Exocrine Pancreatic Secretions

Question 1

What does pancreatic juice consist of?

Answer 1

Pancreatic juice consists consists of hydrolases as well as sodium bicarbonate

Question 2

What is hydrolase

Answer 2

Hydrolase is a pancreatic digestive enzyme which is secreted from the exocrine acini

Question 3

Where is the aqueous alkaline solution secreted from

Answer 3

It is secreted from the epithelial cells lining the small ductules and larger ducts which lead from the acini

Question 4

When is pancreatic juice juice secreted?

Answer 4

Pancreatic juice is secreted most abundantly in response to the presence of chyme in the upper portions of the small intestine.

Question 5

What are the aqueous components of the pancreatic juice

Answer 5

It can be divided into acinar cell secretion as well as ductule cell secretion/output.

Question 6

Discuss acinar cell secretion

Answer 6

80% of pancreas comprise of acinar cells which secrete small volume of isotonic fluid containing pancreatic digestive enzymes

The acinar fluid resembles plasma in its conc. of soduim,chloride, bicarbonate and potassium

It constitutes the basal exocrine secretion, but is equal to only about 2% of the maximal secretory rate of pancreatic juice

Question 7

Discuss the ductule cell secretion/output

Answer 7

Comprise about 4% of the pancreas.

Large volumes of water and Sodium-Bicarbonate to neutralize the acidic chyme is emptied into the stomach into the duodenum is primarily secreted by the ductule cells

Question 8

Discuss what happens at various rates of secretion

Answer 8

At all rates of secretion, pancreatic juice is essentially isotonic with plasma.

At low rates of secretion, the ionic composition remains to be a solution of Na+ and Cl-

As the rate of secretion increases in response to stimulation, Na+ and HCO3- predominate.

The ductule cells, including the centroacinar cells, and even some of the epithelial cells lining the intralobular ducts, are responsible for the high bicarbonate content.

Question 9

Secretion of Bicarbonate

Answer 9

The ductule cells possess of a
mechanism to secrete HCO3 - against both its chemical and electrical gradient into the ductule lumen

1. Stimulated ductule cells activates aCl-/HCO3-antiporter in the apical membrane.

This exchange process is based on a mechanism
known as secondary active
countertransport. (Why?)

Secretion of HCO3- depends on high
luminal Cl-, which is possible when
the Cl channels (2)are activated by cAMP in response to stimulation by secretin.

The secretin-stimulated secretion can have a HCO3-concentration as high as 145 mmol/L in the ductule lumen.

This provides a large quantity of alkali in the pancreatic juice.

The increased cAMP also let H+-pumps (3) move to fuse with the basolateral membrane. These Na+/H+ antiporters represents a secondary active transport mechanism.

The role of Na+,K+-ATPase on the basolateral membrane is that of primary active transport (4), creating an electrochemical gradient for Na+ to move into the cell on the H+ -pump (3), in exchange for H+,which leaves the cell.

CO2 now diffuses readily into the cell (5), combining with OH- of water to form HCO3-.

The formation of HCO3-is catalysed by carbonic anhydrase (CA). The continued movement of H+
across the basolateral membrane drives this reaction and leads to a build-up of HCO3-, resulting
in the movement of HCO3-across the apical membrane in exchange for Cl-
(1).

Much of the luminal Na+ diffuses through paracellular space (6).

Most of the Na+and HCO3-in pancreatic juice is derived from plasma.

The movement of these ions into the duct lumen also creates an osmotic gradient that causes osmosis of water

Question 10

What is the role of bicarbonate in the pancreatic juice

Answer 10

It flows through the duct system,esp the larger intralobular ducts and even extralobular ducts, the HCO3 - moves down its concentration gradient, leaving the ducts in exchange for Cl-

This Cl-, HCO3 - exchange mechanism is not effective when the secretory rate begins to increase, and pancreatic juice will contain primarily HCO3-at concentrations of 115 up to 145 mmol/L.

But at low secretory rates, there is enough time for the
exchange to occur and Cl- becomes the predominant anion

Question 11

How does the secretion of pancreatic digestive enzymes occur

Answer 11

They are secreted by acini though the stimulation of Cholecystokinin(Duodenal hormone) and Acetylcholine(Parasympathetic neurotransmitter)

They contain proteolytic enzymes.

Question 12

Name the proteolytic Enzymes

Answer 12

Trypsin

Chymotrypsin

Carboxypolipeptidase

Pancreatic alpha-amylase

Pancreatic lipase

Cholesterol esterase

Phospholipase

Question 13

Trypsin .

Answer 13

is an endopeptidase, splitting peptide bonds on

the C-terminal side of Lys and Arg

Question 14

Chymotrypsin

Answer 14

An Endopeptidase, hydrolyses the peptide bond on C-terminal side of aromatic
amino acids (Phe, Tyr, and Trp). 

These two enzymes thus split whole
and partially digested proteins into peptides of various sizes but do not cause release of individual amino acids.

Question 15

Pancreatic alpha-amylase

Answer 15

Hydrolyses polysaccharides such as starches and glycogen to form
disaccharides and a few trisaccharides.

Question 16

The main enzymes for fat digestion:

Answer 16

Pancreatic Lipase

Cholesterol Esterase

Phospholipase

Question 17

Pancreatic lipase

Answer 17

Which is capable of hydrolysing

triacylglycerols into free fatty acids and 2-monoacylglycerols.

Question 18

Cholesterol esterase

Answer 18

Hydrolyses cholesterol esters

Question 19

Phospholipase

Answer 19

Splits fatty acids from phospholipids

Question 20

Prevention of autodigestion of the pancreatic tissue

Answer 20

Proteolytic enzymes are released into the pancreatic ducts in their inactive forms
trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.

They only become activated when entering the duodenal and jejunal lumen.

The reason is the localisation of the enzyme called enterokinase (enteropeptidase), which is expressed on the surface of enterocytes of the upper intestinal mucosa under influence of CCK stimulation.

Enterokinase hydrolyses trypsinogen present in chyme into trypsin plus a short peptide. Active trypsin can then also convert other trypsinogen molecules, as well as chymotrypsinogen and procarboxypolypeptidase into their active peptides.

Thus, once a small amount of trypsin is
formed, a catalytic chain reaction of activating all protease precursors within the lumen of the
duodenum and jejunum occurs.

Pancreatic acini secrete a peptide called trypsin inhibitor (or Kazal inhibitor) that
complexes with any small amount of trypsin which may find its way into the pancreatic
ductal system.

Therefore, any activation of the proteolytic enzymes while they are still
in the pancreatic ducts is inhibited, preventing digestion of the pancreas itself. With
inflammation or severe injury of the pancreas or when a duct becomes blocked, large
quantities of pancreatic juice may accumulate in the damaged area and the effect of
trypsin inhibitor overwhelmed, in which case activated trypsin can initiate autoproteolysis of the entire pancreas within a few hours.

The condition is called acute
pancreatitis. In 5% of cases the condition is extremely serious and even lethal because
of accompanying circulatory shock when the enzymes leak into the abdominal cavity,
resulting in the digestion of blood vessels, formation of a haematoma, and generalised
peritonitis.

Acute pancreatitis in any case leads to a lifetime of pancreatic insufficiency.

The presence of high concentrations of alpha-amylase in the blood can confirm the diagnosis
of acute pancreatitis.

Question 21

Prevention of autodigestion of the pancreatic tissue

Answer 21

Proteolytic enzymes are released into the pancreatic ducts in their inactive forms
trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.

They only become activated when entering the duodenal and jejunal lumen.

The reason is the localisation of the enzyme called enterokinase (enteropeptidase), which is expressed on the surface of enterocytes of the upper intestinal mucosa under influence of CCK stimulation.

Enterokinase hydrolyses trypsinogen present in chyme into trypsin plus a short peptide. Active trypsin can then also convert other trypsinogen molecules, as well as chymotrypsinogen and procarboxypolypeptidase into their active peptides.

Thus, once a small amount of trypsin is
formed, a catalytic chain reaction of activating all protease precursors within the lumen of the
duodenum and jejunum occurs.

Pancreatic acini secrete a peptide called trypsin inhibitor (or Kazal inhibitor) that
complexes with any small amount of trypsin which may find its way into the pancreatic
ductal system.

Therefore, any activation of the proteolytic enzymes while they are still
in the pancreatic ducts is inhibited, preventing digestion of the pancreas itself. With
inflammation or severe injury of the pancreas or when a duct becomes blocked, large
quantities of pancreatic juice may accumulate in the damaged area and the effect of
trypsin inhibitor overwhelmed, in which case activated trypsin can initiate autoproteolysis of the entire pancreas within a few hours.

The condition is called acute
pancreatitis. In 5% of cases the condition is extremely serious and even lethal because
of accompanying circulatory shock when the enzymes leak into the abdominal cavity,
resulting in the digestion of blood vessels, formation of a haematoma, and generalised
peritonitis.

Acute pancreatitis in any case leads to a lifetime of pancreatic insufficiency.

The presence of high concentrations of alpha-amylase in the blood can confirm the diagnosis
of acute pancreatitis.

Question 22

Regulation of the pancreatic secretion-Acetylcholine

Answer 22

Released when parasympathetic vagus nerve fibres carry impulses to the pancreas which binds to the muscarinic receptors on the basolateral surface of acinar cells.

Intracellular Ca2+ levels rise intiating phosphorylation of structural and regulatory protiens

Question 23

Acetylcholine

Answer 23

Released when parasympathetic vagus nerve fibres carry impulses to the pancreas which binds to the muscarinic receptors on the basolateral surface of acinar cells.

Intracellular Ca2+ levels rise, initiating
phosphorylation of structural and regulatory proteins involved in the fusion
of secretory granules with the apical membrane and subsequent discharge of
the enzymes.

Although activation of gastro-pancreatic vagovagal reflexes has been described as a mechanism responsible for cholinergic impulses,
most acetylcholine is released as part of the cephalic phase of pancreatic
control.

Question 24

Cholecystokinin (CCK)

Answer 24

a polypeptide containing 33 amino acids, is secreted by the I-cells of the
duodenal and upper jejunal mucosa when chyme enters the small intestine.

The I-cells release CCK into the interstitial space in response to smaller peptides and amino acids (products of partial protein digestion) present in the intestinal lumen, and also by the presence of long-chain fatty acids (products of partial fat digestion).

Circulating CCK has a half-life of 5 minutes. Its main functions are:

 Increased pancreatic acinar fluid rich in enzymes when CCK binds to CCK-A receptors on
acinar cells, increasing the intracellular Ca2+ levels.

 Rhythmical contractions of the wall of the gallbladder (with simultaneous relaxation of the
sphincter of Oddi).

 Competitive inhibition of gastrin’s effect on gastric emptying and secretion.

 Stimulating the expression of enterokinase on the brush border of small intestinal enterocytes

Question 25

CKK main functions are:

Answer 25

1. Increased pancreatic acinar fluid rich in enzymes when CCK binds to CCK-A receptors on
   acinar cells, increasing the intracellular Ca2+ levels.
2. Rhythmical contractions of the wall of the gallbladder (with simultaneous relaxation of the
   sphincter of Oddi).
3. Competitive inhibition of gastrin’s effect on gastric emptying and secretion.
4. Stimulating the expression of enterokinase on the brush border of small intestinal enterocytes

Question 26

Causes of Acute Pancreatitis

Answer 26

G.E.T.S.M.A.S.H.E.D

G-all stones

E-thanol

T-rauma

S-teroids

M-umps

A-utoimmune

S-corpion venom

H-Hypothermia/Hyperlipidemia

E-RCP

D-rugs

Question 27

Secretin

Answer 27

Secretin is a polypeptide, containing 27 amino acids, that is present in an inactive form,
prosecretin, in so-called S-cells of the duodenal and jejunal mucosa.

Secretion occurs mainly in
response to acidic chyme in the lumen (pH of 4.5 or below), but also by peptides and amino acids
(products of protein digestion) present in the intestinal lumen.

It has a half-life of 5 minutes

Question 28

Functions of Secretin

Answer 28

1. Secretion of a bicarbonate solution by the ductule
   cells of the pancreas and thus an alkaline watery juice.
2. Inhibits gastric secretion.
3. The secretin-dependent bicarbonate-rich pancreatic juice serves to:

3.1 Neutralise the acidic chyme
emptied into the duodenum from the stomach which blocks further
peptic activity by the gastric juices in the duodenum, an essential protective mechanism to
prevent development of duodenal mucosal damage.

3.2 Secretin-dependent bicarbonate
secretion also provides an appropriate pH for action of the pancreatic enzymes, which function
optimally in a slightly alkaline or neutral medium, at a pH of 7.0 to 8.0.

Question 29

1. Phases of pancreatic secretion

Answer 29

Pancreatic secretion also occurs in three phases, the same as for gastric
secretion-cephalic
phase, the gastric phase, and intestinal phase

Question 30

2. Phases of pancreatic secretion

Answer 30

Acidic chyme enters the duodenum casing enteroendocrine cells of the duodenal wall to release secretin, whereas fatty protein-rich chyme induces release of Cholecystokinin

CKK and Secretin enter the bloodstream

Upon reaching the pancreas,CKK induces the realeae of enzyme-rich pancreatic juice.

Secretin causes copious secretion of bicarbonate richpancreatic juice

Question 31

Secretion of Bile by the liver

Answer 31

Bile secretion is the principal digestive function of the liver. Bile
production is about 600 to 1000 ml/day. The liver cells secrete bile
continually, but most of it is normally stored in the gallbladder until needed
in the duodenum.

Question 32

Functions of Bile:

Answer 32

1. By far the most abundant substances secreted into the bile are the bile salts, responsible for the role that bile plays in lipid digestion and absorption.-
   Bile salts:
   (i) help to emulsify the large lipid droplets, enabling pancreatic lipase to act on the fat,
   and
   (ii) they aid in absorption of the digested fat end products
   by the intestinal epithelial cells (enterocytes).
2. Bile serves as a means for excretion of several important waste
   products from the blood, including bilirubin and cholesterol.

Question 33

What are the main components of Bile

Answer 33

Bile Salts

Bile Pigment

Cholesterol

Alkaline electrolyte solution

Question 34

Storage and concentration of bile in the gallbladder

Answer 34

The capacity of the gallbladder is about 30-60ml

Storage over a 12 hour period can result in bile being stored in about 450ml

This occurs because of active transport of Na+
through the gallbladder epithelium, followed by secondary absorption of Cl- and
water, concentrating the remaining bile constituents.

Question 35

Composition of bile

Answer 35

Water
Bile salts
Bilirubin
Cholesterol

Question 36

Bile secretion and release

Answer 36

Secretin via bloodstream stimulate liver ductal secretion

Vagal stimulation causes weak contractions of the gallbladder

CKK causes gallbladder contraction as well as relaxation of the sphincter of oddi

Question 37

Bile Salts/Acids

Answer 37

The liver synthesises about 0.2-0.6 grams of bile salts daily.

Cholesterol is the precursor which is converted to either cholic acid or chenodeoxycholic acid in about equal quantities.

These two
molecules retain the steroid ring structure, but contain more OH-groups than cholesterol as well
as a 5-carbon side chain (with a polar carboxyl group).

The next step is conjugation of the bile
acids. They combine principally with glycine and to a lesser extent with taurine to form the
amides glyco- and tauro-conjugated bile acids.

Conjugation of bile salts lowers the pK of the bile salts, making them more ionised at the pH
environment of chyme in the intestinal lumen, which means that they act as better detergents.

Also, being ionised, the bile acids are present mainly as sodium salts. Therefore, the term
“bile salts”. (Both bile acids and bile salts are used interchangeably).

Question 38

Differentiate and list the primary and secondary bile acids

Answer 38

Primary bile acids:

• conjugated cholic acid
• conjugated chenodeoxycholic acid
• crucial in fat digestion and absorption

Secondary bile acids: -deconjugated, dehydroxylated - bacterial action in colon

• Cholic acid>Deoxycholic acid
• Chenodeoxycholic acid>lithocolic acid

Question 39

Secretion of bile:

Answer 39

Hepatocytes-initial secretion of bile acids, cholesterol and organic constituents

Through biliary system to gallbladder-concentration of bile

Question 40

Bile salts:

Answer 40

Bile salts are amphipathic( contains hydrophobic
& hydrophilic domains can mix with fat &
water) structures

→ -OH groups on α side of rings
→ formation of water soluble molecular aggregates called micelles which form ‘groups’ that ‘stick
together

Question 41

Enterohepatic recirculation of bile salts:

Answer 41

The secondary active transport absorbs
primarily conjugated bile salts and occurs in the terminal ileum.

The mechanism is a Na+-bile salt cotransport system powered by basolateral
Na+,K+-ATPases.

Secondary bile salts are absorbed
passively throughout the small intestine

Overall, more than 95% of the bile salts are reabsorbed into the portal blood. In the liver they are all reconjugated, but often not
rehydroxylated.

These bile salts, together with some newly synthesised primary bile acids, are again secreted by the liver.

The Steroid nucleus cannot be degraded in the
body and therefore is is excreted in faeces as:
− bile acids
− free cholesterol

Higher (more often) enterohepatic
recirculation> higher quantities of
bile secreted less absorption
of bile salts>
increased liver
production

Excessive excretion>
diarrhoea without loss of fat

Question 42

Cholesterol:

Answer 42

• Cholesterol almost completely insoluble in bile/chyme
– association with bile salts and lecithin  micelles
– micelles carry hydrophobic bile substances to GIT for excretion
Normal:
1–2g cholesterol/day secreted into bile – excreted in faeces
= major route for removal of steroid nucleus from body:
 free cholesterol
 bile salts

Question 43

What are substances which increase the rate of bile production

Answer 43

Choleretics

Question 44

Causes of gallstones:

Answer 44

1. Too much absorption of water from bile.
2. Too much absorption of bile salts from bile.
3. Too much secretion of cholesterol in the bile.
4. Inflammation of epithelium-Cholesterol begins to precipitate, usually forming
   many small crystals of cholesterol on the surface of the inflamed mucosa.