LECTURE 5

Pancreas + Bile

Learning outcomes:

1. Structure of pancreas.

2. Functions + secretion of pancreatic juice

3. Functions + secretion of bile.

4. Consequences of pancreatic and biliary disease.

Organisation of the pancreas →

• The pancreas set up with the main pancreatic duct running through it, which then branches out into lobular ducts.

• These lobular ducts lead to the lobules, which then divide into intercalated ducts that end in acini.

• Inside the acini, you have pancreatic acinar cells producing enzymes and Centro acinar cells releasing bicarbonate and water.

• The acinar cells are full of endoplasmic reticulum for enzyme production, while the Centro acinar cells have cilia to help move pancreatic juice towards the duodenum and ileum.

The Exocrine Pancreas →

Secretes pancreatic juice containing enzymes + bicarbonate.

Pancreatic enzymes are secreted by the acinar cells + the Centro acinar cells lining the pancreatic ducts secrete bicarbonate ions + water.

What the constituents of pancreatic juice →

- Protease enzymes break peptide bonds in proteins.

- Pancreas produces inactive precursors of proteases to prevent auto digestion.

- Trypsinogen is activated to trypsin by enterokinase in the duodenum.

- Trypsin triggers activation of chymotrypsinogen and procarboxypeptidase.

- Regulation by trypsin inhibitor prevents premature activation.

- Protein digestion starts in the stomach with pepsin.

- Carbohydrates are partially digested in the mouth by salivary amylase.

- Pancreatic alpha-amylase completes carbohydrate digestion.

- Pancreatic lipases break down fats efficiently compared to stomach lipases.

- Bile salts are necessary for lipase function.

- Phospholipase A2 acts on phosphatidylcholine.

Control of pancreatic secretion:

- Pancreatic secretion is about 1.5 liters per day and is controlled by hormones and nervous stimulation.

- Secretin is released in response to stomach acid reaching the duodenum, stimulating the production of an alkaline fluid rich in bicarbonate.

- Secretin secretion stops when the pH is elevated, creating a negative feedback loop.

- Cholecystokinin is released in response to fatty acids and peptides in the duodenum, stimulating the secretion of enzymes into the duodenum to break down fats and proteins.

Enzyme Secretion:

- Pancreatic enzyme secretion is highly nerve-regulated, primarily by the vagus nerve.

- In the cephalic phase, even the thoughts or smell of food can stimulate the pancreas via vagal stimulation.

- In the intestinal phase, CCK feedback stimulates the enteric nervous system, leading to enzyme secretion.

- Hormones like astral choline and gastrin releasing peptide play a crucial role in enzyme secretion.

- Enzyme secretion is inhibited by sympathetic stimulation.

- At a cellular level, CCK binds to CCK1 receptors, while acetylcholine binds to M1 and M3 muscarinic receptors, signaling via different pathways.

- The end result of these pathways is an increase in intracellular calcium, leading to enzyme exocytosis from zymogen granules into the pancreatic duct.

Duct - HCO3- + H20 secretion:

- Secretin binds to the secretary in receptor on the basolateral surface of the ductal cells.

- This binding leads to an increase in cyclic GMP, which then stimulates the cystic fibrosis transmembrane regulator, allowing chloride and bicarbonate to be released into the lumen.

- Chloride drives the chloride bicarbonate exchange pump, releasing two bicarbonate ions for every one chloride ion entering the cell.

- The bicarbonate increase inside the cell creates concentration gradients across the apical membrane.

- Sodium flowing into the cell down its concentration gradient drives bicarbonate into the cell.

- The bicarbonate released, along with bicarbonate produced via the dissolution of carbonic acid using Carbonic anhydrase, helps drive the transporter.

- Both the basolateral transporter and Carbonic anhydrase are necessary for efficient bicarbonate secretion.

- Inhibiting Carbonic anhydrase reduces bicarbonate secretion by 50%, emphasizing the importance of both mechanisms.

- If the cystic fibrosis transmembrane regulator is not functioning correctly, there will be reduced bicarbonate secretion into the fluid, leading to less watery pancreatic juice.

Pancreatitis:

- Pancreatitis is an inflammatory condition largely caused by gallstones entering the pancreatic duct from the gallbladder.

- About 17 to 25 percent of cases are due to chronic alcohol consumption over about five years, which creates free radicals leading to inflammation of the pancreas.

- Hypertriglyceridemia, a condition with elevated triglycerides, can also lead to pancreatitis, especially from a high-fat diet increasing chylomicrons that may block pancreatic capillaries, causing ischemia and excessive lipase production.

- Toxins like organophosphates found in insecticides and scorpion bites can lead to pancreatitis by stimulating excessive acetylcholine, causing inflammation.

- Animal models show that an abundance of CCK can activate zymogens within acinar cells, inhibiting secretion and leading to the retention of active enzymes in the pancreas, eventually causing breakdown.

- Trials with a synthetic inhibitor called gab x 8 have shown mixed results in preventing pancreatitis.

Bile:

- The picture shows the liver, the common bile duct leading from the liver, the gallbladder that stores bile between meals, and the pancreas that also connects to the common bile duct.

- There is a sphincter of Oddi, a tight skeletal muscle, which can close off the common bile duct to prevent bile from entering the duodenum.

- The liver secretes about 700 milliliters of bile per day.

Composition + function of Bile:

- Bile contains bile salts necessary for transporting digested fats through the duodenum.

- Cholesterol and lecithin, a phospholipid found in egg yolk and soybeans, are also part of bile for fat digestion and emulsification.

- Bile salts are crucial transporters, with 90% being reabsorbed for intrahepatic circulation.

- Bilirubin, a breakdown product of hemoglobin, steroids, and heavy metals like Mercury and Lead are found in bile.

- Bicarbonate in bile helps neutralize acid in the small intestine.

Formation of Micelles:

- Micelles are crucial for mixing fats with aqueous fluids as fats naturally separate due to their hydrophilic head and hydrophobic side chains.

- Bile salts, with a similar structure to phospholipids, help form micelles by arranging themselves with lecithin.

- The micelles have a core that contains partially digested fat, aiding the fats in passing through the aqueous layer for absorption in the duodenum.

Bile Secretion:

- Bile is secreted through a process involving the portal vein delivering nutrients from the small intestine, mixing with fluid from the hepatic artery, and draining through sinusoids into the liver.

- Hepatocytes in the liver have bile canaliculi that drain into the common bile duct, with different transporters on basolateral and canaliculi membranes for specific functions.

- The liver produces plasma proteins that enter the sinusoids, while bile constituents are transported across the canaliculi membrane and down the common bile duct.

- Bile secretion involves transporters for bile salts, organic anions, cholesterol, bicarbonate, and water, with the gallbladder storing and concentrating bile between meals.

How is bile secretion controlled:

- Coloretics and choleretic substances stimulate bile secretion by the liver.

- Secretin is released in response to increased acid or hydrogen ions to stimulate bile secretion.

- The vagus nerve is crucial for bile secretion and the proliferation of Kalonji sites that move bile through canaliculi.

- Bile salts are recycled and stimulate the liver to produce more bile.

- Sympathetic nervous system activity inhibits this process.

- Cholecystokinin (CCK) stimulates bile release from the gallbladder and is triggered by peptides and fatty acids.

- CCK causes gallbladder contraction and relaxation of the sphincter of Oddi to allow bile to enter the duodenum.

- Nutrients in the duodenum trigger CCK release, leading to gallbladder contraction.

- CCK receptors in the gallbladder initiate gallbladder contraction upon binding with CCK.

What happens when we get malabsorption in biliary disease?

• When there's malabsorption in biliary disease, it can lead to some issues.

• If the bile ducts are blocked by gallstones, bile gets trapped in the gallbladder, affecting fat digestion and absorption.

• This can result in fatty, oily, and smelly stools known as steatorrhea. Additionally, undigested fats draw water into the large intestine, causing loose stools or diarrhea.

• Moreover, the lack of fats for absorption can lead to deficiencies in fat-soluble vitamins. Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood if not excreted, causing jaundice with a yellow tint on the skin.

Gallstones:

• Gallstones are quite common in the Western world, affecting between 1 in 4 and 1 in 20 adults.

• They are more prevalent in females, those with a high-meat diet, type 2 diabetes, and obesity.

• Gallstones are linked to excessive cholesterol mobilization in the liver, leading to crystallization and increased biliary secretion.

• There may also be a genetic predisposition to gallstones.