Gastrointestinal Physiology

DIGESTION & ABSORPTION

proteins, fats and complex CHO are broken down, digested, principally in the small intestine
the products of this digestion, plus the vitamins and minerals cross the mucosa and enter the
portal blood or lymph, absorption
orderly process, involving a large number of digestive enzymes, originating in the saliva, stomach,
SI and exocrine pancreas
the action of these enzymes is aided by the action of HCl in the stomach and by bile in the SI

the mucosa of the SI has a brush border made of numerous microvilli

this is covered by a layer of neutral and amino-sugars, the glycocalyx
the membranes of the mucosal cells contain glycoprotein enzymes which hydrolyze CHO and
peptides
the glycocalyx is made, in part, of the CHO portions of these glycoproteins which extend into the
intestinal lumen
next to the brush border and the glycocalyx is a 100-400 µm unstirred water layer (UWL)
the mucous coat overlying the mucosa is also a significant barrier to difusion
processes involved in the absorption of substances include,
a. diffusion
b. facilitated diffusion
c. solvent drag
d. active transport
e. secondary active transport
f. endocytosis
 Gastrointestinal Physiology

Carbohydrates CHO

Digestion
the principal dietary CHO is composed of,
a. polysaccharides
b. monosaccharides
c. disaccharides

starches, polymers of glucose and their derivatives, are the only polysaccharides of importance to
humans
in glycogen, glucose molecules are joined by 1-4~ linkages, with some chain branching by 1-6α
linkages
amylopectin, which ~ 80-90% of dietary starch, is similar but has less branches
amylose possesses only 1-4~ linkages and is a straight chain
glycogen is found in animals, whereas the later two are of plant origin
the disaccharides lactose & sucrose are also ingested, along with the monosaccharides glucose &
fructose
starch is first degraded by ptyalin, the α-amylase of saliva
however, the optimal pH for this is 6.7 and activity is terminated by gastric acidity
once in the SI, pancreatic α-amylase is added
both of these attack the 1-4α linkages but spare,
a. the 1-6α linkages
b. the 1-4α linkages next to branch points
c. the terminal 1-4α linkages

thus, the end products of this digestion are,

a. the disaccharide maltose
b. the trisaccharide maltotriose
c. larger polymers of glucose with 1-4α linkages
d. branched polymers, ~ 8 units, the α-limit dextrins

these are further digested by the oligosaccharidases located at the outer portion of the membrane
of the microvilli,
a. maltase
b. lactase
c. sucrase
d. α-limit dextrinase

in many mammals and some races of humans, intestinal lactase activity is high at birth, declines to
low levels in childhood and remains low subsequently
 Gastrointestinal Physiology

low levels being associated with intolerance of milk as lactose remains in the GIT and acts as an
osmotic agent prior to being broken down by bacteria in the colon
however, most Caucasians retain their lactase activity but most adult blacks are intolerant

Absorption
hexoses and pentoses are rapidly absorbed across the intestinal mucosa
these then enter the capillaries which drain to the portal vein
glucose and Na+ share the same symport, thus a high [Na] at the mucosal surface facilitates
glucose absorption
due to the action of the basal Na-K-pump → secondary active transport
the same mechanism also transports galactose
fructose utilizes a different carrier, and its absorption is independent of luminal Na+
→ facilitated diffusion
insulin has minimal effect on the intestinal transport of sugars, as is the case for reabsorption in
the proximal nephron
both are essentially normal in diabetes but are depressed by the drug phlorhizin
the maximal rate of glucose absorption is ~ 120 g/h
 Gastrointestinal Physiology

Proteins & Nucleic Acids

Protein Digestion
begins in the stomach, where pepsins cleave some of the peptide linkages
these are secreted in an inactive form, as pepsinogens, and are activated by the low luminal pH
there are a large number of these, however, they can be divided into two distinct
immunohistochemical groups,
a. pepsinogen I - found only is HCl secreting region
b. pepsinogen II - also found in the pyloric region

maximal acid secretion correlates with pepsinogen I levels, and patients with high circulating
levels have a 5 times higher incidence of ulceration
pepsins hydrolyse bonds between an aromatic AA, such as tyrosine or phenylalanine, and a
second AA
thus, the products of this digestion are diverse peptides
the optimum pH ~ 1.6-3.2, therefore action is terminated on exit from the stomach
the pH in the duodenal cap ~ 2.0-4.0, but the rest of the duodenum is ~ 6.5

in the SI, these smaller peptides are further fragmented by proteolytic enzymes of the pancreas,
which may be divided into the,
a. endopeptidases - trypsin, chymotrypsin & elastase
b. exopeptidases - carboxydipeptidases

and the aminopeptidases of the brush border

some di and tripeptides are absorbed and finally broken down by intracellular peptidases
thus, the final digestion of peptides occurs in three locations,
a. the lumen
b. the brush border
c. within the cell

Absorption
the l-AA's are absorbed more rapidly then their d-AA isomers and following a meal there is a
sharp transient rise in the nitrogen content of portal blood
the d-isomers are absorbed soley by passive diffusion
whereas, most of the l-isomers are actively transported from the lumen
there are 4 seperate systems,
a. neutral AA's
b. basic AA's
c. proline, hydroxyproline and glycine
d. dicarboxylic AA's - glutamic and aspartic acids
 Gastrointestinal Physiology

there is a separate system for the di & tri-peptides

transport is linked to Na+ and is facilitated by an increase in luminal [Na], as for glucose
from the cells, diffusion of AA's into the portal blood is passive
absorption is rapid in the duodenum and the jejunum, but slow in the ileum
of the digested protein,
a. ingested food → 50%
b. GIT secretions → 25%
c. desquamated mucosal cells → 25%

only ~ 2-5% of protein in the SI escapes in the stools, most of the protein found is due to bacteria
and cellular debris from the colon
in infants moderate amounts of undigested proteins are also absorbed
the IgG secreted in maternal milk enters the circulation by endocytosis, although this transfer is
relatively minor for humans

absorption of protein antigens takes place in large microfold cells (M cells), which are specialized
epithelial cells which overly aggragates of lymphoid tissue → Peyer's patches
these cells present the antigens to lymphoblasts, which are activated and enter the circulation
they eventually return to the mucosa, where they secrete secretory IgA in response to exposure
to the same antigen

Nucleic Acids
pancreatic nucleases split the nucleic acids to nucleotides
these are subsequently split in the nucleosides and phosphoric acid by enzymes at the brush
border
these are further broken down to their constituent sugars and purine and pyrimidine bases
the bases are absorbed by active transport
 Gastrointestinal Physiology

Lipids

Fat Digestion
significant digestion begins in the duodenum with pancreatic lipase being the most important
this hydrolyses the 1 & 3 bonds of triglycerides (TG) with relative ease but the 2 bond at a slower
rate
the principal metabolites are FFA's and 2-monoglycerides
this acts on fats which have been emulsified, but cannot act without the protein colipase, which is
secreted by the pancreas
this binds to the surface of the droplet, displacing the emulsifying agents and anchoring the lipase
most of the dietary cholesterol is in the form of cholesterol esters, and pancreatic esterase
hydrolyses these in the lumen
fats are finely emulsified in the SI by the detergent action of the bile salts, lecithin, and
monoglycerides → particles 200-5000 nm
bile salts alone are relatively ineffective
when the [bile salts] is high, as after a meal and gallbladder contraction, lipids and bile salts
interact spontaneously to form micelles ~ 3-10 nm
these generally contain FFA's, monoglycerides and cholesterol
micellar formation further solubilizes the lipids and provides a mechanism for their transport to
the brush border, through the UWL by diffusion
lipids enter the cells by passive diffusion and are rapidly esterified, maintaining the concentration
gradient for diffusion
unlike the ileal mucosa the uptake of bile salts by the jejunum is low, and these diffuse back into
the intestinal lumen
thus, bile salt micelles solubilize lipids, transport them across the UWL, and maintain a saturated
concentration of lipids at the mucosal cell
pancreatectomized animals, or those with pancreatic insufficiency, suffer steatorrhoea, due to,
a. lipase deficiency
b. depressed micellar formation
due to low HCO3from the pancreas
the acid environment prevents incorporation of FFA's into micelles

this is also why patients with excess gastric acidity secrete fatty stools

Fat Absorption
monoglycerides, cholesterol and FFA's from micelles enter the mucosa by passive diffusion
the subsequent fate of FFA's depends upon their size,
a. FFA < 10-20C → portal blood as FFA
b. FFA > 10-12C → reesterified to TG

in addition, some of the absorbed cholesterol is esterified

the TG and cholesterol esters are covered by a layer of protein, cholesterol and phospholipid to
form chylomicrons, which enter the lymphatic circulation
 Gastrointestinal Physiology

most of the TG is formed by acylation of absorbed 2-monoglycerides at the SER, though, some is
also formed from glycerophosphate from the glycolytic pathway
the acylation of glycerophosphate and the formation of lipoproteins occurs in the RER
CHO moeities are added to proteins in the golgi apparatus, and the conmplete chylomicrons are
released by exocytosis
the majority of absorption occurs in the proximal SI and on a normal diet less than 5% appears in
the stools, most of this coming from cellular debris
these processes are not fully mature at birth, and infants fail to absorb nearly 10-15% of their
dietary fat

Absorption Of Cholesterol And Sterols

cholesterol is readily absorbed if bile salts, FFA's and pancreatic juices are present
absorption is said to be limited to the distal SI
almost all of the absorbed cholesterol is incorporated into chylomicrons, which then enter the
lymphatics
closely related sterols of plant origin are poorly absorbed
some of these reduce the absorption of cholesterol, probably by competing with cholesterol for
esterification with FFA's
 Gastrointestinal Physiology

Water & Electrolytes

Water, Sodium & Potassium

water balance in the GIT

1. Input: 9000 ml
i. Ingested: 2000 ml
ii. Endogenous secretions: 7000 ml
salivary glands 1500
stomach 2500
bile 500
pancreatic 1500
intestinal 1000
2. Reabsorption: 8800 ml
i. jejunum 5500
ii. ileum 2000
iii. colon 1300
3. Excretion in stools: 200 ml

thus, 98% of the fluid load is reabsorbed

only small amount s of water move across the gastric mucosa, however, water moves freely
across the SI in accordance with osmotic gradients
Na+ is actively transported from the lumen by pumps located in the baso-lateral cell membranes
in the ileum and jejunum, this is facilitated by aldosterone
luminal membrane transport is variably coupled to glucose, AA's or other substances
the absorption of sodium is facilitated by the presence of the cotransported solutes
→ the use of NaCl & glucose solutions in diarrhoeal illnesses
some E.coli and V.cholera produce a toxin which activates adenylate cyclase and increases cAMP
this increases Clsecretion from the mucosa, and inhibits the function of the mucosal carrier for
Na+, reducing NaCl reabsorption
however, the symport for glucose/Na+ is unaffected
duodenal contents may be hyper or hypo-osmotic, but the time the jejunum is reached the
contents are iso-osmotic
in the colon, Na+ is actively pumped into the lumen and water follows
 Gastrointestinal Physiology

for the majority, the movement of K+ is by passive diffusion

the net movement being determined by the potential difference between the lumen and intestinal
capillaries, leading to,
a. jejunum -5 mV [K+] ~ 6 mmol/l
b. ileum -25 mV [K+] ~ 13 mmol/l
c. colon -50 mV [K+] ~ 30 mmol/l

with the lumen negative and concentration being in the lumen

thus, the loss of ileal of colonic fluids by diarrhoea leads to severe hypokalaemia

Chloride & Bicarbonate

in the ileum and colon, Clis actively reabsorbed in exchange for HCO3--
this results in the intestinal contents becoming more alkaline

Vitamins & Minerals

Vitamins
absorption of the water soluble vitamins is rapid and efficient
the fat soluble vitamins, A, D, E, & K require normal fat absorption
a deficiency of either bile salts or pancreatic juices will result in deficient absorption
most are absorbed in the proximal SI, though, B12 is absorbed in the ileum
along with intrinsic factor secreted by the stomach

Calcium
absorption ranges from 30-80% and occurs mainly in the proximal SI
some absorption is by passive diffusion, though, active transport is stimulated by Vit. D3
this stimulates the formation of Ca++ binding protein in the mucosal cells
the exact relationship of these proteins to increased Ca++ absorption is unsettled
this is under feedback control and GIT absorption is one of the main regulators of the plasma
Ca++ levels
absorption is also facilitated by lactose and protein
it is inhibited by phosphates & oxalates, as these form insoluble salts
 Gastrointestinal Physiology

Iron

1. average daily losses

i. men ~ 0.6 mg
ii. women ~ 1.2 mg
losses for females vary considerably
2. average intake ~ 20 mg
but absorption is equal only to daily losses
3. absorption ~ 2-3%
4. normal plasma iron
i. men ~ 130 µg/dl
ii. women ~ 110 µg/dl

more readily absorbed in the ferrous (Fe++) state

however, most dietary iron is in the ferric form (Fe+++)
gastric secretions dissolve the iron and enable reduction to the ferrous state
this is the reason iron deficiency anaemia follows gastrectomy
ascorbic acid is another reducing agent in the diet which favors the conversion of the ferric the
ferrous ion
haem is also absorbed and the attached Fe++ is released by the mucosal cells
absorption is an active process occurring mainly in the proximal SI
mucosal transferrin binds iron in the lumen and transfers it across the brush border
most of this is then transferred directly to the blood stream, but a significant amount is bound to
apoferritin in the mucosal cells
this iron is lost when the cells desquamate
this protein combines with iron to form ferritin
each ferritin molecule may contain as many as 4500 molecules or iron, which exist in a micelle of
ferric-hydroxyphosphate, contained within the protein
ferritin molecules in lysosomal membranes may aggregate in deposits of > 50% iron
→ haemosiderin

approximate distribution in the body,

a. haemoglobin ~ 70%
b. myoglobin ~ 3%
c. ferretin ~ 27%

ferritin is also found in the plasma, but most iron is bound to transferrin
this polypeptide has 2 binding sites and total saturation is usually ~ 35%

in iron deficiency, the amount of ferritin is decreased and a greater fraction enters the plasma
in overload, ferritin stores are large and absorption from the intestine is decreased → mucosal
block
 Gastrointestinal Physiology

REGULATION OF GASTROINTESTINAL FUNCTION

Functional Anatomy
there is some local variation, however, in general there are 3 layers of smooth muscle, 2
longitudinal & 1 circular
the wall is lined by mucosa and , except in the case of the oesophagus, is covered by a serosa
the serosa continues into the mesentry, which carries the nerves, blood vessels, and lymphatics

Innervation
there are two major networks of nerve fibres which are intrinsic to the GIT, the,
a. myenteric plexus of Auerbach
between the outer lonitudinal and middle circular layers of muscle
b. submucous plexus of Meissner
between the middle circular layer and the mucosa

these plexuses are interconnected and they contain nerves with processes which originate from
receptors, either in the wall of the gut or the mucosa
there are also an enormous number of interneurons
the mucosal receptors include,
a. mechanoreceptors, sensitive to stretch
b. chemoreceptors, sensitive to changes in the contents of the lumen

neurons innervate all of the muscular layers of the gut wall, other neurons innervate hormone
secreting cells
these constitute a complex enteric nervous system, which some authorities include as a third
division of the autonomic system
there are a total of ~ 106 neurons
the secreted neurotransmitters include,
i. ACh
ii. enkephalins
iii. VIP
iv. CCK
v. NA
vi. gastrin releasing peptide GRP
vii. Substance P
viii. neurotensin
 Gastrointestinal Physiology

coordinated motor activity of the gut occurs in total absence of extrinsic innervation
extrinsic innervation is from both the PNS & SNS
the preganglionic PNS fibres consist of ~ 2000 vagal efferents plus efferents from the sacral
nerves
they generally end on cholinergic nerves in either of the intrinsic systems
the SNS fibres are postganglionic, but many of them end on postganglionic cholinergic neurons,
where they inhibit ACh secretion
others innervate blood vessels, producing vasoconstriction, while others end directly on intestinal
smooth muscle

Circulation
see CVS notes on special circulations

Gastrointestinal Hormones
there are a large number concerned with the regulation of GIT motility and secretion
when given in large doses their functions frequently overlap, however, in physiological levels
their actions appears discrete
many of these fall into one of 2 families,
a. gastrin family - gastrin 34
- CCK 39
b. secretin family - secretin
- GIP
- glucagon
- VIP
- glicentin
c. others - motilin
- substance P
- somatostatin 14
- GRP

Gastrin
produced by G cells of the lateral walls of the gastric antral mucosa
receptors mediating gastrin responses to changes in the luminal contents are present in the
microvilli
like many other cells of the GIT secreting hormones, these contain amines related to NA & 5HT
and are of neural crest origin → APUD cells
there is a second type of gastrin secreting cell found throughout the GIT, the TG cell
this contains G34 but lacks G17
gastrin is also found in the pancreatic islets in foetal life and gastrin secreting tumors occur in the
pancreas
it is also found in the CNS, where it appears to act as a central neurotransmitter
displays both macroheterogeneity & microheterogeneity
 Gastrointestinal Physiology

the former referring to differences in peptide length, the later to differences in molecular structure
due to differing AA's
three main forms are found, G34, G17, & G14 gastrins
all possess the same C-terminal tetrapeptide, which in itself has gastrin activity (~ 10% of G17)
the G17 form is the principal agent in the regulation of gastric acid secretion
the two smaller peptides have half lives of 2-3 mins, whereas the larger G34 up to 15 mins
inactivation is primarily in the kidney and SI
the physiological effects include,
a. gastric acid secretion
b. pepsin secretion
c. increased gastric motility
d. ? increased tone of the gastro-oesophageal sphincter
e. stimulates insulin & glucagon secretion after a protein meal
NB: atropine does not inhibit the response,
the transmitter probably being gastrin releasing peptide GRP

also direct stimulation from the products of protein digestion, ie. AA's
acid in the antrum inhibits secretion, providing a negative feedback loop

Cholecystokinin
secreted by the cells of the upper SI
results in both
a. increased secretion from the pancreas, and
b. contraction of the gallbladder

like gastrin, it displays both macroheterogeneity & microheterogeneity

prepro-CCK is processed into many fragments, from CCK4 to CCK58
the major active fragments secreted by the duodenum & jejunum are probably CCK8 & CCK12
the half life is ~ 5 mins, but little is known about its metabolism
it is also found in cells in the ileum and colon, in parts of the CNS, and in nerves in many parts of
the body
other actions of the hormone include,
a. augmentation of the action of secretin
b. inhibits gastric emptying
c. increases the secretion of enterokinase
d. has a trophic effect on the pancreas
e. may enhance the motility of the SI and colon

both CCK and gastrin stimulate the secretion of glucagon from the pancreas in response to a
protein meal, and may be the "gut factor" responsible in vivo
the action on the gallbladder may be mediated by cGMP
 Gastrointestinal Physiology

secretion from the proximal GIT is stimulated by peptides, AA's and FFA's of more than 10 C
length
as bile increases digestion, a positive feedback loop exists, secretion being terminated by the
passage of contents distally

Secretin
first demonstrated by Bayliss and Starling in 1902, that the excitatory effect of duodenal
stimulation on pancreatic secretion was due to a blood-borne factor
subsequent research led to the discovery of secretin
from this research, Starling introduced the term hormone to characterise chemical messengers
secreted by cells located deep within the glands of the proximal SI
the AA sequence is very similar to that of glucagon, VIP & GIP
its half life is ~ 5 mins, little is known about its metabolism
secretin increases the formation of bicarbonate by the duct cells of the pancreas and biliary tract
thus, it causes a watery, alkaline pancreatic secretion
its action is mediated by cAMP
other effects include,
a. augments the action of CCK in stimulating pancreatic secretion of digestive enzymes
b. decreases gastric acid secretion
c. increases pyloric tone

secretion of secretin is increased by the presence of the products of protein digestion and by acid
in the proximal duodenum
the increased alkaline secretion acts to neutralize the acid products entering the upper SI

GIP
GIP is a 43 AA peptide found in the mucosa of the duodenum and jejunum
its secretion is stimulated by the presence of glucose and fat
it also stimulates the release of insulin, and evidence is accumulating that this is the GIT factor in
physiological β-cell stimulation

VIP
a 28 AA peptide found in many of the nerves of the GIT
also found in the blood but the half life is only 2 mins
it markedly stimulates intestinal secretion of water and electrolytes
other actions include,
a. inhibition of gastric acid secretion
b. dilatation of peripheral blood vessels

it is also found in neurons of the CNS, where it coexists with ACh

in many tissues it potentiates the action of ACh
 Gastrointestinal Physiology

THE STOMACH

Functional Anatomy
in the pyloric and cardiac regions of the stomach the glands secrete mucus
in the body, including the fundus, the glands contain
a. parietal cells (oxyntic) → HCl & intrinsic factor
b. chief cells (zymogen, peptic) → pepsinogens

these mix in the necks of the glands with mucus

several of the glands open into a common chamber, a gastric pit
the blood vessel and lymphatic supply is extensive
the PNS innervation comes from the vagi
the SNS innervation comes from the coeliac plexus

Gastric Secretion
the average daily secretion of gastric juice ~ 2500 ml
the hydrochloric acid secreted by the stomach has a number of functions,
a. kills many bacteria
b. aids protein digestion
c. provides the necessary pH for the activity of pepsin
d. stimulates the flow of bile and pancreatic juices

also contains mucus, which protects the mucosal lining against potential tissue damage
this is secreted by cells in the necks of the glands and from the surface
each glycoprotein molecule is made up of 4 subunits joined by disulphide bridges and the mucus
forms a flexible gel that coats the mucosa
the mucosa also secretes bicarbonate into the mucus, forming an unstirred layer with pH ~ 7.0
the unstirred layer, plus the surface membranes of the mucosal cells and the tight junctions
between them, form the mucosal bicarbonate barrier which is responsible for the protection of the
stomach
substances which tend to disrupt the barrier include,
a. ethanol
b. bile acids
c. aspirin and other NSAIDs

prostaglandins stimulate mucus secretion, and their synthesis is inhibited by the NSAIDs
the electrolyte content varies with the rate of acid secretion
at low rates of secretion the [Na] is high, but as the rate of acid secretion increases the [Na] falls
and [HCl] rises
 Gastrointestinal Physiology

Pepsinogen Secretion
these are secreted by the chief cells as inactive precursors, the pepsinogens

Hcl Secretion
transport of H+ from the cytoplasm to the lumen of the canaliculi is by an active H+-K+-ATPase in
the membrane of parietal cells
there is evidence that the pump is synthesized in tubulovesicular structures at rest, and is then
inserted into the membrane during stimulation of acid secretion
it is difficult to obtain pure samples, however, secretion may be an isotonic solution of essentially
pure HCL, with a pH as low as 0.87
the cytoplasm is similar to other cells, being around pH ~ 7.0, the H+ being pumped against an
enormous concentration gradient
the primary source of the secreted H+ ion is from the ionization of water, being immediately
extruded in exchange for K+
external K+ ions are not required for secretion, K+ readily diffusing across the membrane
the presence of the H-K-pump is almost entirely limited to the parietal cells
Cl- is also actively transported into the gastric juice
for each H+ secreted an OH- ion is neutralized by another H+ supplied from the dissociation of
carbonic acid
the HCO3formed is secreted into the interstitium in exchange for Cl-
the mucosa contains an abundance of carbonic anhydrase
the stomach has a negative respiratory quotient → the venous blood has a lower PCO2 than the
arterial blood

acid secretion is stimulated by,

a. H2 histamine receptors → cAMP
b. M1 muscarinic receptors → Ca++
c. gastrin receptors → Ca++

the intracellular events interact, such that activation of one receptor type potentiates the response
to another
histamine comes from cells resembling mast cells, ACh from PNS endings and gastrin via the
circulation

Gastric Motility & Emptying

when food enters the stomach the organ expands = receptive relaxation
followed by well developed peristaltic contractions, most marked in the distal half, occurring at ~
3/min
the pyloric sphincter has only limited function in the rate of emptying of the stomach
this appears to be normal even if the pylorus is resected
apparently the antrum, pylorus and upper duodenum function as a unit, coordinating the rate of
emptying
the peristaltic contractions of the stomach are coordinated by the gastric slow wave
 Gastrointestinal Physiology

a wave of depolarization of smooth muscle cells spreads from the circular muscle of the fundus to
the pylorus every 20 seconds
this is also termed the basic electrical rhythm

Regulation Of Gastric Emptying And Secretion

regulation is by both neural and humoral mechanisms
the neural components are local autonomic reflexes, involving cholinergic neurons, plus impulses
from the CNS via the vagus
vagal stimulation results in,
a. release of gastrin-releasing peptide
b. release of gastrin
c. secretion of acid & pepsin, via ACh

regulation of secretion of acid is usually divided into cephalic, gastric, and intestinal influences,
though these overlap
the cephalic influences are primarily mediated through the vagus,
a. food in the mouth
b. conditioned responses - smell, sight, thoughts
c. emotional responses

→ diencephalon and limbic systems

the gastric influences are mediated by local reflex mechanisms and responses to gastrin,
a. food in the stomach
b. stretch and chemical stimuli, mainly AA's, on the mucosa
→ receptors entering Meissner's plexus
→ postganglionic parasympathetic neurons
→ parietal cells which secrete acid

the reflex arc is totally within the wall of the stomach

these neurons are the same as those which mediate the cephalic phases of secretion
the products of protein digestion also bring about an increased secretion of gastrin

the intestinal influences are mediated by reflex and hormonal feedback mechanisms from the
mucosa of the small intestine
fats, CHO and acid in the duodenum inhibit the secretion of gastric acid, gastric motility and
pepsin secretion
these effects are probably brought about by the secretion of GIP & secretin
gastric acid secretion is increased following removal of large amounts of the small intestine, in a
roughly proportional manner
 Gastrointestinal Physiology

hypoglycaemia acts via the CNS and vagal efferents to stimulate acid and pepsin secretion
the stimulation produced by insulin is the result of hypoglycaemia
other stimulants include,
a. caffeine
b. alcohol

Regulation of Gastric Emptying and Secretion

CHO leaves the stomach within a few hours

protein rich foods leave more slowly, and emptying is slowest for fat rich meals
the rate of emptying is determined by the osmolality of the contents reaching the duodenum
hyperosmolality is sensed by duodenal osmoreceptors which initiate a decrease in the rate of
emptying
products of protein digestion and acid initiate a neurally mediated decrease in gastric motility, the
enterogastric reflex
this is also produced by distention of the duodenum

Peptic Ulcer
related to a breakdown of the barrier which normally protects the mucosa from autodigestion
in patients with duodenal and prepyloric ulcers, excessive acid secretion also plays a role
however, this is not the case for other gastric ulcers
there is a correlation between the levels of pepsinogen I, maximal acid secretion and the incidence
of peptic ulceration
resting gastrin levels do not appear to be elevated, but their gastrin responses to stimulation are
greater than normal
their parietal cells are also hyperresponsive to gastrin stimulation
acid secretion is clearly involved in Zollinger-Ellison syndrome, where gastrinomas, usually in the
pancreas, result in continued acid hypersecretion
treatment is aimed at a reduction in the secretion of acid and enhancing the mucosal barrier
1. gastric H2 receptors can be blocked with cimetidine or ranitidine
2. cholinergic M1 receptors can be blocked with atropine or the more specific antagonist
pirenzipine
3. alternatively the H+-K+-ATP'ase can be inhibited by omperazole
 Gastrointestinal Physiology

Other Functions of the Stomach

HCL kills many of the ingested bacteria
parietal cells secrete intrinsic factor, necessary for the absorption of cyanocobalamin
this cobalt containing vitamin is necessary for normal erythropoeisis, deficiency resulting in
megaloblastic anaemia
in pernicious anaemia, deficiency of intrinsic factor is due to idiopathic atrophy of the gastric
mucosa
intrinsic factor is a glycoprotein, MW = 45,000, the complex binding to specific receptors in the
terminal ileum
trypsin is required for this proces to be efficient, thus deficiency can also occur in pancreatic
insufficiency
in the blood stream, B12 is bound to transcobalamin II
 Gastrointestinal Physiology

THE EXOCRINE PANCREAS

Functional Anatomy
compound alveolar gland resembling the salivary glands
granules containing the digestive enzymes, zymogen granules, are formed in the cells and
discharged by exocytosis
the small duct radicals coalesce to form a single duct, of Wirsung, which usually joins the
common bile duct at the ampulla of Vater
the ampulla opens through the duodenal papilla, and is surrounded by the sphincter of Oddi
there may be an accessory duct, of Santorini, entering more proximally

Composition of Secretion
juice is highly alkaline, with a high [HCO3--]
dialy secretion ~ 1500 ml
bile and intestinal juices are also alkaline or neutral, and these three secretions neutralize
duodenal contents, raising the pH to ~ 6.0-7.0
the powerful proteolytic enzymes are secreted as inactive proenzymes
trypsinogen is converted to trypsin by enterokinase / enteropeptidase, secreted by the duodenal
mocosa
secretion is increased by the hormone CCK
trypsin then converts other inactive enzymes to their active forms,
a. chymotrypsinogens → chymotrypsin
b. proelastase → elastase
c. procarboxypeptidase → carboxypeptidase
d. trypsinogen → trypsin

*(d) forming a (+)'ve feedback

deficiency of enterokinase leads to protein malnutrition

the pancreas normally also contains a trypsin inhibitor, to protect againt autodigestion
phospholipase A is activated by trypsin, splitting a fatty acid from lecithin, forming lysolecithin
the later product damages cell membranes and its formation from lecithin in bile is involved in
acute pancreatitis
a small amount of α-amylase normall leaks into the circulation

Regulation Of Secretion
primarily under hormonal control
secretin causes copious secretion of very alkaline pancreatic juice, relatively poor in enzyme
precursors
it acts on the epithelial cells of the small duct radicals, which secrete HCO3--, rather than the
acinar cells
as the rate of secretion increases, [Cl-] falls and [HCO3--] rises in a reciprocal fashion
secretin also stimulates bile secretion
 Gastrointestinal Physiology

CCK results in secretion of juice rich in proenzymes, acting on acinar cells

with the release of zymogen granules
vagal stimulation also causes a smaller but similar increase in secretion
both act via an increase in intracellular [Ca++]
 Gastrointestinal Physiology

LIVER & BILARY SYSTEM

Functional Anatomy
organised into lobules
within which, blood flows from branches of the portal vein to a central vein, through sinusoids
lined with hepatic cells
the sinusoidal capillaries have large fenestrations, allowing plasma close contact with the cells
generally, there is only one layer of cells per sinusoid, creating a large area of contact
blood from the hepatic artery also enters the sinusoids
the central veins coalesce to form hepatic veins which drain to the IVC
the average transit time for portal blood is ~ 8.5 s
there are a large number of tissue macrophages, Kupffer cells, which are anchored to the
endothelium
each hepatocyte is adjacent several bile canaliculi, which coalesce to form the right and left
hepatic ducts
these join outside the liver to form the common hepatic duct
the cystic duct drains the gallbladder to for the common bile duct
the mucous membranes of the cystic duct form the spiral vales of Heister

Functions of the Liver

the liver is the largest gland in the body
functions include,
1. formation of bile
2. CHO and intermediary metabolism
3. AA and ammonia metabolism
4. protein/glycoprotein synthesis and degradation
5. lipid metabolism - FFA's, TG and cholesterol
6. hormone synthesis & metabolism
7. detoxification of drugs and toxins
8. immune defence against agents entering the portal circulation
 Gastrointestinal Physiology

Compositon Of Bile
bile is made up of,
a. bile pigments
b. bile salts
c. other substances - lecithin, FFA's, cholesterol
d. alkaline electrolyte solution - similar to pancreas

average daily secretion ~ 500 ml

some components are reabsorbed in the terminal ileum → enterohepatic circulation

the bile pigments are the glucuronides of bilirubin & biliverdin, and are responsible for the
golden yellow color

the bile salts are the sodium and potassium salts of bile acids conjugated to glycine or taurine
the acids are based on the cyclopentanoperhydrophenanthrene nucleus
there are two principal, or primary bile acids, formed by the liver,
1. cholic acid
2. chenodeoxycholic acid

95% of these are reabsorbed in the terminal ileum, the remaining 5% entering the colon
these are acted upon by bacteria forming the secondary bile acids,
1. deoxycholic acid - most of this is absorbed
2. lithocholic acid - insoluble and mostly excreted in the stools ~ 99%

average daily synthesis ~ 0.2-0.4 g

the total bile salt pool ~ 3.5 g
this recycles 6-8 times/day and 2 times/meal

these salts have a number of important actions,

a. combine with lipids to form micelles → hydrotropic effect
b. with monoglycerides and phospholipids → emulsify fats
c. activate lipases in the SI

in the absence of bile salts, ~ 25% of ingested fat appears in the feces, and there is severe
malabsorption of the fat soluble vitamins
 Gastrointestinal Physiology

Bilirubin Metabolism & Excretion

bilirubin is formed in the RES by the breakdown of haemoglobin
the globin moiety is split-off and returned for re-use
the haem group converted to biliverdin and most of this is then converted to bilirubin
this is then transferred to the liver via the circulation, bound to plasma albumin
free bilirubin enters the hepatocytes where it is bound to cytoplasmic proteins, allowing continued
diffusion
conjugation to glucuronic acid is catalysed by glucuronyl transferase, located primarily on the
SER
each bilirubin binds 2 glucuronide molecules, which are derived from uridine
diphosphoglucuronic acid (UDPGA)
this is then transported against a concentration gradient into the bile canaliculi
some of this escapes into the bloodstream where it is excreted by the kidney
the intestinal mucosa is relatively impermeable to bilirubin glucuronide
however, it is permeable to unconjugated bilirubin and urobilinogens, a series of colorless
derivatives formed in the GIT by bacterial action
consequently, there is some reabsorption, most of which enters the bile again but some of which
is excreted in the urine

Jaundice
normal plasma bilirubin ~ 3.5-17.0 umol/l
clinical jaundice is seen when the plasma bilirubin ~ 34 umol/l (2 mg/dl)
hyperbilirubinaemia may result from,
1. excess production- haemolytic anaemia
2. decreased hepatic uptake
3. altered intracellular binding or conjugation
4. decreased secretion into the bile
5. intra, or extrahepatic biliary obstruction
NB: (a-d) → predominantly unconjugated bilirubinaemia
(e) → mixed bilirubinaemia