Pancreatic and Biliary Secretion by 1L72T6

VIEWS: 5 PAGES: 5

									                      Pancreatic and Biliary Secretion
                              April 26, 2004

Structure of the Pancreas—The pancreas is a gland with dual function. It functions as
both an endocrine and exocrine organ. This lecture will concentrate on the exocrine
function of the pancreas. The functional unit of the pancreas consists of acinar and ductal
cells. The acinar cells are the site where the inactive forms of enzymes are produced.
The ductal cells are responsible for producing secretions of water and electrolytes.

Pancreatic Secretions—The initial secretions of the pancreas are the NaCl type of
secretions. As there is an increase in flow, the levels of Cl- decrease and HCO3 increase in
the secretions. The levels of K+ and Na+ remain constant even as flow rates increase. At
its lowest secretory rate, Cl- is similar to plasma.

Secretin is a hormone released from the cells of the small intestine. It is responsible for
most of the pancreatic fluid secretion and is released from the small intestine in response
to acid in the stomach. The pH in the duodenal lumen must be 4.5 or lower in order for
secretin to be released. The peak for secretin release is around a pH of 3.0 while no
secretin is released at a pH above 4.5. When secretin is released by the small intestine,
the plasma secretin levels rise. This causes an increase in the bicarbonate secretion of
the pancreas. The increased amounts of bicarbonate flows into the small intestine where
it aids in the neutralization of the intestinal acid. Once the pH reaches greater than 4.5,
there is negative feedback to inhibit the release of secretin.

There are advantages to maintaining the pH within the duodenal lumen at nearly
neutral values through the bicarbonate secretions. First of all, this causes inactivation of
pepsin coming from the stomach. This inhibits the breakdown of mucosal protein within
the small intestine. Another advantage of maintaining the pH is that it prevents mucosal
damage by the acid that comes down from the stomach. This also optimizes the pH
that is necessary for activity of the pancreatic and brush border enzymes. Finally,
maintaining the pH increases the solubility of bile acids and fatty acids. Otherwise, if
the environment remained acidic, they would precipitate out.

Pancreatic Enzymes—Digestive enzymes produced by the pancreas are synthesized in
the rough endoplasmic reticulum. They are then transported to the golgi complex where
they are packaged into large vesicles to protect the rest of the pancreas from being
damaged. They are then converted to zymogen granules in preparation for exocytosis
into the lumen.

The pancreas secretes many proenzymes and enzymes that are involved in the digestion
of all types of food (fat, carbohydrate, and protein). Most of the enzymes are secreted as
inactive proenzymes. This is to prevent them from attacking and digesting the pancreas.

Of the enzymes produced in the pancreatic juice 80-90% are proteases. Examples of
these include trypsinogen, chymotrypsinogen, proelastase, and procarboxypeptidase.
About 7% of the enzymes present in the pancreatic juices are amylases. About 2% of
enzymes present are lipases. These include lipase, prophospholipase and non-specific
esterase. Less than 1% of the enzymes in the pancreatic juices are nucleases such as
DNAase and RNAase.

Trypsinogen is an inactive proteolytic enzyme that is produced in the pancreas and is
secreted in its inactive form. It is converted to trypsin by enterokinase. Enterokinase is
an enzyme that is found on the brush border. The trypsin that formed is responsible for
converting other zymogens to active enzymes.

Regulation of Pancreatic Secretion—The primary control of pancreatic secretions is
humoral. However, there is also neural control.

Cholecystokinin (CCK) is the main controlling substance of the pancreas. The release
of CCK is stimulated by free fatty acids, peptides, amino acids, and releasing peptides.
These stimulate the I-cells to produce CCK which enhances enzyme release from the
acinar cells.

CCK also acts through the vago-vagal reflexes to control pancreatic secretion. CCK
interacts with neural sensory receptors in the small intestine and increases vagal afferent
discharge. This stimulates vagal afferent input to the dorsal vagal complex which leads
to activation of the vagal efferents. The result is that Ach, VIP, GRP, and substance P are
released by the pancreas.

The release of CCK is enhanced during meal digestion by two substances: monitor
peptide and CCK-releasing peptide. During the interdigestive period, these proteins are
broken down by trypsin and are unable to enhance CCK secretion. In the digestion
period, the trypsin activity is diluted so that these factors remain present in sufficient
enough amounts to stimulate the release of CCK.

Secretin is another form of humoral regulation of pancreatic secretion. Acid, free fatty
acids, and releasing peptides stimulate the S-cells to produce secretin. Secretin acts on
the acinar and ductal cells to enhance enzyme release from them. Its main action is on
the ductal cells.

There is a synergistic effect of secretin and CCK to work together to enhance activity of
the pancreatic cells. Bicarbonate and enzyme production are enhanced by combining
CCK and secretin activity.

Phases of Pancreatic Secretion—The three phases of digestion also are important in
pancreatic secretion. The cephalic phase accounts for 25% of pancreatic secretions.
This phase is stimulated by the anticipation, sight, smell, mastication, or taste of food.
The stimulatory/regulatory pathway is a vagal pathway. The response is an increase in
the release of pancreatic enzymes and in some bicarbonate.
The gastric phase accounts for about 10-20% of the enzyme secretion of the pancreas. It
is stimulated by distension of the stomach and is regulated by the vagal regulatory
pathway. It is also stimulated by amino acids and peptides to release gastrin. The result
is an increase in enzyme and bicarbonate secretion.

The intestinal phase is the most important phase of pancreatic secretion, accounting for
50-80% of the pancreatic enzyme secretions. It is stimulated by oligopeptides, essential
amino acids, fatty acids, gastric acid. The intestinal phase is regulated by the vagal
pathway, enteropancreatic reflexes, CCK, and secretin release. The result is enhanced
secretion of enzymes and bicarbonate.

Other Regulators—There are other factors which are involved in the modulation of
pancreatic secretion. Peptide hormone YY (PYY) has been previously discussed for its
effect on GI functions . The presence of fat in the GI tract causes decreased acid
secretion, delayed gastric emptying, decreased transit rate, and decreased colon motility.
It also causes a decrease in the amount of pancreatic secretion. Pancreatic polypeptide
is produced by the islet cells. It modulates total pancreatic secretion by acting in a
negative feedback mechanism on the dorsal vagal complex.

Chronic Pancreatitis—Dr. Pasley showed a slide in lecture explaining the consequences
on a deficiency in lipases. The result of this is that there is diarrhea with steatorrhea
leading to bulky, fatty, and smelly stools. This occurs b/c the GI tract is unable to digest
and store fat. This leads to a major caloric deficiency. (This isn’t something I really
understood, so don’t take my word alone for it! However, the paragraphs below is what
the old syllabus has to say)

Chronic pancreatitis is one of the most common pancreatic disease. It is often associated
with a history of chronic alcohol abuse and may take many years to develop.
Malabsorption doesn’t occur until the pancreatic secretory capacity is reduced to about
10% of normal. In pancreatitis, there is decreased secretion of digestive enzymes. This
results in the maldigestion of macronutrients that leads to major caloric loss and
decreased vitamin B12 absorption. The decreased absorption of B12 is due to a decrease
in its release from haptocorrin. This leads to decreased intrinsic factor vitamin B12
complex.

Pancreatic insufficiency is treated by pancreatic enzymes that are given orally at a low
pH. They are often put into an acid-resistance enteric coated tablet so that they can be
delivered to the small intestine where the acid-resistant coat dissolves (at a pH of around
6 or greater) and the enzymes are released.

Biliary Tract—The liver lobule is the basic functional unit of the liver. Each lobule is
composed of hepatic plates that radiate from around the central vein. Each hepatic plate
(also called hepatic cords) is 1-2 cell layers thick and between adjacent cells are tubular
canals called bile canaliculi.
Portal blood that returns from the GI tract and the blood from the hepatic arteries flows
through the sinusoidal spaces between the hepatic plates and into the central vein. From
here they flow into the vena cava. The cells of the hepatic plates are called hepatocytes.
They absorb bile acids from the portal blood and secrete them into the canaliculi. Bile
flows countercurrent to the sinusoidal blood flow and empties into bile ducts. The bile
ducts are found in the septa of adjacent liver lobules and come together to form large
ducts. These are the right and left hepatic bile ducts that join to form the common hepatic
and common bile ducts.

During the interdigestive state, bile is stored in the Gallbladder. During this time period,
the sphincter of Oddi is contracted and the glallbladder is relaxed so that bile can flow
into the gallbladder for storage.

Bile Composition—Bile is made up mainly of water (96% according to the lecture
slides). A small percentage of bile composition is in the form of solutes. Of the solutes,
bile acids are the major component. It is kept in solution by cholesterol and
phospholipids. Other solutes in bile include cholesterol, electrolytes, bilirubin, and
protein.

Look at figure 27.14 (p. 494) in Rhoades and Tanner. This figure shows the components
of total bile flow.

Bile acids—Bile acids are cholesterol derivatives and serve as the body’s only way to get
rid of cholesterol. The primary bile acids are synthesized from cholesterol conjugated
with taurine or glycine to become cholic acid and chenodeoxycholic acid. Secondary
bile acids (deoxycholic acid and lithocholic acid)are produced in the lumen of the small
intestine. Intestinal bacteria convert primary bile acids into secondary bile acids via the
enzyme 7 α-dehydroxylase. Bile composition is a combination of primary and secondary
bile acids.

There is some passive reabsorption of bile acids, but the main mechanism for bile acid
reabsorption is an active reabsorption mechanism. This takes place in the ileum and the
bile acids are returned to the liver via circulation. Lithocholic acid is insoluble and is
hepatotoxic, so it is not reabsorbed. About 95% of the bile acids are reabsorbed during a
meal. The bile acids that aren’t reabsorbed pass into the colon.

The migrating motor complex is responsible for returning bile acids to the enterohepatic
circulation during the interdigestive state. The MMC helps to push bile acids to the
terminal ileum. Here they are absorbed into the portal circulation and transported back to
the liver.

Bile acids regulate their own synthesis from cholesterol by negative feedback through
the enterohepatic circulation. Bile acid synthesis is coupled to cholesterol synthesis. If
there is a decrease in the amount of bile acids returned to the liver, there is an increase in
bile acid synthesis and vice versa.
If the ileum is surgically removed, there is a decrease in the amount of bile acids that are
reabsorbed. As a result, the synthesis of bile acids must be increased to keep up with the
lack of absorption. The result of the bile acids not being reabsorbed is fatty, watery
diarrhea.. This bile acid diarrhea can also be due to an increased load of bile acids.

Regulation of Biliary Secretion—CCK is released under stimulation of a meal. This is
the primary stimulus for contraction of the gallbladder and relaxation of the sphincter of
Oddi.

CCK stimulates this activity by both neural and humoral pathways. CCK activates
sensory neurons with CCK receptors. This initiates vagal afferents to the dorsal vagal
complex. In the dorsal vagal complex, signals lead to activation of vagal efferents that
interact with the enteric nervous system of the gallbladder and sphincter of Oddi. At the
gallbladder, these efferents stimulate Ach release which causes gallbladder contraction.
At the sphincter of Oddi, the enteric nerves release VIP and NO to cause relaxation.

The result of these actions is that bile can be moved from the gallbladder into the bowel.

Cholelithiasis—This is more commonly known as gallstones. Most gallstones are made
up of cholesterol. Causes of gallstones include: too much absorption of water form bile,
too much absorption of bile acids from bile, too much cholesterol in the bile, and
inflammation of epithelium.

Gallstones can block the bile ducts and prevent hepatic secretions from entering the gut.
The result is severe pain in the right upper quadrant.

The main treatment for gallstones is a laproscopic cholecystectomy (gallbladder
removal). In a new therapy, oral bile salts are being given to change the composition of
bile and cause the stones to break up.

								
To top