Pancreatic and Biliary Secretions

Question 1

Answer 1

• Like the salivary glands, ultrafiltration occurs at the acinus, which provides a driving force for fluid flux, and the digestive enzymes are produced in and secreted by acinar cells.
• However, the acini are not as highly vascularized as those of the salivary glands rather the ductal cells secrete HCO3 - and also a large volume of fluid.

Question 2

Two General Products of the Exocrine Pancreas

Answer 2

• bicarbonate and concomitant aqueous solution to neutralize the stomach
• digestove enzymes that are capable of digesting all major fodstuffs

Question 3

Enzymatic Component: Acinar Cells

Answer 3

• The proteolytic enzymes of the pancreas are synthesized in inactive forms (e.g., trypsinogen, chymotrypsinogen) whereas amylase is released in its active form.
• Enzyme containing granules are expelled into the lumen of the acinus by exocytosis after a stimulus (elevated Ca2+).
• Also secreted with the enzymes is trypsin inhibitor (aprotinin) to prevent premature activation of trypsin within the pancreatic ducts; this assures that the proteolytic enzymes are normally activated only after reaching the intestinal lumen.
• Enteropeptidase, secreted by the intestinal mucosa, cleaves the precursor enzymes thereby activating them.
• The primary precursor upon which enteropeptidase acts is trypsinogen.
• Once activated, trypsin cleaves and thereby activates the other precursor enzymes. If flow from the pancreas is blocked, premature activation of trypsin can occur within the ductal system. Subsequent activation of digestive enzymes leads to breakdown of the pancreatic ducts and resultant pancreatitis.

Question 4

Active Bicarbonate Secretion

Answer 4

• Active Bicarbonate Secretion is carried out by the pancreatic ductal cells.
• Since the ductal system in the pancreas is extensive, a large surface area for HCO3 - secretion exists.
• A critical component required for the activation of HCO3 - secretion is a cAMP activated Cl- channel (CFTR) located in the luminal membrane.
• The hormone Secretin increases cAMP in the ductal cells that activates Cl- movement into the lumen. The increased luminal Cl is exchanged for cellular HCO3 - thereby driving HCO3 - secretion.
• In Cystic Fibrosis, pancreatic fluid and HCO3 secretion are dramatically decreased due to the absence or defect in this Cl- channel. The low flow can lead to abnormal protease activation within the pancreatic ducts leading to pancreatitis.
• Production of large amounts of HCO3 - relies on carbonic anhydrase (CA).
• In ductal cells, HCO3 - produced by CA is transported across the apical membrane to the lumen in exchange for Cl- (HCO3 - /Cl- anti-porter) while Cl- outward flux is CFTR dependent.
• The H + produced by CA leaves the cell via a basolateral Na+ /H+ exchanger. Thus, the Na+ gradient is used to drive H+ to the blood.
• Recall that secretion of HCl into the stomach results in an “alkaline tide” (high HCO3 - ) in the venous blood leaving the stomach.

-Mixing of blood from the stomach with H+ laden venous blood from the pancreas in the portal vein, assures that blood pH is near neutral prior to entering the liver.

Question 5

Neural Regulation of Pancreatic Secretion

Answer 5

• Neural signals are short term initiating signals which arise centrally (parasympathetic), and travel via the vagus to the pancreas where they stimulate secretion by primarily acinar cells, and to a lesser degree ductal cells.
• Thus, during the cephalic phase, neural impulses initiate secretion of primarily enzymes into the acinus. In addition, increases in acinar blood flow are observed mildly elevating ultrafiltration. The net effect is an initial secretion high in enzyme content.
• When food enters the stomach (gastric phase), stimulation of mechanoreceptors initiates reflexes whose afferent signals travel centrally via the vagus nerve. Afferent ENS signals (from the alimentary canal) elicit efferent signals that also travel via the vagus to initiate pancreatic secretions. This type of reflex is termed Vagovagal.
• At most 10-20% of the pancreatic exocrine secretory response is initiated during the Cephalic and Gastric phases via vagal signaling.
• As fat products, H+ and small peptides enter the small intestine (intestinal phase), vagovagal reflexes initiated by alimentary chemoreceptors continue to stimulate primarily digestive enzyme secretion from acinar cells.

Question 6

Endocrine Regulation of Pancreatic Secretions

Answer 6

• Hormones provide strong stimulatory signals of long duration driving pancreatic secretion during Intestinal Phase.
• Secretin, whose release from duodenal S cells is stimulated by fat or H+ in the intestine, stimulates ductal epithlial cells to secrete HCO3.
• Cholecystokinin (CCK) release from intestinal I cells is stimulated by peptides and fat within the intestine. CCK stimulates enzyme secretion from acini.
• At least 60% of all pancreatic secretion occurs during the intestinal phase, and is driven by these endocrine factors.
• CCK also regulates gene expression of proteases and lipases, thus the absence of fat in a meal causes down regulation of enzymic activities.
• Although the exact mechanisms are unknown, diet composition modulates pancreatic enzyme expression so that pure vegetarians often down-regulate expression of specific proteases and lipases.

Question 7

Independent Regulation of HCO3 -and Enzyme Secretion from the Pancreas

Answer 7

• Injection of HCL bringing the intestinal lumen pH to < 6.0 stimulates secretion of an alkaline fluid from the pancreas. Anti-secretin antibodies injected into the blood block this response (not shown) demonstrating the effect is primarily mediated by secretin.
• Injection of amino acids into the intestine stimulates enzyme secretion with little effect on secretion of HCO3 - and water. This response is because amino acids stimulate the release of CCK, but not release of secretin.
• On the other hand, injection of emulsified fat stimulates both processes because fats initiate release CCK and to a lesser extent Secretin.

-Even though secretin secretion is not strongly stimulated by fat, the potentiating effects of the two hormones elicit a strong secretion of fluid and HCO3.

•The responses shown in the Figure primarily depend on the release of Secretin or CCK from the intestinal endocrine cells. They also are driven to a much lesser extent by vagovagal reflexes. For example, if the intestinal lumen is significantly distended when these solutions are injected, this distension activates ascending neural pathways that subsequently lead to higher levels of pancreatic secretions than are observed with the hormonal stimulation alone indicating a role for vagal reflexes (neural acetylcholine release) in potentiating hormonal driven secretion.

Question 8

Answer 8

Question 9

Answer 9

Question 10

Answer 10

Question 11

Potentiation

Answer 11

• The Concept of Potentiation is critical to pancreatic function where each individual effector stimulates secretion by only a fraction relative to the combination of two effectors acting through independent second messenger pathways (e.g. CCK and Secretin).
• The absence of a response to an agonist, which in combination with another factor “potentiates” the activated response, is a clear demonstration of this principal.
• Figure Legend: The amount of HCO3 - released to the common ductal system is plotted relative to the concentration of hormone in the blood. Even high levels of CCK do not activate ductal cell secretion in the absence of secretin. However, CCK clearly enhances the rate of HCO3 - secretion relative to that observed with secretin alone.

Question 12

Answer 12

Question 13

Bile Canaliculi

Answer 13

• Bile canaliculi are minute channels between hepatocytes into which bile is secreted.
• Bile ducts are channels that drain the canaliculi.
• Large bile ducts from each lobe of the liver combine to form the common bile duct.

Question 14

Gall Bladder

Answer 14

•The Gallbladder, an appendage of the common bile duct, acts as a storage receptacle where bile is concentrated during fasting. Bile moves to the intestine via the common bile duct, which combines with the pancreatic duct just prior to the entrance to the intestine.

Question 15

Sphincter of Oddi

Answer 15

• The region of smooth muscle at the entrance to the duodenum is called the Sphincter of Oddi.
• Activity in this sphincter controls movement of bile and pancreatic secretions into small intestine.

Question 16

Bile Production

Answer 16

• The gallbladder can hold up to 4 gms of bile, while the liver can synthesize between 0.2-0.6 gms per day.
• Average fat intake is about 65 gms per day. To emulsify this amount of fat at least 35 gms of bile are required.
• Thus, the amount of available bile is not sufficient to digest this fat load in one pass.
• Our ability to assimilate this amount of fat is due to the ability of the ileum to reabsorb bile acids after they traverse the small intestine, then extraction of the bile acids from portal vein blood by hepatocytes with subsequent secretion back into the biliary tract and subsequently the lumen to continue fat digestion.

Question 17

Composition of Bile

Answer 17

• Bile is composed of a variety of organic and ionic constituents.
• Exretory Component

Some of the constituents do not serve a digestive purpose but rather are secreted by the liver into the alimentary canal for excretion from the body.

•Secretory Component

Question 18

Excretory Component of Bile

Answer 18

• This excretory component includes bile pigments (e.g., bilirubin), as well as, a variety of hepatic metabolites including drug metabolites.
• Bilirubin is a hydrophobic end product of hemoglobin degradation that is actively absorbed from blood by hepatocytes and secreted into canaliculi with the bile acids.

-This compound provides much of the coloration of stool; blockage of the bile duct network and loss of bilirubin excretion to the canal is the cause of increased blood bilirubin and the coloration associated with jaundice.

Question 19

Secretory Component of Bile

Answer 19

• The functional secretory component consists primarily of bile, cholesterol, lecithin and fatty acids.
• The major components are the primary bile acids, chenodeoxycholic and cholic acid synthesized from cholesterol in hepatocytes, also known as cholangiocytes.
• Bile acids are then conjugated with glycine or taurine and secreted as Na+ salts. These salts are more soluble than the acid forms.
• Secondary bile acids are formed by dehydroxylation of primary bile acids by bacteria in the distal small intestine and colon.
• The secondary bile acids are deoxycholic acid and lithocholic acid.

•The epithelial cells lining the bile canaliculi and ductal network also contribute a watery HCO3 -containing secretion similar to that elaborated by pancreatic ductal epithelial cells.

Question 20

Composition of Liver Bile Relative to Gall Bladder Bile

Answer 20

• The Gall Bladder stores bile during periods of inactivity. While in the gall bladder, water and specific anions are removed. The resulting gall bladder bile is concentrated (net volume loss) with respect to the concentration of both bile salts, and the other organic components.
• The components transported to the blood that drive water removal are NaCl and NaHCO3 -

Question 21

Functions of Bile Secretions

Answer 21

• Bile salts provide a detergent reaction within the intestine where they act to emulsify fat droplets contained in food.
• This action breaks up fat particles into smaller globules and increases and modifies the surface area of the lipid that digestive enzymes can attack.

Question 22

Enterohepatic Circulation of Bile Salts

Answer 22

• After bile performs its function within the intestine, it is absorbed at the level of the ileum into the portal blood. As the portal blood passes through the liver sinusoids, bile is absorbed by hepatocytes and then secreted again into the biliary network.
• The entire bile pool is circulated 2-3 times per meal.
• The cycling of bile between intestine and blood is referred to as the enterohepatic circulation.
• Little bile salt reabsorption occurs in duodenum or jejunum, which allows bile salts to aid fat metabolism without being reabsorbed.
• 90-95% of bile is absorbed from the ileum by specific transporters.
• Bile that enters the large intestine is converted to secondary bile acids, which can be absorbed passively to a limited extent.

-The bile salts are returned to the liver via portal blood, and are taken up by hepatocytes.

•Also recycled by the enterohepatic pathway are compounds like the lipid soluble vitamins (e.g., Vitamin D) and many drugs such as cardiac glycosides and indomethacin.

Question 23

Regulation of Bile Secretion

Answer 23

• Bile is continuously secreted by the liver during the digestive period. Between meals, bile is diverted from the enterohepatic circulation into the gall bladder. Excess fluid volume is reabsorbed by the gallbladder and bile is concentrated. Mechanisms that regulate bile secretion act either to alter the rate of bile secretion, or to contract the gall bladder thereby mobilizing the stored and concentrated bile.
• Neural Vagovagal Reflexes
• Hormonal

Question 24

Regulation of Bile Secretion - Neural Vagovagal Reflex

Answer 24

• Neural vagovagal reflexes activated by sensory receptors for taste, smell, or sight of food mildly activate gall bladder contraction (Cephalic Phase).
• However, bile does not reach the lumen until there is mechanical activity in the stomach and small intestine, because it is this contractility that allows the Sphincter of Oddi to open; i.e., motility within the duodenum causes the Sphincter to relax resulting in small amounts of bile being squirted into the duodenum with each wave of contractility.
• Thus, during the Cephalic phase, some pancreatic enzymes and bile are secreted into the ductal system, from where they can then be released into the intestine immediately upon arrival of chyme into the stomach and duodenum.

Question 25

Regulation of Bile Secretion - Hormonal

Answer 25

• The primary stimulus for bile “secretion” to the intestinal lumen is hormonal.
• Cholecystokinin is released from intestinal I cells by the products of fat digestion. Free fatty acids and triglycerides within the intestinal lumen provide strong stimuli for cholecystokinin release which in turn causes strong contraction of the gall bladder, and thereby emptying of the stored bile into the enterohepatic circulation.
• On the other hand, acid in the duodenum stimulates secretin release, which primarily activates the secretion of the bile acid independent fraction; i.e., HCO3 - and water from ductal epithelial cells.

Question 26

Regulation of Bile Acid Production and Secretion

Answer 26

• The primary regulator of bile acid production is the concentration of bile acids in the portal blood and bile canaliculi. Bile in the portal blood is actively absorbed by hepatocytes, which increases the concentration of bile acids in the hepatocytes. The elevated cell bile concentration inhibits the enzyme cholesterol 7-hydroxylase that is required for the synthesis of primary bile acids.
• Therefore, when bile concentration in portal blood is high, bile synthesis is inhibited and secretion is stimulated thereby facilitating the enterohepatic circulation of bile.
• As bile concentration in the blood and thereby hepatocytes decreases following a meal, new bile synthesis is initiated because inhibition of cholesterol 7-hydroxylase is reduced.
• Once the gall bladder is full, the concentration of bile within the hepatic ducts increases. The elevated ductal bile concentration inhibits further secretion from hepatocytes leading to elevated intracellular bile and inhibition of new bile synthesis. This mechanism provides precise control over the size of the bile acid pool.

Question 27

Answer 27

Question 28

Bile Duct Obstructions

Answer 28

•Obstructions lead to buildup of bilirubin in the blood causing symptomatic jaundice. Furthermore, the absence of bile for digestion leads to high fat content in stool (steatorrhea). Since the color of stool is due to pigments in bile, the absence of bile leads to white colored stools (acholic).

Question 29

Ileal Resection

Answer 29

•Since bile is absorbed from the alimentary canal in the ileum, resection leads to limited enterohepatic circulation of bile salts. Bile salts, which reach the colon, act both as an osmotic agent and also as a secretory stimulant in the colon; i.e., cause diarrhea.