Choudhury GI Physiology Flashcards
Salivary glands
and secretion
submandibular: serous/mucous
sublingual: serous/mucous
parotid (largest): serous
smaller glands: mucous
(buccal, lips, tongue, palate)
Functions of Saliva:
Taste Lubrication Protection Digestion Speech Not essential for life
Saliva – composition & function
water, mucus- facilitates speech, dissolving, tasting food, swallowing; food into cohesive bolus
alpha amylase- carbohydrate digestion, cleaves a-1,4 glycosidic bonds in starch,
lingual lipase, ribonucelase- initiates fat digestion, hydrolysis of dietary lipid RNA digestion
lysozyme- antibacterial (bacillus and streptococcus), innate and acquired immunity
lactoferrin- chelates iron (inhibits microbial growth)
lactoperoxidase- antibacterial (kills bacteria in milk and mucosal lining)
glycoprotein of IgA- secretory IgA- immunologically active against virus and bacteria
EGF, NGF- mucosa growth adn protection
kallikrein- activates bradykinin- dilates arterioles, constricts veins, increases blood flow to secretory glands
bicarb- minimizes tooth decay (neutralizes bacterial acid), neutralizes refluxed gastric acid into lower esophagus (heartburgn)
hypotonis, low osmolality– taste (carbs and fats, not protein)
Two types of salivary glands:
- serous (parotid- secretes nonviscous saliva composed of water, electrolytes and enzymes)
- mixed (submandibular, sublingual- secretes viscous saliva rich in mucin glycoproteins)
salivary Acini:
primary secretion-saliva, plasma (H2O, Na+, Cl-, K+, HCO3-, amylase)
salivary Myoepithelial cells:
motile, contracts, expels saliva
salivary glands- ductal
modifies secretion by modifying electrolytes, Na+, Cl- reabsorbed K+, HCO3- secreted
Striated duct epithelium tight junction - H2O cannot leave duct
**Ductal cells are water impermeable, water is not
absorbed along with the solute, water remains
in lumen and saliva is secreted hypotonic relative
to plasma
Salivary secretion – acinar & ductal cells
Initial saliva is produced by acinar cells
Subsequently modified by ductal
epithelial cells
Salivary ducts are impermeable to water
and sodium is continually reabsorbed
Lumen of ductal cells contains
3 transporters:
- Na +- H + exchange,
- Cl - HCO 3 exchange, and
- H +- K + exchange
Basolateral membrane contains:
- Na +/K + ATPase and Cl channels
Net absorption of Na + & Cl causes
NaCl in saliva lower than in plasma
Net secretion of K + and HCO 3 causes
K + and HCO 3 in saliva higher than in
plasma
Salivary secretion – rate & composition
**Ionic composition of saliva changes as salivary flow rate changes
Duct cells modifies the composition of saliva
At highest flow rates (4 mL/min), final saliva resembles plasma (high Na+, Cl-, low K+)
as the ductal cells have less time to modify the saliva
At lowest flow rates (< 1 mL/min), final saliva is dissimilar to plasma (low Na+, Cl-, high K+)
as saliva has more contact time with ductal cells, more Na+ and Cl- are reabsorbed, which
decreases their concentration and more K+ is secreted (hypotonic)
Salivary secretion - regulation
Salivary secretion and composition are controlled mainly by the ANS and to a lesser extent by hormones
Parasymp plays a major role
Parasymp stimulates & inhibits profoundly than Symp
Stimulated: by smell, taste, sound, sight, chewing, spicy or sour tasting foods, smoking.
Inhibited: by sleep, fear, anti-cholinergic & anti-depressant medication, dehydration, fatigue.
Modulated: by blood secretion, myoepithelial cell contraction, hormonal secretion.
Xerostomia
dry mouth due to absence of saliva production (drugs, radiation treatment, autoimmune disease).
buccal infections/dental caries
very common symptoms
Sjogren’s syndrome
autoimmune process-targets salivary and lacrimal glands
glandular atrophy and decreased saliva production (xerostomia), dry eyes (keratoconjuctivitis sicca)
difficulty in chewing, swallowing and speech.
dry oral mucosa, superficial ulceration, buccal infections/dental caries
Drooling
excessive salivation due to increase nervous stimulation
treatment: anticholinergics and surgical removal of sublingual glands
Parkinson’s, tumors of mouth/esophagus
increased saliva production due to unusual local reflexes and increase neurological stimulation
Cystic fibrosis
elevated Na+, Ca2+ and protein in saliva, sweat, pancreatic fluid & bronchial secretion
CF patients lacks CFTR or chloride transporter
Addison’s
increase Na+ in saliva (↓ Na+ reabsorbed)
Primary aldosteronism & Cushing’s
decrease Na+ in saliva (↑ Na+ reabsorbed), salivary NaCl is zero, increase K+ levels
Digoxin therapy
increase Ca2+ & K+ in saliva
Esophagus
motility
Esophageal motility is under both voluntary and involuntary control, peristalsis
Esophagus muscle composition:
- upper third (UES)– skeletal muscle, under voluntary control
- middle third – mixture of skeletal and smooth muscle
- lower third (LES) – smooth muscle, regulated by autonomic nervous system and enteric nerve plexus
Swallowing and opening of UES
- relaxation of UES and allows food to enter esophagus from pharynx, sphincter then closes
- coordinated by the brain stem, initiates local reflex and swallowing causes primary peristalsis
- distention of esophagus causes secondary peristalsis
Opening of LES
- when not eating LES remains closed (tonically constricted) due to sphincter pressure by diaphragm
- when eating, LES relaxes in response to swallowing and distention of esophagus
- this relaxation is mediated both by vagal stimulation and intrinsic properties of LES
Common disorders of esophageal function
GERD: gastroesophageal reflux disease, common
Barrett’s esophagus: special type of GERD
Dysphagia: difficulty in swallowing
Achalasia: failure of LES to relax, food in LES
Incompetent LES: failure of LES to contract
Diffuse Esophageal Spasms: uncoordinated
esophageal contraction
Hiatal Hernia: moves LES into thoracic cavity, increased
gastro-esophageal reflux
Barrett’s esophagus
(pre-cancerous lesion):
it is most often diagnosed in people who have long-term GERD (chronic inflammation)
this condition is recognized as a complication of GERD
a condition in whichcolumnar cells replace squamous cell in themucosa of esophagus
the main cause of Barrett’s esophagus is thought to be an adaptation to chronic acid
exposure fromreflux esophagitis
its importance lies in its predisposition to evolve into esophagealcancer
it develops in about 10–20% of patients withchronic GERD.
Achalasia
** bird’s beak
Achalasia (failure to relax):
special form of dysphagia
complete lack of peristalsis within esophagus
LES does not relax and increased LES pressure
food is retained at the level of LES
caused by:
- nerve degeneration (enteric nervous system)
- lack of NO synthase, VIP, etc
- Chagas disease (infection protozoa: Trypanosoma cruzi)
Diffuse Esophageal Spasms
diffuse esophageal spasms (DES) are irregular, uncoordinated, and sometimes powerful
–> CORKSCREW appearance
in some, very hot or very cold foods may trigger an episode
Hiatal Hernia
a hiatus hernia or hiatal hernia is the protrusion (or herniation) of the upper part of the stomach into the thorax through a tear or weakness in the diaphragm
in hiatal hernia, it is easier for stomach acids to come up into the esophagus
this causes a burning feeling in the throat and chest
symptoms similar to GERD
stomach secretions
Proximal portion secretes:
HCl, pepsinogen, intrinsic factor,
mucus, bicarbonate, water
Distal portion secretes:
gastrin, mucus, somatostatin
(endocrine, paracrine actions)types of stomach secretory epithelial cells
surface epithelial cells- secrete thick, viscous, alkaline mucus
mucus neck cell- mucus and bicarb (thin, watery mucus)
parietal cell- HCl, intrinsic factor
chief cell– pepsinogen, renin
Endocrine cell– Enterochromaffin-like cells secrete histamine, G cells secrete Gastrin, D cells secrete somatostatin
Oxyntic glands
are located in the fundus and body/corpus of stomach, contain three types of cells.
1. The parietal (oxyntic) cells secrete
- HCl (protein breakdown, pepsinogen activation, kills most microbes)
- intrinsic factor (IF) (necessary for the absorption of vit. B12 by the ileum)
2. Peptic (chief) cells secrete - Pepsinogen – converted to pepsin
3. Mucous cells secrete - Mucus (thick/thin mucous)
Pyloric glands
are located in the antrum & pyloric regions of stomach, contain G & some mucous cells.
1. G cells secrete - Gastrin (hormone) – stimulates parietal cells (HCl) & peptic cells (pepsinogen) 2. Mucous cells secrete - Mucous (thick/thin mucous)
somatostatin
stimulated by acid in the stomach
inhibits gastric acid secretion
gastrin
stimulated by Ach, peptides, amino acids
stimulates gastric acid secretion
gastric secretions- inverse relationship
between luminal conc of
H+ and Na+ as a function of the rate of gastric secretion
Acid secretion from parietal cells
Stomach’s parietal cells actively secrete H+ & Cl- by two separate pumps
Secreted H+ is derived from H2CO3 generated within the cell
CO2 is either metabolically produced in cell or diffuses from plasma
Secreted Cl- is transported into the parietal cell from the plasma.
HCO3- generated from H2CO3 dissociation is transported into the plasma in exchange for the secreted Cl-
The pH of secreted HCL is about 0.8 and has
H+ conc of 3 M fold higher compared to blood
It requires a lot of energy and H+ - K+ ATPase or
“proton pump” in cannalicular membrane is
key player
Receptors on parietal cells
**Agonists: ACh, Gastrin and Histamine all stimulate parietal cell to secrete acid
ACh binds to M3 receptors
Gastrin binds to CCKB receptors (gastrin 1500 X potent than histamine in releasing HCl)
Histamine binds to H2 receptors
**Inhibitors: Somatostatin and PGs directly binds to parietal cell and inhibits Histamine
Somatostatin binds to SST receptors
PGs binds to PGs receptors
Parietal cell pathophysiology
Excessive secretion due to gastrin-secreting tumor (zollinger-Ellison) may lead to peptic ulcer. Hypochlorhydria from atropic gastritis –> G. cell hyperplasia; increased gastrin –> increased risk of gastrinoma
Destruction of parietal cells in pernicious anemia (atrophic gastritis) –> Vit B12 deficiency (macrocytic anemia)
pathophysiology of Mucus cells
NSAIDS–> decreased prostaglandins–> decreased activity of mucous cells –> peptic ulcer
Pathophys of G cells
May be elevated in Zollilnger-Ellison syndrome or with prolonged administration of proton pump inhibitor
Regulation of Gastric acid secretion from parietal cell
Direct stimulation of parietal cell
- ACh released from vagus nerve binds to M3 receptors
- Histamine released from ECL cell binds to H2 receptors
- Gastrin released from G cell binds to CCKB receptors
- All three agonists synergistically stimulate and
- ** potentiate acid secretion from parietal cell
Indirect stimulation of parietal cell
-ACh released from vagus nerve binds to M3
receptors on ECL cell and release histamine
-Gastrin released from G cells binds to CCKB
receptors on ECL cell to release histamine
-Histamine released from ECL cell (by action of
ACh & gastrin) binds to H2 receptors on
parietal cell
Gastric secretion - alkaline tide
Secretion of H+ into lumen is balanced by secretion of an equal amount of HCO3- into blood
Increased pH of venous blood leaving stomach following a meal is alkaline & referred to as alkaline tide
Phases of gastric acid secretion
Cephalic Phase: 30% of total gastric acid secretion
Gastric Phase: 50-60% of total gastric acid secretion
Intestinal Phase: 10% of total acid secretion
-Secretin, GIP, and CCK
Vagotomy (cutting of vagus nerve):
inhibits gastric acid secretion
- used to treat peptic ulcers
- side effects: delay in gastric emptying, diarrhea
Selective vagotomy:
-cutting vagal nerves supplying parietal cells
only
Cephalic Phase: 30% of total gastric acid secretion
conditioned reflexes- impulses to medulla oblangata which stimulates vagus nerve: -ACh acts on parietal cells to release acid -ACh acts on ECL cells to release histamine -ENS stimulate G cells to release gastrin -Chief cells release pepsinogen -Inhibits D cells, reduce release of somatostatin (somatostatin inhibits gastrin release)
Gastric Phase: 50-60% of total gastric acid secretion
food distends gastric mucosa -vagus & ENS reflexes activated -increase in acid and pepsinogen secretion -peptides (peptones) & a.a stimulate gastrin release
Intestinal Phase: 10% of total acid secretion
peptides in duodenum stimulates gastrin secretion -chyme containing lipids or acid (pH 2) inhibits impulses from medulla oblangata and decrease vagal nerve stimulation, decrease acid secretion -duodenum releases 3 hormones-inhibits acid secretion
** -Secretin, GIP, and CCK
Stimuli of the phases of gastric secretion
cephalic: sight, smell, taste, chewing
gastric– distension, increased peptides, H+ concentration
Intestinal phase
distention
incrased H+ concentration, osmolality and nutrient concentration
Rennin (Chymosin)
Rennin or Chymosin is produced bygastric chief cells inhuman infants
Rennin secretion - maximal first few days after birth
Secreted as inactive pro-enzyme (pro-chymosin) that is activated
on exposure to acid
Proteolytic enzyme - causes milk to curdle in stomach
Milk retained in stomach and released more slowly
Rennin replaced by secretion of pepsinogen as major gastric protease
Pepsinogen secretion
Pepsinogen is an inactive, secreted form of pepsin
Secreted by peptic (chief) and mucous cells of
oxyntic glands, pyloric gland and duodenum
Chief cells stimulated by ACh (M3), histamine (H2), gastrin/CCK (CCKA receptors) to release pepsinogen
ACh also stimulates parietal cells to secrete acid.
Hypersecretion or damaged to gastric mucosal
barrier is associated with peptic ulcers
HCl converts pepsinogen to pepsin
Pepsin converts more pepsinogen to pepsin
- proteolytic enzyme, optimal pH 1.8 - 3.5
Pepsinogen Secretion
Two signals stimulate secretion of pepsinogen
Vagal stimulation – mediated by Ach
Direct response to gastric acid
Intrinsic Factor (IF)
IF is a glycoprotein secreted by parietal cells (fundus area)
It is required for the absorption of vitamin B12 (cobalamin)
Complex of IF + Vit B12 binds to cubulin (the receptor in terminal ileum)
Receptor mediated endocytosis (Vit B12 absorption)
Absence of IF results in Vit B12 not absorbed
Vit B12 required for final maturation of erythrocytes
Absence of IF and Vit B12 results in defective erythrocyte production or
Pernicious anemia, neurological disturbances
(numbness in extremities and weakness)
Vit B12 deficiency caused by:
Decreased dietary intake (vegan)
Decreased absorption
- gastric resection
(decreased IF)
- autoimmune disease
(antibody against parietal
cells and IF)
All leads to decrease Vit B12
level and prenicious anemia
This produces macrocytic anemia (megablastic anemia) as B12 is required for DNA synthesis in RBC progenitor cell in bone marrow. Inflammation destroys parietal cells and chief cells, reducing acid secretion causing hypochloremic metabolic alkalosis Loss of feedback mechanism, gastrin levels rises sharply. Prolong B12 deficiency causes neurological symptoms
Mucus Secretion - Gastric Mucosal barrier
Mucus secreted by surface cells acts as a
diffusion barrier for H+ and pepsin
Mucus layer traps HCO3- alkaline solution
HCO3- titrates H+ and inactivates pepsin
Ulcer formation
Agents causing mucosal damage:
H. Pylori ( > 80%)
Zollinger-Ellison syndrome, tumor
that causes excessive secretion of
gastrin, which stimulates acid
hyper-secretion.
NSAIDS (aspirin) inhibits COX-1
- COX-1 forms PGs
- PGs protects gastric mucosa
Alcohol
Bile acids
Stressful situations
- physical
- emotional
Acid and pepsin break through mucosal barrier
Acid stimulates histamine release
Histamine stimulates parietal cells to release acid
Acid diffuses through broken barrier
Vicious cycle continues
Aspirin and ulcers
Aspirin (a weak acid) is easily
absorbed in low pH of the stomach
Once absorbed it acts by acid
stimulating histamine release and
disruption of local mucosa
Aspirin suppresses protective
mucosal barrier productionPeptic Ulcer Disease:
Referred due to pathogenesis related to injurious
effects of gastric acid and pepsin
Both Gastric ulcer disease and Duodenal ulcer disease
Ratio of gastric ulcer to duodenal ulcer is 1:4
Gastric ulcer disease:
Occurs in the gastric mucosa
Increased acid secretion (H. pylori increases gastrin secretion,
** - Gastrinoma or Zollinger-Ellison syndrome (increases gastrin secretion)
Pepsin remains active for too long
Failure in mucosal defense mechanisms (NSAIDS, H. pylori)
Duodenal ulcer disease:
Occurs in the duodenum
Increase acid secretion in the gastric region
Pepsin remains active for too long
Decrease bicarbonate secretion from pancreas (pancreatitis)
we see 2-3x more parietal cells than normal
easier to get duodenal ulcer than gastric ulcer because fewer protective functions here
Gastric Acid Determination
Serum gastrin levels and gastric acid secretion used to evaluate gastric function
Pentagastrin is used to stimulate acid secretion
Gastrinoma or Zollinger-Ellison syndrome:
Pancreatic islet cell adenoma results - gastrin secretion gastric acid secretion both at rest
and after meal. Gastric and/or duodenal ulceration due to acid and pepsin activity
Atrophic Gastritis: lack parietal cells
Chronic inflammation of gastric mucosa due to H.pylori gastric acid
Pernicious anemia
autuimmune condition, antibodies against parietal cells and/or IF H+ and
somatostatin inhibition of gastrin, therefore gastrin but no H+
IF, therefore no Vit B12 absorbtion manifests as pernicious anemia-leads to neurological disorders
Helicobacter pylori – the bacterium causing peptic ulcer disease
H. pylori found in 95% patients with DU and 100% patients with GU (when alcohol, aspirin, NSAIDS are eliminated)
Gram negative bacterium
High urease activity-high NH4+ activity
- can withstand acid environment - NH4+ damages epithelial cells (GU) - increases acid secretion (DU)
Agents that stimulate & inhibit H + secretion by gastric parietal cells
Histamine potentiates effects of gastrin & ACh on parietal cells via H2 to release acid
Inhibiting H2 will decrease H+ release in the stomach
PPIs inhibits proton pump and decreases H+ release, increases gastric pH
Long term side effects of PPIs usage are:
- Peumonia; Clostridium difficle growth in gut; Osteoporosis
Pancreatic secretions:
The exocrine secretions of the pancreas that drain into the small bowel are derived from two distinct cells, ductal cells and acinar cells
Acinar secretions are enzyme-rich secretions that provide the enzymes necessary for digestion
for carbohydrates, proteins, nucleic acids, and lipids
Ductal secretions are HCO3 rich and neutralize acidic chyme to allow for proper function of pancreatic enzymes
pancreatic cells
acinar cells secrete digestive enzymes
duct cells secrete aqueous NaHCO2 solution
Hormonal control of pancreatic exocrine secretion
acid in duodenal lumen–> secretin release from duodenal mucosa–> carried by blood to pancreatic duct cells –> secretion of aqueous NaHCO3 solution into lumen (neutralizes acid)
Fat and protein products in duodenal lumen –> CCK release from duodenal mucosa (carried by blood to pancreatic acinar cells)–> secretion of pancreatic digeestive enzymes into duodenal lumen
The story of CCK and Secretin
- Chyme entering
duodenum causes duodenal
enteroendocrine cells to
release CCK and secretin - CCK and secretin
enter the blood
stream - CCK induces secretion of
enzyme rich pancreatic juice.
Secretin causes secretion of
HCO3- rich pancreatic juice
4. Bile salts and to a lesser extent, secretin transported via blood stream stimulate liver to produce bile more rapidly.
5. CCK (via blood stream) causes gall bladder to contract and hepato- pancreatic sphincter to relax. Bile enters duodenum.
- During cephalic and
gastric phases, vagal
nerve stimulates
gall bladder to contract.
Role of CCK in pancreatic exocrine secretion
CCK- potent stimulus of acinar secretion
acts on CCK-B receptors
via stimulation of vagal afferents duodenum
vago-vagal refelxes stimulate cholinergic
(ACh) and noncholinergic (GRP, VIP) NTs
HCO3- secretion from ductular cells
potentiates secretin effect of HCO3- secretion
CCK has multiple effects in duodenal cluster
coordinates GI activity (secretion) to food
contracts gall bladder
relaxes the sphincter of Oddi
slows gastric motility
retards gastric emptying
Factors causing CCK release
CCK is synthesized and stored in I cells (endocrine cells) in duodenum
release is modulated by body’s needs for CCK and controlled by CCK-RP (releasing peptide)
CCK-RP is released in response to fatty acids, aromatic amino acids, etc. into duodenum
monitor peptide (MP) and CCK-RP controls release of CCK
CCK increases enzymatic secretion from pancreas
large quantities of proteins in duodenum, CCK are released by CCK-PR and MP
presence of too much protein in diet, then both protein and peptides (CCK-RP/MP) compete
for trypsin and other proteolytic enzymes and both are are degraded slowly
when little or no protein in diet then trypsin degrades the peptides (CCK-RP/MP) and terminates
the release of CCK
peptides regulate release of CCK so that it can match its need in the duodenum
Role of secretin in pancreatic exocrine release
Secretin released from S cells in duodenal mucosa, stimulates pancreatic ductular cells when acidic chyme enters duodenum to neutralize H+
pancreatic secretions volume increases from low volume protein rich fluid to high absolute volume
as the secretory rate rises, the pH and bicarbonate concentration also rises
concentrations of Cl- and HCO3- are inversely related to those of Na+ and
H+ in stomach
Factors causing secretin release
S cells in duodenal mucosa acts as pH meters
S cells secretes secretin when pH falls due
to entry of acidic chyme
Secretin binds to receptors on
- pancreatic ductular cells
- epithelial cells lining bile ducts
- duodenum
Cells stimulate to secrete HCO3-in duodenum
Increase in pH will inhibit secretin release
Fatty acid meals evoke secretin release
Secretin release is sensitive to pH
Achlorhydric
( unable to secrete gastric acid)
- secondary to disease
- on drugs, proton pump inhibitors, bicarbonate
fail to release secretin even in presence of a
fatty meal
Signs of malabsorption and indigestion appears
if pancreatic secretions falls below
10%
With loss of pancreatic exocrine function, as may occur in pancreatitis or pancreatic
insufficiency, fewer digestive enzymes are secreted, which impairs nutrient digestion
and absorption
The most common causes of pancreatitis are * alcohol abuse and gallstones
Other well established but less common causes include significant hereditary
pancreatitis, marked hypercalcemia and hypertriglyceridemia, abdominal trauma, and
various drugs such as azathioprine.
In the genetic disease * cystic fibrosis, thick secretions into the pancreatic duct may
obstruct the duct and cause pancreatic insufficiency
Usually * fat digestion is affected to the greatest extent, resulting in a fatty diarrhea
(steatorrhea)* in which the feces may float, have an oily appearance, and be
particularly foul-smelling.
These patients are often treated with supplementary pancreatic enzymes.
Steatorrhea
fat in the stool-early sign of pancreatic dysfunction
60% fat and 30-40% proteins and carbohydrates not absorbed
reduced pancreatic enzyme (lipase) and bicarbonate secretion
low pH inactivates lipase
Pancreatitis: (acute and chronic)
retention of secretion in pancreas leads to autodigestion of pacreatic tissue
obstructive (gallstone occluding pancreatic duct, or a malignancy)-acute
hereditary-expression of a mutated trypsin molecule that is resistant by
trypsin inhibitors. Trypsin digests pancreatic tissue-chronic
inflammation of the pancreatic tissue (alcohol abuse)-chronic
Drugs and Toxins causing trouble with the pancreas
Immunosuppresants, anticonvulsants, thiazides
Autoimmune affecting the pancreas
celiac disease, IgG4,
Genetic abnormalities
affecting the pancreas
weak SPINK1, CFTR, CTRC genes and insult by alcohol, gallstones, etc may precipitate pancreatitis – both acute and chronic
Cystic fibrosis:
autosomal recessive genetic mutation in the CFTR Cl channel
Primarily affects caucasians
Lack chloride transporter at apical membrane
Leads to decreased water, HCO3, & Cl excretion, with concentration of
protein in acinar ducts and blockage…. gland autodigestion/destruction
Progressive pulmonary and pancreatic insufficiency - chronic
Primary aldosteronism: (excess aldosterone)
salivary NaCl close to zero
salivary K+ increases to high levels
Kwashiorkor:
reduction in pancreatic secretion except amylase
(protein digestion impaired)
