Secretion of the Pancreas, Gall Bladder and Liver




The Pancreas weighs 100g, but it secretes over 10 times its weight in one day. It has both an endocrine and exocrine function. The endocrine function is primarily in the islets of Langerhans which have four types of cells: insulin secreting (60-80% of total), glucagon secreting (15-20%), somatostatin and pancreatic polypeptides. The exocrine pancreas structure has acinar and ductal cells. The acinar cells make the digestive enzymes and the duct cells make the aqueous component. The acini are organized around the terminal end of a duct with zymogen granules facing the lumen. The insular-acinar axis is the connection between the exocrine and endocrine pancreas. The islet cells have arterioles but few venules. Almost all of the blood that comes into the islets goes on to the acinar tissue. These acinar cells are dependent on insulin for growth. Insulin also promotes secretion from acinar cells when the acinar cells are stimulated by other hormones. The ductal cells are responsible for the large volume of bicarbonate rich fluid which is in pancreatic juice. This fluid is added to the enzymatic fluid that was secreted from the acinus as it flows down the intralobular duct. At both a slow and fast flow rate of pancreatic juice the concentration of both sodium and potassium is equal to that of plasma. However bicarbonate concentrations increase with increasing flow rate and chloride concentrations reciprocally decrease at higher flow rates. This ensures that at all flow rates the final tonicity of pancreatic juice will always be equal to that of plasma. The bicarbonate secreted by ductal cells is predominantly derived from plasma (93%). The process involves an Na/K ATPase, a Cl/HCO3 antiporter, carbonic anhydrase and depends on the intracellular chloride concentration. This is kept low by a cAMP controlled chloride channel at the apical border of both ductal and acinar cells. In cystic fibrosis this Cl channel (called CFTR) is defective and doesnít respond to cAMP which causes mucus plugging of the pancreatic duct. Ductal cells are very sensitive to secretin and VIP hormones, both of which increase cAMP levels. CCK has little effect on bicarbonate secretion from ductal cells when acting alone but it can potentiate the effect of secretin. The digestive enzymes of pancreas are involved in digestion of large complex molecules. They include the proteinases: trypsinogen, chymotrypsinogen, procarboxypeptidase and proelastase. It also produces pancreatic amylase (for carbohydrate breakdown), lipase (lipid breakdown), procholipase I and II and prophospholipase A2. Trypsinogen is cleaved to form trypsin at a lysine AA. This process is initiated in the intestine by enterokinase which activates trypsin to cleave the other trypsinogens. Trypsin also can activate all the other pancreatic proenzymes. The enzymes are all secreted in a nonactive form to prevent autodigestion of the secreting cells. The body has numerous mechanisms to prevent autodigestion:


All digestive enzymes except lipase and amylase are synthesized in an inactive form Enterokinase, the activating enzyme of the trypsin cascade, is physically separated from trypsin since it is found in the small intestine. The digestive enzymes within the acinar cells are packaged into zymogen granules. The intracellular Ca concentration is kept low which prevents trypsinogen activation. Acinar cells synthesize pancreatic secretory trypsin inhibitor (PSTI) which inactivates trace levels of trypsin. If excessive levels of trypsin build up in the cell it will autodigest itself, thereby inactivating itself. The liver produces two inhibitors which are found in the blood, alpha1 antitrypsin and beta2 macroglobulin which inhibit any trypsin found in bloodstream.In one form of hereditary pancreatitis, there is a genetic defect in one of the trypsinogen genes which loses the ability of trypsin to inactivate itself at very high levels. Intracellular calcium is the most important determinant of pancreatic secretion. It is also stimulated by elevated cAMP. The nervous system stimulates secretion via parasympathetics from the vagus which have cholinergic receptors on the cells. The sympathetic nervous system inhibits pancreatic secretion. Acetylcholine and gastrin releasing peptide are the neurotransmitters which the vagus uses to stimulate secretion. They activate Ca dependent secondary messengers (PLC, IP3, DAG) which results in the release of zymogen granules. VIP is a neuropeptide used by intrapancreatic nerves which increases the levels of cAMP and accentuates the effects of ACh. CCK and secretin are two hormones released from the duodenum which stimulate pancreatic secretion after ingestion of a meal via cAMP. CCK probably modulates its effect via stimulation of vagal nerves. There are 3 phases of pancreatic stimulation:

cephalic- initiated by sight and smell of food and mediated by vagus. Accounts for 25% of pancreatic secretion during a meal. Gastric- caused by gastric distention via vagal-vagal reflex. 10% of pancreatic secretion. Intestinal- caused by food in the intestine eliciting the secretion of CCK and secretin into duodenum and by stimulation of vagal fibers.Duodenal acidification causes release of secretin and stimulates the vagus to activate ductal cells to release a bicarbonate rich fluid. Proteins stimulate the secretion of CCK into blood which causes the acinar cells to secrete proteinases. Inhibitory hormones include somatostatin, pancreatic polypeptide, and peptide YY. Mostly these inhibit cholinergic nerves. Somatostatin is the most potent.


LIVER AND GALL BLADDER Each lobule of the liver is organized around a central vein and blood flows from the periphery, from the hepatic artery and the sinusoids. Because of fenestrations in the endothelial cells which line the sinusoid, each hepatocyte is in direct contact sinusoidal blood. Biliary canaliculi lie between adjacent hepatocytes and bile flows in the reverse direction of the blood. The canaliculi drain into bile ducts at the periphery of the lobules. The liver performs multiple functions: regulates metabolism of carbohydrates and lipids, synthesizes proteins and other molecules, stores vitamins and iron, degrades hormones and inactivates and excretes drugs and toxins.


Carbohydrates: when the level of glucose in the blood is high, some of the glucose is converted into glycogen, which is then deposited into the liver. When the blood glucose level is low, glycogen in the liver is broken down to glucose (glycogenolysis) which then gets released into the blood stream. The liver also has the ability to perform gluconeogenisis, the conversion of amino acids, lipids, or simple carbohydrates into glucose.


Lipids: Absorbed lipids leave the intestines in chylomicrons in the lymph. Along the way it is converted and changed into chylomicron remnants which are rich in cholesterol. These remnants are taken up by the hepatocytes and degraded. The hepatocytes also synthesize and secrete VLDL. VLDLs are then converted into other types of serum lipoproteins, HDL or LDL. These lipoproteins are the major source of cholesterol and triglycerides that supply most other tissues of the body. The liver is also involved in bile synthesis and bile is the only route of excretion of cholesterol from the body. So the hepatocyte is the principal source of cholesterol for the body while also the major site of excretion of cholesterol.

Proteins: When proteins break down by catabolism, some of the amino acids deaminate and form ammonia. The ammonia can not be further broken down by most tissues and toxic levels of ammonia can accumulate. The ammonia can be dissipated by conversion to urea which takes place mainly in the liver. The liver also synthesizes all the non-essential amino acids. It also synthesizes all the major plasma proteins, which includes the lipoproteins, albumins, globulins, fibrinogens, and other proteins involved in blood clotting.


Storing Vitamins: These vitamins include A, D, and B12 so that during transient deficiencies it can protect the body. Next to hemoglobin in the RBCís, the liver is the most important storage site of iron. The liver transforms, breaks down and excretes many hormones, drugs and toxins.

The liverís role in digestion is with the secretion of bile. Bile, produced by hepatocytes, contains bile acids, cholesterol, phospholipids, and bile pigments. All of these constituents are secreted by hepatocytes into the bile canaliculi, along with an isotonic fluid that resembles plasma in its electrolyte concentrations.


The secretory function of the liver resembles that of the exocrine pancreas. In both the primary secretion is isotonic to plasma and the levels of Na, K, and Cl are close to plasma levels. When stimulated by secretin, the ductular epithelial cells contribute an aqueous secretion with a high bicarbonate concentration. So, similar to pancreas, in both the ducts change the isotonic to plasma solution and add bicarbonate.


Between meals, bile is diverted into the gallbladder. The gallbladder epithelium extracts salts and water from the stored bile and concentrates the bile acids fivefold to twentyfold. Cholocystokinin (CCK) is the most potent stimulus for emptying of the gallbladder. Bile acids emulsify lipids and thereby increase the surface area available to lipolytic enzymes. Bile acids then form mixed micelles. Micelles increase the transport of the products of lipid digestion to the brush border surface. The epithelial cells (intestines) actively absorb bile acids, mainly in the terminal ileum. Only about 10-20 percent of bile acids escape absorption and are excreted. What happens to the rest, is that bile acids return to the liver and are taken up again by the hepatocytes. This concept is known as enterohepatic circulation- that the entire bile acid pool is recirculated two or more times in response to a typical meal.


About 60% of bile is bile acids (Cholate, deoxycholate, chenodeoxycholate, lithocholate), 22% phospholipids, while smaller composition including cholesterol and bile pigments. Bile acids make up 65% of dry weight of bile. Primary bile acids are the major bile acids synthesized by the liver (cholic acid and chenodeoxycholic acid). The presence of the carboxyl or hydroxyl groups added (after it started as cholesterol) makes it more of a polar compound. Secondary bile acids are deoxycholic acid and lithocholic acid. When bile acids are released they are amphipathic in that there is a hydrophobic and hydrophilic side. When they create micelles the hydrophilic side faces outward and the hydrophobic side faces inward, allowing the lipids to accumulate inside. Bile acid micelles form when the concentration of bile acids exceeds a certain limit, the critical micelle concentration. Hepatocytes also secrete phospholipids and cholesterol in bile. The predominant phospholipid is lecithin. One of the major routes for cholesterol to excreted is into the bile. The secretory mechanism into the bile canaliculi of the phospholipids and cholesterol involves exocytosis. When aging RBCís are degraded in the reticuloendothelial system, the porphyrin moiety of hemoglobin is converted into bilirubin. Bilirubin is released into plasma where it is bound by albumin. The bilurubin is glucoronidated in the liver into bilirubin glucoronide and that is secreted into the bile.

Secretion of bile duct epithelium: The epithelial cells that line the bile ducts secrete an aqueous secretion that accounts for 50% of total volume of bile. This secretion is isotonic and contains Na and K concentrations similar to plasma. However, the concentration of bicarbonate is greater and the concentration of chloride is less then that in the plasma.


Gallbladder and bile concentration: Between meals, the tone of the sphincter of Oddi, which guards entrance of the common bile duct into the duodenum, is high and diverts the bile flow into the gallbladder. The gallbladder has capacity to hold 15-60 cc of fluid, in humans. The gallbladder concentrates the bile acids as it absorbs the sodium and releases it out the lateral side while chloride and bicarbonate gets driven with it. When that happens the water follows it out as well. This allows the gallbladder to concentrate its contents from 5 to 20 fold. (The "standing osmotic gradient mechanism for fluid absorption was first proposed for the gallbladder).


Emptying of gallbladder begins several minutes after the start of a meal. Intermittent contractions of the gallbladder force bile through the partially relaxed sphincter of Oddi. During the cephalic and gastric phases of digestion, gallbladder contraction and relaxation of the shincter are mediated by cholinergic fibers in the vagus nerve and by gastrin released from the stomach. The highest rate of gallbladder emptying occurs during the intestinal phase of digestion, with the strongest stimulus for this emptying being CCK.


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