Download Pancreatic Secretions

GI Review- MK 2015
Regulatory Substances:
Regulation
CCK
Substance
(Cholecystoki
nin)
Gastrin
Motilin
Secretin
Somatostatin
D-cells
(pancreatic
Islets, GI
stimulates
mucosa)
-Decrease in
gastric acid and
pepsinogen
secretion
-Decrease in
pancreatic and
small intestine
fluid secretion
-Decrease in
gallbladder
contraction
-Decrease in
insulin and
glucagon release
-Increased by
acid
-Decreased by
vagal
stimulation
Source
I cells –
Duodenum,
jejunum
G-Cells
(antrum of
stomach)
Small intestine
S-cells
(duodenum)
Action
-Increased
pancreatic
enzyme
secretion
-Increased
gallbladder
contraction
-Decrease in
gastric emptying
-Increase
relaxation of
Oddi
-Increased
gastric +H
secretion
-Increase
growth of gastric
mucosa
-Increase
gastric motility
-Produces
migrating
motor
complexes
(MMCs)
-Increased
pancreatic
HCO3secretion
-Increased by
fatty acids and
aminoacids
-Increase by
stomach
distention/alkali
nization, aa,
peptides, vagal
stimulation
-Decreased by
stomach pH<1.5
-Increased in
ZollingerEllison
Syndrome
-Increased by
chronic PPI use
(Protein pump
inhibitors)
-Phenylalanine
and tryptophan
are potent
stimulators
Regulation
Notes
-CCK acts on
neural
muscarinic
pathways to
pancreatic
secretion
-Slows down
emptying incase
pH too low & if
very fatty food
ingested
-Decreased
gastric acid
secretion
-Increased bile
secretion
-increase in
fasting state
-Increased by
acid, fatty
acids in lumen
of duodenum
Nitric
Oxide
Increase
smooth
muscle
relaxation,
including
lower
esophagea
; sphincter
(LES)
-Increased
HCO-3
neutralizes
gastric acid in
duodenum,
allowing
pancreatic
enzymes to
function.
-Inhibitory
hormone
-Antigrowth
hormone effects
(inhibits
digestion and
absorption of
substances
needed for
growth)
Histamine
ECL
Enterochrom
affin-like
-Gastric
mucosa
-Release
histamine
binds H2
receptors
-Increase
H+ secretion
- Stimulates
parietal
cells to also
release H+
-Increase by
distention and
vagal
stimulation
-Decreased
by adrenergic
input
-Increased by
H+
Motilin
receptor
agonists (eg
erythromycin)
are used to
stimulate
intestinal
peristalisis
Vasoactive
intestinal
polypeptide
(VIP)
Parasympathet
ic ganglion in
sphincters,
gallbladder,
small intestine
-Increase
intestinal
water and
electrolytes
secretion
-increase
relaxation of
intestinal
smooth muscle
and sphincters
-Opens LES
-Loss of
NO
secretion
is
implicated
in
Increase
d LES
tone of
achalasia
(no
relaxation)
VIPomanon-a, non-b
islet cell
pancreatic
tumor that
seceretes VIP.
-W-watery
-D-diarrhea
-Hhypokalemia,
-Aachlorhydria
(WDHA
Syndrome)
Cimetidine:
blocks H2
receptors and
blocks the
action of
histamine on
parietal cells.
GI Secretory Products:
Product
Intrinsic Factor
Source
Parietal Cells
(stomach)
Gastric Acid
Parietal cells (stomach)
Pepsin
Chief cells (stomach)
Action
-Decrease stomach pH
Protein digestion
HCO3Mucosal cells (Stomach, duodenum,
salivary glands, pancreas) and Brunner
glands (duodenum)
Neutralizes acid
-Increase by histamine,
Ach, gastrin
-Decreased by
somatostatin, GIP,
prostaglandin, secretin
Gastinoma:
gastrinsecreting tumor
that causes high levels of
acid secretion and ulcers
refractory to medical
therapy
Increased by vagal
stimulation, local acid
-Increased by pancreatic and biliary
secretion with secretin
Active pepsinogenpepsin by
H+ (HCl)
-HCO3- is trapped in mucus that covers the
gastric epithelium
-Vitamin B12-binding
protein (required for
B12 uptake in
terminal ilium)
Regulation
Notes
Autoimmune
destruction of parietal
cellsChronic
gastritis and
pernicious anemia
(megoblastic)
Pancreatic Secretions:
Enzyme
Alpha-amylase
Role
Starch digestion
Notes
Secreted in active
form
Lipase,
phospholipase A,
colipase
Fat digestion
Proteases
Trypsinogen
Protein digestion
-Converted to active enzyme
trypsin activation of other
proenzymes and cleaving of
additional trypsinogen
molecues into active trypsin
(positive feedback)
-Converted to trypsin by
enterokinase/enteropeptidase,
a brush-border enzyme on the
duodenal and jejunal mucosa
-Includes trypsin,
chymotrypsin, elastase,
carboxypeptidases
-secreted as proenzymes
also known as zymogens
Interstitial cell of Cajal:
Type of interstitial cell found in GI and acts as a pacemaker by creating bioelectrical slow wave potential which leads to contraction
of the smooth muscle. The resulting depolarization initiates calcium ion entry and contraction. Slow waves organize gut contractions
that are the basis for peristalsis and segmentation.
Vitamin/Mineral Absorption (iron first bro)
Iron: Absorbed as Fe+2 in the duodenum
Folate Absorbed in jejunum and ileum
B12: Absorbed in terminal ilieum along with bile acids, requires intrinsic factor
Bile Acids& Salts:
Bile Acid & Salt Synthesis:
1.) Liver cholesterol becomes primary bile acids cholic acid and chenodeoxycholic acid
2.) Enzyme needed is (ER-associated cytochrome P450) 7-alpha-hydroxylase (present only in the liver)
which is a regulatory step.
3.) Allosteric stimulator is cholesterol and inhibitor would be bile acids
4.) Bile acids then bind to glycine and taurine, the negative charge on the carboxyl on the
amino acids, bile salts more amphipathic
5.) Move into the intestines where it becomes secondary bile salts by bacteria
– deoxycholic acid & lithocholic acid. This is due to deconjunction and dehydroxylation by intestinal bacteria.
6.) Reabsorbed from ileum then to the portal vein to liver. (Enterohepatic circulation)
7.) Some bile salts are released into the feces
Bilirubin Pathway:
1.)RBC is broken down by macrophages and there is a Heme group and a globin. The globin
gets broken down and to amino acids and reused to make erythrocytes .
2.) The heme group, gets released and the Fe+2 is released and goes back to the bone to synthesize
new red blood cells. Thus we have a Heme left (Porpherin) which is a ring structure. This ring structure
is then opens becoming bilirubin. Bilirubin is bright yellow and with increase accumulation of this you will see yellow
discoloration of the skin, eyes known as jaundice.
3.)It must be removed as it is toxic to the body. Bilirubin is now water soluble thus it is attached to albumin
and it carries it through the blood to the liver. Once inside UDP-Glucuronyl transferase attaches
Glucuronic acid to the bilirubin, making it less toxic and more water soluble. These are known as
conjugated bilirubin this get excreted into the bile then into the intestines. This gets acted upon by the bacteria in the
intestines to produce stercobilinogen, which is the precursor to stercobilin and occurs via oxidatio
4.)Stercobilin gives feces the brown colour. Uro-bilinogen can be excreted through the kidneys where Urobilinogen gets
oxidized into Urobilin, the substance which gives the yellow color of urine.
Parietal Cells
1.)
From the lungs we have CO2 produced from aerobic metabolism which joins with H2O via a reversible reaction with the
enzyme Carbonic anhydrase forms H2CO3 (Carbonic Acid).
2.)
The H2CO3 produced will break into H+ and HCO3- (Bicarbonate)
3.)
HCO3- will go through the basolateral side of the cell into the blood via a co-transporter.
4.)
While HCO3- is moved into the blood, Cl- is brought into the cell.
5.)
The H+ produced will move to the apical luminal surface of the cell while bringing in a K+ into the cell. This is done via
K+/H+ATPase
6.)
H+ expelled from the cell binds with Cl- brought in from the blood to the luminal surface, forming HCl in the lumen of
the stomach.
This exact same process occurs in pancreatic cells, but instead bicarbonate is released into the lumen and H+ into the blood.
Gastric Ulcers:
Contains Alkaline
outside
H.Pylori
Once bound to the
stomach lining,
releases urease
CO
Urease breaks down
Ammonia
Ammonia dissolves
in water forming
ammonium
hydroxide (Alkali)
Stress/Smoking
Embeds itself into
lining
Vasoconstriction
Gastric Ulcer
Decrease in mucous
production, thin layer
Thin protective layer
Ulcer
NSAIDs
Saliva- Acinus Cells:
1.)
2.)
3.)
4.)
5.)
6.)
Begins Isotonic to the surrounding solution
The ductal cells reabsorb Na+ and Cl-, while K+ and HCO3- is secreted into the Acinar duct
Saliva becomes Hypotonic, more Na+ and Cl- are leaving in comparison to K+ and HCO3- coming in. Also due to the
fact that ducts are impermeable to water. Thus saliva is dilute relative to plasma.
High flow rate: high levels of Na+ and Cl- in saliva due to decreased time for exchange
Low flow rate: Lowest levels of Na+ and Cl- in saliva due to increased time for exchange
HCO3- increases when you stimulate salivation because there will be increase metabolism and bicarbonate production in
the cells increase.
Acinar cells are stimulated:
Parasympathetic----CN VII (facial) CN IX (Glossopharyngeal)---- Ach------- Muscarinic cells----IP3 Ca+:
Increase: Conditioning, food, nausea, smell
Decrease: Dehydration, Fear, Sleep
*Atropine can act on cells inhibiting parasympathetic stimulation of saliva by blocking muscarinic cells*
Sympathetic----T1-T3----NE-----Beta cells-- cAMP
Biliary Tract:
Right &
Left
Hepatic
Duct
Common
Hepatic
Sphincter
of Oddi
Common
Bile Duct
Cystic Duct
Pancreatic
Duct
Oxynitic Glands
Empty their secretory products via ducts into the lumen of the stomach. Opens as ducts on the gastric mucosa called pits, which are
lined by epithelial cells. Deeper in the gland are parietal cells and chief cells. Found in the fundus and body of the stomach. Simple
almost straight tubes. Acid-secreting and they secrete HCL, Intrinsic factor, chief cells and parietal cells.
Cephalic phase:
Smell and taste releases HCl by Ach mechanism. Stimulate ECL to secrete histamine to increase HCl realease in the stomach.
Vago vagal reflex
Active during the receptive relaxation of the stomach in response to swallowing of food (prior to it reaching the stomach). When food
enters the stomach a "vagovagal" reflex goes from the stomach to the brain, and then back again to the stomach causing active
relaxation of the smooth muscle in the stomach wall. Caused by stomach distention, stretch receptors signal the brain and then
stimulate the vagus.
Gastric Phase:
When food gets in contact with the stomach, secretion of enzymes.
Pancreas Secretion:
Pancreatic lipase, amylase, proteases
*Produces bicarbonate rich pancreatic juice
Low flow rate  composed mainly of Cl- and Na+
High flow rate  composed mainly of HC03- and Na+ (S-cellsincrease in bicarbonate production)
Regardless of flow, pancreatic secretions are isotonic
This is because pancreatic ducts are permeable to H20
Glucose & Galactose regulation:
1.)
2.)
3.)
4.)
Glucose and galactose are transported from the intestinal lumen into the cells
by a Na+-dependent cotransporter (SGLT1) in the luminal membrane.
The sugar is transported “uphill” and Na+ is transported “downhill”
Transported from cell to blood by facilitated diffusion (GLUT2)
Na+/K+ pump in basolateral side help to keep intracellular [Na+] low,
thus maintaining the Na+ gradient across the luminal membrane
Poisoning of the Na+/K+ pump will decrease the gradient and thus
glucose and galactose will not be absorbed.
Fructose regulation:
Fructose is transported via facilitated
diffusion. Cannot be absorbed against
concentration gradient.
Lactose intolerance
-results form the absence of brush border lactase and, thus, the inability to hydrolyze lactose to glucose and galactose for absorption.
Non-absorbed lactose and H2O remain in the lumen of the GI tract and cause osmotic diarrhea.
Pancreatic proteases:
1.)
2.)
3.)
4.)
5.)
Trypsinogen is activated to trypsin by
a brush border enzyme, enterokinase
Trypsin can convert
chymotrypsinogen, proelatase, and
procarboxypeptidase A and B to their
active forms. (Even tyrpsinogen is
converted to trypsin via trypsin
The pancreatic proteases degrade each
other and are absorbed along with dietary
protein.
If there is damage to the enterocytes
would not have active Trypsin thus would
not be able to digest proteins.
If pancrease is destroyed, then no
trypsin then will have cystinuria
proteins in the urine.
Lipid digestion
Stomach:
1.) Mixing in the stomach break into droplets to increase surface area for digestion by pancreatic enzymes
2.) Lingual lipases digest some of the ingested triglycerides to monoglycerides and fatty acids. However; most of the
ingested lipids for digestion in the intestine by way of pancreatic lipases
3.) CCK slows gastric emptying
Small Intestine
1.) Bile acids emulsify the fat in small intestine increasing surface area
2.) Pancreatic lipase: hydrolyze FA, MAG, cholesterol, and lysolecithic
3.) The hydrophobic products of lipid digestion in micelles by bile acids.
Absorption of Lipids
1.) Begins in the small intestine because chylomicron carries dietary lipids. In the intestine, the cells produce Apo B48 which then
join with the dietary lipids making Apolipoprotein – nascent chylomicron
2.) In the Figure you can see that the nascent chylomicron contains TAG, CE, Apo-B48, Cholesterol and the size of the letters
shows the amount. Greatest is Tag>cholesterol and > cholesterol ester
3.)This nascent chylomicron enters the systemic circulation, but first additional proteins are needed. HDL acts as a reservoir,
transferring APO-CII and Apo E to nascent chylomicron. You then call this a chylomicron, which now contains Apo C II, APO
E, APO B48.
4.) As it enters the capillaries, it will be the tag inside the chylomicron which is acted on by LPL. This then releasing FFA to the EHT
and glycerol which is released to the blood stream and goes to the liver.
5.)The location of the LDL enzyme, it is anchored to the endothelial cells via heparin sulfate. LPL will thus act on TAG within the
chylomicron.
6. )The activator of this enzyme is Apo-C II, therefore chylomicron must have this. The APO C-II will activate the enzyme LPL
causing it to cleave off the TG, 2 MAG, and glycerol.
7.) In type II diabetes, you have insulin, but it is not functioning correctly. These patients have hyperlipidemia, increased lipids in
the blood. This is because insulin increases the gene expression of LPL. Thus, in diabetic patients you have hyperlipidemia,
hyperglycemia.
8.)Chylomicrons will be converted into chylomicron remnant. Once this has occurred, Apo C11 will be given back to HDL. In the
chylomicron remnant remains include CE, cholesterol, small amount of TAG, APO E, and APO B48.
9.)The remnant chylomicron will then be taken up by the liver via the APO-E receptor. In the liver it will join with lysosome and
degradation occurs.
Steatorrhea:
Pancreatic disease:
(eg, pancreatitis, cystic fibrosis), in which the pancreas cannot synthesize enzymes (pancreatic lipase)
Hypersecretion of gastrin:
In which gastric H+ secretion is increased and the duodenal pH is decreased. Low duodenal pH activates pancreatic lipase
Ileal resection:
Leads to a depletion of the bile acid pool because the bile acids do not recirculate to liver. No vitamin B12 absorption thus leads to
macrocytic anemia.
Bacterial overgrowth:
Lead to disconjunction of bile acids and their “early” absorption in the upper small intestine. In this case, bile acids are not present
throughout the small intestine to aid in lipid absorption.
Decreased number of intestinal cells for lipid absorption
Abetalipoproteinemia
Failure to synthesize apoprotein B, leads to inability to make chylomicrons
Vitamins
Fat soluble
DAKE – incorporated into micelles and abrobed along with other lipids
Water Soluble
C&B- are absorbed via Na+ dependent cotransport mechanisms.
-B12 absorbed in the ileum and requires intrinsic factor (secreted from parietal cells)
Gastrectomy results in pernicious anemia
Calcium:
-absorption in small intestine, all dependednt on adequate amounds of vitamin D, 1,25-dihydroxycholecalciferol, which is
produced in the kidney. 1,25-dihydroxycholecalciferol induces synthesis of an intestinal Ca+2 binding protein, calbindin D-28K.
- Vitamin D deficiency or chronic renal failure results in rickets in children and osteomalacia in adults
Iron
-Abrobed as heme iron (bound to myoglobin or hemoglobin) or as free F2+2.
-Heme iron is degraded and Fe+2 is released and becomes transferrin and transports it from the small intestine liver to storage sites
in the liver and from the liver to bone marrow for synthesis of hemoglobin
-Most common iron deficiency is the most common cause of anemia.
Secretion of electrolytes and H2O by the intestines:
-Cl- is the primary ion secreted into the intestinal lumen. It is transported through Cl- channles in the luminal membrane that are
regulated by cAMP
-Na+ is secreted into the lumen by passively following Cl-. H2O follows NaCl to maintain isosmotic conditions.
Cholera Disease:
-Vibro cholera (cholera toxin) causes diarrhea by stimulating Cl- secretion.
-Cholera toxin catalyzes adenosine diphosphate (ADP) ribosylation of the alpha subunit of the Gs protein coupled to
adenylyl cyclase, permanently activating it.
-Intracellular cAMP increases; as a result Cl- Channels in the luminal membrane open.
-Na+ and H2O follow Cl- into the lumen and lead to secretory diarrhea
-Sometimes strains of Escherichia coli causes diarrhea by similar mechanism.
Questions:
A 35-year-old man developed gastric ulcer due to H.pylori infection. Which of the
following substances enables these organisms to survive the acidic environment?
NH3
NO
Uric acid
Glycine
Correct. Through the enzyme urease these organisms generate ammonia
which neutralizes the acid and protects them. Ref: my lecture on Peptic
Ulcer.
Which of the following is an inhibitor of HCl secretion of parietal cells of the stomach?
Histamine
Acetyl Choline
Gastrin
Somatostatin
Nor-Adrenaline
Correct. Somatostatin inhibits the secretion by binding to its receptors on
the parietal cells. It also inhibits histamine secretion by ECL cells. Ref: My
lecture on Gastric Secretion.
A 45-year-old woman underwent cholecystography, was found to contract her gall
bladder normally. Which of the following cells are responsible for secretion of the
hormone that contracts gall bladder?
D cells
ECL cells
I cells
S cells
G cells
Correct. The 'I' cells of the duodenum secrete Cholecystokinin (CCK) which
contracts gall-bladder. Ref: My lecture on bile secretion.
Which of the following substances is conjugated with taurine in the liver?
Bile Acids
Bilirubin
Biliverdin
Bilinogens
Correct. Bile acids are conjugated with glycine and taurine to make them
soluble in water. Ref: My lecture on bile secretion.
1. The intestinal flora of a cow (ruminant) was free of the microorganism Diphyllobotrium latum. D.
latum synthesized the vitamin cofactor B12 which binds to a molecule secreted by a cell located in the
epithelium of the gastric mucosa. Which of the following molecules bind to B12?
A) Intrinsic factor.
B) Bicarbonate
C) Pepsinogen
D) Mucin E0 Hydrogen
Answer:A
2. A 56-year old man was diagnosed with cancer of the middle 1/3 of the esophagus. Surgery removed
the entire esophagus and attached the cardia of the stomach to the pharynx. 4 months post-surgery he
complained of pain which was similar to that of patients suffering from heartburn (pyrosis).
Investigations (scopy) found gastric juice in the pharynx and development of a different epithelium
(metaplasia) in the mucosa of the pharynx. The epithelium of the pharynx has converted (metaplasia) to
which of the following?
A) Simple columnar
B) Simple cuboidal
C) Squamous
D) Stratified squamous
E) Smooth muscle
Answer:?
Barrett's esophagus[edit]
Main article: Barrett's esophagus
Prolonged esophagitis, particularly from gastric reflux, is one factor thought to play a role in the
development of Barrett's esophagus. In this condition, there is metaplasia of the lining of the lower
esophagus, which changes from stratified squamous epithelia to simple columnar epithelia. Barrett's
esophagus is thought to be one of the main contributors to the development of esophageal cancer.[3]