GI Secretory Functions Part 2

Digestive Period

Digestive period: ◦Delivered into duodenum due to CCK which contracts gallbladder and relaxes the Sphincter of Oddi. ◦After emulsification of lipids and absorption, most bile salts are reabsorbed from the terminal ileum to the portal vein and sent back to liver. ◦Small portion of bile salts are deconjugated to yield bile acids, which can be reabsorbed by passive diffusion. Lower than 10% daily bile acids are eliminated into feces. ◦During the digestive period, bile acid biosynthesis is inhibited.

Bile Acid/Salt Enterohepatic Circulation

-250-1500 ml of bile enter the duodenum daily -Bile salts may be deconjugated by bacteria in the GI tract, resulting in bile acids -The majority of the bile acids/salts are reabsorbed and returned to the liver (<10% is excreted) -Returned bile acids/salts are actively taken up by hepatocytes -In the hepatocytes, bile salts are directly secreted; bile acids are (re-) conjugated and secreted. •The enterohepatic circulation controls the rates of bile acids synthesis and transport. •Bile acids exert feedback inhibition on cholesterol 7 -hydroxylase, such that when return of bile acids from the intestine is high, the synthesis of new primary bile acids is reduced. Conversely, interruption of the enterohepatic circulation relieves this feedback inhibition, increasing the rate at which cholesterol is converted to bile acids. Absorption of conjugated bile acids is an active process, while absorption of deconjugated bile acids is passive.

Hepatic Secretion

-Bile: (0.25 to 1 L)daily -Components of bile: bile salts (conjugates of bile acids), bile pigments (e.g. bilirubin), cholesterol, phospholipids (lecithins), proteins, electrolytes (similar to plasma, isotonic with plasma) The liver produces bile, a lipid-rich solution with a role in elimination of hydrophobic solutes. Bile is a micellar solution in which bile acids, products of hepatocytes produced by the metabolism of cholesterol, form mixed micelles with phosphatidylcholine. Remember the composition of bile.

Regulation of Bile Acids

-Cholerectics: substances that increase secretion of bile. -Bile salts: stored in the gall bladder, and are secreted during meal into duodenum. Reabsorption from the ileum via the enterohepatic circulation carries them back to liver. -Regulation by cholesterol (loss: secreted into the bile or conversion to bile acids) -Increase bile synthesis by interrupting enterohepatic circulation, thus decrease cholesterol Cholesterol is lost from the body in two forms—by being secreted intact into the bile or after conversion to bile acids. The sole excretory pathway of cholesterol in health is via the bile as no cholesterol or bile acids are excreted in urine. Bile acid synthesis can be increased by interrupting the enterohepatic circulation (via drugs to enhance cholesterol elimination).

Functions of Bile

-Digestion and absorption of fats -Endogenous synthesis of bile salts -Absorption of fat soluble vitamins -Cholerectic and cholagogue action -Laxative (cleansing action) -Bacteriostatic action -Cholesterol excretion -Excretion of bilirubin (product of hemoglobin degradation). -Lubrication due to mucus -Alkaline helps in neutralizing acid chyme -Bile acids are actively absorbed and recirculated through enterohepatic circulation.

Pancreatic Enzyme Secretion

-Enzymes for digesting carbohydrate, protein, fat (and nucleic acids). --Proteases (80% of proteins; trypsinogen the most important (40%), amylolytic enzymes, lipases, nucleases, colipases, trypsin inhibitors, monitor peptide -Most proteases are packed and stored as inactive precursors along with trypsin inhibitor. -Activation of zymogens takes place in the lumen of the duodenum. -Secretion activated by Ach and CCK (induced by fatty acids, amino acids, and peptides) -Consequences of untimely enzyme activation (e.g. due to mutation or trauma): pancreatitis A trypsin inhibitor is a serine protease inhibitor that reduces the biological activity of trypsin. These enzymes are stored in their inactive forms (the active form is toxic that can digest the pancreas). Only during the disease, particularly if the secretions are retained in the pancreas for a prolonged period, the enzymes become inappropriately activated resulting in the very painful condition of pancreatitis.

Cystic Fibrosis

-Mechanisms underlying bicarbonate secretion in the pancreatic duct are critical in pancreatic function. -Therefore genetic disorder of cystic fibrosis, where mutations leads to abnormal function of the CFTR chloride channel. -Pancreatic enzyme synthesis and secretion may be normal but the relative inability of the ducts to secrete bicarbonate and water means that the enzymes can not be flushed properly from the organ and limited quantities reach the intestinal lumen. The enzymes that do reach are inactive. -Due to the action of retained proteolytic enzymes that become inappropriately activated and damage the tissue, patients with severe CFTR mutations are known to have pancreatic insufficiency.

Enterohepatic Circulation

-Receives most venous blood after a meal via portal vein. -Some substances circulate continuously between the liver and intestine. -A passage of solutes through three different environments: ◦The portal vein and the sinusoids into which it empties ◦The biliary system ◦The intestinal lumen •Some substances circulate continuously between the liver and intestine, in a circuit known as the enterohepatic circulation. The enterohepatic circulation involves passage of solutes through three different environments—the portal vein and the sinusoids into which it empties, the biliary system, and the intestinal lumen •Thus, a solute that enters into the enterohepatic circulation is transported into hepatocytes and secreted into bile, then reabsorbed from the intestinal lumen. •Examples are: bile acids, certain drugs and their metabolites.

Role of Pancreas

-The main source of digestive enzymes which are produced in great excess -Unlike digestive enzyme produced by the stomach and the saliva, pancreatic function is necessary for adequate digestion and absorption. -Nutrition is impaired if production of pancreatic enzymes falls bellow 10% of normal levels, or if the outflow of the pancreatic juice into the intestine is physically obstructed. •Distinguish between the exocrine pancreas, responsible for producing secretions that flow out of the body, and the endocrine pancreas, the site of synthesis of various important hormones that regulate whole body homeostasis, the main one being insulin.

Pancreatic Secretions

-The pancreas acts as an exocrine gland by producing pancreatic juice which empties into the small intestine via duct. -The pancreas also acts as an endocrine gland to produce insulin. -Plays an important role: ◦in digestion of lipids, proteins, and carbohydrates ◦In metabolism (produces insulin) ◦In neutralizing the pH to become suitable for the action of pancreatic digestive enzymes.

Pancreatic Pathophysiology

-While pancreatic insufficiency is relatively rare, fat absorption is the first affected by alterations in pancreatic out of enzymes, such as lipase. -Pancreatic lipase is most sensitive to inactivation by low pH. -Steatorrhea, or fat in the stool, may be an early sign of pancreatic dysfunction. Pancreatic enzymes are produced in excess of those needed for normal digestion. Thus, pancreatic insufficiency is relatively rare. However, under specific conditions, it can occur, causing maldigestion and malabsorption. Fat absorption is usually the first affected due to a relatively limited supply of lipase and because pancreatic lipase is most sensitive to inactivation by low pH (i.e., steatorrhea).

Regulation of Pancreatic Secretion

Acinar cells (responsible for enzymatic secretion) ◦Have receptors for CCK and muscarinic receptors for ACh ◦CCK is most important stimulant I cells secrete CCK in presence of amino acids and fatty acids in intestinal lumen ◦ACh also stimulates enzyme secretion Ductal cells (responsible for aqueous secretion of HCO3-) ◦Have receptors for CCK, ACh, and secretin ◦Secretin (from S cells of duodenum) is major stimulant Secreted in response to H+ in intestine ◦Effects of secretin are potentiated by both CCK and ACh •Pancreatic secretion is regulated by CCK and secretin. •CCK release in response to protein and fats is triggered by CCK-releasing peptide (CCK-RP) and monitor peptide. •Release of monitor peptide is neurally mediated by ACh and GRP. •Secretin senses the acidity of the luminal contents. As the pH falls secretin is released from the S cells and travels through the bloodstream to bind to receptors on pancreatic duct cells, as well as on epithelial cells lining the bile ducts and the duodenum. •These cells, in turn, are stimulated to secrete bicarbonate into the duodenal lumen, thus causing a rise in pH that will eventually shut off secretin release. •The pancreas is the main site for bicarbonate secretion, although duodenal epithelial cells also secrete bicarbonate to protect them from gastric acid. Patients with duodenal ulcers have abnormally low levels of duodenal bicarbonate secretion both at rest and in response to luminal acidification.

Cellular Basis of Pancreatic Secretion

Acinar cells that secrete their products via a process of granule exocytosis. ◦Calcium-dependent signaling pathways play the most prominent role in enzyme secretion. The membrane transport events underlie ductular ion secretion. ◦Prominently driven by cAMP, with calcium playing the subsidiary role. •Acinar cells express receptors for CCK as well as acetylcholine, GRP, and VIP. •These receptor use phospholipase C-dependent pathway resulting in increases in cytoplasmic calcium, which is the most quantitatively significant for acinar secretion, with cAMP-dependent signaling playing a subsidiary or modifying role. •The primary stimulus of duct cell secretion is secretin, which binds to a basolateral receptor that links via a G-protein to adenylyl cyclase. The primary target of the cAMP thereby generated is protein kinase A, which phosphorylates the CFTR chloride channel localized to the apical membrane of the cell. This channel allows outflow of chloride ions, which can exchange for bicarbonate across an apical chloride/bicarbonate exchanger to provide for movement of bicarbonate ions into the duct lumen

Hepatic Pathophysiology

Acute Liver failure: A sudden and significant loss in metabolic capacity of the liver for detoxification and bile secretion. (Initially present with Jaundice). ◦Hepatitis, Fibrosis, and Cirrhosis: Inflammation and reversible and irreversible deposition of excess collagen in the liver, respectively. ◦Alcoholic Cirrhosis: Malfunction as fibrotic hardening of the liver alters several aspects of structure and function. ◦Viral Hepatitis: Hepatitis B, C and D viruses causing chronic hepatitis, and hepatitis A and E viruses causing acute viral hepatitis. ◦Portal Hypertension: increase in resistance to blood flow across the liver. Impairment of liver function and destruction of hepatocyte and replacement with fibrous tissue.

Why we need a gallbladder

BILE ACIDS ARE: •Dangerous amphipaths toxic to enterocytes •Subject to loss with rapid intestinal transit •Subject to modification by intestinal bacteria SOLUTION: •BAG THEM (hence the gallbladder) •To keep the bag small: develop mechanisms for concentration of bile •To protect the bag: secrete mucin •To empty detergents when needed (during a meal): develop Neurohumoral control

Blood and Bile Flow in Opposite Directions

Blood: •Deoxygenated blood from stomach or small intestine-> Hepatic Portal Vein-> venules-> sinusoids-> central vein-> hepatic vein-> vena cava Bile: •Bile produced in hepatocytes-> secreted into canalicul-> bile ductules-> common duct-> gall bladder-> bile duct-> small intestine

Cholestasis

Cholestasis: production of bile is impaired or bile flow is obstructed. ◦Primary biliary cirrhosis (PBC) and primary sclerosingcholangitis (PSC): PBC is an autoimmune slowly progressive, inflammatory destruction of cholanogiocytes lining small to medium-sized intralobular bile ductules. PSC is characterized by inflammation and fibrosis of both the intra and extrahepatic bile ducts. ◦Congenital biliary atresia: pediatric condition in which the intrahepatic bile ducts do not form properly. ◦Obstructive jaundice: is blockage of one of the extrahepatic bile ducts with gallstone. ◦Cholesterol gallstones: increase in cholesterol to point of insolubility in bile.

Pancreatic Secretion

Complete digestion of food requires action of both pancreatic and brush border enzymes. ◦Most pancreatic enzymes are produced as zymogens. ◦Trypsin (when activated by enterokinase) triggers activation of other pancreatic enzymes. Pancreatic trypsin inhibitor attaches to trypsin. ◦Inhibits its activity in the pancreas.

Pancreatic Acinar Cell Secretory Products

Composition: bicarbonate, Na+, K+ and water emitted by the epithelial cells lining the pancreatic ducts. This neutralizes stomach acid so that digestive enzymes can work more effectively. There are four main groups of enzymes secreted by exocrine pancreas—proteases (80%), amylolytic enzymes, lipases, and nucleases. Other proteins are also produced that modulate the function of pancreatic secretory products, such as colipase and trypsin inhibitors. The pancreas secretes monitor peptide, which is an important feedback mechanism linking pancreatic secretory capacity with the requirements of the intestine for digestion. Of the proteases, trypsinogen, the inactive precursor of trypsin, is by far the most abundant, accounting for approximately 40% by weight of pancreatic secretory products.

Anatomical Consideration: Pancreas

Endocrine pancreas (endocrine cells in islets of Langerhans; hormone synthesis. eg. insulin) Exocrine pancreas (series of blind ended ducts terminating in acini; enzyme synthesis) secretes ~1 L/day into duodenum ◦Fluid consists of -HCO3- and enzymes HCO3- neutralizes H+ delivered to duodenum from stomach -Enzymatic portion digests carbohydrates, proteins, and lipids into absorbable molecules Pancreatic Exocrine Glands ◦Comprises ~90% of pancreas -Rest of pancreatic tissue is endocrine pancreas and blood vessels ◦Acinar Cells -Specialized secretory cells (secr. mainly proteins) -Contain zymogen granules and secrete enzymatic protein portion of the juice via exocytosis ◦Ductular Cells -Line the intercalated ducts -Secrete aqueous HCO3- component, dilute the pancreatic juice to make it basic -Modifies composition of juice (dilutes it and makes it alkaline)

Pancreatic Secretion: Intestinal Phase

Intestinal phase accounts for 60-70% of the total pancreatic secretion in response to a meal and is the most important. It is controlled mainly by CCK and secretin. During the intestinal phase, ductular secretion is strongly activated and increased. Ductular secretion during this phase is driven primarily by the action of secretin on receptors localized to the basolateral pole of duct epithelial cells.

Bile Pigment Excretion

Jaundice (3x increase in Bilirubin) ◦Hemolytic: blood type mismatch, allergy, drug ◦Hepatocellular: hepatitis, cirrhosis, drug abuse ◦Obstructive: gallstone, congenital ◦Neonatal: increase in RBC lysis + insufficient liver uptake and secretion.

Pancreas Fluid Secretion

Major Functions •Neutralizes acid •Optimizes digestion The CFTR chloride channel plays a crucial role in secretion (allows outflows of Cl- ions, in exchange for HCO3-; moves HCO3- into duct lumen) CFTR activity is required for fluid secretion -CF patients: fluid shortageà maldigestion (ducts unable to secrete HCO3 and H2O, enzyme cannot flush out) Inducers •Major: secretin (activating PKA that in turn activates CFTR)

Regulation of Bile Secretion

Neural: vagal stimulation mediates increase in bile production and secretion prior to consumption of a meal. Hormonal: fat and protein in the duodenum cause release of CCK, which increases bile secretion by contraction of the gallbladder and concomitant relaxation of the sphincter of Oddi. Secretin is stimulated in response to acidity in the duodenal chyme. This hormone stimulates the pancreas to release bicarbonate and neutralize the acid. CCK stimulates the gall bladder to release bile and pancreas to release pancreatic juices.

Pancreatitis

Patient who experiences retention of pancreatic enzymes within the organs may experience the painful consequences of auto-digestion of the pancreatic tissue. ◦Retained pancreatic secretion due to obstruction (e.g. gallstone or a malignancy) ◦Inflammation in alcoholics.

Pancreatic Enzymes

Proteolytic enzymes Trypsin, chymotrypsin and carboxypeptidase digest proteins -Enterokinase from the duodenal mucosa and attached to the brush border activates trypsinogen to trypsin. -Trypsin activates chymotrypsinogen to chymotrypsin -Trypsin activates procarboxypeptidase to carboxypeptidase. Glycolytic enzymes •secreted as active enzymes •pancreatic α-amylase •cleaves starch and glycogen into di- and trisaccharides Lipolytic enzymes •secreted as active enzymes •pancreatic lipase •glycerol + fatty acids

Roles of the Liver

Roles of liver: 1. The largest organ 2. First site of processing nutrient-derived byproducts -Secretes bile acids and ch -Synthesizes 80% plasma proteins -Metabolism CHO, fats, AA -Stores CHO as glycogen -Maintains adequate glucose -Metabolizes FA to ketone bodies -Scavenges cholesterol from plasma -Intercepts absorbed nutrients -Inactivates toxin and drugs -Digestion and absorption of nutrients -Secretes hormones -Detoxifies blood substances

Secretion of Pancreatic Juice

Secretion of pancreatic juice and bile is stimulated by: -Secretin: ◦Occurs in response to duodenal pH < 4.5. ◦Stimulates production of HC03- by pancreas. ◦Stimulates the liver to secrete HC03- into the bile. -CCK: ◦Occurs in response to fat and protein content of chymein duodenum. ◦Stimulates the production of pancreatic enzymes. ◦Enhances secretin secretion. ◦Stimulates contraction of gall bladder and relaxation of the sphincter of Oddi

Pancreatic Secretion: Flow Rates

The concentration of Cl and HCO3- varies with the rate of flow of the pancreatic juice: 1. Low flow rate (long contact time): no secretin stimulation; more time for absorption of HCO3- and exchange for Cl-. Therefore, the concentration of HCO3 will be low and the concentration of Cl will be high in pancreatic juice. 2. High flow rate (short contact time). Stimulated by secretin; less time for absorption of HCO3 and exchange for Cl-. Therefore, the concentration of HCO3- will be high and the concentration of Cl- will be low in the pancreatic juice. Secretin stimulates high flow rates in the acinar and ductular cells of the pancreas. During periods of low flow, the ductular cells aren't as active and so most of the pancreatic secretion is from acinar cells. Therefore, there will be mainly Cl- in the secretion. During periods of high flow, all of the ductular cells are actively secreting HCO3- into and picking up Cl- from the acinar secretion. Therefore, there will be mostly HCO3- in the secretion.

Bicarbonate Ion Production in Pancreas

•1-CO2 diffuses to the interior of the ductule cells from blood and combines with H2O by carbonic anhydrase to form H2CO3 which will dissociate into HCO3- and H+ . The HCO3- is actively transported into the lumen. •2- The H+ formed from the dissociated H2CO3 is exchanged for Na+ ions by active transport through blood, which will diffuse or actively be transported to the lumen to neutralize the -charges of HCO3- . •3- The movement of HCO3- and Na+ ions to the lumen causes an osmotic gradient that causes water to move from blood to ductulecells of the pancreas and eventually producing the HCO3- solution.

Bile Acid Metabolism

•Bile acids are synthesised in hepatocytes from cholesterol •Excreted into the bile and pass into duodenum •Primary bile acids •Cholic acid and chenodeoxycholic acid are conjugated with glycine or taurine which increases their solubility •Secondary bile acids •Primary bile acids converted by intestinal bacteria into deoxycholic and lithocholic acid •Bile acids act as detergents - main function lipid solubilisation •Have both hydrophobic and hydrophilic end and in aq solution aggregate forming micelles In humans, the only bile acids generated directly from cholesterol by endogenous enzymes are the primary bile acids, chenodeoxycholic acid and cholic acid. In the distal small intestine or the colon, they are acted on by bacterial enzymes to yield secondary bile acids.

Bile Secretion

•Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin •Two processes involved in bile acid secretion -Bile salt dependent -Bile salt independent •Bile salt dependent •Uptake of bile acids (and other organic/inorganic ions) across the basolateral (sinusoidal) by transport proteins - driven by Na-K-ATPase in basolateral membrane •Sodium and water follow passage of bile acids •Bile salt independent •Water flow is due to other osmotically active solutes e.g. glutathione, bicarbonate

Anatomy of Bile Flow

•Canaliculi (adjacent hepatocytes): initial biliary secretion •Ductules (ducts-bile conduits+mucus) •Sinusoids •Gallbladder

Functions of Liver

•Glucose metabolism: glucose is converted to glycogen, stored in hepatocytes, & released to maintain normal blood glucose. •Ammonia conversion: ammonia (a potential toxin) is a byproduct of glucogenesis and is converted to urea (in liver) which can be excreted in the urine. Ammonia produced by intestinal bacteria is also removed from portal blood for urea synthesis/excretion •Protein metabolism: including almost all plasma proteins: •Blood clotting factors are synthesized in the liver. (Vitamin K is required by the liver for synthesis of clotting factors). •Albumin, alpha & beta globulins •Transport proteins •Fat metabolism: fatty acids can be broken down for production of energy and ketones. Also produces cholesterol and other complex lipids. •Vitamin & iron storage: A, B, D, B-complex, iron & copper are stored in large amounts. •Drug and toxin metabolism: alcohol, barbiturates, opioids, sedative agents, anesthetics,etc. •Bile formation: stored in gallbladder and emptied into intestine as needed •Bilirubin excretion: bilirubin is derived from the breakdown of hemoglobin, removed from the liver, modified to make it more water soluble, and then excreted in the bile.

Anatomical Features of Liver

•Hepatocytes: Metabolic processing, synthesis of plasma proteins, nutrient storage, activation of vitamin D •Kupffer cells: the resident macrophages •Hepatic portal circulation: venous and arterial liver blood supply •Lobules: functional units of the liver •Gall bladder: Stores and concentrates bile •Sphincter of Oddi: regulates hepatic and pancreatic secretion into duodenum

Interdigestive Period

◦Bile acids are synthesized, conjugated and secreted. ◦Bile is delivered to and stored in gallbladder, until CCK signals secretion.