Pancreatic secretion and bile

• Describe the organisation of the exocrine pancreas

  The exocrine pancreas is composed of one million ‘berry-like‘ clusters of cells called acini, which are connected by short intercalated ducts that drain into a network of interlobular collecting ducts and in turn drain into the main pancreatic duct. This duct runs the length of the pancreas and units with the common bile duct.

  
• Describe the function of the exocrine pancreas

  This is termed the lobule and consists of acini and ducts. The acini consists of pancreatic acinar cells; centroacinar cells, which are an extension of the duct, secrete bicarbonate solution. The pancreatic acinar cells are packed with ER to produce enzymes, and zymogen granules to store them prior to secretion. Ductal cells are ciliated in order to sweep pancreatic secretions through the ducts, and powered by numerous mitochondria.
• Describe the function of pancreatic juice

  1. Digestion of proteins- regulated by trypsin inhibitor
  2. Trypsinogen converted to trypsin (digestive enzyme) by an enterokinase
  3. Chymotrypsinogen converted to chymotrypsin, serine protease, by trypsin
  4. Procarboxypeptidase converted to carboxypeptidase, removes C-terminal amino acids, by trypsin
  5. Digestion of carbohydrates- alpha amylase
  6. Digestion of fat- lipase + bile salts
  7. Neutralisation of gastric acid by bicarbonate
  8. protects mucosa
  9. optimum pH for enzymes ~7
• Describe hormonal control of pancreatic secretion (secretin)

  • Post-prandial release of acid, and some fat metabolites, stimulate secretion of secretin from S-type enteroendocrine cells in the duodenum; stimulating pancreatic acinar cells to secrete alkaline juice, rich in bicarbonate ions, but low in enzyme content
  • Negative feedback- increase in pH, reduces secretin release
• Describe the hormonal control of pancreatic secretion (cholecystokinin)

  • Presence of fatty acids and amino acids in the duodenum stimulates secretion of cholecystokinin (CCK) from enteroendocrine cells in the duodenum, which causes pancreatic acinar cells to secrete enzymes in the form of zymogen granules.
  • Positive feedback- enzyme action increases fatty acid and amino acid levels, which stimulates further cholecystokinin secretion. Loop only stops when chyme leaves the duodenum.
  • This hormone acts synergistically with secretin to enhance pancreatic juice secretion
• Describe neural control of pancreatic secretion

  • Parasympathetic stimulation of the pancreas by the vagus nerve causes release of a small amount of pancreatic juice rich in enzymes. The sight and smell of food is sufficient for this response to occur.
  • Sympathetic activity inhibits pancreatic secretion.
• Describe stimulation of enzyme secretion in the pancreas

  Acetylcholine and CCK act on M1 and M3 muscarinic receptors and CCK1 receptors on pancreatic acini (all GPCRs). This increases intracellular calcium, which promotes secretion of zymogen granules.
• Describe pancreatitis

  This is characterised by inflammation of pancreas, which is due to auto digestion of the pancreatic mucosa by pancreatic enzymes. This results in poor pancreas function, which results in incomplete digestion of fats and proteins in the duodenum, known as pancreatic insufficiency, and therefore malabsorption.
• Describe how secretin stimulates HCO3- and water secretion

  Secretin binds to basolateral membrane receptors to stimulate a rise in cAMP. This activates CFTR to transport chloride and bicarbonate ions across the apical membrane into the lumen of the duct, which in turn increases extracellular Cl- concentration. This drives the Cl- HCO3- exchanger and causes efflux of 2 HCO3- ions for every Cl- ion entering the cell. This process is coupled with the secretion of large volume of pancreatic fluid. Na+ HCO3- transporter moves Na+ down its conc. gradient with HCO3- ions to maintain their gradient.
• Describe the change in pancreatic function in cystic fibrosis

  Dysfunctional CFTR leads to reduced bicarbonate secretion, which hence reduces the volume of pancreatic juice secretion and reduces pH. This means that the pancreatic fluid is thicker and is more difficult to flush through the ducts, leading to obstruction and pancreatic insufficiency.
• Describe the major causes of pancreatitis

  The most common cause is gall stones, which can move out of the gallbladder and block the pancreatic duct. Chronic alcohol consumption is the next biggest cause (17-25% of cases), it is thought that toxic metabolites of alcohol, such as free radicals, can damage pancreatic

  acinar cells, as well as sensitising the pancreas to damage by other factors. Toxins such as cholinesterase inhibitors can leads to increased levels of ACh, which overstimulates pancreatic acinar cells.
• Describe the link between hyperglycaemia and pancreatitis

  Hyperglycaemia leads to overproduction of chylomicrons, which can enter the circulation and, in some cases, block the pancreatic asp, leading to ischaemia and increased release of lipase. Increased lipolysis will cause release of inflammatory mediators, leading to inflammation, oedema and necrosis in the pancreas.
• Describe secretion of bile

  700ml of bile is secreted by the liver per day, in response to secretin, produced by the duodenum. Bile is stored in the gall bladder and is released upon contract of the gall bladder, which is stimulated by CCK. Bile then travels down the common bile duct to the duodenum. The sphincter of Oddi is a muscular valve which open to allow bile and pancreatic juice to enter the duodenum. If this fails then bile and pancreatic juice backs up in the bile duct causing severe abdominal pain.

  
• Describe the composition and function of bile

  1. Bile salts, cholesterol and lecithin- emulsification of fats
  2. bilirubin, steroids and heavy metals- excreted waste products
  3. bicarbonate ions- neutralise stomach acid

  90% of bile salts are reabsorbed to be reused by the liver in forming new bile, this is known as the enterohepatic circulation.
• Describe the formation of micelles

  Fats must be broken up in order for digestion to occur. Lecithin is a phospholipid, which has a highly water soluble end, and a lipid soluble end which dissolves in the fat layer in the duodenum. When this fat layer is agitated by the contraction of the gut, the fat globules become fragmented, which increases the surface area of the fat droplets and allows them to be taken up into micelles. Micelles are formed by bile salts and arrange themselves to the polar head is outside and sterol nucleus encompasses digested fats.
• Describe bile secretion

  Secreted in two stage process:

  1. Bile salts, cholesterol, bilirubin and drugs are secreted by specific transporters on the canalicular membrane into the canaliculus, which empties into the bile duct.
  2. In the bile duct, bicarbonate ions and water are added to the bile. The gall bladder then stores the bile between meals and reabsorbs water which concentrates it.
• Describe stimulation of bile secretion by the liver

  Choleretics, such as secretin, released from S cells in the ileum, in response to protons. The vagus nerve can also stimulate secretin mediate bile secretion and proliferation of cholangiocytes, which regulate bile flow through the canaliculi. Bile salts themselves can stimulate bile secretion as they re-enter the liver via enterohepatic circulation.
• Describe stimulation of bile release from the gall bladder

  Cholecystokinin and the peptides and fatty acids which stimulate its release from the duodenum. CCK increases ACh released from vagal efferent nerves terminating on gall bladder neurones, leading to contract of gall bladder. It also acts on CCK1 receptors on the smooth muscle of the gall bladder, stimulating the relaxation of the sphincter of Oddi.
• Describe malabsorption in biliary disease

  Damage to hepatocytes by viral or alcoholic hepatitis leads to failure to produce bile. Gall stones prevent delivery of bile due to blocking of bile ducts, which results in failure to absorb fats, leading to their presence in faeces (Steatorrhea). The presence of fats in the faeces also increases osmotic potential, which draws water into the GI tract and, because fat soluble vitamins rely of micelles for absorption, prevents vitamin absorption. Also prevents excretion of bilirubin, which builds up in the skin and causes jaundice.