in volume
(c) stimulates bile secretion
Discuss Bile (non-objective)
Bile:
A yellow-green,alkaline solution containing bile salts, bile pigments, cholesterol, neutral fats, phospholipids, and electrolytes
Bile salts are cholesterol derivatives that Emulsify fat, Facilitate fat and cholesterol absorption, Help solubilize cholesterol.
Enterohepatic circulation recycles bilesalts
The chief bile pigment is bilirubin, a waste product of heme
Bile salts are amphipathic, i.e. they contain both a hydrophobic end (steroid nucleus) and a hydrophilic end. All contain the same hydrophobic end, but the hydrophilic ends differ.
Non-conjugated bile salts have a pK of ca. 7, i.e., at a pH of 7 only half are ionized, i.e., only half are effective amphipaths.
Bile salts are conjugated with glycine (75%) or taurine (25%) in the liver. Glycine conjugates have a pK of 3.7; taurine conjugates have a pK of 1.5. Therefore, at pH 7 virtually all conjugated bile salts are anionic, i.e., they are very water soluble.
The term biliary tree is derived from the arboreal branches of the bile ducts. The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts. Within the liver, these ducts are called intrahepatic (within the liver) bile ducts, and once they exit the liver they are considered extrahepatic (outside the liver). The intrahepatic ducts eventually drain into the right and left hepatic ducts, which merge to form the common hepatic duct. The cystic duct from the gallbladder joins with the common hepatic duct to form the common bile duct. Bile either drains directly into the duodenum via the common bile duct, or is temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the second part of the duodenum together at the ampulla of Vater. The sphincter of Oddi is a muscular valve that controls the flow of digestive juices (bile and pancreatic juice) through the ampulla of Vater into the second part of the duodenum.
Order of flow: Bile ducts -> hepatic ducts -> common bile duct -> duodenum cystic duct -> gall bladder
When the sphincter of Oddi is open bile is free to flow into the duodenum. When it is closed it is diverted into the Gallbladder.
Bile is stored and concentrated in gall bladder. CCK contracts the gall bladder and relaxes the Sphincter of Oddi. It is necessary for digestion & absorption of lipids as well as elimination of cholesterol and bile pigments.
Composed of bile acids (~50%), phospholipids (~25%), cholesterol (~4%), bile pigments (~2%), inorganic ions and IgA.
Hepatic production of bile acids is the major route of cholesterol and steroid hormone breakdown.
Bile returns to the liver bound to albumin. It is taken up by the liver by specific transporters: sodium taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptide (OATP).
Bile acid independent secretion of watery bicarbonate is stimulated by secretin.
Bile acid dependent secretion by hepatic perenchymal cells = stimulation to secrete bile by bile returning to liver in portal blood. Synthesis of bile is inhibited by returning bile via negative feedback.
Enterohepatic circulation of bile acids: Most bile acid are reabsorbed as conjugated bile salts (BA-Z-) in the terminal ileum through an Na+- coupled cotransporter (ASBT). Bacteria deconjugate a small amount of the bile salts to unconjugated bile acids (H-BA), which are passively absorbed by nonionic diffusion. Bacteria also dehydroxylate primary bile acids to secondary bile acids. Some are captured and returned to the liver others are excreted in the feces. Bile salt malabsorption caused by terminal ileum resection can cause chronic diarrhea. Bile acid sequestrants is often an effective treatment.
Certain bile constituents, especially bile pigments, bile salts, cholesterol, lecithin and fatty acids are concentrated in the gallbladder. This results from (1) the active transport of Na+, Cl- and HCO3- out of the lateral membranes of gallbladder epithelial cells (pulling water out), and (2) continued micellar formation.
The gallbladder empties due to the Vagus & CCK.
Physical forms adopted by bile salts in solution. Micelles are cylindrical. Above the critical micelle concentration (CMC) bile salts are spontaneously self associated into mixed micelles. These micelles serve as solvents for hydrophobic waste products to be removed from the body and hydrophobic components of the diet to be captured from the intestine.
Cholecystitis is the inflammation of the gallbladder caused most commonly by the blockage of the cystic duct by a gallstone. This causes a backup of bile in the gallbladder potentially damaging this organ.
Formation of gallstones. Cholesterol gallstones are the most common type which occur in the U.S. (pigment stones are more common in parts of the Far East and Africa). Cholesterol gallstone formation may be divided into three stages:
1. supersaturation of cholesterol - occurs in the liver. 2. nucleation and precipitation - seeding of cholesterol crystals or microstones - probably occurs in the gallbladder. 3. growth of microstones to form macrostones
