Giles Kisby
GE Y1 Alimentary
Alimentary:
Spring Term:
LECTURES:
Learning Outcomes – Year 1 (2013)
Autumn Term:
These session objectives may include tasks you should be able to carry out after you have
completed the relevant activity. They provide you with a way to assess how well you are keeping
up with the material. Note that they are also provided to the external examiners as a guide to what
you should know at the end of the course.
The overall learning objectives of this course are:
of the normal alimentary system.
the pathophysiological processes involved.
.
Specific objectives of each session are as follows: (order of presentation differs from year to year)
Lecture 1 Introduction: the Burden of GI disease Julian Walters
entary tract
Lecture 2 Structure and functional relationships: GI Motility
Andrew Thillainayagam.
tion
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Tutorials: Review of nutrition Gary Frost
Digestion & cell transport Julian Walters
ses associated with impaired nutrition
Lecture 3 Acid secretion Kevin Murphy
on
Lecture 4 Gastro-oesophageal reflux disease Jonathan Hoare
athophysiological processes involved
-oesophageal reflux disease
disorders of acid secretion 3
Lecture 5 Intestinal absorption Julian Walters
consolidate knowledge of the mechanisms of protein and lipid absorption
Lecture 6 Malabsorption Julian Walters
ms may result from malabsorption
Lecture 7 Pancreatic exocrine function Kevin Murphy
erent functions of the pancreas
Lecture 8 Abdo pain & Pancreatitis Lakshmana Ayaru
abdominal pain
c diseases
Lecture 9 GI hormones & Appetite control Kevin Murphy
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ntrol
Lecture 10 Intestinal immune system Jonathan Nolan
appreciate innate and adaptive immune mechanisms
Lecture 11 Inflammatory bowel diseases Tim Orchard
s)
Lecture 13 Genetic & environmental effects on development of colonic neoplasia
Horace Williams
ome of the environmental factors that influence neoplasia
Lecture 14 Liver structure and function Heather Lewis
functions of the liver
Lecture 15 Bilirubin & jaundice; Bile secretion & cholestasis Shahid Khan
gation and treatment of diseases producing jaundice
nisms that produce cholestasis
Lecture 16 Pathophysiology of Portal hypertension Ameet Dhar
entions in portal hypertension
Lecture 17 Liver failure Harry Antoniades
ntroduced to treatment options
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Lecture 19 Mechanisms of liver injury: alcohol Harry Antoniades
Lecture 18 Mechanisms of liver injury: viral Marco Purbhoo
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LECTURES:
03/12/13: GI structure and function relationships: Dr
Andrew V Thillainayagam
Los (from booklet):
ifferent areas
Notes:
-
-
-
-
THE DIGESTIVE TRACT
o Mouth and pharynx
o Oesophagus
o Stomach
o Sphincter of Oddi
o Small Intestine
o Large Intestine
o Anus
Functions of the GI Tract:
o motility,
o secretion,
o digestion,
o absorption
Motility: Movement of of food through the GI tract.
o Ingestion:
 Taking food into the mouth.
o Mastication:
 Chewing the food and mixing it with saliva.
o Deglutition:
 Swallowing the food.
o Peristalsis:
 Rhythmic wave-like contractions that move food through GI tract.
Structure of the GI tract: 4 layers:
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o
o
o
o
1. Mucosal layer:
 epithelial cells (enterocytes)  role varies with location: absorptive an
secretory functions
 lamina propria = layer of connective tissue under the epithelial, containing
blood vessels, nerves and lymphatic vessels (Peyer’s patches) [ie includes
these structures too]
 the muscularis mucosae: thin layer of smooth muscles [changes the shape
and surface area of the epithelial cell layer]
 GALTs present
2. submucosa: layer of connective tissue rich containing the submucosal plexus
(=Meissner’s plexus)
 Submucosa layer consists of collagen, elastin, glands, and the blood vessels
of the gastrointestinal tract
 Peyers patches present
3. muscularis externa – radial/circular and longitudinal smooth muscles + Auerbach
plexus (=myenteric plexus ; is between these two muscle layers) (nb is in
communication with Meissner’s plexus)
 When circular muscle contracts, it results in shortening of a ring of smooth
muscle, which decreases the diameter of that segment. When longitudinal
muscle contracts, it results in shortening in the longitudinal direction, which
decreases the length of that segment.
4. Serosa [serous membrane]: connective tissue continuing through the
mesenteries (a thin membranes rich in blood and lymphatic capillaries) and the
peritoneum (a double layer membrane surrounding the abdominal organs)
-
The wall of the gastrointestinal tract has two surfaces, mucosal and serosal. The mucosal
surface faces the lumen, and the serosal surface faces the blood
-
Muscularis externa
o Responsible for segmental contractions and peristaltic movement through the GI
tract.
o Contractions of these layers move food through the tract; pulverize and mix the
food.
o Subsets: [The fibres communicate through gap junctions]:
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o
-
-
-
-
-
 Inner circular layer of smooth muscle.
 Outer longitudinal layer of smooth muscle.
Myenteric plexus located between the 2 muscle layers.
 Is the major nerve supply to GI tract.
 Fibres and ganglia from both sympathetic and parasympathetic nervous
systems access it.
 The parasympathetic NS stimulates smooth muscle contraction
The vagus nerve innervates the upper gastrointestinal tract, including the striated muscle of
the upper third of the esophagus, the wall of the stomach, the small intestine, and the
ascending colon. The pelvic nerve innervates the lower gastrointestinal tract, including the
striated muscle of the external anal canal and the walls of the transverse, descending, and
sigmoid colons.
Postganglionic neurons of the parasympathetic nervous system are classified as either
cholinergic or peptidergic. Cholinergic neurons release acetylcholine (ACh) as the
neurotransmitter. Peptidergic neurons release one of several peptides, including substance
P and vasoactive inhibitory peptide (VIP); in some instances, the neuropeptide has not yet
been identified.
vagovagal reflexes: mechanoreceptors and chemoreceptors in the gastrointestinal mucosa
relay afferent information to the CNS via the vagus nerve, which triggers reflexes whose
efferent limb is also in the vagus nerve. Such reflexes, in which both afferent and efferent
limbs are contained in the vagus nerve, are called vagovagal reflexes.
Sympathetic nerves to the gut include both afferent and efferent fibres. Thus, as with the
parasympathetic innervation, sensory and motor information is relayed back and forth
between the gastrointestinal tract and the CNS, coordinated by the submucosal and
myenteric plexuses.
Enteric:
o The intrinsic or enteric nervous system can direct all functions of the gastrointestinal
tract, even in the absence of extrinsic innervation.
o The enteric nervous system is located in ganglia in the myenteric and submucosal
plexuses and controls the contractile, secretory, and endocrine functions of the
gastrointestinal tract (see Fig. 8-3).
o these ganglia receive input from the parasympathetic and sympathetic nervous
systems, which modulate their activity.
o These ganglia also receive sensory information directly from mechanoreceptors and
chemoreceptors in the mucosa and send motor information directly to smooth
muscle, secretory, and endocrine cells. Information is also relayed between ganglia
by interneurons.
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GI Motility and Functional GI Disorders
o Gastro-oesophageal Reflux Disease
o Gastroparesis
o Biliary dyskinesia
o Levator ani syndrome
o Noncardiac chest pain (NCCP)
o Achalasia: disorder of the esophagus, which affects the ability of the esophagus to
move food toward the stomach.
o Dyspepsia
o Irritable bowel syndrome (IBS)
o Chronic constipation
o Faecal incontinence
-
Importance of GI Motility Disorders
o Gastrointestinal motility and its disorders are important areas for the health of the
developed world.
o GI motility and functional bowel disorders affect up to 25% of the population.
o These disorders comprise about 40% of GI problems for which patients seek health
care.
o GI motility disorders pose a heavy burden of illness, decreased quality of life, and
decreased work productivity.
-
Upper GI Symptoms: [all are more common in females]
o Heartburn
o Regurgitation
o Dysphagia
o Bloating
o Postprandial Fullness
o Early Satiety
o Nausea
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o
o
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Vomiting
Belching/Burping
Swallowing
o Oral phase. The oral phase is initiated when the tongue forces a bolus of food back
toward the pharynx, which contains a high density of somatosensory receptors. As
previously noted, activation of these receptors then initiates the involuntary
swallowing reflex in the medulla.
o Pharyngeal phase. The purpose of the pharyngeal phase is to propel the food bolus
from the mouth through the pharynx to the esophagus in the following steps:
 (1) The soft palate is pulled upward, creating a narrow passage for food to
move into the pharynx so food cannot reflux into the nasopharynx.
 (2) The epiglottis moves to cover the opening to the larynx, and the larynx
moves upward against the epiglottis to prevent food from entering the
trachea.
 (3) The upper esophageal sphincter relaxes, allowing food to pass from the
pharynx to the esophagus.
 (4) A peristaltic wave of contraction is initiated in the pharynx and propels
food through the open sphincter. Breathing is inhibited during the
pharyngeal phase of swallowing.
o Esophageal phase. The esophageal phase of swallowing is controlled in part by the
swallowing reflex and in part by the enteric nervous system. In the esophageal
phase, food is propelled through the esophagus to the stomach. Once the bolus has
passed through the upper esophageal sphincter in the pharyngeal phase, the
swallowing reflex closes the sphincter so food cannot reflux into the pharynx. A
primary peristaltic wave, also coordinated by the swallowing reflex, travels down the
esophagus propelling the food along.
 If the primary peristaltic wave does not clear the esophagus of food, a
secondary peristaltic wave is initiated by the continued distention of the
esophagus. The secondary wave, which is mediated by the enteric nervous
system, begins at the site of distention and travels downward.
o
o
o
o
A programmed all-or-none reflex
[Voluntary] oral phase:
 Chewing and moving the bolus of food back is mainly voluntary (striated
muscle)
[Involuntary] pharyngeal phase:
 Pressure of bolus on pharynx triggers involuntary reflex (smooth muscle)
 Tongue prevents food from moving back
 Uvula elevated, sealing nasal passage
 Larynx elevates and closure of glottis
 Respiration briefly inhibited
 Pharyngeal muscles force bolus back
[Involuntary] esophageal phase:
 Peristaltic waves move bolus through esophagus
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


o
o
manometer : An instrument used for measuring the pressure of liquids and
gases; can be used to follow the peristaltic waves
ie high pressure behind the bolus
drop in pressure at lower sphincter lets food through
Lower esophageal sphincter is regulated by vagal signaling: [see image]
 Vagal inhibitory fibres active  relaxation phase
 Vagal excitatory fibres active  closing phase
 Opening of the lower esophageal sphincter is mediated by peptidergic fibers
in the vagus nerve that release VIP as their neurotransmitter. VIP produces
relaxation in the smooth muscle of the lower esophageal sphincter.
 At the same time that the lower esophageal sphincter relaxes, the orad
region of the stomach also relaxes, a phenomenon called receptive
relaxation.
Intrathoracic location of the esophagus
 Therefore low pressure environment
 The lower intraesophageal pressure creates two problems: keeping air out
of the esophagus at the upper end, and keeping the acidic gastric contents
out at the lower end: spincters at either end help avoid these problems
 Conditions in which intra-abdominal pressure is increased (e.g., pregnancy
or morbid obesity) may cause gastroesophageal reflux
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Functional Anatomy of the Oesophagus:
o Muscular tube 25cm long: oropharynx to stomach
o Upper third
 muscle striated
 mucosa stratified squamous
o Middle third
 muscle smooth
 mucosa stratified squamous
o Lower third
 muscle smooth
 mucosa stratified squamous / simple columnar
o The function of the oesophagus is to deliver swallowed food to the stomach where
mixing & emptying of the food occurs.
o There is a transition zone in the proximal oesophagus where a mixture of both types
of muscle are present in the oesophageal wall. The smooth muscle is organised into
two functionally separate layers. The inner circular layer has its axis perpendicular to
the long axis of the oesophagus, whereas the outer longitudinal layer has its axis
parallel to the long axis.
o There are 3 functionally distinct regions: the UOS, body & LOS.
o These smooth muscles receive input from the CNS via efferent fibres in the vagus
nerves.
-
lower esophageal sphincter:
o tonic contraction
 70% pressure reduction by atropine
 mostly neurogenic (signals originate from nerves)
 myogenic tone derives from intracellular calcium
o Diurnal variation
 Lowest after meals
 Highest during sleep
o 3-4cm long
o Angle of Hiss
 oblique angle of entry of bolus creates flap valve
o Intra-abdominal LOS
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o
o
o
 ~2cm intra-abdominal
 maintains LOS competence during straining
thicker than adjacent oesophagus
5mmHg pressure gradient across it (higher pressure in stomach)
resting pressure 10-25mmHg (ie pressure squeezing the esophagus)
o
Hiatus Hernia: associated events shown on diagram:
Gastric Functions
o 1. Digestion
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
o
o
o
a) gastric motility:
 food storing
 food “processing”
 food emptying
 b) acid secretion
2. Hormone production & release
3. Immune organ (stomach, and gut generally)
Control of the Fundus is Distinct from Control of Antrum:
 Top of stomach: [fundus]
 Low pressure, low frequency waves [slow, sustained contractions]
 These generate pressure gradient from proximal to distal stomach
(to move food down)
 Accommodation occurs here with meals
o this means the top of the stomach relaxes to allow food to
enter
o Fundus accommodation = receptive relaxation
o Mediated by NO, NANC, VIP
 Bottom of stomach: [antrum (&body &duodenum)]
 High pressure, high frequency waves [peristaltic contractions]
 These grind food and push it through pylorus
 Emptying depends on this antral grinding
o Propulsion-Retropulsion mechanism in the antrum gives
forward/backward movement of food until ready to exit to
duodenum
 In fact Most antral contractions are RETROGRADE:
facilitates mixing of food
 Particle size of food reduced to <2mm: if too large it
gets pushed back to body to be reground
o “Quality” of food regulates gastric emptying: equal volume
of an all protein meal will exit stomach in a shorter time
than a mixed protein/lipid meal will.
 Emptying rate approximately 2-5 kCal/min
 Is why mars bars make you feel full
o Gastric emptying requires duodenal relaxation
 i.e. to give pressure gradient across antroduodenum
o Two major factors slow or inhibit gastric emptying
o (i.e., increase gastric emptying time):
 The effect of fat is mediated by CCK, which is
secreted when fatty acids arrive in the duodenum.
In turn, CCK slows gastric emptying, ensuring that
gastric contents are delivered slowly to the
duodenum and providing adequate time for fat to
be digested and absorbed.
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

The effect of H+ is mediated by reflexes in the
enteric nervous system. H þ receptors in the
duodenal mucosa detect low pH of the intestinal
contents and relay this information to gastric
smooth muscle via interneurons in the myenteric
plexus.
o Full set of emptying determinants:
 Gastric Volume
 increase volume accelerates emptying
 Osmolarity
 high osmolarity (many solutes) slows gastric
emptying
 duodenal osmoreceptors sense osmolarity
 Nutrients
 fat meals (slows emptying via CCK)
 protein meals (slows emptying via gastrin,
CCK)
 pH
 high acidity in stomach accelerates gastric
emptying
 duodenal and jejunal receptors sense acidity
 can be influenced by hormones, mood, time
of day
 motility patterns
 (mood, drugs)
 enteric nervous system
 (diseases, mood, food)
 via gastric pacemaker
 Vagal stimulation
 accelerates emptying
 Sympathetic stimulation
 inhibits emptying
 Dopamine
 inhibits emptying (note Parkinson’s
treatments)
 Opiates
 inhibits emptying
Peristaltic waves are induced by gastric pacemaker (3/min):
o no role in proximal stomach contractions or accommodation
 Proximal stomach – electrically silent [though prob
some elec activity at the very top (fundus)]
 Distal stomach – recurring electrical potentials (slow
waves, 3/min)
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

o
o
o
o
plateau phase present on the action
potential due to voltage-gated Ca2+ channels
(ie same as with heart)
For duration of active signal there will be
muscle tension/contraction
dictates peristalsis in distal stomach and in to duodenum
cellular substrate of the pacemaker are the interstial cells of
Cajal (ICCs)
can get tachy/bradycardia and arrhythmias just as with
heart
Changing rate:
 Parasymp and gastrin inc frequency of APs and force
of contraction
 Sympa, secretin, GIP [ie from K cells] decrease
frequency of APs and force of contraction
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o
-
“Interprandial” Electrical Activity:
 Function: to rid stomach of undigested food
 During fasting, there are periodic gastric contractions, called the migrating
myoelectric complexes, which are mediated by motilin. These contractions
occur at 90-minute intervals and function to clear the stomach of any
residue remaining from the previous meal.
 Cyclic contractile activity (“migrating motor/myoelectric complexes” =
MMCs)
 Phase I: general quiescence (45-60mins)
 Phase II: increased motor activity (30mins)
 Phase III: Vigorous contractions, pylorus open (10mins)
 Phase IV: gradual return to quiescence
 Equivalent system exists in the stomach:
 migrating myoelectric complexes occur every 90 minutes to clear
the small intestine of residual chyme.
Diabetic Gastroparesis [=delayed gastric emptying – diabetes is the most common cause:
Over time, high blood glucose levels can damage the vagus nerve]
o Possible symptoms
 Nausea and Vomiting
 Bloating
 Abdominal pain and reflux
 Early satiety
o Recurrent vomiting
 not always associated with delayed gastric emptying
o Bloating correlates with delay
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Sphincter of Oddi
o muscular valve that controls the flow of digestive juices (bile and pancreatic juice)
through the ampulla of Vater into the second part of the duodenum
-
Small Bowel = small intestine
o Hollow muscular tube
 Inner circular muscle layer
 Outer longitudinal layer
 Innervated by enteric nervous system plus vagal & sympathetic neurons
from the extrinsic nervous sytem
o Responsible for
 Mixing & dispersion of chyme [Chyme is the semifluid mass of partly
digested food expelled by the stomach into the duodenum]
 Segmentation contractions: mix contents to promote digestion &
absorption:
o Is a repeated forward and backward movement with no OVR
movement
 Movement of non-nutrient materials through to colon [ie nutrients should
have been absorbed so not present]
 Peristaltic contractions: is responsible for this movement
o Gastric activity (3/min), duodenal activity (10/min)
o The peristalsis is detectable by manometry
 [Each of the above contraction patterns is coordinated by the enteric
nervous system: ie the slow waves and their associated APs give
contractions but it is the coordination by the enteric nervous system that
determines which type of movement occurs]
 Movements of muscularis mucosae
 These are to aid absorption at the edge of the lumen
o Postprandial contractile patterns vastly different from fasting motility patterns
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
-
Fasting: prob just the periodic gastric contractions, called the migrating
myoelectric complexes; These contractions occur at 90-minute intervals and
function to clear the stomach of any residue remaining from the previous
meal.
Colonic neuromuscular physiology
o NB illiocecal sphincter exists to prevent backflow there
o 1. The more frequent low amplitude “slow waves” produce gradual back and forth
movement
 Slow waves are not action potentials, but rather oscillating depolarization
and repolarization of the membrane potential of the smooth muscle cells If,
at the plateau or the peak of the slow wave, the membrane potential is
depolarized all the way to threshold, then action potentials occur “on top
of” the slow wave; the contraction, or tension, occurs slightly after the burst
of action potentials
 The greater the number of action potentials on top of the slow waves, the
larger the phasic contraction.
 even sub-threshold slow waves produce a weak contraction basal
contractions, or tonic contractions. However, if slow waves depolarize the
membrane potential to threshold, then action potentials occur on top of the
slow waves, followed by much stronger contractions, or phasic contractions.
 Each portion of the gastrointestinal tract has a characteristic frequency of
slow waves, with the stomach having the lowest rate (3 slow waves per
minute) and the duodenum having the highest rate (12 slow waves per
minute).
 The characteristic frequency of slowwaves is not influenced by neural or
hormonal input, although neural activity and hormonal activity do modulate
both the production of action potentials and the strength of contractions.
 It is believed that slow waves originate in the interstitial cells of Cajal: Just as
the sinoatrial node is the pacemaker of the heart, the interstitial cells of
Cajal can be considered the pacemaker for gastrointestinal smooth muscle.
o 2. The less frequent but higher amplitude “giant waves” generate mass movement
 Mass movements occur in the colon and function to move the contents of
the large intestine over long distances, such as from the transverse colon to
the sigmoid colon.
 Mass movements occur anywhere from 1 to 3 times per day.
 Water absorption occurs in the distal colon, making the fecal contents of the
large intestine semisolid and increasingly difficult to move.
 A final mass movement propels the fecal contents into the rectum, where
they are stored until defecation occurs.
 gastrocolic reflex: a long arc reflex: Distention of the stomach by food
increases the motility of the colon and increases the frequency of mass
movements in the large intestine. [“why might need the bathroom after a
meal!!”]
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o
o
-
Poorly understood because of relative inaccessibility
Regional specialisation for motor functions
 Right colon: water absorption
 Contractile activity propagates orally and aborally
 Formation of solid stool begins here
 Left colon mainly a reservoir
 Rectum, anal sphincters & pelvic floor muscles
 Coordinated neuromuscular work of defecation
Defacation:
o As the rectum fills with feces, the smooth muscle wall of the rectum contracts and
the internal anal sphincter relaxes in the rectosphincteric reflex [can relax from
para, ab pressure/filling, or conscious control (prob conscious forced defecation)
o Defecation will not occur at this time, however, because the external anal sphincter
(composed of striated muscle and under voluntary control) is still tonically
contracted. However, once the rectum fills to 25% of its capacity, there is an urge to
defecate.
o When it is appropriate, the external anal sphincter is relaxed voluntarily, the smooth
muscle of the rectum contracts to create pressure, and feces are forced out through
the anal canal.
o The rectum stretches as it fills up; The anus copes with this rectal filling
o The rectum ampulla acts as a temporary storage facility for the unneeded material.
As the rectal walls expand due to the material filling it, stretch receptors from the
nervous system located in the rectal walls stimulate the desire to defecate. This urge
to defecate arises from the reflex contraction of rectal muscles, relaxation of the
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internal anal sphincter, and an initial contraction of the skeletal muscle of the
external anal sphincter.
[ie internal sphincter relaxes (prob to allow for more room), external sphincter
contracts as shown in the below experiment of a balloon being inflated in the
rectum]:
o
o
o
If the urge is not acted upon, the material in the rectum is often returned to the
colon by reverse peristalsis, where more water is absorbed and the faeces is stored
until the next mass peristaltic movement of the transverse and descending colon. If
defecation is delayed for a prolonged period the fecal matter may harden, resulting
in constipation. If defecation occurs too fast, before excess liquid is absorbed,
diarrhea may occur.[2]
When the rectum is full, an increase in intra-rectal pressure forces apart the walls of
the anal canal, allowing the fecal matter to enter the canal. The rectum shortens as
material is forced into the anal canal and peristaltic waves push the feces out of the
rectum. The internal and external anal sphincters along with the puborectalis
muscle allow the feces to be passed by muscles pulling the anus up over the exiting
feces
FI can be divided into those people who experience a defecation urge before
leakage (urge incontinence), and those who experience no sensation before leakage
(passive incontinence or soiling).[5] Urge incontinence is characterized by a sudden
need to defecate, with little time to reach a toilet. Urge and passive FI may be
associated with weakness of the external anal sphincter (EAS) and internal anal
sphincter (IAS) respectively. Urgency may also be associated with reduced rectal
volume, reduced ability of the rectal walls to distend and accommodate stool, and
increased rectal sensitivity.[3]

PASSIVE INCONTINENCE


Structural / functional lesion of internal sphincter
URGE INCONTINENCE

Structural / functional lesion of external sphincter


Impaired rectal compliance
Abnormal rectal content
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Continence Mechanisms
o Anatomical factors
 Anorectal angle [nb changes for defecation as puborectalis relaxes]
 sphincter alignment
o Reservoir elements
 Rectal compliance/accomodation
 Colonic compliance/accomodation
o Sensorimotor elements
 Anorectal angle
 Rectal sensation
 Anal sensory nerves
 Internal anal sphincter
 External anal sphincter
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03/12/13: The burden of GI diseases: Professor Julian
Walters
Los (from booklet):
alimentary tract disease
Notes:
-
Organs of the Alimentary System
o Mouth and Oesophagus
o Stomach
o Duodenum
o Liver
o Biliary system
o Pancreas
o Small intestine
 duodenum, jejunum & ileum
o Large intestine
 colon, rectum & anus
-
Functions of the Alimentary System
o Digestion of food
o Absorption of nutrients
o Motility from mouth to anus
o Barrier
o Immunological
o Endocrine
o Metabolic
-
Symptoms of Digestive Diseases
o General
 Anorexia
 Weight loss
 Anaemia
o Upper GI Tract
 Haematemesis and Melaena
 Nausea & vomiting
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o
o
o
-
 Dysphagia, odynophagia
 Heartburn, acid regurgitation & belching
 Chest pain
 Epigastric pain
Liver & Biliary
 RUQ pain
 Biliary Colic
 Jaundice
 Dark Urine / pale stool
 Abdominal distension (Ascites)
Mid GI Tract & Pancreas
 Abdominal pain
 Diarrhoea / steatorrhoea
 Distension
Lower GI Tract
 Abdominal pain
 Bleeding
 Constipation
 Diarrhoea
 Incontinence
Signs of Digestive Diseases
o General
 Cachexia
 Obesity
 Lymphadenopathy
 Anaemia
 Jaundice
 Stigmata of chronic liver disease
o Hands
 Koilonychia
 Leuconychia
 Clubbing
 Palmar erythema
 Dupytrens contracture
 Tremor
 Tachycardia
o Abdomen
 Organ enlargement
 Mass
 Tenderness
 Distension
o Anus & Rectum
 Haemorrhoids
 Fistula
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


Fissure
Rectal masses
Proctitis
-
General statistics
o 5% of British adults suffer from long-standing illness of the digestive tract
o Digestive Diseases in UK are responsible for:
 12% of all deaths - totalling 64,061 in 2002
 1 in 8 of all admissions to general hospitals
 1 in 4 main operations within general hospitals
o Number of liver related deaths is on the rise (but not as high as eastern block
countries)
-
Contrasting Patterns of Major Diseases
o Worldwide
 Malnutrition
 Enteric infections
 Viral hepatitis and consequences
 Gastric cancer
o UK
 Dyspepsia / indigestion / abnormal bowels
 Liver disease due to alcohol and obesity
 Colon cancer
-
Burden of Disease
o Prevalence / Incidence
o Morbidity
 Reduced quality of life
 Inability to work
o Mortality
o Health cost
 Individual
 Taxpayer
-
Main Causes of Chronic Liver Disease in UK
o 4 - 6% of UK population have abnormal LFTs:

- Chronic hepatitis B (0.5 – 2.0%)
 hepatitis B virus (HBV)
 Worldwide 350 Million chronically infected, 1 Million deaths per
year:
 Uncommon in UK but common in many countries from which
immigrants often come from (eg china, india, SS Africa)
 Outcome of HBV Infection:
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o

o
o
-
Fulminant Infection: infection that occurs suddenly and
quickly, and is intense and severe to the point of lethality,
i.e. it has an explosive character
o Self-limiting: In medicine, the term may imply that the
condition would run its course without the need of external
influence, especially any medical treatment
- Chronic hepatitis C (0.4 – 1.0%)
 Outcome of HCV Infection:
Increasing percentages with

- Alcohol related steatohepatitis

- Obesity related steatohepatitis (NAFLD)
Complications of cirrhosis are the major cause of death in alcoholics
Dyspepsia:
o = indigestion
o describes pain or discomfort in the upper abdomen
o Common reason for 1o / 2o care consultations
o High NHS costs
o Effects on Quality of Life
o Risk of complications
o
o
o
o
40% of adults suffer with dyspepsia
2% consult their GP
£600,000,000 for endoscopies and drugs
£100,000,000 for OTC medications
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o
-
Comparative prevalence:
Helicobacter pylori
 found in 50% of the world’s population
 Geographic distribution is closely linked to socio-economic development
 Gram-negative, spiral bacterium
 Colonises the gastric mucosa
 Infection persists for life unless treated

Chronic gastritis 
 85% - no long term effects
 1% gastric adenocarcinoma or lymphoma
 14% - peptic ulceration
o Peptic ulceration affects up to 10% population
o Estimated to cause up to:
 16,500 deaths each year in USA
 2,000 deaths each year in UK
o NSAIDS (Nonsteroidal anti-inflammatory drugs) & H. pylori
are factors linked to the disease
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-
Cancer in the GI Tract:
o Colorectal Neoplasia
 Lifetime incidence
 Polyps 25%
 Carcinoma ~6%
 Genetic & dietary factors
 Prevention by colonoscopic screening
 Surgery for cancer
 Prognosis excellent at early stages (5 year survival)
 Duke’s A
95%
 Duke’s B
85%
 Duke’s C
50%
 Duke’s D
15%
o Liver cancer
 most is metastatic
 primary liver cancer (hepatocellular and cholangio carcinomas) 2000
cases pa
 primary liver cell cancer (HCC) higher in cirrhosis
 can be detected at an early stage by ultrasound scanning
 50% 5 year survival
 cholangiocarcinoma increased 20 fold in last 20yrs; no treatment.
o Cholangiocarcinoma
 bile duct cancer
 an increasing problem
o Pancreatic cancer
 95% adenocarcinoma of pancreatic duct
 difficult to diagnose early
 one of the poorest survival rates (2% at 5y)
-
Inflammatory Conditions of the Intestine
o Ulcerative colitis & Crohn's disease (IBD)
 1 in 400 people in the UK
 8,500 new cases are diagnosed every year
 Genetic effects on intestinal immune response
 Morbidity & increased mortality
 Sepsis, drugs and surgery
o Coeliac Disease
 1% of UK population
 Genetic sensitivity
 Gluten-free diet
 Villi become inflamed and flattened
-
Biliary Diseases and Conditions
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o
Gallstones
 About one in ten people in Britain
 especially women, overweight, middle aged or over
 Can cause:
 Biliary colic
 Cholecystitis
 Obstructive jaundice
 Gallbladder carcinoma
 Acute pancreatitis [via reflux of bile]
-
Pancreatic Diseases
o Acute pancreatitis
 Mild to life-threatening
 Blockage of pancreatic duct
 Back-up of pancreatic enzymes causing severe inflammation
 Ethanol (ie alcohol cause) or gallstones in 80%
o Chronic pancreatitis
 Permanent damage to pancreas
 Alcohol excess main cause
 Can greatly impair Quality of Life
-
Intestinal Diseases and Conditions
o An estimated 200 million people around the world, on any given day, suffer from
diarrhoea
o Water and Food-borne infections
o Viruses
o Bacteria
o Parasites
o Clean water supply essential
o Enormous global indirect costs
-
Large Bowel Diseases & Conditions
o Irritable bowel syndrome (IBS)
 IBS is very common
 1 in 3 of population at one time or another
 1 in 10 people suffer symptoms bad enough to go to a doctor
 Constipation-predominant vs Diarrhoea-predominant
 Bloating / pain / mixed
-
Anal Diseases & Conditions
o Faecal incontinence (soiling) may affect 1 in 20 people
o About half the population has haemorrhoids by age 50
o Over half the over 70's population of the UK have diverticula of the large intestine
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Economic Burden of GI Disease
o Summary of costs
 Mortality & lost years
 Absence from work
 Morbidity
 NHS prescription costs
o Total >
£10 billion
o In 2002, 60 million prescriptions for GI drugs
 Classes of drug (BNF)
 Antacids
 Antispasmodics
 Ulcer-healing
 Chronic diarrhoeal agents
 Laxatives
 Haemorrhoid treatment
 Stoma care
 Intestinal secretion drugs
-
Summary:
o Diverse group of conditions
o Major impact on health
o Significant economic burden
o Significant impact on Quality of Life
GE Y1 Alimentary
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05/12/13: Pancreatic exocrine function: Dr Kevin
Murphy
Los (from slides):
•
•
•
Describe the basic structure and function of the pancreas.
Describe the two major components of pancreatic juice.
Describe the mechanisms involved in the secretion of these two components of pancreatic
juice.
Notes:
•
Pancreatic development:
• A foregut derivative arising at the foregut-midgut junction
• Dorsal and ventral buds
• Ventral bud is part of hepatobiliary bud; then moves posteriorly to join dorsal bud
and fuse with it; drains to major papilla
• Dorsal bud may lose its duct so accessory duct not always present
• [Duodenum rotates to form a C shape – ventral bud swings round to lie adjacent to
the dorsal bud – both buds fuse – Ventral bud duct becomes uncinated process
containing main pancreatic duct]
• Islet tissue most abundant in tail of pancreas
•
Pancreas extends from C-shaped duodenum to hilum of spleen
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Pancreas Endocrine and exocrine roles:
o Endocrine = secretes to systemic circulation
 [Secretion into the blood stream to have effect on distant target organ
(Autocrine/Paracrine) - Ductless Glands]
 Usually effects distant organs
 Eg insulin, glucagon, somatostatin, pancreatic polypeptide [&prob ghrelin]
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
o
o
Insulin: anabolic hormone, promotes glucose transport into cells
and storage as glycogen, reduces blood glucose, promotes protein
synthesis and lipogenesis
 Glucagon: Increases gluconeogenesis and glycogenolysis (increases
blood glucose)
 Somatostatin: “Endocrine cyanide”
 pancreatic polypeptide
o secreted by the pancreas in response to ingestion of
carbohydrates, proteins, or lipids.
o Pancreatic polypeptide inhibits pancreatic secretion of
HCO3 and enzymes, although its physiologic role is
uncertain.
Exocrine = secretion is to to systemic circulation
 [Secretion into a duct to have direct local effect]
 Fluid is transported via a duct from the gland
 Distribution restricted by where duct leads
Two parts to the pancreas: [red on image below]
 Endocrine - 2% of gland
 Islets of Langerhans
 Secretes hormones into blood - Insulin & Glucagon (also
Somatostatin and Pancreatic Polypeptide)
 Regulation of blood glucose, metabolism & growth effects (Endocrine course)
 Derived from the branching duct system
 Lose contact with ducts – become islets
 Differentiate into α- and β-cells secreting into blood


Islet tissue most abundant in tail of pancreas
Islet composition:
o

α-cells (A) form about 15-20% of islet tissue and secrete
glucagon
o β-cells (B) form about 60-70% of islet tissue and secrete
insulin
o δ-cells (D) form about 5-10% of islet tissue and secrete
somatostatin
o The islets are highly vascular, ensuring that all endocrine
cells have close access to a site for secretion
Exocrine - 98% of gland. [yellow on image below]
 Secretes (Pancreatic Juice) into duodenum via pancreatic
duct/common bile duct.
 Digestive function (covered in this lecture)
 Acini are grape-like clusters of secretory units
 Acinar cells secrete pro-enzymes into ducts
 TWO components of pancreatic juice:o Acinar cells: low vol, viscous, enzyme-rich
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o

 Amylases, proteases eg trypsinogen, lipases
Duct & Centroacinar cells: high vol, watery, HCO3-rich.
 Aqueous component is secreted by the centroacinar
cells and then modified by the ductal cells.
Bicarbonate Secretion
o Duct & centroacinar cells
 Centroacinar and ductal cells produce the initial
aqueous secretion, which is isotonic [Having the
same concentration of solutes (ie OVR) as the blood]
and contains Na, K, CL, HCO3-. This initial secretion
is then modified by transport processes in the ductal
epithelial cells
o Juice = RICH in bicarbonate ~ 120 mM (mmol/L) - (plasma
~25 mM). pH 7.5-8.0
o Neutralises acid chyme from the stomach
 prevents damage to duodenal mucosa
 Raises pH to optimum range for panreatic enzymes
to work
 Washes low volume enzyme secretion out of
pancreas into duodenum
o Fall in pH stimulates increased secretion of bicarbonate:
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o
o
Pancreatic bicarbonate secretion stops when pH is still acid
because Bile also contains bicarbonate and helps neutralise
the acid chime too. Additionally Brunners glands in small
intestine secrete alkaline fluid
Mechanism of Bicarbonate Secretion at pancreas:
 carbonic anhydrase catalyses HCO3 formation:
H2O + CO2  H2CO3  H+ + HCO3 Separation of H+ and HCO3-: H+ exits to blood [ie
acidification of pancreatic blood is observed]
[Na/H exchange at basolateral membrane into
bloodstream] while HCO3- exits to lumen
[Cl/HCO3 exchange at lumen]
o Exchange driven by electrochemical
gradients
 High ec (blood) Na compared to
ic (duct cell) [Na gradient into
cell from blood maintained by
Na/K exchange pump: Uses ATP
- Primary active transport; K
returns to blood via K-channel]
 High Cl in lumen compared to ic
(duct cell) [Cl returns to lumen
via Cl-channel (just accept this
fact despite it having to go up a
conc grad]
+
 Na moves down gradient via paracellular
(“tight” junctions)
 H2O follows the Na+
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o
o

Aside: Same reaction in gastric parietal cells (acid) and
pancreatic duct cells (alkaline)
 In stomach, H+ goes into gastric juice, HCO3- into
blood. Gastric venous blood is alkaline
 In pancreas, HCO3- secreted into juice and H+
into blood. Pancreatic venous blood is acidic
Ion levels in ducts differ individually to those in plasma
(though OVR isotonic) [but reason for flow rate inc giving
more HCO3 is that there must be a high secretin level which
will be giving both effects]
Acinar Cell Enzyme Secretion at pancreas:
o Enzymes for digestion of fat (lipases), protein (proteases)
and carbohydrates (amylase) are synthesised and stored in
zymogen granules
o Proteases are released as inactive pro-enzymes ~ protects
acini and ducts from auto-digestion
 trypsinogen, chymotrypsinogen, proelastase,
procarboxypeptidase A and procarboxypeptidase B
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
o
o
 trypsin, chymotrypsin, elastase,
carboxypeptidase A, and carboxypeptidase B
Pancreas also contains a trypsin inhibitor to prevent
trypsin activation
Enzymes become activated ONLY in duodenum
 Protein digestion is started in the stomach by
pepsin, which acts in acid conditions.
 When the chyme enters the duodenum, the pepsin
that is mixed into it comes as well, but is soon
inactivated by the alkaline conditions.
 The pancreas produces a cocktail of proteases, all
released as precursors.
 The duodenal brush border produces enterokinase,
which cleaves the trypsinogen between a valine and
an isoleucine [Enterokinase (enteropeptidase) converts trypsinogen to trypsin]. [ie only occurs at
duodenum]
 This active form of trypsin can activate the other
proteases in the same way and some lipolytic
enzymes (note lipase secreted in active form but
requires colipase, which is secreted as precursor
o
o
by pancreas then activated by trypsin) (Note:
lipases require presence of bile salts for effective
action re emulsification) [including further trypsin,
chymotrypsin, etc].
 Nb Brush border enzymes are digestive enzymes
located in the membrane of the brush border
(microvilli) on intestinal epithelial cells: ie in the
memb so not themselves degraded; will aid
digestionpanctreatic enz
 All the proteases are fairly short lived as they are
digested themselves.
Blockage of pancreatic duct may overload protection and
result in auto-digestion (= acute pancreatitis)
Altered Pancreatic Enzyme Function
 Pancreatic secretions adapt to diet e.g. high protein,
low carbs, increases proportion of proteases,
decreases proportion of amylases
 Pancreatic enzymes (+ bile) are essential for normal
digestion of a meal. Lack of these can lead to
malnutrition even if the dietary input is OK. (unlike
salivary, gastric enzymes)
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
Anti-obesity drug Orlistat inhibits pancreatic lipases
– but side effects include fat in faeces
(Steatorrhoea):
 Increased faecal fat – occurs when
pancreatic lipase secretion significantly
reduced
 Steatorrhoea Eg cystic fibrosis, chronic
pancreatitis, Orlistat – a weight loss agent
which inhibits pancreatic lipase and hence
intestinal fat absorption
o
Pancreatic disease may involve BOTH exocrine and endocrine effects
 eg cystic fibrosis, chronic pancreatitis
 deficiency of all pancreatic enzymes
 nb Dietary protein cannot be absorbed if it is not digested by
proteases to amino acids, dipeptides, and tripeptides. The absence
of trypsin alone makes it appear as if all of the pancreatic enzymes
are missing, since trypsin is necessary for the activation of all
precursor enzymes
o
Control of secretion at pancreas:
The enzymatic and aqueous portions are regulated separately: The aqueous
secretion is stimulated by the arrival of H in the duodenum, and the enzymatic
secretion is stimulated by products of digestion (small peptides, amino acids, and
fatty acids).
 Initial cephalic phase
 Reflex response to sight/smell/taste of food
 Ie nervous activity involved with cortical stimuli involved in sending
sensory information to brain and returning motor activity to gut
 Enzyme-rich component only. “mobilises” enzymes
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

 Low volume
Gastric phase
 Stimulation of pancreatic secretion originating from food arriving in
the stomach
 Same mechanisms involved as for cephalic phase in that it is also
nervous and only/mainly enzymes released (not
bicarbonate/aqueous):
Ie nervous activity involved with vagus nerve involved in sending
sensory information to brain and returning motor activity to gut
Intestinal phase (= 70-80% of pancreatic secretion)
 Hormonally mediated when gastric chyme enters duodenum.
 BOTH components of pancreatic juice stimulated (enzymes + HCO3 juice flows into duodenum)
o Acinar cells:
 The pancreatic acinar cells have receptors for CCK.
 The I cells are stimulated to secrete CCK by the
presence of amino acids, small peptides, and fatty
acids in the intestinal lumen.
In addition, ACh stimulates enzyme secretion and
potentiates the action of CCK by vagovagal reflexes.
Ductal cells:
 The pancreatic ductal cells have receptors for CCK,
Ach [these are only for potentiation], and secretin
(secretin is the main stimulant)
 Secretin is secreted in response to H in the lumen of
the intestine, which signals the arrival of acidic
chyme from the stomach.

o

The effects of secretin are potentiated by both CCK
and Ach [ie but Ach and CCK don’t act much
themselves].
o
The two components of pancreatic juice are separately controlled
 Bicarbonate secretion is controlled by release of a hormone - Secretin (via
cAMP signalling)
 S-cells at duodenum detect H+ that has exited from stomach with
some food [H+ and fatty acids are the stimuli]
 In response releases secretin to blood
 Secretin is detected at the pancreatic duct triggering HCO3secretion [The function of secretin is to promote the secretion of
pancreatic and biliary HCO3]
o Neutralises the acid to prevent denaturation of pancreatic
lipases
 Secretin also inhibits the effects of gastrin on the parietal cells (H
secretion and growth).
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
Enzyme secretion is controlled by vagal reflex and by a hormone Cholecystokinin (ie CCK) (via Ca2+/PLC signalling)
 C-cells at duodenum [duodenal and jejunal mucosa] detect peptides
and fat; In response release CCK to blood
o Books and internet actually call the cells with this function
“I-cells”:
o CCK is secreted by the I cells of the duodenal and jejunal
mucosa in response to two types of physiologic stimuli:
 (1) monoglycerides and fatty acids (but not
triglycerides), and
 (2) small peptides and amino acids.
 The functions of cholecystokinin (CCK) are coordinated to promote
fat digestion and absorption [its actions will also lead to inc carb
digestion/absorbtion too]. Triggers:
o Contraction of the gallbladder with simultaneous relaxation
of the sphincter of Oddi ejects bile from the gallbladder into
the lumen of the small intestine. Bile is needed for
emulsification and solubilisation of dietary lipids.
o Secretion of pancreatic enzymes. Pancreatic lipases digest
ingested lipids to fatty acids, monoglycerides, and
cholesterol, all of which can be absorbed. Pancreatic
amylase digests carbohydrates, and pancreatic proteases
digest protein.
o Secretion of bicarbonate (HCO3 -) from the pancreas. This
is not a major effect of CCK, but it potentiates the effects of
secretin on HCO3 secretion.
o Growth of the exocrine pancreas and gallbladder. Since the
major target organs for CCK are the exocrine pancreas and
the gallbladder, it is logical that CCK also has trophic effects
on these organs.
o Inhibition of gastric emptying. CCK inhibits or slows gastric
emptying and increases gastric emptying time. This action is
critical for the processes of fat digestion and absorption,
which require a considerable amount of time. CCK slows the
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



delivery of chyme (partially digested food) from the stomach
to the small intestine, ensuring adequate time for the
subsequent digestive and absorptive steps.
At acinus proenzymes are secreted (along with trypsin inhibitor
which protects pancreas)
Switching Off CCK:
o Cephalic phase ends when meal eaten
o Absorption of fats and peptides removes local luminal
stimulus for CCK release from mucosa
o Possibly other mechanisms
The C-terminal five amino acids (CCK-5) are identical to those of
gastrin and include the tetrapeptide that is minimally necessary for
gastrin activity. Thus, CCK has some gastrin activity.
CCK also stimulates bile secretion
o
Stimulus Interaction
 CCK alone - no effect on bicarbonate secretion
 CCK can markedly increase bicarbonate secretion that has been stimulated
by secretin [CCK potentiates secretin-induced secretin release]
 Vagus nerve has similar effect to CCK
 Both help give rapid pH drop once secretin secretion occurs
 Secretin NO EFFECT on enzyme secretion
o
During a meal:
 Food mixed, digested in stomach, pH 2
 Chyme squirted into duodenum
 H+ ions in duodenum stimulate release of secretin, stimulating release of
pancreatic juice (plus bile and Brunner’s gland secretions) to raise pH to
neutral/alkaline.
 Peptides + fat in duodenum cause sharp rise in CCK, vagal nerve, stimulating
pancreatic enzyme release, peaks by 30 mins, continues until stomach
empty.
 CCK potentiates effects of secretin on aqueous component (necessary
because most of duodenum not at low pH but if pH falls then rapid response
needed).
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05/12/13: Abdominal pain and pancreatitis: Dr Ayaru
Los (from slides):
•
•
•
•
•
To be able to list conditions that produce abdominal pain
To describe some features of the enteric nervous system
To recognise the symptoms of acute and chronic pancreatitis
To appreciate the mechanisms that cause pancreatitis
To be introduced to the therapeutic principles of pancreatic diseases
Notes:
-
Pain components
o Sensory-discriminative [ie the classic pain pathway]
 localise pain
 Assess its intensity
o Affective-motivational [ie in some patients other factors than direct pain stimulation
contribute to the perception of pain]
 Emotional response
o Cognitive-evaluative [ie in some patients other factors than direct pain stimulation
contribute to the perception of pain]
 Attention, anticipation and memory of the experience
-
The Brain Gut-Axis: the relationship between digestive health and cognitive, mental and
behavioral conditions: Relavant components:
• Brain (Interneurons)
• Autonomic nervous system
• Enteric nervous system (ENS – efferent and afferent)
• GI Motility i.e. peristalsis
• Secretion
• Visceral sensitivity
• Mucosal Function and permeability
• Serotonin, CRF, VIP
•
Efferent (Motor)
• Functions
• GI Endocrine
• Motility
• Effector Cells
• Smooth Muscle
• Secretory
• Chief
• Parietal
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•
•
•
•
•
•
-
Enterocytes
Pancreatic exocrine
Afferent (Sensory)
• Intrinsic pathway afferent neurons (IPANs)
• Mechanical
• Stretch
• Tension
• Thermal
• Osmotic
• Chemoceptors
• Acid
• Glucose
• Amino-acids
Myenteric (Auerbach’s) Plexus
• Parasympathetic
•
and sympathetic NS
• Acetylcholine
• Excitatory
• Muscle contraction
• Secretion
• Endocrine
• Vasodilation
Submucosal (Meissner’s) Plexus
• Sympathetic NS (noradrenaline)
• Sensory
• Regulates blood flow
• Controls epithelial cell function
Localisation of Pain
• Bilateral sympathetic innervation of bowel and organs- midline
diffuse pain
• Foregut/midgut/hindgut origin predicts location
• Parietal peritoneum- innervated by spinal nerves which also
innervate overlying skin.
• more localised pain
Benign causes of abdominal pain
o Upper abdominal discomfort
 gallbadder-gallstones
 stomach/oesophagus-dyspepsia/reflux
 pancreas-pancreatitis (acute and chronic)
o Lower abdominal discomfort
 bowel-Irritable bowel syndrome, crohns disease
 pelvic-endometriosis
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Irritable Bowel Syndrome (IBS) and The Brain-Gut Axis
o Diagnosis:
 Functional cause of abdo pain
 Recurrent Abdo Pain (RAP) >3 months plus two of….
 Relieved by defecation
 Onset associated with a change in stool frequency
 Onset associated with a change in stool form or appearance
 Supporting symptoms
 Altered stool frequency
 Altered stool form
 Altered stool passage (straining and/or urgency)
 Abdominal bloating or subjective distension
 Subtypes
 IBS-D (diarrhoea predominant)
 IBS-C (constipation predominant)
 IBS-M (mixed diarrhoea and constipation)
 IBS-A (alternating diarrhoea and constipation)
o Serotonin and the Gut
 5HT3 and 5HT4 receptors detect serotonin to mediate its effects
 95% of the body’s serotonin is in the gut
 Regulates gut movement [prob inc peristalsis]
 Tegaserod is a 5HT4 agonist
o Aetiology
 The ‘Brain-Gut Axis’
 ENS signals via afferent pathways to midbrain, thalamus and cortex
o Memory
o Cognition
o Affect
 Patients with IBS show visceral hypersensitivity to identical stimuli
and different brain areas become active when the stimuli is applied
to healthy gut areas (ie there is a mental component of the disease)
 Organic pathology in IBS [ie is not just mental; also a physical
component often – its just that it is hard to detect these aspects
unless the patient is operated on and sample tests made]
o Colonic inflammation and small bowel inflammation- post
infectious IBS
o Laparoscopic full-thickness jejeunal biopsy samples infiltration of lymphocytes into the plexi and intraepithelial
lymphocytes in a subset of patients.
o Enteroendocrine cells in postinfectious irritable bowel
syndrome appear to secrete high levels of serotonin,
increasing colonic secretion and possibly leading to
diarrhea.
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o
o
Epidemiology
 10-20% prevalence
 Female 2-3:1 Male
 Age <35 years
 20-50% of GI OPD new referrals
 $1.7 billion USA medical costs
 $20 billion USA worker absenteeism
 Childhood:
 8% children experience functional abdominal pain; 18-61% will
develop pain 5-30 years later
 Strong link between a history of childhood sexual or physical abuse
and subsequent IBD
 61% report unsatisfactory relationship with parents (ie those with
IBD)
[ie both of the above further point to a mental component to the
disease]
Treatments
 Dietary advice

o
-
Treatment is vs Mental: Antidepressants [serotonin bad in gut
but good at brain so use reuptake inhibitors]
 Tricyclic antidepressants The majority TCAs act as serotoninnorepinephrine reuptake inhibitors (SNRIs) by blocking the
serotonin transporter (SERT) and the norepinephrine transporter
(NET)
 SSRIs: selective serotonin reuptake inhibitors[serotonin bad in gut
but good at brain so use reuptake inhibitors]
 Biofeedback
o Learn to consciously control involuntary responses
o Information about a physiologic process is relayed back to
the patient
 Psychotherapy / Psychological therapies
 Cognitive behavioural therapy (CBT)
 Hypnotherapy
Summary
 Functional cause of abdominal pain
 Some recent evidence of organic pathology
 Significant cost implications
 ‘Brain-gut axis’
 Psychological therapies most effective
A Pancreatic Mass:
o Patient Presents
 Painful obstructive jaundice
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

Loss of appetite
Weight Loss







o
o
Dilated biliary tree
biliary sludge present
Distended gall bladder with multiple small echogenic foci
Bulky pancreatic head
jaundiced
1cm mass within pancreatic head
Amylase levels high [occurs when release from pancreas area occurs
because the pancreas is diseased or inflamed]
 Abnormal liver function tests
Differential Diagnosis
 Pancreatic mass and obstruction
 Chronic pancreatitis
 Autoimmune pancreatitis
 Adenocarcinoma pancreas
 [actual example diagnosis: pancreatic inflammatory mass  CBD stricture
 biliary sludge  Chronic pancreatitis]
Treatment:
 stent inserted
 Good drainage initially but stent can become blocked
 Is therefore sometimes better to perform a surgical procedure
 A Cholecystectomy may be performed: is the surgical removal of the
gallbladder
-
Signalling molecules known as paracrine factors diffuse over a relatively short distance (local
action), as opposed to endocrine factors (hormones which travel considerably longer
distances via the circulatory system)
-
Pancreatitis:
o Pancreas
 Exocrine [to “outside”]
 Lipase, Trypsin, etc
 Endocrine [to blood]
 Insulin
 Glucagon
 Somatostatin [is both endocrine and paracrine in its action:
paracrine at gut where is released from cells of both the stomach
and intestine; endocrine release occurs from pancreatic delta-cells
of islets of Langerhans and from hypothalamus] [is often referred to
as a peptide hormone; inhibitory hormone]
o Acute pancreatitis symptoms:
 Acute upper abdominal pain-can last for days
 Nausea and vomiting
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o
o
 Raised amylase
Causes [these are the main ones]
 Gallstones
 Alcohol
 Autoimmune
 Hereditary
Progression:
 Inappropriate activation of pancreatic enzymes
 ↓
 Auto-digestion of the pancreatic tissue
 ↓
 Necrosis of acinar cells
 ↓
 Immune response ie. inflammatory infiltrates

o
o
o
Chronic changes: perilobular fibrosis, duct distortion, and altered pancreatic
secretions
Pain


Occurs in 80-90% patients [ie not all pancreatitis patients get pain]
Possibilities:
 Recurrent (type A)
 Continuous (type B)
 None at all
 Epigastric, radiates through to back
 Can lead to anorexia, weight loss
 Alleviation associated with exocrine insufficiency?
 Often need opiate analgesia
 Multifactorial
 Extrapancreatic eg. Biliary strictures
 Pancreatic eg. Pseudocysts
 Increased intrapancreatic pressure
 Pancreatic duct or parenchyma → tissue ischaemia
 Inflammation
 Alterations in pancreatic nerves
 Increase in nerve fibre diameter
 Neurogenic inflammation.
Pancreas stone / concretion formation:
 Increased protein concentrations
 ↓
 Form proteinaceous ductal plugs
 ↓
 Ductal plugs may calcify
 ↓
 Further obstruct the pancreatic ducts
Cycle / sequence:
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

o
o
o
o
Episodes of acute pancreatitis occur giving necrosis / pancreatic damage
Episodes are separated by periods when the concretion is not causing
damage but the prev damage largely remains and instead fibrosis occurs
 Thus damage accumulates through time
Consequences of pancreatitis:
 Malabsorption
 35% exocrine insufficiency
 Pancreatic lipase, faecal elastase, faecal fat collection
 Steatorrhoea & weight loss
 Lipids first (not digested), then carbs and proteins
 Pancreatic enzyme supplements (e.g. Creon) with meals can help
ease problems
 Diabetes [due to pancreas damage]
 Incidence
o Japan: 35.1% (Ito et al J Gastro 2007)
o France: 32% (Levy et al Gastro Clin Bio 2006)
 Type IIIc (American Diabetes Association)
 Destruction of insulin and glucagon producing cells
 Diabetic condition often fragile, often require insulin
 50% 10 year survival
 Pancreatic cancer
 Pseudocyst: ie a potentially big cyst in abdomen
 Biliary tree compression
Hereditary Pancreatitis
 High-Penetrance
 Protease, Serine 1 ( PRSS1) [trypsin]
 Arg  His mutation in exon 3
 Removes ‘self-destruction’ site
 Trypsin resistant to digestion
 93% of those with the mutation get chronic pancreatitis
Diagnosis
 Histology (rarely available)
 Biochemistry
 faecal elastase, faecal fat collection, pancrealauryl test
 Imaging (Endoscopic, radiological)
 Calcification (90% late stage)
 Marked ductal abnormalities
Treatment:
 Lifestyle modification
 Analgesia
 Enzyme supplements
 Insulin
 Endoscopic multiple stents
 At 1 year 84% asymptomatic when multiple stents placed
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


-
Longer term benefit unproven
Strictures may not be related to pain!
May be inferior to surgery
Summary
o List conditions that produce abdominal pain
o Features of the enteric nervous system
o Symptoms of acute and chronic pancreatitis(e.g.Abdo pain, symptoms of
malabsorption)
o mechanisms that cause pancreatitis (necrosis-fibrosis, genetics)
o Therapeutic principles of pancreatic diseases (e.g endoscopy and surgery)
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05/12/13: Gastroesophageal reflux disease ‘GORD’:
Dr Jonathan Hoare
Los (from booklet):
Lecture 4 Gastro-oesophageal reflux disease Jonathan Hoare
describe some of the pathophysiological processes involved
-oesophageal reflux disease
Notes:
-
GORD
o General:
 Symptoms or mucosal damage produced by the abnormal reflux of gastric
contents into the esophagus”
 Gastroesophageal reflux disease (GORD) is notable for its prevalence, variety
of clinical presentations, underrecognised morbidity, and substantial
economic consequences
o Gastroesophageal Junction [GOJ]:
 Not a true sphincter: just a thickening of muscle acting with diaphragm
constriction and angle of His (flap able to flip across the entrance up the
esophagus)
 Mechanisms to prevent reflux
 Oesophageal sphincter
 Crura / diaphragm
 Angle of His (flap valve)
 Prevents reflux of gastric contents
 Opens for swallowing
 Vents gas selectively – belching
 Opens for vomiting
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o
o
Epidemiology
 10 to 20 % prevalence in the Western world (at least weekly heartburn
and/or acid regurgitation)
 Less common in asia as less fat in diet
 We only get GORD due to the changes to the stomach / esophagus angle
that occurred when we changed from four to two legs
Causes / Pathophysiology
 Hypotensive lower oesophageal sphincter (LES)
 transient lower oesophageal relaxations / belching due to the
‘sphincter’ being too loose
 not a sphincter: 4cm zone of increased tone
 minority of GORD patients have low fasting pressure (<10mmHg)
 many factors decrease LES!
o gastric distension, fat, chocolate, caffeine, alcohol, smoking,
drugs
 Anatomic disruption of the GO junction
 “hiatus hernia”
 75% patients with GORD have HH / 35% normal
 Age / obesity contribute to risk
 disruption of phrenoesophageal membrane
 Low LES pressure and HH is more than additive in terms of GORD
risk
 HH leads to increased LER tensions generally as stomach now in
hiatus
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

o
o
Summary of potential causes of GORD ie via delayed oesophageal acid
clearance
 [hiatus hernia / weak LOS]
 Gastropariesis: dsmotility: decreased peristalsis and acid removal
 severe oesophagitis causing fibrosis
 cigarette smoking
 hyposalivation → decreased neutralisation
Note: FACTORS ARE ADDITIVE AND LEAD TO REFLUX IN MOST PATIENTS
PROB NOT ONE CAUSE
Symptoms
 retrosternal burning/regurgitation
 atypical chest pain/waterbrash/dysphagia
 chronic cough/globus/[also a possible link to worsening/causing asthma:
patients with asthma 60% more reflux symptoms by some sources but “jury
still out/prob not that important”]
Pathology
 oesophagitis
 stricture
 Barrett’s oesophagus
 refers to an abnormal change (metaplasia) in the cells of the lower
portion of the esophagus. lining of the esophagus is replaced by cells
usually found lower in the gastrointestinal tract / stomach
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

The main cause of Barrett esophagus is thought to be an adaptation
to chronic acid exposure from reflux esophagitis
 The medical significance of Barrett esophagus is its strong
association with esophageal adenocarcinoma, a particularly
lethal cancer.
adenocarcinoma (odds ratio of 43 if severe reflux ie enhances reflux risk
43x)
o
Diagnosis
 Typical history
 heartburn / regurgitation
 Atypical history
 dysphagia / odynophagia / water brash / globus / asthma /chest
pain / cough / hoarse voice
 Who to investigate further?
 Response to anti-acid treatment often enough
 Non-responders / Unusual history would require severe symptoms
to look for complications
 New symptoms at age when concerned may develop cancer (ie later
in life) may also warrant further investigation
 The options for further investigation:
 Endoscopy (visual inspection)
 Ph manometry (follow pH changes in esophagus through 24hrs)
o
NERD: Non-erosive reflux disease
 70% patients with symptoms do not have erosive oesophagitis; other
possibilities and their causes:
1. symptoms but normal 24hour pH
 visceral hyperalgesia (Bernstein test) [increased sensitivity to
visceral stimulation]
2. abnormal 24hour pH but normal mucosa
 problem of pepsin/tight junctions/H+ channels
3. “functional heartburn” (ie unclear underlying cause)
 i.e. symptoms not due to acid reflux
 Bernstein test -ve
o
GORD Treatment:
 Lifestyle modification!
 bed elevation, diet, meal times, weight loss, clothing, salivation,
smoking
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


 trials show doesn’t work (non-compliance)
Medical therapy
 simple antacids / alginates
o Bicarbonates (Rennies) / milk
o Alginates (Gaviscon)
 histamine 2 receptor antagonists: H2RAs (non covalent interactions)
o ACh from vagus nerve signals at H-Cells which produce
histamine in response
o The action of histamine on parietal cells (specifically the
histamine H2 receptors) in the stomach is increased
production of acid by these cells (so this is supressed)
o cimetidine / ranitidine
 proton pump inhibitors
o Total market approx. 15-20 billion dollars
o Proton pump inhibitors (PPIs) have targets such as
Gastric hydrogen potassium ATPase (also known
as H+/K+ ATPase and form covalent interactions)
o Esomeprazole [only L-isomer active] / omeprazole /
lanzoprazole
o [nb these tratments have been linked to C. difficile
colonisation due to the reduced acid production]
What to do if poor response ?
 review compliance
 increase acid suppression
 change PPI – esomeprazole
 add H2 antagonist at bedtime
 Refer for surgery!
Surgical therapy
 side effects
o dysphagia/inability to vomit/perforation etc.
 economically similar to medical treatment but more risky
 only 50% off PPI at 3 years anyway
 no proven efficacy against Barrett’s or cancer prevention
 reserve for difficult patients



Nissen’s fundoplication
o In a fundoplication, the gastric fundus (upper part) of the
stomach is wrapped, or plicated, around the lower end of
the esophagus and stitched in place, reinforcing the closing
function of the lower esophageal sphincter.
Keyhole “minimally invasive surgery”
o Laparoscopic nissen fundoplication (LNF) is a type of keyhole
surgery where the above is done except Laparoscopically
Endoscopic anti-reflux procedures
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o
o
radiofrequency ablation is being for patients with Barrett’s
oesophagus to reduce the risk of development of
oesophageal carcinoma
Summary
 Consequences of GORD
 oesophagitis/stricture/Barrett’s/csncer
 Diagnosis
 history/endoscopy/ph studies
 Treatment
 simple antacids/H2RAs/PPIs/surgery
 Other interesting current issues
 asthma/C.diff/anti-reflux procedures
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06/12/13: Review of nutrition: Gary Frost
Los (from booklet [are with respect to this lec and the
one immediately below]):
review the principles of nutrition
Los (from slides): [is a tutorial but presented as a
lecture]


To have a basic understanding on the importance of nutrition in human health
Need to understand basic requirements [not in booklet so may not have to know:]
o Understand population change
o Understanding change in requirements from health to disease
o The importance of energy intake
o Understanding individual nutrient deficiencies
Notes:
-
Energy
o If nutrients are to be used effectively the bodies demand for energy needs to be met
first. [ie only then is energy used for other tasks]. This is basic survival
o Major public health problems are associated with energy intake
 malnutrition
 Mostly driven by abnormal energy balance
 It most often refers to undernutrition resulting from inadequate
consumption, poor absorption, or excessive loss of nutrients, but
the term can also encompass overnutrition, resulting from
overeating or excessive intake of specific nutrients
 Areas with undernutrition (eg sub-Saharan Africa) closely match to
areas with poor life expectancy; areas with overnutrition (eg USA)
match to worsening life expectancy
 Obesity/overnutrition is associated with increased risk of many
cancers
 The world we live in has changed: Normal biological response to a
world in which we are not suited [ie food now more easily available]
 disastrous consequences for weight and health.
 Malnourishment correlates to length of stay in hospital (nb the
sedentary lifestyle and illness influences are often the reasons here)
 Weight gain
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

Energy in exceeds energy out: reasons:
[Obesity can only occur when energy intake remains higher than
energy expenditure for an extended period of time]
o Increase intake
o Decrease expenditure
o Decrease in metabolic rate
Starvation:
 Ketones become the major energy source
 Body begins energy conservation measures
 Some brain cells are still dependent on glucose, so a little
gluconeogenesis occurs from protein catabolism
 Lean Body Mass is a component of body composition, calculated by
subtracting body fat weight from total body weight: total body
weight is lean plus fat
o Iteratively from -10% LBM to -40% LBM the effects are:
impaired immunity  decreased healing  no healing 
death, usually from pneumonia [“leptin has beneficial
direct effects on the immune system!]

General
o The energetic requirements of a body are composed of the
basal metabolic rate and the physical activity level. This
caloric requirement can be met with protein, fat,
carbohydrates or a mixture of them. Glucose is the general
metabolic fuel, which can be metabolized by any cell.
Fructose and some other nutrients can only be metabolized
in the liver, where their metabolites are transformed either
into glucose and stored as glycogen, both in the liver and in
the muscles; or into fatty acids which are stored in adipose
tissue.
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




o
o
o
o
Normal metabolic rate 25-30kcal/kg/d
Carbohydrates: [ie carbohydrates are the main
energy source]
Fat: [Micronutrients as opposed to macronutrients
(protein, carbohydrates and fat), are comprised of
vitamins and minerals which are required in small
quantities: A diet containing some fat is required for
the absorption of these vitamins]
Proteins: [ie proteins are metabolised primarily only
in the context of protein synthesis]
Lean mass compartment: is maintained or
contributed to
Because of the blood–brain barrier, getting nutrients to the
human brain is especially dependent on molecules that can
pass this barrier. The brain itself consumes about 18% of the
basal metabolic rate: on a total intake of 1800 kcal/day, this
equates to 324 kcal, or about 80 g of glucose. About 25% of
total body glucose consumption occurs in the brain.
Glucose can be obtained directly from dietary sugars and by
the breakdown of other carbohydrates. In the absence of
dietary sugars and carbohydrates, glucose is obtained from
the breakdown of stored glycogen. Glycogen is a readilyaccessible storage form of glucose, stored in notable
quantities in the liver and in small quantities in the muscles.
The body's glycogen reserve is enough to provide glucose
for about 24 hours.[citation needed]
When the glycogen reserve is depleted, glucose can be
obtained from the breakdown of fats from adipose tissue.
Fats are broken down into glycerol and free fatty acids, with
the glycerol being utilized in the liver as a substrate for
gluconeogenesis.
When even the glycerol reserves are depleted, or sooner,
the liver will start producing ketone bodies. Ketone bodies
are short-chain derivatives of fatty acids, which, since they
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are capable of crossing the blood–brain barrier, can be used
by the brain as an alternative metabolic fuel. Fatty acids can
be used directly as an energy source by most tissues in the
body.






Lower metabolic rate: 20-25kcal/kg/d
Glucose levels in blood are maintained right up until
the very end of starvation by a switch of all body
tissues that are able to do so to fats as the energy
supply (lipolysis and beta-oxidation)
Similarly lean mass is preserved by hormone level
changes to counter any erosion that may otherwise
occur
Some glucose is required by the brain and this can
be supplemented by ketone bodies derived from
fats at the liver
Nb in an average person the mass of fat and protein
are similar with them both far exceeding the
glycogen stores
Timeline
o After the exhaustion of the glycogen reserve, and for the
next 2–3 days, fatty acids are the principal metabolic fuel. At
first, the brain continues to use glucose, because, if a nonbrain tissue is using fatty acids as its metabolic fuel, the use
of glucose in the same tissue is switched off. Thus, when
fatty acids are being broken down for energy, all of the
remaining glucose is made available for use by the brain.
o After 2 or 3 days of fasting, the liver begins to synthesize
ketone bodies from precursors obtained from fatty acid
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
breakdown. The brain uses these ketone bodies as fuel, thus
cutting its requirement for glucose. After fasting for 3 days,
the brain gets 30% of its energy from ketone bodies. After
40 days, this goes up to 75%.[6]
o Thus, the production of ketone bodies cuts the brain's
glucose requirement from 80 g per day to about 30 g per
day. Of the remaining 30 g requirement, 20 g per day can be
produced by the liver from glycerol (itself a product of fat
breakdown). But this still leaves a deficit of about 10 g of
glucose per day that must be supplied from some other
source. This other source will be the body's own proteins.
o After several days of fasting, all cells in the body begin to
break down protein. This releases amino acids into the
bloodstream, which can be converted into glucose by the
liver. Since much of our muscle mass is protein, this
phenomenon is responsible for the wasting away of muscle
mass seen in starvation.
o However, the body is able to selectively decide which cells
will break down protein and which will not. About 2–3 g of
protein has to be broken down to synthesize 1 g of glucose;
about 20–30 g of protein is broken down each day to make
10 g of glucose to keep the brain alive. However, this
number may decrease the longer the fasting period is
continued in order to conserve protein.
o Starvation ensues when the fat reserves are completely
exhausted and protein is the only fuel source available to
the body. Thus, after periods of starvation, the loss of body
protein affects the function of important organs, and death
results, even if there are still fat reserves left unused. (In a
leaner person, the fat reserves are depleted earlier, the
protein depletion occurs sooner, and therefore death occurs
sooner.)
o The ultimate cause of death is, in general, cardiac
arrhythmia or cardiac arrest brought on by tissue
degradation and electrolyte imbalances.
Timeline
o 0 hours: Glucose still used as primary fuel.
o 0 – 6 hours: Glycogen is broken down to produce glucose for
the body. Also gluconeogenesis begins: convert glycerol and
glucogenic amino acids into glucose for metabolism
o 6 – 72 hours: Glycogen stores are used up and the body
breaks down fatty acids. Ketone bodies are produced to
help feed the brain. Gluconeogenesis continuing with new
glycerol supply and the acetyl coA from B-ox]
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o
-
The body's rate of protein loss is greatest during the first 72
hours. After several days of starvation the body adapts and
starts to conserve protein
Components of Energy Expenditure
o Obligatory energy expenditure: Depending on an individual’s level of physical
activity, between 50 and 80 percent of the energy expended each day is devoted to
basic metabolic processes (basal metabolism), which enable the body to stay warm,
breathe, pump blood, and conduct numerous physiological and biosynthetic
activities, including synthesis of new tissue in growing children and in pregnant and
lactating women.
o Adaptive thermogenesis, another small but important component of energy
expenditure, reflects alterations in metabolism due to changes in ambient
temperature [Includes action at brown adipose tissue mitochondria, shivering],
hormone production, emotional stress, or digestion: Digestion and subsequent
processing of food by the body also uses energy and produces heat. This
phenomenon, known as the thermic effect of food (or diet-induced thermogenesis),
accounts for about 10 percent of daily energy expenditure, varying somewhat with
the composition of the diet and prior dietary practices. Regulated by brain.
o Physical activity: Finally, the most variable component in energy expenditure is
physical activity, which includes exercise and other voluntary activities as well as
involuntary activities such as fidgeting, shivering, and maintaining posture. Physical
activity accounts for 20 to 40 percent of the total energy expenditure, even less in a
very sedentary person and more in someone who is extremely active
-
Changes with Ageing [contributes to malnutrition susceptibility]
o Decline in body size
o Increase in body fat
o Decline in muscle mass
o Decline in liver mass
o Decline in kidney mass
o Decline in total body water [Effects drug dosage and toxicity]
o Requirement for energy falls
-
Regulation of feeding
o Average human eats 900,000 kcals per year.
o A 3% error would result in an extra 27,000 kcals per year
o This would result in an extra 10lb weight gain per year
o This does not happen
-
PERIPHERAL SIGNALS REGULATING APPETITE
o ANS
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

o
o
o
Visceral sensory neuronal signalling occurs to input into appetite
[nucleus of the solitary tract - this nucleus collects all of the visceral sensory
information from the vagus and relays it to the hypothalamus and other
targets. Information includes blood pressure and gut distension: ie then
presumably inc/dec appetite]
Leptin:
 produced by adipose tissue
 Leptin functions by binding to the leptin receptor.
 Leptin acts on receptors in the hypothalamus of the brain, where it inhibits
appetite
Ghrelin:
 hunger-stimulating peptide and hormone that is produced mainly by cells
lining the fundus of the human stomach and cells of the pancreas
 The ghrelin receptor is a G protein-coupled receptor. Ghrelin binds to the
GHSR1a splice-variant of this receptor which is present in high density in the
hypothalamus; ie where it signals for “hunger”
 Ghrelin levels increase before meals and decrease after meals
Peptide YY (aka PYY)
 peptide released by cells in the ileum and colon in response to feeding.
 In humans it appears to reduce appetite.
 Acts at hypothalamus
-
Alcohol as an energy source:
o Although alcohol is an energy source, how the body processes and uses the energy
from alcohol is more complex than can be explained by a simple calorie conversion
value (8). For example, alcohol provides an average of 20 percent of the calories in
the diet of the upper third of drinking Americans, and we might expect many
drinkers who consume such amounts to be obese. Instead, national data indicate
that, despite higher caloric intake, drinkers are no more obese than nondrinkers
(9,10). Also, wh en alcohol is substituted in for carbohydrates (ie replaces carbs),
calorie for calorie, subjects tend to lose weight, indicating that they derive less
energy from alcohol than from food (summarized in 8).
o The mechanisms accounting for the apparent inefficiency in converting alcohol to
energy are complex and incompletely understood (11), but several mechanisms
have been proposed. For example, chronic drinking triggers an inefficient system of
alcohol metabolism, the microsomal ethanol-oxidizing system (MEOS) (1). Much of
the energy from MEOS-driven alcohol metabolism is lost as heat rather than used to
supply the body with energy.
-
Nb Dietary reference values are set to give a range that covers people two standard
deviations either side of the mean: ie for sat fats would be 2SD below the estimate average
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intake (=mean requirement) to avoid overfeeding half the population while for vitamins
would quote 2SD above mean requirement to avoid underfeeding half the population
o Iron (ferrin) deficiencies common in females, esp young
o Ca2+, Mg, riboflavin, Vit A commonly deficient in men and women – esp if young
and esp if women
o Niacin (=vitB3) is used to make nicotinamide: Deficiency of Niacin = “Pellagra”
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06/12/13: Digestion & Cell Transport: Julian Walters
Los (from booklet [are with respect to this lec and the
one immediately above]):
vant to intestinal absorption.
Notes:
-
Nutrient absorption
o Nutrient absorption results from a complex series of processes in the gastrointestinal tract:
 Digestive enzymes
 Salivary (amylase)
 Gastric
 Pancreatic (and biliary secretions)
 Intestinal
 Transport of the products through the mucosa
 Absorption:
 Brush-border
 Cytoplasmic
 Basolateral
 Post-mucosa
o Specific genes are expressed at various sites in the gastro-intestinal tract to produce
the proteins involved in digestion and transport
-
Gastric activity associated with eating is divided into three stages called the cephalic phase,
gastric phase, and intestinal phase, based on whether the stomach is being controlled by the
brain, by itself, or by the small intestine, respectively. These phases overlap and all three can
occur simultaneously
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o
Cephalic Phase
 The cephalic phase is the stage in which the stomach responds to the mere
sight, smell, taste, or thought of food. About 30% of total acid secretion
occurs BEFORE food enters the stomach. These sensory and mental inputs
converge on the hypothalamus, which relays signals to the medulla
oblongata. Vagus nerve fibers from the medulla stimulate the enteric
nervous system of the stomach which, in turn, stimulates gastric secretion.
 30% total HCL secretion
 Two mechanisms promote HCl secretion in the cephalic phase.
 The first mechanism is direct stimulation of the parietal cell by vagus
nerves, which release ACh.
 The second mechanism is indirect stimulation of the parietal cells by
gastrin. In the indirect path, vagus nerves release GRP at the G cells,
stimulating gastrin secretion; gastrin enters the circulation and
stimulates the parietal cells to secrete HCl.
 Chain of Events
 Sensory stimuli from food activate dorsal motor nucleus of vagus
nerve in the medulla (activating the parasympathetic nervous
system). Insulin induced hypoglycemia also stimulates the vagus
nerve. This results in four distinct physiological events.
o 1.) In the body of the stomach, the vagal postganglionic
muscarinic nerves release acetylcholine(ACh) which
stimulates parietal cell [stomach epithelial cells that secrete
gastric acid (HCl); located in glands found in the fundus] H+
secretion.
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o
o
o
2.) In the lamina propria [layer near the surface of mucous
membranes] of the body of the stomach the ACh released
from the vagal endings triggers histamine secretion from
ECL cells [Enterochromaffin-like cells]. Histamine then also
stimulates H+ secretion from parietal cells.
3.) In the antrum, peptidergic postganglionic
parasympathetic vagal neurons and other enteric nervous
system neurons release GRP [Gastrin-releasing peptide] [ie
GRP is the neurocrine - peptides that are synthesized in
neurons of the gastrointestinal tract and released following
an action potential – see table below] which stimulates
antral G cells to produce and release gastrin. Gastrin
stimulates acid secretion by directly stimulating parietal
cells as well as by promoting histamine secretion by ECL
cells. [gastrin also stimulates growth of the gastric mucosa –
“trophic effect”]
4.)In both the antrum and corpus [=body of stomach], the
vagus nerve inhibits D cells, thus reducing their release of
somatostatin [somatostatin acts on the acid-producing
parietal cells via G-coupled receptor to reduce secretion]
and reducing background inhibition of gastrin release.[2]
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[ie this diagram aggregates the cells; not all in same position so don’t all share any common gastric
glands]

Activation of Gastric Chief Cells
 A gastric chief cell is a cell in the stomach that releases pepsinogen,
gastric lipase [The only lipolytic enzyme in gastric secretion; cleaves
off a single fatty acid from triglycerides to generate diglycerides (DG)
and fatty acids; gastric lipase performs 20-30% of total triglyceride
digestion] and chymosin
 Gastric chief cells are primarily activated by ACh [ie vagus]. However
the decrease in pH caused by activation of parietal cells further
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activates gastric chief cells. Alternatively, acid in the duodenum can
stimulate S cells to secrete secretin which acts on an endocrine path
to activate gastric chief cells.
o These complementary pathways ensure that pepsinogen is
secreted only when the gastric pH is low enough to convert
it to pepsin.
o
Gastric Phase
 50-60% of total gastric acid secretion occurs during this phase.
 The gastric phase is a period in which swallowed food and semidigested
protein (peptides and amino acids) activate gastric activity. Ingested food
stimulates gastric activity in two ways:
 Distention (Stretching) Path
 by stretching the stomach and by gastric contents stimulating
receptors in the stomach. Stretch activates two reflexes: a short
reflex mediated through the myenteric nerve plexus, and a long
reflex mediated through the vagus nerves and brainstem.[1]
 1.) Vagovagal Reflex Distention activates an afferent pathway which
in turn stimulates efferent response from the dorsal nucleus of the
vagus nerve. Stimulation of acid secretion occurs as it does in the
cephalic phase.
o The first mechanism is direct stimulation of the parietal cell
by vagus nerves, which release ACh.
o The second mechanism is indirect stimulation of the parietal
cells by gastrin: vagus nerves release GRP at the G cells,
stimulating gastrin secretion; gastrin enters the circulation
and stimulates the parietal cells to secrete HCl.
 2.)Local ENS Pathway Activated ENS releases ACh stimulating
parietal cells to secrete acid.[2]
 In addition to these physiologic mechanisms, alcohol and caffeine
also stimulate gastric HCl secretion.
 Chemical Activation
 As dietary protein is digested, it breaks down into smaller peptides
and amino acids, which directly stimulate the G cells [ie those in the
stomach antrum] to secrete even more gastrin – a positive feedback
loop that accelerates protein digestion. As discussed earlier gastrin
stimulates by activating parietal cells and causing ECL to produce
histamine (histamine stimulates parietal cells to produce acid). Small
peptides also buffer stomach acid so the pH does not fall excessively
low.
 Gastric secretion is stimulated chiefly by three chemicals:
acetylcholine (ACh), histamine, and gastrin. ACh is secreted by
parasympathetic nerve fibers of both the short and long reflex
pathways. Histamine is a paracrine secretion from the
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
o
enteroendocrine cells in the gastric glands. Gastrin is a hormone
produced by enteroendocrine G cells in the pyloric glands.
 All three of these stimulate parietal cells to secrete hydrochloric acid
and intrinsic factor. The chief cells secrete pepsinogen in response
to gastrin and especially Ach, and ACh also stimulates mucus
secretion.
Inhibitory Pathway
 Low intragastric pH stimulates antral D cells to release somatostatin.
Somatostatin inhibits gastrin release from G cells. Reduced gastrin
secretion reduces acid secretion.
o Direct: In the direct pathway somatostatin binds to
receptors on parietal cells
o Indirect: In the indirect pathways (not shown in the figure),
somatostatin inhibits both histamine release from ECL cells
and gastrin release from G cells
Intestinal Phase
 5-10% of gastric secretion occurs during this phase.
 The intestinal phase is a stage in which the duodenum responds to arriving
chyme and moderates gastric activity through hormones and nervous
reflexes. The duodenum initially enhances gastric secretion, but soon
inhibits it.
 Duodenal Stimulation of Gastric Secretion
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

Presence of partially digested proteins and amino acids in the
duodenum acid secretion in the stomach is stimulated by three
methods.
o 1.) Peptones [a soluble protein formed in the early stage of
protein breakdown during digestion] stimulate duodenal G
Cells to secrete gastrin.
o 2.) Peptones stimulate an unknown endocrine cell to release
an additional humoral signal, "enterooxytonin".
o 3.) Amino Acids absorbed by the duodenum stimulate acid
secretion by unknown mechanisms.
Duodenal Inhibition of Gastric Secretion
 The acid and semi-digested fats in the duodenum trigger the
enterogastric reflex – the duodenum sends inhibitory signals to the
stomach by way of the enteric nervous system, and sends signals to
the medulla that (1) inhibit the vagal nuclei, thus reducing vagal
stimulation of the stomach, and (2) stimulate sympathetic neurons,
which send inhibitory signals to the stomach. Chyme also stimulates
duodenal enteroendocrine cells to release secretin and
cholecystokinin. They primarily stimulate the pancreas and gall
bladder, but also suppress gastric secretion and motility. The effect
of this is that gastrin secretion declines and the pyloric sphincter
contracts tightly to limit the admission of more chyme into the
duodenum. This gives the duodenum time to work on the chyme it
has already received before being loaded with more.[1] The
enteroendocrine cells also secrete glucose dependent insulinotropic
peptide. Originally called gastric-inhibitory peptide, it is no longer
thought to have a significant effect on the stomach, but to be more
concerned with stimulating insulin secretion in preparation for
processing the nutrients about to be absorbed by the small intestine
 [somatostatin signalling by D-cells in response to H+ also prob
occurs as on diagram above]
-
NB salivary glan (3x paired glands) role in digestion; not covered but pos in Los?
-
Lipid digestion
 Lipid digestion proceeds at a rapid pace in the duodenum, where lipid
emulsion droplets are attacked by pancreatic lipolytic enzymes that are
secreted at a maximum rate following cholecystokinin stimulation.
 The four lipolytic enzymes are lipase, colipase, phospholipase A2, and
cholesterol esterase.
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



Colipase is an obligate cofactor for lipase action. It is secreted by the
pancreas in an inactive form, procolipase, which is activated in the
intestinal lumen by trypsin. Colipase first attaches to a triglyceride
(TG) molecule on the surface of an emulsion droplet and serves as
an anchor for lipase, which then hydrolyzes ester bonds and
releases fatty acids (FA) and monoglycerate (MG)
 Phospholipase A2 acts on phospholipids [principally lecithin] to
produce lysolecithin (phosphatydl choline with one of its two FAs
removed (not further degraded) and fatty acids.
 Cholesterol esterase (CE) [=cholesterol ester hydrolase] hydrolyzes
fatty acid from cholesterol ester leaving free cholesterol.
The released lipolytic products are water insoluble and aggregate in
multilamellar vesicles at the boundary of the emulsion droplets.
Multilamellar vesicles gradually decrease in size as the lipolytic products are
transferred to and solubilized by bile acid micelles
Bile acids are amphipaths (ie, they have both hydrophilic and hydrophobic
properties). The structural formula of cholic acid, a primary bile acid, is
illustrated. The steriod nucleus is the hydrophobic part of the molecule, and
the three hydroxyl groups and one carboxylic group are the hydrophilic
counterparts. Bile acids form multimolecular aggregates called micelles
Mixed micelles (containing fat breakdown products) diffuse from the
intestinal lumen across to the brush-border membrane of the enterocytes;
the lipolytic products are taken up by diffusion across the lipid bilayer of the
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micelle and brush-border membrane [don’t worry about detail of this
mechanism]

The lipolytic products are resynthesized to triglycerides (TG), phospholipids,
and cholesterol esters in the endoplasmic reticulum (ER) of the
enterocytes [two different pathways can be used to achieve this – one used
in fasting state, the other in the post-absorptive state]
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

-
Protein digestion
o 8 aa’s are essential
o The proteolytic enzymes secreted by pancreatic acini upon cholecystokinin
stimulation are released as proenzymes and are activated in the duodenal lumen.
Three of the enzymes are endopeptidases (trypsinogen, chymotrypsinogen,
proelastase) and two are exopeptidases (procarboxypeptidase A and B). Trypsinogen
is activated to trypsin by enteropeptidase, which is a brush border peptidase.
Trypsin, in turn, further activates trypsinogen conversion and also activates all the
other proteolytic proenzymes
o
o
-
Apoproteins (A-I, A-IV, and B48) are synthesized in the endoplasmic
reticulum of the enterocyte and added to the lipid vesicles containing
triglycerides, phospholipids, and cholesterol ester; the result of combining
the molecules is Chylomicrons and VLDLs (ie prot/lipid combos) [nb prob
mainly chylomicrons – the VLDLs are more formed by the liver]
Nb release is to lymph (not direct to blood)
The oligopeptides and amino acids (AA) generated by intraluminal proteolysis
diffuse to the brush border of the enterocytes where oligopeptides must undergo
further hydrolysis to amino acids, dipeptides, and tripeptides before absorption can
take place. The presence of so many different peptidases is required because of the
chemical diversity of amino acids.
Transports facilitate the movement of both AAs and di/tri peptides into the cell;
further peptidases degrade the di/tri peptides so that only AAs exit on the
basolateral side
Carbohydrate Digestion
o Salivary amylase
o Pancreatic amylase
o Brush-border enzymes
 Sucrase
 Maltase
 Isomaltase
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o
o
o
 Lactase
 Trehalase
Transport:
 Active transport
 Facilitated diffusion
 Passive transport
Vectorial flow occurs: Different transport systems at apical and basolateral
membranes
 Energy requirements are present
Background pump info:
 1. Pumps: Direct ATP usage

2. Exchangers: use gradients at the site of the transporter (one favourable,
one unfavourable) often are secondary active transport with gradient of one
set up elsewhere allowing the driven transport of the other molecule

3. Cotransporters: use gradients at the site of the transporter (one
favourable, one unfavourable) often are secondary active transport with
gradient of one set up elsewhere allowing the driven transport of the other
molecule
 Eg Na/Bile salt cotransporters at terminal illeum

4. Channels: passive transport down grad
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-
Overview of transport network for NaCl transport:
o The movement of Na across the gut wall is what then leads to water proceeding to
exit too
o Na/K/2Cl transporter pumps Cl to cell so that it can exit on lumen side [further K
then enters as Na pumped out then the K moves out down its grad]
o Cyctic fibrosis affects the Cl lumen secretion channel
o The Na exit due to the Na/K pump sets up a grad for Na entry to drive Gluc entry
(gluc can then move out cell down its grad on the basolateral side)
o Electroneutral Na absorption can also occur (further down the gut) [a similar thing
occurs in the kidneys]; Cl and Na entry is driven by ions produced from carbonic
anhydrase with subsequent release of Na to basolateral side by the aforementioned
Na/K pump
-
Overview of transport network for CHO, proteins, lipids transport:
o Enzymes:
 Glucoamylase = gluc + gluc
 Lactase = gluc + gal
 Sucrose = gluc + Fructose
o Na/Gluc transporter can act on both gluc and gal despite the name
o Fructose enters separately: fructose channel
o Proteins: Na coupled or H+ coupled AA/di/tri transport
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o
Lipids: brush border transporter is “FAT” – fatty acid transporter; FABP (fatty acid
binding protein) is present in cytoplasm and is involved in the process
SGLT1 = Sodium-glucose transport protein1
09/12/13: The Intestinal Immune System: Dr Jonathan
Nolan
Los (from booklet):
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recognise conditions of normal and abnormal immune response in the GI tract
Notes:
-
The Intestinal Immune Challenge
o Surface area of GI tract >400sq.m
o Massive antigen load
 Resident flora >10^14 bacteria
 only 10^13 cells in human body
 Dietary antigens
 Exposure to pathogens
o State of restrained activation is required
o Tolerance vs. active immune response
-
Non-immune GI Tract Defences
o Secretions
 Salivary lysozyme
 Gastric acid: C. difficille prevalence rises when proton pump inhibitors are
used
 Pancreatic enzymes
 Bile acids
o Peristalsis
o Bacterial flora
 Niche occupation
 C. difficille prevalence rises when antibiotics are used: best known for
causing antibiotic-associated diarrhea (AAD)
 Commensal bac supress pathogens via competition for resources
-
Multiple Layers of Protection
o Epithelium
 Complex contribution to immunity
 Conditions and regulates immune responses
o Innate immunity
 Immediate
 No immune memory
 Complement, neutrophils, dendritic cells, macrophages, eosinophils,
basophils, mast cells, NK cells,
o Adaptive immunity
 Slower response (>96hrs)
 Improved quality of response upon re-encounter (memory)
 Lymphocytes (B, T, NKT)
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Nb the largest constellation of bacteria is in the colon: ie because those that survive
upstream immune defences are free to proliferate here and peristalsis is slower here
The Epithelial Barrier
o Mucus layer
 Secreted by Goblet cells
 Part adjacent to wall is the glycocalyx: firm layer of mucus
o Epithelial monolayer
 Tight junctions
 Antimicrobial peptides
 IgA secretion (shuttled from Lamina propria by B cells) [ie IgA is monomer in
blood then dimer after having traversed epithelial cells]
 [also: bac recog via PRRs without inflam and MHCII without costim]
 [also produce TGFB, retinoic acid and TSLP]
o Paneth Cells
 Bases of crypts
 Bacterial recognition (TLRs/NLRs)
 Secretion of defensins & lysozyme
Epithelial Cells can present antigen [not just passive; have been shown to have certain
limited immune functions]:
o Capture antigen by pinocytosis (not phagocytosis)
o Can express MHC class I, MHC class II, MIC-A, MIC-B, HLA-E, CD1d: involved in
activation of T cells
o But: Epithelial cells lack co-stimulatory molecules (CD80, 40) thus T cell stimulation
results in anergy or induction of regulatory T cells [ie classical T cell response does
not ensue]
o Professional APCs (esp DCs) more important
o Can express PRR – TLR, NOD2 [but fail to give the inflammatory response
characteristic of the action of these molecules when on other cell types]
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-
Healthy intestinal epithelium provides signals to DCs to promote tolerance in steady state
o Eg. Produce TSLP [Thymic stromal lymphopoietin:known to play an important role in
the maturation of T cell populations through activation of antigen presenting cells],
TGF-B, Retinoic Acid
-
General aspects of Innate Immunity:
o Pathogen recognition
 Pattern recognition receptors (PRR)
 Recognise pathogen associated molecular patterns (PAMPs) on pathogens
and commensals
 Toll-like receptors (TLRs)
 Cell surface and intracellular distribution
o Lipopolysaccharide (LPS)
o Peptidoglycan (PG)
o Flagellin
o RNA/DNA
 NOD-like receptors (NLRs)
 Intracellular receptors
o Subunits of LPS/PG
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o
o
o
o
o
o
o
Mycobacterial equivalents
Single strand viral DNA
Phagocytosis
Intracellular killing
Cytokine secretion
Amplification of immune response
Directs adaptive immunity
-
Myeloid Cell Activation
o Myeloid cells – monocyte origin
 Macrophages & Dendritic cells
o Recognition of microbial products activates cell
 Phagocytosis into vesicle
 Intracellular killing within phagosome (macrophage)
 Cytokine secretion
 Upregulate recruitment molecules (integrins)
 Attract other immune cells (chemokines)
 Activate other immune cells (cytokines)
 Activates markers on surface to initiate adaptive response
 MHC presentation of processed peptide to T-cells
 Co-stimulatory molecules (CD80, CD86)
-
Gut Antigen Presenting Cells
o Macrophages
o Dendritic cells
 primary, most potent APC
 Specific localisation in gut
 lamina propria
 Peyer’s patches
o Gut resident APCs more tolerogenic than APCs at other sites – favour tolerance
rather than active immune response
o Within the gut there is anatomical segregation of the expansive, tolerogenic lamina
propria (“Effector Sites”) and the more immunologically active secondary lymphoid
tissues (eg peyers patches) where responses are more strongly favoured (“Inductive
sites”)
o May receive tolerogenic signals from epithelium
•
Gut Associated Lymphoid Tissue
o Inductive sites:
o Organised lymphoid tissue
 Gut Associated Lymphoid Tissue (GALT) [are MALTs]
 Peyer’s patches
 Isolated lymphoid follicles
 Appendix
o Mesenteric lymph nodes
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o
Effector Sites
o Intra-epithelial and lamina propria lymphocytes
-
Transepithelial antigen capture
o Some subsets of DC can reach between enterocytes whilst maintaining epithelial
integrity – via expression of tight-junction proteins (Occludin and ZO-1)
o Permits sampling of luminal antigen without antigen entry across epithelial layer
o Specific subsets of DCs only
o Physiological role not known
-
3 Signals from APCs determine adaptive response
o APCs direct adaptive cells via 3 signals
o Peptide (within MHC-I or –II) to TCR
o Co-stimulatory signals (CD80/86)
 To CD28 (activating) or CTLA-4 (inhibitory)
o Cytokines
 Polarise to a T-cell subset
 IL12 – Th1
 IL4,-5,-13 – Th2
 IL1,-6,-21, TGFb – Th17
-
Peyer’s Patch Structure:
o M cells allow a form of sampling with antigen allowed to pass through holes at the
cells
o SED: sub epithelial dome contains DCs which interface between the antigens and the
lymphoid cells
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o
Segregated B and T cell areas exist at the patch (exit of activated cells is first out
through the lymph; will home to the necessary tissues)
-
Gut Homing
o Priming of naïve lymphocytes in gut (MLN or PP) by APCs imprints gut homing
o Up-regulate specific integrins on lymphocytes (α4β7, CCR7) [C-C chemokine
receptor type 7]
o Requires retinoic acid
o Following differentiation into mature effector T-cell, return to gut
o Integrins on T-cell recognise ligands on blood vessels in gut and enter tissues –
‘homing’
-
Lymphoid cell differentiation:
o Different T cells are generated depending on the threat experienced
o T cell roles and the cytokines the secrete are shown in the below diagrams:
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-
Imbalance of inflammatory cytokines in Crohn’s disease occurs:
o Inflammatory TH1/17 response favoured over a suppressive Treg response
o Detail in a later lec
-
B-cells: secretory IgA
o IgA
 Dimer
 Does not fix COMPLEMENT!
 Does not activate DCs
 Homeostatic/tolerising function?
o From plasma B cells in GIT
o Requires shuttling through epithelial layer to lumen
o >3g produced per day
o 90% specific for commensal bacteria
o prevents bacterial adhesion, aids clearance
-
Immune homeostasis in the healthy gut
o Sampling of commensals and food antigens
 Epithelial cells
 DCs
o Continuous protective signalling with commensal bacteria
o Separate inductive and effector sites for lymphocyte activation
-
Summary
o Specific anatomy of GI immune system
 GALT, PP, MLNs
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o
o
o
o
 Allows interaction of immune cells with flora & pathogens
Role of epithelial cells in regulation
Innate processes
Adaptive responses
Gut homing
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09/12/13: Inflammatory bowel disease: Professor Tim
Orchard
Los (from booklet):
learn about pathological processes that may be implicated in IBD
Notes:
-
IBD:
o
o
o
Common inflammatory disorders of the gut affecting young adults casuing chronic ill
health
There is no cure (except surgery in UC)
Treatment aims to minimise symptoms and prevent complications
-
Inflammatory bowel disease
o Chronic relapsing inflammtory disorders of the GI tract
o Normally taken to mean Ulcerative Colitis (UC) and Crohn’s disease
 Ulcerative Colitis
 Often associated with Amoebiasis [refers to infection caused by the
amoeba Entamoeba histolytica]: specifically this called Amoebic
colitis
 Crohn’s disease
 TB infection or Yersinia infection may be associated with Crohn's
disease
o Other inflammatory conditions of the gut include
 Microscopic colitis
 Behcet’s disease
 Systemic vasculitis
o Important to distinguish from infections
-
Ulcerative Colitis
o Starts in the rectum goes round the colon to a variable degree
o Often a very sharp demarcation
o Inflammation confined to the mucosa
o M=F
o Diagnosed in young adulthood -25-35 yrs
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o
o
2nd peak now appearing in 50-60’s
Commoner in NON-Smokers
 Often starts after giving up
-
Crohn’s disease
o Can affect anywhere from mouth to anus
o Discontinuous
 Skip lesions
o Inflammation is transmural [goes right the way through the gut wall (deeper than
UC)]
o Usually diagnosed in young adults but can occur in children and older people
o F>M (1.5:1)
o Commonest site is the terminal ileum (~40%)
o Extensive small bowel disease occurs but is rare (~5%)
-
UC vs Crohns [common to be asked differences in exam]
o UC
 Confined to colon
 Superficial [ie not as deep as Chron’s]
 Continuous; Always involves the rectum
 M=F
 NO granulomas [Granuloma: an inflammation found in many
diseases. It is a collection of macrophages]
 Fistulae [abnormal connection or passageway between two
epithelium-lined organs or vessels: may be between parts of gut or to
the skin] & strictures [narrowings] rare
 More common in non smokers
 UC: mixed Th1 and Th2 and Th17 response
 pANCA [perinuclear Anti-neutrophil cytoplasmic antibodies]: UC
 HLA, Th17 genes (IL23R), adhesion molecules
 Cancer
o Crohn’s
 Anywhere from mouth to anus; Often spares the rectum
 Full thickness (transmural)
 Patchy (skip lesions)
 F>M (1.5:1)
 Granulomas (~60%)
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





-
Fistulae & strictures common [due to the nature of how the disease
penetrates through the wall]
Rose thorn ulcers
CD: Th1 and Th17 type response
Anti-saccaromyces cervisiae (ASCA): Crohn’s
Autophagy genes, NOD2, HLA, Th17 genes (IL23R), adhesion
molecules
Cancer
Aetiology
o Complex: Combo of Susceptibility Genes and Environmental Factors:
 Genetic
 Autophagy genes: Crohn’s [ie failure of the initiation of autophagy]
 NOD2 (CARD15): terminal ileal Crohn’s
o Pattern recognition molecule [stimulates inflam by nfkb
signalling but mutaions to these genes reduces this action]
o Recognises common parts of bacteria (Muramyl Dipetide)
o Part of the innate immune system
o Similar to Toll-Like Receptors (TLRs)
o Plays an important role in initiating autophagy
o Changes to this gene which affect the reaction to gut
bacteria are associated with Crohn’s disease
 HLA: Colonic Crohn’s and UC
 Polymorphisms in the Th17 pathway: UC & CD [eg Il 23 receptor
mutations]
 Genes involved in maintaining mucosal integrity
o Adhesion molecules
 As of November 2012 there are 163 genes associated with IBD in
genome wide association studies
o 100 are associated with both UC and Crohn’s
o 30 with UC alone
o 33 with Crohn’s disease alone
o Most genes confer an increased risk of only 1.1-1.4
 Environmental
 Luminal bacteria [dysbiosis seen in IBD]
 Other theories
 Mycobacterium paratuberculosis [ie from cows]
 MMR??? [in fact there is no connection in big studies]
 Antibodies (unlikely to be pathogenic: these are prob just a symptom)
 Anti-saccaromyces cervisiae (ASCA): Crohn’s
 pANCA [perinuclear Anti-neutrophil cytoplasmic antibodies]: UC
o Disordered immune response to luminal bacteria
o There are differences between UC and Crohn’s:
 CD: Th1 and Th17 type response
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o
-
The Human Gut microbiome
o Rapidly colonises gut after birth
o Comprises more than 1014 organisms
o Weighs 1-2 kg
o More than 400 species
o An individuals flora is immunologically distinct
o Symbiotic relationship with host: Our Gut Flora Helps Prevent Colonisation by
Pathogens through competition contributing to pathogen death
o Probiotics [potential treatment]
o
-
 UC: mixed Th1 and Th2 and Th17 response
The innate immune system is also likely to play a key role in the pathogenesis [eg
poor functioning of neutrophils leading to disruptive adaptive immune response]
Dysbiosis in IBD:
 Higher concentrations of:
 Bacteroides
 Enterobacteriae
 Mucosal bacteria
 Unusual phylogenetic groups
 Lower concentrations of:
 Bifidobacteria
 Lactobacilli
 Clostridia species
 F. prauznitzii
 Lower diversity
Symptoms depend on the site of the inflammation
o Colitis
 Bleeding
 Mucus
 Urgency
 Diarrhoea
o Perianal
 Anal pain
 Leakage
 Difficulty passing stool
o Small bowel disease
 Abdominal pain
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o
 Weight loss
 Tiredness/lethargy
 Diarrhoea
 Abdominal mass [eg gut sticking together in crohn’s]
Other symptoms
 Arthritis
 Axial – Ankylosing Spondylitis [bamboo spine giving breathing
difficulties]
 Peripheral
 Skin
 Erythema nodosum
 Pyoderma gangrenosum
 Eyes
 Anterior uveitis
 Episcleritis/Iritis
 Liver
 PSC: Primary sclerosing cholangitis
 Autoimmune hepatitis
-
Diagnosis
o Colonoscopy and biopsy
o MRI / Small bowel follow through [radiologic examination involving barium of the
small intestine from the distal duodenum/duodenojejunal junction to the ileocecal
valve]
o Capsule endoscopy [disposable]
o Routine blood tests
 FBC
 ESR CRP
 U&Es Creat LFTs
o NB Stool cultures to exclude infection
-
IBD: Aims of management
o Establish the diagnosis
 Stool cultures
 Inflammatory markers
 Consider rectal biopsy
 Differentials include
 Infection (esp amoebic and yersinia)
 Appendicitis
 Bacterial overgrowth
 Bile salt malabsorption
o Induce clinical remission
 Acute severe disease
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



Systemically unwell
Diarrhoea [if salts not removed the water will not exit]
UC: Truelove and Witts Criteria
o BO>x6/day
o Tachycardia
o Pyrexia >37.5
o Anaemia
 Admit the patient
 AXR [abdominal x-ray]
 Is there colonic dilatation?
 Is there evidence of perforation?
 If either is YES – Call the surgeons!
 In the short term
o Resuscitate the patient
o iv steroids (hydrocortisone)
o Consider iv antibiotics
 Longer term:
o Iv hydrocortisone
o Rectal hydrocortisone suitable for topical (ie via anus)
application: suitable for left sided colitis
o Monitor clinical status & FBC ESR CRP daily
o If no better after 3-4 days consider Ciclosporin:
 Immunosuppressant: lower the activity of T cells
and their immune response
 Used in severe UC, when there is poor response to
steroids
 Prevents the requirement for urgent surgery in 60%
 Given intravenously initially then orally until steroids
are tapered off
 Azathioprine should be added in
 Watch for opportunistic infections
 Side effects – Hypertension, renal failure, gum
hypertrophy, hyperaesthesia
o If no better after 5-7 days consider colectomy
o If there is any acute deterioration consider colectomy
o “It is better to send the patient home without a colon than
to bury them with it”
Active disease
 Overview [mix of UC and CD treatments]:
o 5-ASA: (=Mesalazine) (or Sulphasalazine from which it is a
metabolite), topically/oral:
 bowel specific anti-inflam drug
o Steroids – Orally, topically, intravenously
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

Immunosuppresants – Azathioprine, Methotrexate (mild
immunosuppressive, antiproliferative, anti-inflammatory),
ciclosporin
o Immune modulators – anti-TNFa,
o Other Treatments:
 Methotrexate
 Effective in 40% of steroid dependent
Crohn’s patients
 Side effects- nausea, rash, mucositis &
hepatic fibrosis
 Budesonide (steroid)
 Absorbed in ileum and right colon
 90% metabolised in 1st pass through liver
 Reduced systemic side effects
 Probiotics
 Worms!
Crohn’s Active disease:
o 5ASA – not effective
o Steroid therapy oral/topical/iv
o Diet – Elemental [completely pre-digested material: Fas,
AAs, etc] / Polymeric [semi-predigested]
o Azathioprine for steroid resistant/dependent disease or
fistulae
o Infliximab in very difficult disease:
 Chimeric monoclonal antibody to TNFa
 60-80% response in patients with steroid refractory
Crohn’s disease
 Up to 55% of Crohn’s fistulae achieved closure
 Given as an infusion over 2 hours
 Response for 8-12 weeks
 Longer duration of response in patients on
Azathioprine
 Very expensive!
o Surgery for difficult or stricturing disease
UC Active disease:
o Mild to moderate
 5 ASA therapy (= 5-aminosalicylic acid = Mesalazine
= Sulfasalazine)
 Use topically if disease left sided
 Enemas, foams or suppositories
 Oral dose as high as can be tolerated to 4g daily
 If fails consider dual topical/oral therapy with
steroid and 5ASA
o Moderate to severe
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o
o
o
Oral prednisolone [type of steroid] starting at 40mg
daily and reducing
 20-30% do not respond
 If fails admit for iv therapy or consider Azathioprine
and Mercaptopurine (6-MP) [both are
immunosupressives]:
 for steroid resistant/dependent disease or
fistulae
 Maximal effect seen after 3 months
treatment but continuing improvement
seen for 6 months
 2-2.5mg/kg daily dose
 Long term treatment is probably safe
 Regular monitoring of WBC and LFT’s
required
 Side effects: pancreatitis, hepatitis, fever,
rash, neutropenia
Surgery is an option for persistently troublesome disease
 Subtotal Colectomy
 Followed by completion proctectomy
[remove the rectum] or Ileal pouch anal
anastomosis [surgically constructed internal
reservoir situated where the rectum would
normally be and formed from small
intestine material]
 End ileostomy [surgical procedure to link
the end of the small intestine to an opening
in the abdomen (stoma)] vs pouch
o Patient preference is important
o Decreased fecundability in female
pouch patients
o 40-50% prevalence of pouchitis
o BO 5-7/day
o Good cosmetic result
Alleviate symptoms
Maintain remission
 Maintaining remission - UC
 5-ASA – Mesalazine, Sulfasalazine
 Reduces relapse rate by aprox. 60%
 In persistently or recurrently active disease consider Azathioprine
 Maintaining remission – Crohn’s
 5ASA may help surgically induced remission
o Effect is small and very little help in medically induced
remission
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
Very little trial data
o Consider Azathiorpine in high risk patients
o Infliximab in difficult patients
-
Treatment options
o Factors influencing treatment:
 Severity of disease
 Site of disease
 Small bowel
 Large bowel
 Disease extent
 Patient preference: Informed discussion with patient
o Use a drug
 That is clinically effective
 Which the patient can tolerate
 That causes the minimum side effects
-
Long term issues
o Malignancy [both UC and CD are associated with an increased risk of cancer]
 High risk groups
 Extensive disease
 PSC patients with colitis
 Colonoscopic surveillance in high risk patients from 8-10 years after
diagnosis
 Colonoscopy every 2 years with biopsies
 Looking for dysplasia
 Prophylactic colectomy in patients with dysplasia
o
o
Stricturing
Fistulisation
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09/12/13: Gastric Acid Secretion: Dr Kevin Murphy
Los (from booklet):
•
•
•
Los (from slides):
•
•
•
•
Describe the basic structure and function of the stomach.
List the different cell types found in the stomach epithelium and their roles.
Describe the mechanism by which gastric acid is secreted.
Explain how gastric acid secretion is regulated.
Notes:
-
The stomach
o Functions: Break food down into smaller particles (due to acid & pepsin); mix and
hold food and release at a controlled rate into duodenum; kill parasites & certain
bacteria
o Invaginates into mucosa with blind ended tubular glands
o The four major components of gastric juice are hydrochloric acid (HCl), pepsinogen,
intrinsic factor, and mucus.
 Together, HCl and pepsinogen initiate the process of protein digestion.
 Intrinsic factor is required for the absorption of vitamin B12 in the ileum,
and it is the only essential component of gastric juice.
 Mucus protects the gastric mucosa from the corrosive action of HCl and also
lubricates the gastric contents. [should any pepsin penetrate the mucus, it is
inactivated in the relatively alkaline (high HCO3 environment]:
 peptic ulcer disease is due to an imbalance of mucus level vs HCL
level eg due to H. pylori, NSAIDs, stress, smoking, alcohol influence
o Gastric ulcers: mucosal barrier is defective. A major
causative factor in gastric ulcers is the gram-negative
bacterium H. pylori. Surprisingly, in persons with gastric
ulcers, net H secretory rates are lower than normal
because some of the secreted H leaks into the
damaged mucosa. In gastric ulcer disease, the secretion
o
rate of gastrin is increased as a result of the reduced net H
secretion. (Recall that gastrin secretion is inhibited by H)
Duodenal ulcers: more common than gastric ulcers and form
because H secretory rates are higher than normal. H. pylori
colonizes gastric mucus but has key role here too:
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
o
o
o
o
1. inhibit somatostatin secretion from D cells in the
gastric antrum. Since somatostatin normally inhibits
gastrin secretion from G cells, “inhibition of
inhibition” results in increased gastrin secretion,
which leads to increased H secretion by gastric
parietal cells. In this way, there is an increased H
load delivered to the duodenum.
 2. The gastric H. pylori infection spreads to the
duodenum and inhibits duodenal HCO3- secretion.
Zollinger-Ellison syndrome (gastrinoma): a tumor (usually in
the pancreas) secretes large quantities of gastrin. The high
levels of gastrin have two direct effects: increased H
secretion by parietal cells and increased parietal cell mass.
Delivery of increased amounts of H to the duodenum gives
ulcer and also causes steatorrhea because low duodenal pH
inactivates the pancreatic lipases necessary for fat digestion.
Different regions:
 Cardia:
 Mucus only
 Body & Fundus:
 Mucus, HCl, pepsinogen
 Antrum:
 Mucus and Gastrin
Absorption in the stomach
 Limited physiological absorptive function
 Very few substances absorbed in the stomach
 Almost impermeable to water.
 Alcohol does transfer across here [therefore fast acting]
 Aspirin: can causes ulcers, as reduces prostaglandin synthesis, thus reducing
inflammatory response to injury and reducing cell turnover.
Muscle:
 Small and large intestine have 2 layers smooth muscle - Circular and
Longitudinal
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

Stomach has 3rd smooth muscle layer: “Oblique”: on the inside of the other
two. Powerful contractions to grind food into small particles before entry
into duodenum (larger particles retained)
Nb the whole of the stomach actually has a further muscle layer: muscularis
mucosae [thin layer of smooth muscle found in most parts of the
gastrointestinal tract, located outside the lamina propria mucosae and
separating it from the submucosa: throws the mucosa into folds]
The thickness of the muscle wall increases from the proximal stomach to
the distal stomach.
 The orad region is proximal, contains the fundus and the proximal
portion of the body, and is thin walled.
o Its function is to receive the food bolus: Distention of the
lower esophagus by food produces relaxation of the lower
esophageal sphincter and, simultaneously, relaxation of the
orad stomach, called receptive relaxation. [a vagovagal
reflex (involving VIP)]
 The caudad region is distal, contains the distal portion of the body
and the antrum, and is thick walled to generate much stronger
contractions than the orad region.
o Contractions of the caudad region mix/digest the food and
propel it into the small intestine.
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o
o
Mucosa of Stomach
 Simple columnar epithelium throughout (single layer of cells)
 Epithelium secretes protecting mucus-HCO3- blanket
 Blind-ending simple glands throughout (called crypts in intestine)
 Glands secrete into pits in stomach [ie the mucus secreting cells are in the
neck of the glands and secrete to the pits which are the wider upper parts of
the glands]
 No villi (only in small intestine only)
Gastric Glands:
 In gastric body and fundus [prob inc pyloric region too; is a general term]
 Proliferative neck region
 Mucus-secreting pit [see below image]: protects stomach lining from HCl
and Pepsin:
 Surface mucus cells of gastric pits secrete adherent blanket of
mucus
 Mucus contains glycoproteins called mucins. Carbohydrate section
prevents pepsin from digesting the protein.
 Mucus traps alkaline fluid released by epithelial (non-parietal) cells.
 Forms protective barrier.
 1. Gastric glands with G cells and mucus cells [pyloric glands]
 At antrum of the stomach
 configured similar to the oxyntic glands but with deeper pits
 The G cells secrete gastrin, not into the pyloric ducts but into the
circulation. [will then act on parietal cells]
 The mucous neck cells secrete mucus, HCO3. Mucus and HCO3 have
a protective, neutralizing effect on the gastric mucosa.
 2. Gastric glands with Chief and Parietal Cells [gastric oxyntic glands: parietal
= oxyntic]
 Chief Cell
o Gastric Chief Cell
o Protein-secreting epithelial cell
o Abundant RER
o Golgi packaging and modifying for export
o Masses of apical secretion granules
o Secretes pepsinogen [initial activation is by HCl to pepsin as
in image below; then positive feedback: don’t confuse with
trypsin activation]
 Parietal cell:
o Many mitochondria to provide energy for membrane
pumps/exchangers
o Cytoplasmic tubulovesicles and Internal canaliculi
 Canaliculi are deep infoldings which serve to
increase the surface area for secretion. The
membrane of parietal cells is dynamic; the numbers
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o
o
o
o
of canaliculi rise and fall according to secretory
need. This is accomplished by the fusion of
canalicular precursors, or "tubulovesicles" [contain
many of the H+/K-ATPase ("proton pumps")], with
the membrane to increase surface area, and the
reciprocal endocytosis of the canaliculi (reforming
the tubulovesicles) to decrease it.
Rich in carbonic anhydrase
Secrete <1 M hydrochloric acid
Secrete Intrinsic factor and R protein (important in B12
absorption)
Secretion stimulated by: [“potentiation” occurs: multiple
effects greater than their sum]
 Vagus ACh
 Histamine
 Gastrin
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Mechanism of gastric acid secretion
o Intracellular [Na+] & [Cl-] low compared to extracellular fluid
o Intracellular [K+] high compared to extracellular fluid
o Carbonic anhydrase separate H+ and HCO3- ions; K+ pumped in is allowed to exit on
lumen side (potassium leak channels) to facilitate H+/K+ exchange (ATP has to be
used here) [H+ released to lumen]; Cl- exchanged with HCO3- at serosal membrane
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o
o
-
(blood side) with subsequent exit of Cl- by unclear means (possibly ATPase) [HCO3released to blood]
H+/K+ ATPase pump present in tubulovesicle membranes [H+, K+-ATPase localised to
tubulovesicles and canaliculi: not on blood side etc]; Intercalated into canaliculi on
activation - creates 106 fold H+ gradient
H+ pump inhibited by omeprazole (Losec) [The H+K+ATPase is a primary active
process that transports H+ and K+against their electrochemical gradients (uphill).
H+K+ATPase is inhibited by the drug omeprazole, which is used in the treatment of
ulcers to reduce H secretion]
Control of acid secretion
o Negative feedback control
o Stimulus - Response - Effect - Feedback reduces stimulus
o To understand regulation, need to identify what initiates, sustains and then
terminates a process
 Neural control - intrinsic and extrinsic
 Humoral control - secreted by gut (eg: secretin - pancreas) and secreted by
other glands (eg: ne from adrenal cortex - salt uptake in colon)
 Paracrine control - local “hormones” - (eg: histamine in stomach)
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
o
o
o
o
Regulate absorption, secretion, motility and blood flow in an integrated
manner
Control of Parietal Cell
 Parietal cell has receptors for Acetylcholine (Ach - neurotransmitter), Gastrin
(G-hormone) and Histamine (H -paracrine).
 All these can stimulate acid secretion
 Ach from Vagus nerve: direct effect, also stimulates gastrin and histamine
release
 Gastrin from G-cell in gastric antrum: direct effect and release histamine
 Histamine from ECL- cells in gastric mucosa: direct effect
 Response to the 3 stimuli is greater than the simple algebraic sum of their
individual effects - Amplification
 Control more complex than shown. Various inhibitory mechanisms
modify/oppose stimulation. Eg: Somatostatin (peptide hormone from Dcells in gastric antrum) can inhibit gastrin release
Cephalic phase - neural reflex in response to sight, smell and taste food. Stimulates
before food enters stomach.
 Initiation - Vagus reflex starts acid before food enters stomach by both
direct and indirect stimulation
Gastric phase – paracrine and hormonal stimulation due to histamine and gastrin
 Maintenance - Stretch of stomach wall by contents causes further release
of gastrin (reflex involving intrinsic nerves)
Intestinal phase - products digestion in duodenum may influence acid secretion + or
 Ie at first is stimulatory with gastrin secretion occurring in response to the
gastric secretion but if too much gastric secretion builds up and the pH
decreases and the intestine requires time to digest the food then inhibitory
signalling via somatostatin from D-cells and nervous reflexes occurs.
 Reduced gastrin secretion follows due to reduced G-cell stimulation
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

[PYY also is secreted (is mainly secreted by cells of the ileum and colon) to
reduce appetite]
Termination -Cessation vagal stimulants (food), emptying stomach reduces
wall stretch- reflexes decrease. Other inhibitory mechanisms from small
intestine [as above]
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09/12/13: Gastrointestinal hormones and appetite
control: Kevin Murphy
Los (from booklet):
•
•
•
Los (from slides):
1)
2)
3)
4)
5)
The role of gut hormones in regulating GI function.
The gut hormones responsible for regulating stomach acid and pancreatic juice secretions.
The major hypothalamic circuits regulating appetite.
The role of leptin in the regulation of body weight.
How gut hormones can influence short term appetite.
Notes:
-
1) Gut hormones.
o Have roles in:
 i) Acid secretion
 ii) Pancreatic secretion
o
o
o
o
o
o
- Produced by endocrine cells in the mucosa or submucosa of the stomach, intestine
and pancreas
- Act on secretory cells located in the wall of the GI tract, pancreas and liver to alter
the rate or the composition their secretions
- Other hormones act on smooth muscle cells in particular segments of the GI tract
and GI sphincters or on the musculature of the gall bladder.
- Can act as paracrine or neurocrine factors.
Stomach:
 Gastrin
 Ghrelin
 Somatostatin
 [also histamine, but is not a hormone as only local effects]
Pancreas:
 Insulin
 Glucagon
 Somatostatin
 Pancreatic Polypeptide
 Ghrelin
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o
o
o
o
o
Duodenum:
 Secretin
 CCK
 Somatostatin
 GIP (gastric inhibitory peptide) [also at jejenum]
 secreted by K cells of the duodenal and jejunal mucosa.
 the only gastrointestinal hormone that is secreted in response to all
three types of nutrients: glucose, amino acids, and fatty acids
 The major physiologic action of GIP is stimulation of insulin
secretion by the pancreatic b cells. This action explains the
observation that an oral glucose load is utilized by cells more rapidly
than an equivalent intravenous glucose load.
 The other action of GIP is inhibition of gastric H+ secretion.
 Homology with secretin so at pharmacological levels will lead to
most of the actions of secretin too
Illeum:
 PYY
 GLP-1
 GLP-2
 Oxyntomodulin
 Neurotensin
 Somatostatin
Colon:
 PYY
 GLP1
 Oxyntomodulin
 Neurotensin
 Somatostatin
Gastrin;
 Gastrin stimulates gastric acid secretion.
Somatostatin
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
o
o
Synthesized in endocrine D-cells of the gastric and small and large intestinal
mucosa [ie throughout GIT as above], pancreas (also hypothalamus).
 Somatostatin is a universal inhibitor
 Inhibition of: gastric secretion, motility, intestinal and pancreatic
secretions, release of gut hormones, intestinal nutrient and
electrolyte transport, growth and proliferation.
 Analogues used to treat neuroendocrine tumours: eg Octreotide
Secretin
 - Major stimulus is the presence of acid in the duodenum (pH falls below
4.5).
 - Stimulates pancreatic bicarbonate secretion.
 - High concentrations: inhibition of gastric acid and gastric emptying.
Cholecystokinin (CCK)
 Secreted by cells most densely located in the small intestine.
 Release stimulated by fat and peptides in the upper small intestine.
 CCK:
 - stimulates pancreatic enzyme release
 - delays gastric emptying
 - stimulates gallbladder contraction.
 - decreases food intake and meal size.
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2) Hypothalamic circuits controlling body weight
o Hypothalamus structure: [as on the coronal image of base of brain below]
 PARAVENTRICULAR NUCLEUS
 Involved in pituitary regulation / Communicates info from
hypothalamus to pituitary
 LATERAL HYPOTHALAMUS
 VENTROMEDIAL HYPOTHALAMUS
 ARCUATE NUCLEUS
 Sits in the circle of Willis
 Key brain area involved in the regulation of food intake.
 Incomplete blood brain barrier: allows access to peripheral
hormones.
o Ie certain areas of the brain such as this are not isolated;
allows for sensing of blood signals
o = circumventricular organs: refers to such brain structures
lacking normal blood brain barrier
 Integrates peripheral and central feeding signals.
 Two neuronal populations:
o Stimulatory (NPY/Agrp neuron)
o Inhibitory (POMC neuron)
[note that these neuronal populations are mutually
exclusive: neurons are either one or the other]
[note the cell bodies of these neurons are present at these
regions but the axons spread throughout brain to act as
illustrated below]
 Other brain regions involved in appetite control:
o Signals from higher centres.
o Signals from amygdala- emotion, memory.
o Vagal nerves signal to brain stem (nucleus of the solitary
tract), transmitted to hypothalamus.
rd
 [also, 3 VENTRICLE present at this region]
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3) Peripheral signals of body homeostasis
o i) Long Term- Leptin
 Adipostat Mechanism
 Circulating hormone (leptin) is produced by fat: Made by adipocytes
in white adipose tissue.
 Leptin Circulates in plasma and then acts upon the hypothalamus
[activates POMC neurones] [Hypothalamus senses the
concentration of hormone] thereby regulating appetite (intake) and
thermogenesis (expenditure). [Hypothalamus then alters
neuropeptides to increase or decrease food intake]
 Leptin
o Low when low body fat
o High when high body fat
o Hormone that decreases food intake and increases
thermogenesis.
 Perhaps a problem with the regulation of the adipostat mechanism
leads to obesity?
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o
o
ob/ob Mouse lacks ob gene which encodes leptin and the
mouse is fat. Replacement in the ob/ob mouse decreases
weight. 3 ways in which leptin regulatory loop could lead to
obesity: option “C” was found to be true
 A) Failure to produce leptin.
 This is only true in very rare cases of ob/ob
in humans [same effect as mice (always very
hungry)]: here leptin replacement is
effective
 Absence of leptin has profound effects,
including hyperphagia, lowered energy
expenditure, sterility.
 However, leptin is an anti-starvation
hormone rather than anti-obesity hormone:
is a Hormone of Absence: its ‘action’ is
when absent
 Presence of leptin is a signal to the CNS that
system has sufficient fat reserves for normal
functioning- but high leptin has little effect.
 B) Inappropriately low leptin secretion for a given
fat mass.
 C) Leptin resistance.
 TRUE: Obese rodents and humans have high
plasma leptin levels; Leptin does not
decrease body weight in obese humans.
 Leptin circulates in plasma in concentrations
proportional to fat mass.
 Fat humans have high leptin.
 Hormone is present but doesn’t signal
effectively.
 obesity may be due to leptin resistance (or
may just be a symptom of it)
ii) Short term – Ghrelin, PYY
 You feel less hungry after a meal not so much because of lack of bulk in
stomach [will still feel hungry if inflate balloon in stomach] or Nutrients in
circulation [still feel hungry when on a drip] but instead because of
Hormonal Signalling from the gut
 Ghrelin from stomach
 Ghrelin
 Ghrelin is a gastric hormone
 28 amino acid peptide with octanyl at position 3
 High fasting, falls after eating
 At the arcuate nucleus:
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
o Stimulates NPY/Agrp neurons.
o Inhibits POMC neurons.
o Increases appetite
PYY from small and large intestine
 36 amino acid peptide with a tyrosine at both ends.
 Released from the gut into the circulation after a meal as PYY3-36 [a
specific form of the peptide]
 At the arcuate nucleus:
o

-
Inhibits NPY release [a different form of PYY: increases food
intake]
o Stimulates POMC neurons.
o Decreases appetite.
These short term hormones are a potential obesity therapy:
 Gut hormones may represent a novel treatment for obesity.
 Target only relevant circuits.
 Released daily without ‘side effects’.
 Exert effects throughout life without escape.
Obesity is Associated with Comorbidities
o Depression
o Stroke
o Sleep apnoea
o Myocardial Infarction
o Hypertension
o Diabetes
o Bowel cancer
o Osteoarthritis
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o
o
Peripheral
vascular disease
Gout
-
Thrifty Gene hypothesis: [as to why obesity exists]: genes "rendered detrimental by
'progress'"
o Evolutionarily sensible to put on weight.
o Thin humans didn’t survive famines, so didn’t pass their genes on to modern
humans. Ie argues obesity would have been selected for: would allow them to fatten
more quickly during times of abundance
o In modern context of little exercise and high calorie intake, humans readily become
obese.
o Evidence? Populations historically prone to starvation become most obese when
exposed to Western diet and sedentary life-style (e.g. Pima Indians, Pacific
Islanders).
o [Perhaps as societies developed agriculture (Fertile Crescent) and starvation less of a
threat, obesity began to be selected against (is contrary to the below)]
-
Adaptive drift hypothesis: [argues that predation would of selected against obesity and that
current obesity is due to drift (neither positive or negative selection) following the removal
of the threat of predation]
o 10-20K yrs ago, humans learned to defend themselves against predators thus
obesity no longer selected against.
o Putting on body fat then a neutral change (genetic drift). However, unlikely because
of circumstances to put on much weight.
o In current context, the inheritors of these genes become obese.
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09/12/13: Genetic and environmental effects on
development of colonic neoplasia: Horace Williams
Los (from booklet):
•
•
•
•
factors that influence neoplasia
Notes:
-
Colorectal Cancer
o Second commonest cancer/30,000 new cases/year
o Major economic health burden
o 50% of those affected will die from their disease
o Prognosis depends on stage of disease
o Incidence increases with age
o Lifetime risk: 1 in 20
o Env Risk factors:
 Alcohol
 Acromegaly
 Smoking
 Red meat
 Left sided tumours
 Cholecystectomy
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o
o
 Right sided tumours
 Pelvic radiation
Env Protective factors
 Physical activity
 Diet
 High fruit/vegetables
 Low red meat
 Folic acid
 Possibly Fibre
 NSAID’s [non-steroidal anti-inflam drugs]
 HRT (hormone replacement therapy vs menopause)
 Statins
Genetic Factors:
 Genetic: lowest percentage: known responsible genes
 Familial adenomatous polyposis: FAP
o 100% of such patients get the disease
 Hereditary non polyposis colorectal cancer: HNPCC
o 50-80% of such patients get the disease
 Familial: second highest percent of total: Increased risk but exact genes not
known
 One 1st degree relative
8%
st
 Two 1 degree relative
20-25%
st
 One 1 degree relative <45yrs 20-25%
 Sporadic: highest percentage of cases
 Risk on average is 5%
Genetic
Familial
Sporadic
-
Development:
o First is adenomas:
 Seen in similar distribution
 Adenomas precede cancers by 10-15yrs
 Animal models
 Tumours seen arising in adenomatous tissue
 Removing adenomas decreases incidence of cancer
 Co-exist in same patient [ie a patient can have both]
o Screening:
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

o
Colorectal cancer provides an ideal target for screening because of the long
premalignant adenoma stage which can be easily identified endoscopically.
[nb In addition, accompanying these phenotypic changes are a variety of
genetic abnormalities typical of cancers: loss of APC then gain of Kras then
loss of DCC then loss of p53]
Genetic Changes
 Oncogenes (gaining function)
 Behave in a dominant manner
 Tumour suppressor genes (losing function)
 Behave in a recessive manner
 Pathways to CRC
 Chromosomal Instability (CIN)
o Most common mechanism for genetic defects in CRC
o Causes physical loss of wild-type copy of tumour suppressor
genes
 APC 5q = chr5 with APC loss due to chr instab
 P53: 17p = chr17 with p53 loss due to chr instability
 DCC, SMAD2&4
o Two Hit Model: GERMLINE mutation for one copy, then a
SOMATIC mutation later.
o Ie “Loss of Heterozygosity” occurs
 Microsatellite Instability - High (“MSI-H”)
o The condition of genetic hypermutability that results from
impaired DNA Mismatch Repair
o Microsatellites (repeating units of 1-6 bps)
become unstable.
o

Replication error results in a frameshift mutation
inactivating TSGs in HNPCC:
 defective DNA mismatch repair: Mismatch repair
genes (Repair of base pair errors in DNA replication)
are Defective in HNPCC
 Such mismatches arising from the above scenario
are therefore not repaired hMSH2, hPMS1, hPMS2,
hMSH6, hMLH3, MLH1
Methylation
o CpG Island hyperMethylation Phenotype (CIMP):
 Aberrant methylation of cytosine
results in gene silencing


Normally occurs in repetitive sequences outside of
exons
CRC phenotype less methylation but increased in
CpG promoter islands
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

Observed in 15% of sporadic CRC
May occur in alleles prior to conception (Loss Of
Imprinting)
-
Hereditary Non-Polyposis Coli (= HNPCC = Lynch Syndrome)
o Inherited mutation in mismatch repair gene
o 3-5% CRC  30-90% risk of CRC
o Associated malignancies
 (Ovary, Endometrial, Small bowel, Stomach, Hepatobiliary, Ureteric)
o Biennial colonoscopy [every two years]
o Associated screening
o Vs sporadic colorectal cancer (CRC), HNPCC has:
 More right sided lesions
 Increased mucinous component
 Lymphocytic infiltration
 Poorly differentiated
 Better prognosis
-
MYH-Associated Polyposis
o Germline mutation in MYH gene
o Protein repairs oxidative damage to guanine
o Often associated with sporadic APC mutation
o Recessive inherited CRC
o Phenotype identical to FAP
o Carriers may be predisposed to CRC
o Implications for screening FAP families
-
Familial Adenomatous Polyposis
o 1% of CRC
o Risk of CRC 100%
o Surveillance at puberty
o Colectomy if affected
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APC:
o
o
o
o
o
o
o
Inherited defect present in FAP [ie genetic]
Common in sporadic CRC to have the mutation too
APC and familial CRC:
 Ashkenazi Jews
 Germline mutation at codon 1307 in APC
 6% background population
 28% in those with a family history of CRC
 Predisposes to CRC but risk much less than FAP
o
o
o
o
o
o
Most common mutation in human cancer
50-70% of CRC’s
Late event in CRC development
Activated during cell stress
Acts as transcriptional factor for growth inhibitory genes
Induces apoptosis/cell repair
p53
SMAD
o
o
o
o
o
-
K-ras
o
o
o
o
o
o
-
Chromosome 5q21
Mutations result in truncated APC protein
Results in accumulation of ß catenin [ie when mutated  cancer]
Resists apoptosis by binding and activating transcription T-cell factor
On chromosome 18q
Mutations result in inactivation of TGF β signalling
Late event in adenoma carcinoma sequence
SMAD2
 Also associated with pancreatic cancer
SMAD4
 Also seen in juvenile polyposis
Most important oncogene in CRC development
Involved in cell signalling
50% adenomas and CRC
Not confined to dysplastic lesions
 ACF
 Hyperplastic polyps
Early event in CRC development
BRAF mutations have similar effect
Serrated Adenomas
o Histologically hyperplastic/adenomatous
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o
o
o
o
o
37 % give "significant" dysplasia [an abnormality of development]
11% are foci of intramucosal carcinoma
Increased malignant potential
Likely precursor to sporadic MSI-H colon cancer
High incidence of BRAF mutations (cf K-ras in HNPCC)
-
Growth Factor Pathways
o Prostaglandin Signalling
 COX 2 (present in 67% of adenomas)
 COX-2 inhibition [ie NSAIDs] prevents new adenomas and mediates
regression of established adenomas
 15-Prostaglandin dehydrogenase (80% of adenomas)
o Epidermal Growth Factor [EGF]
 Cetuximab counters this
o Vascular Endothelial Growth Factor [vEGF]
 Bevacizumab counters this
-
Clinical importance Genetic Changes
o Predictive
 K-Ras – No response to Cetuximab
 BRAF – No response to Cetuximab
 Sporadic mismatch repair – no response to 5FU but good response to
irinotecan
o Prognosis
 APC - FAP
 Mismatch repair – HNPCC
 Sporadic microsatelite instability – good prognosis
 18q LOH – poor prognosis
o Flat Adenomas
 May represent alternative pathway
 Rapid progression to CRC
 P53 earlier [presumably means p53 change has already occurred]
 May mean are more advanced
o Inflammatory Bowel Disease
 Up to x15 increased risk
 UC = Crohn’s in therms of risk
 Dependent on:
 extent of disease and
 length of diagnosis
 Disease Activity
 Sclerosing cholangitis is an added risk factor
 Genetics of IBD CRC
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o
-
 The mean age 10-20 yrs earlier
 K-Ras mutations less common and occur later
 LOH for p53 occurs earlier than in sporadic cancers
 Dysplasia in UC can be found at distant sites
 Abnormalities of the p53 found in non dysplastic mucosa
 i.e More of a field effect
Acromegaly
 Regular screening starting from 40 yrs
 Frequency dependent on findings at original colonoscopy
 Adenoma or increased IGF-1 levels repeat every 3 years
 Otherwise every 5 years
 Needs total colonoscopy (although may be difficult!)
Conclusions
o Development of CRC dependent on genetic and environmental factors
o Understanding of pathogenesis directs clinical practice
o May lead to a reduction in incidence of CRC
10/12/13: Acute Liver failure: Harry Antoniades
Los (from booklet):
options
Notes:
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Acute Liver failure
o Definition: Encephalopathy in a patient with NO previous liver disease
o Subtypes: hyperacute, acute, subacute:
o
Aetiology
 Viral hepatitis
 Hepatitis A, B, D E, [can also occur from hep C]
 CMV, HSV, [cytomegalovirus and herpes simplex virus]
 Seronegative hepatitis
 Drug related
 Paracetamol
 Anti tuberculous drugs,
 lipid therapies
 Recreational drugs eg cocaine
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

Idiosyncratic reactions
Anticonvulsants, NSAID,
[Drug causes breakdown]:

o
Toxins
 Carbon tetrachloride
 Amanita phalloides [death cap mushroom]
 Vascular events
 Ischaemia VOD [= venooclusive disease],
 Budd-Chiari
 Other
 Acute fatty liver
 pregnancy, liver rupture,
 Heatstroke,
 Wilson’s disease,
 lymphoma,
 carcinoma
 Trauma
Clinical syndrome
 Multisystem involvement [largely due to effects of inflam throughout
body]; effects seen include:
NB. Typical stigmata of chronic liver disease [a mental or physical
characteristic that serves to identify a disease or a condition], with some
exceptions, are very unusual in ALF (more common in subacute LF) [prob
referring to portal hypertension, ascites, etc]
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







-
Systemic inflammatory responses [tachycardic, vasodilated, etc]
Jaundice
Encephalopathy/intracranial hypertension
Renal failure
Haemodynamic failure
Respiratory failure
Haematological failure
Infection
SIRS in acute liver failure
o Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting
the whole body, frequently a response of the immune system to infection
o ALF has striking phenotypic similarities with septic shock:
 hyperdynamic circulation
 Increased CO state
 Profound peripheral vasodilatation
 Effective intravascular depletion
o Occurrence of SIRS in acute liver failure (ALF) is well recognised
o SIRS was present in 40% patients with ALF in absence of infection
o Massive elevations in both pro-(TNF-a, IL-1β, IL-6) & anti-(IL-10) inflammatory
cytokines
o SIRS, independent of infection, is associated:
 severity of organ failure (SOFA, APACHE II) [ie SIRS contributes to the
multiorgan failure]
 ↑ encephalopathy score
 poorer outcome [nb higher ciruculating lvels of IL-6, TNFa-a in non-survivors]
o Macrophages [liver Kupffer cells] are the main orchestrators of systemic
inflammation; achieve this via the mechanisms illustrated below:
 One action of TNF-a is conversion of epithelium with tight junctions to
fenestrated epithelium
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Encephalopathy:
o
I/II: mild disorientation, drowsiness, respond appropriately
o
III: agitation and disorientation, unable to follow commands
o
IV: deep coma
Intracranial hypertension: Major cause of early mortality due to cerebral oedema and
brainstem herniation through foramen magnum [“coning”]: in chronic LF the cerebral edema
is rare due to physiological adaptations
o
Occurs in grade IV encephalopathy:
o
70% hyperacute liver failure
o
55% acute liver failure
o
Up to 15% subacute liver failure
Ammonia & clinical studies
o Raised ammonia conc is present in >90% patients with ALF.
o High circulating ammonia correlates:

encephalopathy

cerebral oedema/raised ICP

high mortality
o Variable threshold concentrations for prediction of cerebral
oedema/complications:
 severe/progression HE [Hepatic encephalopathy]: > 100-150μmol/L*
 Risk of intracranial hypertension: >200μmol/L
o Risk factors for progression & development HE:
 ammonia
 MELD>32
 ?other factors contribute to the development of HE/ICH
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Ammonia & encephalopathy
o Pathogenesis & mechanisms incompletely understood
 Traditional theory: role of glutamine
o hyperammonaemia → ↑ astrocyte glutamine → astrocyte
swelling →cerebral oedema/ICH
[ie liver not clearing ammonia so passes through BBB to
influence astrocytes]
 Experimental models of ALF:
o Changes in neurotransmitter synthesis/release
[impaired glutaminergic neurotransmission (excitatory)
leading to excessive neuroinhibition (characteristic of
encephalopathy in ALF)]
o neuronal oxidative stress/impaired mitochondrial function
o Astrocyte osmotic changes and swelling
-
Neuroinflammation & HE (hepatic encephalopathy) [ie due to both inflam and ammonia
effects]
o Inflammation & metabolic
 mediators (ammonia/lactate) play “synergisitc” role in pathogenesis of HE
o Activated microglial cells:
 tissue macrophages
 activated by inflammatory stimulus
 implicated in other neuroinflammatory disorders
 ↑ pro-inflammatory cytokines (TNF-α, IL-1, IL-6)
 increased production of proinflammatory cytokines in brain in ALF patients
-
Renal failure
o Common 45% of all cases overall
o 75% paracetamol ALF with grade IV encepaholopathy
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o
o
o
o
o
-
-
-
-
Multifactorial - frequently ATN (acute tubular necrosis) rather than HRS
(Hepatorenal syndrome: key cause is altered bloodflow to kidney giving detrimental
effects)
Intolerant of haemodialysis
 Haemodynamics and cerebral oedema
Buffer
 sodium bicarbonate
Anticoagulation
 epoprostenol, regional anticoagulation,
Does NOT respond to terlipressin/any other forms of “renal” inotropes!
Metabolic disorders
o Hypoglycaemia
 reduced gluconeogenesis
o Hyperlactataemia
 reduced hepatic lactate clearance to bicarbonate
o Hypophosphataemia
o Hyponatraemia
o Metabolic acidosis (independent of renal function; due to liver normally clearing
lactate but this function reduced):
 lactic acidosis, peripheral AV shunting (gives tissue hypoxia)
Hepatocellular death:
o Hepatic necrosis markers present
o Hepatic apoptosis markers present
Hepatocyte regeneration:
o Alpha fetoprotein (AFP)
 increase in AFP is interpreted as a sign of dedifferentiated hepatic
regeneration
 ↑ AFP often precedes ↓ INR [The prothrombin time (PT) and its derived
measures of prothrombin ratio (PR) and international normalized ratio (INR)
are measures of the clotting tendency of blood] [INR rise in people with
severe liver disease because the liver fails to make normal amounts of
certain clotting factors] = favourable prognosis
o Serum phosphate
 Hypophosphatemia [low serum phosphate] is frequently observed in
acetaminophen- induced hepatotoxicity [AALF] and is correlated to the
severity of liver damage.
 Hypophosphatemia mechanism:
 ↑ Protein phosphorylation / ↑ATP [ie high liver demand for ATP so
serum phosphate is lowered]
 ↑ hepatic uptake of phosphorus
 Hypophosphataemia correlates with acute liver injury
 >1.2mmol/L indicator of non-survival
Pulmonary complications
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o
o
o
o
Non cardiogenic pulmonary oedema/ALI- occurs in 40% cases
[ie hepatopulmonary syndrome: [syndrome of shortness of breath and hypoxemia
(low oxygen levels in the blood of the arteries) caused by vasodilation (broadening
of the blood vessels) in the lungs of patients with liver disease]]
 Ie not porto-pulmonary hypertension which is for cirrhosis  serotonin to
systemic  lung effects]
Most common in POD ALF [paracetamol-induced ALF]
Other causes:

Aspiration of gastric contents

Neurogenic 2o raised ICP

Primary pneumonia
-
Infection
o Increased risk of bacterial and fungal sepsis [Impaired host defence mechanism, due
to impaired opsonisation, chemotaxis and intracellular killing, substantially increases
risk of sepsis]
o Conventional markers of sepsis (ie. Temp, WCC) are absent in ALF
o Diagnosis difficult in context of progressive MOF
o Common organisms: Staph, streps, coliforms, candida
o 15 - 35% nosocomial infection rate vs 5 - 7 % in general hospital population (CLD)
o Severe sepsis 58% mortality
o Septic shock 98% mortality
-
Haematological complications [poorer clotting, etc]
o Decreased circulating levels:

Dec Fibrinogen

Dec II, V, VII, IX, X
o Platelet dysfunction

Quantitative (70% <100)
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o
-
-

Qualitative
Increased incidence of pancytopenia (haemopahogocytosis) [reduction in the
number of red and white blood cells, as well as platelets]
Investigations
o Baseline

FBC [WBCs would indicate infection]

U&E, LFT

CK [prob for heart function]

Amylase [biomarker of pancreatitis]

Coagulation [re bleeding risk]

Mg2+, PO2- [ie phos as a biomarker]

Haemolysis screen
o Further

Hepatitis serology

Autoantibodies

Serum copper, caeroplasmin, urinary copper

urinary myoglobin

Imaging

Liver biopsy??? [usually would cause to bleed to death so unusual to
be able to make the biomarker tests that as mentioned prev are in
development/use]
Indications for liver transplantation
o Paracetamol
 pH < 7.3
 all 3 of the following within 24 hrs
 PT > 100 INR > 6.5
 Creatinine > 300 µmol/l
 grade 3 - 4 encephalopathy
 Lactate : 4 hrs > 3.5
 Lactate : 12 hrs > 3.5
 Clichy criteria (French)
 Encephalopathy + Factor V < 20% or < 30% if > 30 yrs of age
o Non-Paracetamol
 pH<7.3
 INR > 6.5
 Any 3 of :
 seronegative hepatitis or drug reaction
 Bilirubin > 300 µmol/l
 INR > 3.5
 Age < 10 yrs or > 40 yrs
 J - E > 7 days
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Management of liver failure
o Coagulopathy
 Give FFP [fresh frozen plasma; inc coagulation components]] only when
decision for OLT listing established or significant bleeding
 Platelet support
o Metabolic
 Correct all electrolyte deficiencies
 HCO-3 as temporary measure (8.4% used)
o Nutrition
 Frequent poor recent oral intake ± vomiting
 No evidence for protein restriction in either acute or CLD
 Gastric prophylaxis : role unproven
 PPI [proton pump inhibitors] routinely administered
o Renal failure
 Almost always occurs in hyperacute ALF

Haemodialysis not tolerated

Continous veno-veno haemofiltration

Corrects acidosis and hyperlactataemia
 Use of high volume CVVHF in ALF- achieve metabolic stability and bridge to
OLT.
 Anticoagulation: epoprostanol
o Infection
o Those who fulfill transplant criteria get transplant
o This group get systemic antifungals in addition
o Most patients will be given oral candida prophylaxis (fluconazole)
 Signs of sepsis / SIRS
 Typically:
 Tazocin 4.5g bolus
 (infusion 13.5g/24/hrs)
 Fluconazole/amphotericin
-
Haemodynamics/tissue perfusion
o Invasive monitoring (PICCO,PA catheter)
o Achieve adequate/optimal fluid resuscitation
 1st choice- noradrenaline [to counter peripheral vasodilation]
 2nd line –vasopressin
o Consider hydrocortisone infusiono Functional adrenal insufficiency in ALF: give supplemental steriods
o Synacthen test
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POD = paracetamol overdose
-
N-acetylcysteine (150mg/kg/24hrs)
o Within 24 hours of POD- reduces/prevents liver damage
o Role in improving outcome in late presentation POD (36-80hrs)
o Improved oxygen delivery to tissues-inprovments in cerbral/systemic
haemodynamics
o “Antioxidant” use in ischaemic & toxic insults
o Recent US ALF study demonstrating utility in non-paracetamol ALF- when initiated
early in disease course
-
Neurological
o Intubate/ventilate (grade III)
o Head up 200C
o Sedation +++(decreases cerebral metabolism)
o Temperature (34-350C) [ie make them cold]
o pCO2- 4.5-5
o Insert RJV (measures cerebral oxygen extraction)-55-80%
o Monitor pupillary abnormalities
o Strong Na+ infusion (Na+~150mmol/L)
o Haemofiltration: clearance of ammonia
o ICP: ease using ICP bolt
 If JV saturations outside normal range
 Pupillary abnormalities
 Hypertonia and clonus
 Prior to ICP bolt : coagulation support : FFP / platelets
 Camino system : 5mm burr hole, make hole in dura, catheter inserted
 CT scans - only if there is concern regarding bleed
 Can do EEG and cerebral dopplers if concerned
 ICP: aim <25mmHg; Cerbral perfusion pressure (CPP) >55 (MAP-ICP)
o Liver-brain proinflammatory axis
 Necrotic liver source of “pro-inflammatory”cytokines
 This is associated with ICH; Changes in cerebral blood flow (CBF)
 Removal of inflamed liver improved ICH/CBF
-
Novel therapies?
o Liver assist devices
o MARS/Prometheus- no benefit
o Plasmapheresis: the removal, treatment, and return of (components of) blood
plasma from blood circulation
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Case scenario:
o paracetamol overdose 2 days ago:
 Bloods
o
 ALT high
 Low HCO3; Base excess present [acidosis]
 Advice:
 Fluids and N-acetylcysteine: hope that spontaneous liver regen will
initiate
Same person later on:
 Bloods:

 ALT extremely high
 INR high
 Low platelet count
 Base excess worse
 Cr (Creatinine) and lactate high [indicating liver damage]
Advice:
 Put on emergency transplant list
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The hyperlactataemia due to energy shortage / phosphate shortage and liver failure
meaning is not being removed by being fed into gluconeogenesis
A simplistic appraoch to biomarkers in liver inflammatory disorders is to consider it in 3
components: the hepatic, systemic (circulatory) and end organ compartments and an
understanding of the relationship between events in the liver, it’s effects on the systemic
“circulatory” compartment and on end organ dysfunction.
An inherent problem with using circulating biomarkers here is that we are making
assumptions that what we quantify in the circulation trully reflect intrahepatic events
So, when looking at the available biomarkers in ALF:
We have biomarkers of hepatocyte death, activation of immune responses and metabolic
dysfunction. At the systemic level, this translates to the effects shown. And the effects of
these processes are reflected in terms of deleterious effects due to
immnosuppression/infection, refractory organ failure, and encephalopathy
Hepatocyte necrosis
o Apoptosis has the marker CK-18
o Necrosis has the marker HMGB1
o Necrosis is dominant form of cell death in early APAP.
o Inc necrosis and and a lower apoptosis are associated with patients that had a worse
prognosis or died/required liver transplant.
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10/12/13: Bilirubin, Jaundice, Bile Secretion &
Cholestasis: Dr Shahid A Khan
Los (from booklet):
• To know the metabolic pathways involving bilirubin
• To recognise jaundice and to be able to describe the types of jaundice
• To learn about the investigation and treatment of diseases producing jaundice
• To know the pathway for bile secretion
• To recognise the components of bile and mechanisms of bile secretion
• To be introduced to pathological mechanisms that produce cholestasis
Notes:
-
Overview
o Bile composition/production
o Bile Salts
o Anatomy of biliary system
o Regulation of bile flow and secretion
o Gall bladder function
o Control of flow
o Bilirubin metabolism
o Jaundice
o Investigations for Jaundice
-
Composition of human bile:
o Water
o Bile salts
o Inorganic salts
o Bile pigments: BR(Billirubin: responsible for jaundice), bilivirden
o Fatty acids
o Lecithin
o Fat
o cholesterol
o Alkaline phosphatase
o [&some minor components]
-
Why do we produce bile?
o Cholesterol homeostasis
o Dietary lipid / vitamin absorption
o Removal of xenobiotics/ drugs/ endogenous waste products
 e.g.
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


- cholesterol metabolites
- adrenocortical
- other steroid hormones
-
Bile Production
o 500ml produced/secreted daily
o Golden-yellow colour: due to glucoronides of bile pigments
o 60% bile secreted by hepatocytes (liver cells)
o Up to 40% secreted by cholangiocytes (biliary epithelial cells)
o Bile drains from liver, through bile ducts and into duodenum at duodenal papilla
-
Bile Production: Role of Biliary Tree
o 40% bile secreted by cholangiocytes
o Alters pH, fluidity and modifies bile as it flows through
o H20 drawn into bile (osmosis through paracellular junctions)
o Luminal glucose and some organic acids also reabsorbed
o HCO3- and Cl- actively secreted into bile by AE2 and CFTR mechanism respectively
(Cystic Fibrosis Transmembrane Regulator)
o Cholangiocytes contribute IgA by exocytosis
-
Bile Flow
o Bile flow closely related to conc of bile acids and salts in blood
o Biliary excretion of bile salts and toxins performed by transporters expressed on
apical surface of hepatocytes and cholangiocytes
o These biliary transporters also govern rate of bile flow
o Dysfunction of the transporters is a major cause of cholestasis
o Main transporters include the:
 Bile Salt Excretory Pump (BSEP)
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


-
is responsible for the active transport of bile acids across hepatocyte
canalicular membranes into bile, and secretion of bile acids is a
major determinant of bile flow
MDR related proteins (MRP1 & MRP3)
products of the familial intrahepatic cholestasis gene (FIC1) and multidrug
resistance genes (MDR1 & MDR3).
 MDR1 mediates the canalicular excretion of xenobiotics and
cytotoxins [at hepatocytes]
 MDR3 encodes a phospholipid transporter protein that translocates
phosphatidylcholine from the inner to outer leaflet of the
canalicular membrane [at hepatocytes]
Bile Salts
o Na and K salts of bile acids that have been conjugated in liver to glycine and taurine
(cysteine derivative)
o The initial Bile acids are synthesised from cholesterol
 4 acids in humans
 2 PRIMARY Acids (formed in liver):
o Cholic acid Chenodeoxycholic acid
 2 SECONDARY Acids generated due to the action of colonic bacteria
on the primary acids:
o Deoxycholic acid Lithocholic acid
 Cholic acid > chenodeoxycholic acid > deoxycholic acid > lithocholic
acid
o Bile Salts - Function
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


o
o
Reduce surface tension of fats
Emulsify fat preparatory to its digestion/absorption
bile salts emulsify lipids to prepare them for digestion and then solubilize
the products of lipid digestion in packets called micelles.
Bile Salts form Micelles
 Bile salts amphipathic
 One surface has hydrophilic domains, facing OUT
 2nd has hydrophobic domains, facing IN
 Phospholipids are also present in bile and will contribute to micelle
formation
 free Fatty Acids and Cholesterol will become positioned INSIDE
 thus transported to GIT epithelial cells for absorption
Potential cell damage:
 Detergent-like actions make bile salts potentially cytotoxic in high
concentrations
 But cell membranes protected by

other intraluminal lipids: e.g. phosphatidylcholine in biliary
tree compared to the fatty acids in GIT  diff BA behaviour there

their own plasma content (of the cells themselves): of
cholesterol and glycolipids
-
Anatomy of Biliary System
o Liver organised into lobules [hexagons on diagrams below]
o Within lobules blood flows past hepatocytes via highly permeable sinusoids (from
branches of portal v.)
 Blood drains to a central v./each lobule
 Plasma in CLOSE contact with hepatocyte
 Only 1 layer hepatocytes between sinusoids to maximise contact area
between plasma & hepatocytes
 8 seconds = avge. transit time for: blood in portal v  liver lobule  central
hepatic v
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o
Hepatocytes of extreme periportal zone make contact with bile duct lining cells there is a short stretch, Canal of Hering (CoH), where bile flows in channels lined by
a mixture of ‘bile duct lining cells’ [=cholangiocytes] and hepatocytes [see images
below]
 Ie hepatocytes line canaliculi then there is an area of transition called CoH:
CoH are found between the bile canaliculi and interlobular bile ducts near
the outer edge of a classic liver lobule; lined partially by cholangiocytes and
hepatocytes. Bile ducts themselves are lined by cholangiocytes only
 Ie the hepatocytes take up a larger length than the prev diagram suggests (ie
inside lobe area is the fat, BA and ion entry while HCO3, H2O, etc is not until
reaches the acini cholangiocytes)
o
Liver Acini [rhombus on diagram below]
 Singular ACINUS
 “Functional” units
 100,000/human liver
 Each at end of vascular stalk with terminal branches of portal v, hepatic art,
bile duct
 Blood enters centre from portal venule and hepatic arteriole
 Blood flows outward to terminal hepatic venules in periphery
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Billary tree:
o Each hepatocyte is apposed to several bile canaliculi
o these drain to intralobular bile ducts, coalesce to interlobular ducts then to
Right/Left Hepatic Ducts
o Right/Left Hepatic Ducts join outside liver to form Common Hepatic Duct
o Cystic Duct drains the gall bladder
o Cystic Duct unites with Common Hepatic Duct to form COMMON BILE DUCT (CBD)
o CBD joined by Pancreatic Duct prior to entering duodenal papilla
-
Ions and water are secreted into bile by epithelial cells lining the bile ducts:
o The secretory mechanisms are the same as those in the pancreatic ductal cells.
Secretin stimulates ion and water secretion by the bile ducts just as it does in the
pancreatic ducts.
-
Regulation of Bile Flow & Secretion
o Between meals duodenal orifice closed, therefore bile diverted into gall bladder (GB)
for storage [nb the path to gall bladder is not as angled as image makes out]
o Eating causes sphincter of Oddi to relax
 Gastric contents (F.As, A.As > CHOs) enter duodenum causing release of
cholecystikinin, CCK (GIT mucosal hormone)
 CCK causes GB contraction
 When the duodenum is relaxed and duodenal pressure is low, bile is ejected
[ie in pulses]
-
Enterohepatic Circulation
o Liver cells transfer various substances, including drugs, from plasma to bile
o Drugs:
 Many hydrophilic drug conjugates (esp. glucoronide) are concentrated in
bile
GIT  glucoronide hydrolysed  active drug re-released 
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o
reabsorbed  cycle repeated [uptake by hepatocyte and excretion into
canaliculus]
 “reservoir” of re-circulating drug
 can prolong action e.g. morphine undergoes cycling
Bile salts:
 95% bile salts absorbed from small (terminal) ileum: by Na+/bile salt cotransport Na+-K+ ATPase system
 5% converted to 2o bile acids in colon:
 - deoxycholate absorbed
 - lithocholate 99% excreted in stool
 absorbed B.salts travel back to liver and re-excreted in bile
 3.5g bile salt pool re-cycles rapidly in enterohepatic circulation (2x/meal; 6 –
8x/day)
 Terminal Ileal Resection/Disease:
 Reduced bile salt reabsorption and increased fat in stool (because
enterohepatic circulation interrupted and liver can’t increase rate of
bile salt production enough to make it up)
 If bile stopped from entering GIT:
 Up to 50% ingested fat appears in faeces
 malabsorption fat soluble vitamins (A,D,E,K)
o are processed in the same manner as dietary lipids; are
incorporated into chylomicrons
[nb the water soluble vitamins are absorbed by Na
dependant cotransport except for vitB12]
-
Functions of Gall Bladder [stores and modifies bile from hepatic ducts]
o Stores bile (50ml), released after meal for fat digestion
o Concentrates bile by H20 diffusion following net absorption of Na+, Cl-, Ca2+, HCO3
(decreased intra-cystic pH)
 GB can reduce volume of its stored bile by 80 – 90%
 Inc % solids
 Inc % bile salts
 Acidifies bile
-
Effects of Cholecystectomy [nb also occurs as part of liver transplant process]:
o Periodic discharge of bile from GB aids digestion BUT is NOT ESSENTIAL
o Normal health and nutrition exist with continuous slow bile discharge into
duodenum
o Avoid foods with high fat content
-
Bilirubin (BR) Metabolism & Excretion
o BR = H2O-INSOLUBLE, yellow pigment
 75% BR from Hb breakdown
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o
o
o
o
o
o
o
o
 22% from catabolism of other haem proteins
 3% from ineffective bone marrow erythropoiesis
BR and Fe2+/Haem generated at spleen from old RBCs [NB this precess also occurs
to a lesser extent at the liver: this is what makes splenectomy tolerated]  BR
bound to albumin in blood  most albumin dissociates in liver  Free BR enters
hepatocyte  binds cytoplasmic proteins  conjugated to glucoronic acid (UDPGT
from smooth ER)  diglucoronide-BR more soluble than free BR  transported
ACROSS [ie prob against] concentration gradient into bile canaliculi  GIT
TOTAL BR = FREE BR (UNCONJUGATED) + CONJUGATED BR
[nb conjugated = smaller amount]
Urobilinogens = H2O-SOLUBLE, colourless derivatives of BR formed by action of GIT
bacteria
GIT mucosa is permeable to UNCONJUGATED BR and Urobilinogens
Therefore some UNCONJUGATED BR enters enterohepatic circulation  recycled;
and some forms urobilinogens which can also be resorbed
20% urobilinogens reabsorbed into gen.circulation  urine excretion
Some urobilinogens passed in stool as Stercobilinogen
Oxidation of stercobilinogen to stercobilin causes brown colouration of faeces
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-
Jaundice (= Icterus) and Cholestasis
o Cholestasis: cessation of bile flow
o Jaundice: Excess BR in blood (> 34 – 50microM/L)
o (yellow tinge to skin, sclerae, mucous membranes)
o Cholestasis normally results in jaundice
o Jaundice does not necessarily mean there is cholestasis
-
Jaundice Causes:
o Pre-Hepatic:

o
Increased quantity of BR:
o Haemolysis
o Massive Transfusion
o Haematoma resorption
o Ineffective erythropoiesis
 Look for: Hb drop without overt bleeding; BR>>>LFTs
 Ix: Blood film; haptoglobins, LDH
 A. rate of formation of bilirubin > removal
Hepatic: (i.e. Hepatocytes not working)
 Defective uptake
 Defective conjugation
 Defective BR excretion
 Liver Failure:
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o
o Acute/Fulminant
o Acute on Chronic
o Viral hep, EtOH, AID, PBC, PSC etc.
 Intrahepatic cholestasis:
o sepsis, TPN, Drugs
 A. Damage to liver cells stop conjugation &/or excretion. Associated with
severe hepatocellular damage
 B. Failure to form bile
 C. Reflux of bile between hepatocytes
Post-Hepatic:
 Defective Transport of BR by Biliary duct system e.g. common bile
duct stones, HepPancBil malignancy [eg Cholangiocarcinoma], local
LNpathy
 Look out for sepsis (cholangitis)
 Ix:
o - ALP + GGT >> ALT,AST
o - Dilated bile ducts on USS
o - CT or MRCP
 A. Damage to intrahepatic bile ducts
 B. Obstruction of intra or extrahepatic bile ducts
- Gilbert’s Syndrome
o
o
Commonest hereditary cause of increased bilirubin
Up to 5% of the population
o
Autosomal recessive inheritance
o
o
Elevated unconjugated bilirubin in bloodstream
Cause: 70%-80% reduction in glucuronidation activity of the enzyme Uridinediphosphate-glucuronosyltransferase isoform 1A1 (UDPGT-1A1).
o
o
o
-
No serious consequences
Mild jaundice may appear under:
 exertion, stress, fasting, infections
otherwise usually asymptomatic
Jaundice: Investigations
o Blood Tests: “liver screen”
 FBC, LFT, U&Es, INR
 Hepatitis viral serology
 Ferritin/Iron Studies
 Copper/Caeruloplasmin
 Liver Antibodies/Alpha-1 Antitrypsin
 Alpha fetoprotein
 Haemolysis screen
o Imaging
 - Ultrasound abdomen
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
- CT/MRI (+/- ERCP)
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10/12/13: Mechanisms of alcohol toxicity: Dr Harry
Antoniades
Los (from booklet):
appreciate the problems resulting from alcohol
Notes:
-
Proportion Of Risk:
o Environment: 40%
 Social
 Financial
 Job
 Housing
 Friends
 Sense of wellbeing
 Self esteem
 Family
 Social productivity
o Genetics: 60%
 4x Risk in 1o Relatives
 Adopted Away Children 4x Risk
 Animal Breeding test confirm genetic effects
-
Hepatic ethanol metabolism
o 3 major metabolic pathways:
Ethanol is converted to acetaldehyde by:
 1. Alcohol dehyrogenase (ADH) in the cytosol,
 In addition, ADH generates a reduced form of nicotinaminde
adenine dinucleotide (NADH)- which promotes steatosis by
stimulating the synthesis of FFA and opposing their oxidation.
 2. Cytochrome P450 2E1 in ER,
 MEOS (CYP2E1) [microsomal ethanol oxidizing system]
o CYP2E1:
 CYP2E1 is a P450 enzyme
 Is a major enzyme of the hepatic microsomal
ethanol oxidising system (MEOS)
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

-
Implicated in pathogenesis of alcohol induced liver
injury:
 - release of free radicals/ROS
 - upregulated in acute and chronic ethanol
ingestion
3. by catalase in the peroxisomes.
 Occurs to a much lesser extent than the other pathways; of minor
consequence; does produce ROS though
Pathogenesis of liver damage actually poorly understood but most likely:
o The result of direct toxic actions of ethanol or its metabolites (inc acetaldehyde:
toxic) within hepatocytes
 Under conditions of infrequent ethanol exposure, ethanol is oxidized to
acetaldehyde predominately by cytosolic alcohol dehydrogenase (ADH) and
the resultant acetaldehyde is quickly detoxified to acetate by mitochondrialassociated aldehyde dehydrogenase (ALDH): only suffer acetaldehyde
toxicity effects here
 Greater alcohol exposure gives inc MEOS (CYP2E1) role:
 this gives not just acetaldehyde but ROS too;
 inc alcohol concs prob also give inc acetaldehyde levels / slower
clearance too thus further damage
 also CYP2E1 gives Lipid peroxidation products which trigger
apoptosis/necrosis
o The result of ethanol induced immune cell activation which then subsequently gives
cell death / damage
 Cycle then occurs of any apop/necrosis triggering stellate cell activation [The
stellate cell is the major cell type involved in liver fibrosis, which is the
formation of scar tissue in response to liver damage; nb also give some EPO
production]
 Players include: Kupffer cells, Neutrophils, Lymphocytes, inflame cytokines
 Neutrophils:
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o
o
o
-
predominant cellular infiltrate on liver biopsy and correlates
with disease severity
o Induce hepatocyte death:
 production of ROS/oxidative stress
 inflammatory cytokines (e.g. TNF-a, IL-8)
 production of tissue proteases (e.g. Neutrophil
elastase)
 Immune Changes in Alcoholics with Liver Disease [nb some do not
get problems]
o Increase
 1. IgA, IgG, IgM
 2. T lymphocytes (persistently activated)
 3. IL1, TNFalpha, IL6, IL8
 4. Neutrophils and monocytes
o Decrease
 1. B and T Lymphocyte in the blood
 2. Response to tuberculin skin tests (delayed-type
hypersensitivity)
Consequence of all the cellular damage is fibrosis/cirrhosis
Other alcohol effects:
 Drinking a large amount of alcohol, even for only a few days, can lead to a
build-up of fats in the liver.
 Alcohol attacks the gut: permeativity increases
 This is a mechanism of direct alcohol induced immune activation:
o ETOH disrupts the GI barrier function: increases
permeability resulting in increased translocation of
microbial products including endotoxin to the liver.
o Endotoxin (eg LPS) in portal system/liver then signals
through TLR-4 to stimulate macrophages [kupffer cells] (part
of the resident RES system) via nfkb signalling to produce
both hepatotoxic like cytokines such as TNF/ Type 1
interferons and ROS that both contribute to hepatic cell
injury/fibrosis and eventually cirrhosis.
 Wider effects of TNF-alpha:
 CNS: Encephaolopathy; Anorexia; Fever
 Liver: Apoptosis & Necrosis; Collagen Formation
 GIT: Permeability; Gut Stasis
 Musculoskeletal: Muscle Wasting; Osteoporosis
 Other: Neutrophilia; Endothelial permeability; Peripheral oedema
Alcohol Related Liver Injury
o Steatosis [fatty liver] 70% [best to have this compared to the below]
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
o
Steatosis is a very common result of chronic alcohol ingestion, occuring in
many, if not most, human beings and experimental animals that consume
alcohol daily
 Steatosis overview:
 Common
 Reversible
 Few Symptoms
 +/- Hepatomegaly
 Usually picked-up on ‘screening’ LFT’s
Alcoholic hepatitis 6%
 a liver disease characterized by hepatic steatosis, inflammation, and
increased hepatocyte death
 Is usually an intermediate stage between simple fatty liver and cirrhosis
 Carries significant morbidity and, in hospital, mortality.
 Mild forms patients can appear well and be asymptomatic.
 In more severe forms, spectrum of presentations but patients often
jaundiced/malaise/lost appetite/fever/ascites/hepatomegaly/ruq pain/signs
of chronic liver disease/complications of CLD such as ecephalopathy,
variceal haemorrhage, hepatorenal syndrome.
 Histology: INFLAMMATION; NECROSIS; POLYMORPHS; MALLORY
BODIES;STEATOSIS
 Alcoholic hepatitis overview:
 Alcohol related liver damage
 Secondary immune reaction directed against the liver [ie hepatic
inflam occurs]
o jaundice
o fever
o neutrophil leucocytosis
o cholestatic LFT’s
 Treatment of Alcoholic Hepatitis
 General Measures
o stop drinking
o control withdrawal symptoms
o supportive measures
 Vitamins replacement
 Treat infection
 Specific Measures- anti-inflammatory mediators
o Steroids
 Proven to be of benefit in severe alcoholic hepatitis
 Suppression of “organ-specific and systemic
inflammation”:
 inhibition of pro-inflammatory mediators (TNF-a, IL1, IL-6)
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
o
upregulation of anti-inflammator mediators (e.g.
SLPI, IL-10)
 Broad inhibition of immunocyte function (e.g.
granulocytes, monocytes, lymphocytes)
Pentoxyphilline
 phosphodiesterase inhibitor
 weak inhibitor of TNF-a


o
-
increased TNF alpha in alcoholic hepatitis
studies shown linear relationship between TNF
alpha receptors and mortality in alcoholic hepatitis
 ethanol sensitises cells to toxic effect of TNF alpha
Alcoholic cirrhosis 10% [worst to have this]
 Eventually develops in 20%
 Morbidity common
 jaundice
 ascites
 bleeding
 cachexia
 infections
 encephalopathy: Affects Brain Function: reduces Cortical Grey
Matter Volume
 Full CNS/PNS effects:
o Wernicke’s encephalopathy
o Korsakoff’s psychosis
o Optic toxicity
o Autonomic dysfunction
o Peripheral neuropathy
 Liver cancer (HCC)
 Death in most within 10 years
Chronic Alcohol Abusers are more prone to: [inc gut permeability increases infection risk
but also the liver is a key source of complement components so there will be a reduced
immune potential]
o Bacterial pneumonia
o Septicemia
o Tuberculosis
o Hepatitis C
o Less common diseases such as:
 meningitis
 lung abscess
 diphtheria
 cellulitis
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-
Primary Effects of Alcohol on the Immune System:
o Immune susceptibility (gut permeability etc)
o Immunodeficiency: Increased incidence to infectious diseases
o Autoimmunity: Contributes to liver dysfunction and renal disease
-
Metabolic Adaptation (Tolerance)
o Besides CNS adaptation, alcoholics (in the absence of liver disease) often display an
increased rate of blood alcohol clearance. This is called metabolic tolerance or
adaptation. Suggested mechanisms include:
 Induction of ADH.
 Increased reoxidation of NADH.
 Induction of CYP2E1.
 Release of cytokines or prostaglandins which increase oxygen consumption
by the hepatocytes.
-
Zonal Metabolism of Ethanol in the Hepatic Acinus
o Liver injury after chronic ethanol treatment originates in the perivenous zone of the
hepatic lobule. Possible factors to explain this include:
 1. Oxygenation. Oxygenation is low in this zone
 2. Ethanol metabolism by ADH.
 3. Acetaldehyde metabolism by ALDH.
 4. CYP2E1.
 5. Antioxidant levels.
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11/12/13: INTESTINAL ABSORPTION: Julian RF
Walters
Los (from booklet):
• To consolidate knowledge of the mechanisms of protein and lipid absorption
• To review absorption of electrolytes and water
• To appreciate mechanisms of absorption of certain other nutrients
Notes:
-
Transport pathways in small intestinal enterocytes of CHO, proteins, lipids:
[look up if fruc and gal conferted to gluc before transport on blood side]
-
Transport pathways in small intestinal enterocytes of NaCl:
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-
Electrolytes & Water in GI Tract:
o Intake + Secretion = Absorption + Faecal Output
 Secretion:
 Saliva
 Stomach
 Bile
 Pancreas
 Proximal small intestinal crypts
 Absorption:
 Distal small intestinal villi
 Large intestine
-
Calcium Absorption by the Intestine
o Absorption of calcium from dietary sources
 Differing amounts of calcium in foods
 Differing availability of calcium
 Solubility in gastric acid
o Greatest rates of absorption in duodenum & proximal jejunum
 Specific genes expressed in this region
 TRPV6 is a Ca2+ channel [down conc grad into the cell] [“transient
receptor potential” family]
 Calbindin refers to several calcium-binding proteins
o Buffers the Ca conc: millimolar concs overall in cytoplasm
but most bound to calbindin so for diffusion purposes there
appears to be only micromolar levels
 PMCA1 functions to pump calcium (Ca2+) from the cell using ATP.
Will enter blood
o Regulation by the vitamin D hormonal system
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
1,25-dihydroxyvitamin D3 [this is the active form of vit D]
[prots and lipids slower than carbs as more physical digestion required]
[distal ileal cobalamin absorption]

Vitamin B12 Absorption
 B12 (cobalamins) only in animal products [=extrinsic factor]
 Intrinsic factor from stomach [see earlier notes]
 (1) Dietary vitamin B12 is released from foods by the digestive action of
pepsin in the stomach.
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




-
(2) Free vitamin B12 binds to R proteins, which are secreted in salivary
juices.
(3) In the duodenum, pancreatic proteases degrade the R proteins, causing
vitamin B12 to be transferred to intrinsic factor, a glycoprotein secreted by
the gastric parietal cells.
(4) The vitamin B12-intrinsic factor complex is resistant to the degradative
actions of pancreatic proteases and travels to the ileum, where there is a
specific transport mechanism for its absorption.
(5) Absorption in terminal ileum of B12 bound to intrinsic factor
(6) In the epithelial cells the complex is then broken down and B12
transferred to blood where it becomes bound to transcobalamin
Malabsorption of Sugars – Lactose
o Low lactase activity in the small intestinal brush-border membrane (hypolactasia)
results in failure to digest lactose
o Neonates all have high lactase
 Lactase non-persistence is usual adult human phenotype
 Lactase persistence occurs in most (but not all) Northern Europeans [but far
less common in asia]
o Malabsorption of Lactose
 25% N. Europeans
 65-70% Greeks, Italians, Jews, Arabs
 85% Asians, Africans
o Lactose malabsorption in small intestine delivers lactose to the colon
 Lactose breaks down in colon [many more bac here than in small intestine]
producing H2, CO2, lactate and other short chain fatty acids
 Basis of lactose-H2 breath test
o Lactose intolerance is a clinical diagnosis made from history of symptoms after
lactose (in malabsorbers)
 Eg Abdominal pain [functional dyspepsia: dyspepsia without evidence of an
organic disease that is likely to explain the symptoms] and diarrhoea
[osmotic diarrhoea; vs the secretory diarrhoea of cholera (Cl channels kept
open)]
o Sugar Breath Tests
 Principles:
 Fasting breath H2 < 20 ppm
 Only produced by bacterial action on sugars
 Sugar taken by mouth
 Breath samples every 30 mins for 2-3 hours
 Increase of 20 ppm significant
o Mechanisms of Lactase Persistence / Non-persistence
 Genetic basis
 Protein active in childhood but not in adults
 Polymorphisms in lactase gene
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



Heterozygote studies showed cis acting elements
Transcription factors regulating expression of lactase
Developmental switches
Polymorphism 14kb upstream associated with persistence/non-persistence
in Finnish population
-
Malabsorption of Sugars - Fructose and Sorbitol:
o Abdominal pain [functional dyspepsia: dyspepsia without evidence of an organic
disease that is likely to explain the symptoms] and diarrhoea following fruit juices
(especially in children) or diet/diabetic drinks
o Small intestinal malabsorption of these monosaccharides results in metabolism in
colon
o Diagnosis from history and from breath H2 excretion after ingestion of sugar
o Malabsorption of Fructose and Sorbitol = 40-65% overall world population
-
Glucose-Hydrogen Breath Test for Small Intestinal Bacterial Overgrowth:
o Normal breath H2 is low but Small Intestinal Bacterial Overgrowth wil give elevated
H2 levels on breath due to bac metabolism in small intestine
o Causes of Small Intestinal Bacterial Overgrowth
 Gastric surgery & achlorhydria
 Jejunal diverticula
-

Intestinal blind loops after surgery (as in Crohn's)

Intestinal strictures (as in Crohn's)

Fistulae (as in Crohn's disease)

Impaired peristalsis (fibrosis, amyloid, myopathy, neuropathy)
Lactulose Hydrogen Breath Test
o Lactulose not digested or absorbed by small intestine
 Basis of use as laxative
o Broken down by bacteria to give H2
 Normal colonic flora
 Small intestinal flora in SIBO
o Rise in breath hydrogen measures
 SI transit time [ie seeing when peak occurs (implies has reached colon where
the bac are)]
 SI bacterial overgrowth [ie if a very early peak exists]
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Intestinal Absorption: Summary
o To consolidate knowledge of the mechanisms of protein and lipid absorption
o To review absorption of electrolytes and water
o To appreciate mechanisms of absorption of certain other nutrients (Calcium and
vitamin B12)
o To review mechanisms of carbohydrate digestion
o To appreciate genetic variation in nutrient absorption
o To understand the basis for breath hydrogen tests
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11/12/13: Malabsorption: Prof: Julian RF Walters
Los (from booklet):
on
Notes:
-
Malabsorption: Presentation
o Diarrhoea / Steatorrhoea
o Growth failure / Weight loss
-
When to investigate diarrhoea?
o Infectious diarrhoea is common
o rarely lasts longer than 2 weeks
o Chronic diarrhoea has many causes :
 Osmotic
 Secretory eg cholera
 Inflammatory eg colitis
 Often a combination of these is responsible.
-
Steatorrhoea
o Description
 Pale poorly formed stools
 Offensive smell
 Difficult to flush away
 Float
 Oil rings
 Faecal leakage [water/solid both easier to contain by comparison]
o Faecal fat content
 normal range < 6 g / day
-
Nutritional assessment – examination
o Muscle wasting
o Loss of fat
o Oedema / ascites
o low albumin
o (anaemia, skin lesions, hair loss, poor wound healing, purpura etc.)
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o
Anthropometry: taking various measurements of the patient’s body
o
Consider the 7 nutritional aspects:
 F ats
 A mino acids and protein
 C arbohydrates
 E lectrolytes and water
 M inerals
 T race elements
 V itamins
o
Tests for malabsorbed nutrients
 Fats
 Steatorrhoea: clinical +/- faecal fat
 Protein & nitrogen
 Urinary excretion, albumin
 Minerals
 Iron, calcium, magnesium, zinc etc.
 Vitamins
 B12 (cobalamin), D (calciferol), folate, vitamin K, carotene




-
Tubeless tests [but are going out of use]
 (Xylose absorption)
 (Pancreolauryl test)
 (Schilling test)
Faecal Pancreatic Elastase 1
 Stable during passage through GI tract
 Small sample of stool collected
 Monoclonal antibody to human protein - ELISA
 High sensitivity and specificity for diagnosing pancreatic
insufficiency
 Values below 200 µg elastase/g stool indicate exocrine pancreatic
insufficiency
Abdominal X-ray
Wireless Capsule Enteroscopy
Malnutrition causes:
o Increased needs
o Insufficient supply
 Low Food intake
 Malabsorption
 Loss of functional enterocytes
 Pre- and post-mucosal effects
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


-
Single gene disorders
Duodenal histology for malabsorbtion: Subtotal villous atrophy
[shortening] with crypt hyperplasia [lengthening]
 Common Causes of general malabsorbtion:
o Coeliac disease
o Small bowel bacterial overgrowth
 The bac decojugate the bile salts converting them
back to bile acids [these will be in their non ionised
form at this pH: means will easily diffuse out of gut
so lipid absorbtion is reduced]
o Pancreatic insufficiency
o Short bowel syndrome
 Usually after surgery for Crohn's disease, infarction
or trauma
 Less than 200cm of small intestine
 Malabsorption
 Malnutrition
 Electrolyte imbalance
 Progressive weight loss
 Also note: Disorders associated with non-functional transporters can
present in childhood
 Common Forms of Malabsorption of Specific Nutrients:
o Lactose: Lactase non-persistence
o Vitamin B12: Pernicious anaemia (loss of intrinsic factor eg
gastrectomy: is a medical procedure that involves surgically
removing all or part of the stomach)
o Bile salts: Bile salt diarrhoea
Maldigestion
 Reduced gastric tissue/secretion
 Loss of pancreatic tissue
 Impaired bile secretion
 Reduction in intestinal brush-border enzymes
COELIAC DISEASE
o Inflammatory disease of upper small intestine resulting from gluten ingestion in
genetically susceptible individuals
o Coeliac disease was once thought to be only a childhood disease; Now well
recognised to present at any age
o Under-diagnosis in the community may be related to changes in presentation of
Coeliac Disease: possible decline in the severity of the illness due to less reliance on
wheat-based diets
 We now recognise there are many non-specific symptoms
 Good serological tests now enable the diagnosis to be made easily and
reliably
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o
o
Coeliac Iceberg exists with only a small proportion of ‘coeliacs’ suffering
Complicated or Clinically active disease [Lymphoma; Nutritional deficiencies; DH:
DERMATITIS HERPETIFORMIS] with the rest being Subclinical or with just Latent /
potential coeliac disease [Villous atrophy; Subtle histology; Antibodies]
COELIAC DISEASE = GLUTEN SENSITIVE ENTEROPATHY
 GLUTEN
 Is the fraction of cereals that binds (glues) them together
 Gluten actually varies from grain to grain. It's not a specific protein,
but a complex of 2 types of proteins called Prolamins and Glutelins:
the prolamins give the problems in coeliac disease and are the
component generally being referred to
 Are Proteins that are found in wheat, barley, rye
 Specific polypeptides rich in Q and P
 Prolamin egs: A-gliadin (wheat), hordein (barley), secalin (rye)
 In gluten sensitive enteropathy, there are diff types of recognition of
the gluten:
o HLA-DQ, [and certain other HLA varients which will present
the gluten to immune cells]: activated HLA-restricted Tlymphocytes result
o antibody recognition of gliadin [assuming wheat here]
 ie anti-reticulin (ARA), anti-gliadin (AGA) and antiendomysium (EMA) [=anti-tTG] antibodies exist but
seems likely the Antiendomysial antibodies play a
largest role
o antibody recognition of host human transglutaminase
(when has been crosslinked to gluten: neo-antigen
formation [Antigenic proteins formed by metabolic
pathways]): glutens that are crosslinked to tTG are able to
stimulate transglutaminase specific B-cell responses that
eventually result in the production of antibodies
 explains the rise and fall of anti tTG autoantibodies
with gluten intake
 2-gliadin 33-mer detail:
o A 33-mer, residues 57 – 89 of 2-gliadin, is stable in gastric,
pancreatic & intestinal proteases [rich Q/P content ensures
not recognised by enzymes]
o reacts with tTG (crosslinks)
o directly stimulates HLA- restricted intestinal T cell clones
from coeliacs
 Genetic predisposition to immune response
 Risk in first degree relatives approximately 10 - 12%.
 Monozygotic twins: concordance 70%
 HLA associations:
o Class I: HLA-A1, HLA-B8
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o
o
Class II:
 HLA-DR3
 HLA-DQ2 (DQA1* 0501, DQB1*0201 alleles): prob
the most important of the lot
 95% of Northern European coeliac patients
 20% non-coeliac controls
In HLA-matched siblings (ie for the HLAs listed here)
concordance for coeliac disease ~ 30% but Everyone eats
gluten so Other gene(s) must contribute to the inheritability

o
ENTEROPATHY
 Inflammatory damage
 Cell death (apoptosis)
 Histological changes
o Enterocyte apoptosis (villous atrophy)
o Stimulated regeneration (hyperplastic crypts)
 Functional changes leading to malabsorption of nutrients
ANTIBODIES IN COELIAC DISEASE
 IgA class
 Endomysial antibodies
 The endomysium is a layer of connective tissue that ensheaths a
muscle fiber. The endomysium contains a form of transglutaminase
called "tissue transglutaminase" or "tTG" for short, and antibodies
that bind to this form of transglutaminase are called antiendomysial antibodies (EMA). EMA are present in celiac disease.
 Detected by indirect immunofluorescence
 Tissue transglutaminase (tTG) cross-links glutamine residues; then tTG
Autoantigen recognized by endomysial antibodies [ie neo-antigens
produced]
 Measured by ELISA
 High specificity (>95%) & sensitivity in diagnosis
 Useful in monitoring response to treatment

o
IgA tTG autoantibodies (ie vs tTG) fall in number during gluten free
diet and increase upon gluten challenge
DERMATITIS HERPETIFORMIS
 epidermal transglutaminase is the predominant autoantigen
 Vesicular rash
 intense pruritus
 blisters rarely present
 esp. arms & shoulders
 Skin biopsy
 granular IgA deposits
 Associated villous atrophy and gluten-sensitivity
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o
o
o
o
Coeliac disease can present in many ways:
 - Typical disease
 - Atypical disease
 - Silent or asymptomatic disease
Frequent (~50%) clinical features
 Malaise
 Fatigue
 Steatorrhoea
 Diarrhoea
 Weight loss
 Anaemia
 Low Folate
 Low Fe
Common (>25%) clinical features
 Anorexia
 Abdominal pain
 Oral ulcers
 Distension
 Bloating
 Flatulence
 Osteopenia
 Childhood history
 Family history
 Low B12
 Low Albumin
 Low 25-OH vit. D
 High PTH
COELIAC DISEASE IN CHILDREN: [symptoms]:
 Diarrhoea & Steatorrhoea
 Abdominal distension
 Failure to gain weight
 Weight loss
 Lassitude
 Abdominal pain
 Anorexia
 Vomiting
 Irritability
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o
o
o
 Respiratory infections
COELIAC DISEASE: SCREENING POPULATIONS
 In general population, prevalence may be ~1%.
 Groups with prevalence between 1 and 5%:
 Diabetes (Type I)
 Thyroid disease
 Anaemic blood donors
 Irritable Bowel Syndrome
 Osteoporosis
COELIAC DISEASE: PRINCIPLES OF TREATMENT
 Gluten-free diet
 !!!! NO WHEAT, BARLEY, RYE !!!!
 (some pts may also be symptomatic with oats)
 Maintain adequate nutrition
 Gluten-free products on prescription
 Nutritional supplements
o (energy sources, Fe, Ca, vitamin D, folate, etc.)
 Prevent complications
 The Coeliac UK society provides patient support
 List of gluten-free products – updated regularly
COELIAC DISEASE: COMPLICATIONS
 Nutrient malabsorption & impaired nutritional status
 (Slow growth, anaemia, neurological disorders, infertility)
 Small bowel malignancy
 Lymphoma
o Enteropathy-associated T-cell lymphoma (EATL)
 Adenocarcinoma
 (and ? other cancers)
 Osteoporosis / enia [ie due to lack of vitd uptake]
[MMO]
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11/12/13: Mechanisms of liver damage [viral]: Marco
Purbhoo
Los (from booklet):
list viruses that injure the liver and their epidemiological features
Los (from booklet):
•Describe mechanisms leading to hepatocyte damage
•Contrast the mechanisms of Apoptosis and Necrosis
•Compare the serological profiles of acute and chronic viral hepatitis
•Explain how hepatocyte damage can result in cirrhosis
Notes:
-
Summary/preview:
o Liver damage related to both apoptosis and necrosis
o Different viruses cause damage by different routes
o Chronic liver injury due to an ineffective immune response leads to cirrhosis
-
Causes of liver damage:
o Drinking
o Obesity
o Drug abuse
o Sexually transmitted diseases
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[fenestrations allow for immune cell scanning without leaving blood]
-
Liver disease:
o Epithelium
 Hepatocytes  Liver dysfunction
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o
o
o
o
o
o
-
 Cholangiocytes  Cholestasis
Endothelium
 Sinusoids
Sinusoidal pericytes
 Myofibroblasts-stellate cells  Cirrhosis
Immunocytes
 Kuppfer cells
 Lymphocytes (T cells, NKT cells, NK cells)
May be acute:
 Short term
 Can lose function acutely
May be chronic:
 Long term
 Associated with cirrhosis
 Portal hypertension
 Gradual loss of function
Mechanisms:
 Cell death due to cytopathic effect
 infections
 toxins
 Immune mediated damage
 Direct [destroying infected cells]
 Bystander [indirect inflam damage]
Apoptosis vs Necrosis:
o Apoptosis
 Apoptosis or programmed cell death is defined as a mechanism of cellular
suicide which occurs after sufficient cellular damage. It is characteristically
different from cell necrosis in morphology and biochemistry.
 1. Condensation of the nucleus (pyknosis), and the cell shrinks.
 2. Chromosomal fragmentation (karyorrhexis) due to the controlled
digestion of DNA by apoptosis DNAses.
 3. Cytoplasmic blebbing and apoptotic bodies
 The end result of apoptosis is cell death without directly causing
inflammation of the surrounding tissue.
 However, apoptosis can indirectly promote an inflammatory response: [see
image]
 1. Kupffer cells phagocytose apoptotic bodies but in process release
inflammatory cytokines (which can cause apoptosis)
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

2. The release of the contents of apoptotic bodies can act on Kupffer
cells to cause an inflammatory response [also: detection by stellate
cells leads to laying down collagen/fibrosis/cirrhosis]
Causes of apoptosis:
 CTL/NK signalling [cell signalling]
o Fas(on the apoptosing cell)/FasL or TRAIL signalling from
memb  caspases  mt permeability  apop
 Soluable ligand signalling
o TRAIL-R or TNFR at memb signal more directly for mt
permeativity  apop
 ER stress signalling
o Viruses make the cell produce diff prots  many misfolding
 apoptosis
o Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency) is
a genetic disorder that causes defective production of alpha
1-antitrypsin leading to deposition of excessive abnormal
A1AT protein in liver cells  inc apop due to ER stress
[also: excessive neutrophil elastase activation in the lung]
o The underlying causes of nonalcoholic fatty liver disease
(NAFLD) are unclear, although recent evidence has
implicated the endoplasmic reticulum (ER) in both the
development of steatosis and progression to nonalcoholic
steatohepatitis: Non-alcoholic steatohepatitis (NASH) is the
most extreme form of NAFLD, and is regarded as a major
cause of cirrhosis of the liver of unknown cause [saturated
Fas are an ER stress as below and signal for apop 
cirrhosis]
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-
Death ligands and receptors
o Fas-FasL
 ↑Viral hepatitis, Cholestatic liver disease, NASH
 ↓HCC
o TRAIL-DR4/DR5
 ↑ viral hepatitis, steatosis (hepatocytes)
 ↑ PBC, PSC (chlangiocytes)
o TNF-α
 Inc in: Alcohol, viral hepatitis, ischaemia-reperfusion injury
-
Caspases
o Cysteine-dependent aspartate specific proteases
o Synthesized as zymogens and require activation by other caspases to function
o Initiator caspases: 7,8,9,10
o Scaffolding functions
o Executioner (effector)
o Activate DNAse
-
Bcl-2 family of proteins
o Regulate mitochondrial dysfunction during apoptosis
o Pro-apoptotic
 Bax, Bak, Bok, Bid, Bim, Bad, Bmf, Hrk, Noxa, PUMA
o Anti-apoptotic
 Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1
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Effector cells
o Neutrophils
o Natural killer (NK) cells
o T cells: CTLs
 Can signal for death of a target cell indirectly
 via IFN / TNF  apop
 Can signal for death of a target cell directly
 via Fas/FasL signalling  apop
 OR secretion of perforin and granzymes while attached to target cell
 granzyme entry through PM or endosomes  apop
o Activated macrophages
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-
Lysosomal pathway
o Proteases (eg LPM) leaking out of lysosomes can induce apoptosis
o Process can be triggered from death receptor signalling
o Implicated in:
 Cholestasis [condition where bile cannot flow from the liver to the
duodenum]
 NASH (mentioned above) [Nonalcoholic steatohepatitis]
 Ischaemia/reperfusion injury
-
Necrosis
o “Accidental” form of cell death
o Cell and organelle swelling
o Plasma membrane rupture
o Release of cellular constituents
 This can lead to further necrosis: neutrophils become activated due to the
contents of the fractured hepatocytes and produce oxidants and proteases
in response which causes necrosis of other hepatocytes
o Causes:
 ATP depletion (ischaemia/hypoxia)
 Formation of ROS (hypoxia/FA metabolites)
 Toxins (paracetemol): Toxic metabolites of paracetamol  necrosis 
DAMPs released  colatteral damage of nearby cells which apoptose in
response
o Biochemical features of necrosis
 Receptor interacting proteins (RIP1, 2, 3)
 Interact with death receptors and caspases (RIP1+2)
 RIP3 activation→ATP depletion
 Necrostatin (inhibits RIP)
 ↑Mitochondrial permeability (inner and outer leaflets) →↓oxidative
phosphorylation→ATP depletion
-
Apoptosis vs necrosis:
o Nb mt have role in both apoptosis and necrosis: convergence of signalling
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-
Viral hepatitis overview
o Acute
 A,B, C, D, E, non-A-E
 Acute liver damage:
 Death
 Full repair
o Acute and Chronic
 B,C,D
 Chronic:
 On-going process of liver damage
 Healing by regeneration of fibrosis
-
Detecting Viral hepatitis:
o Detect VIRUS (PCR, antigens, etc)
 Diff profiles of DNA and antigen etc through time for acute vs chronic vs
fulminant [see image below]
 Diff antigens present in diff stages of the disease [relavant to below images]
 Eg HBeAg implies active viral replication
 Eg HBsAg just indicates viral envelope
 Abs against these antigens may be neutralising or non-neutralising
depending on accessibility of the antigens
o Detect IMMUNE RESPONSE (detect antibodies)
o Detect LIVER CELL DAMAGE [detect ALT, AST, ALP liver enzymes]
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[constant viral load and constant damage at liver; replacement of hepatocytes with scar tissue
occurs; stellate cells have role in laying down collagen]]
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[so much damage in acute period that gives liver failure; CTL response contributes to this damage]
-
HEV
o
o
o
-
10-20% mortality in Endemic areas
Dafur:
 253 hospital admission with presumed HEV
 39.1% encephalopathy
 17.8% case fatality overall
 31.1% if pregnant
UK
 Increasingly being recognised
 Not necessarily associated with travel to endemic areas
Global Importance of Hepatitis B and C
o Hepatitis B is one of the top 10 causes of death worldwide
o Consequences of chronic hepatitis infection [constant damage and repair]:
 Cirrhosis
 Hepatocellular carcinoma
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-
Fibrosing cholestatic hepatitis:
o is a rapidly progressive, sometimes fatal form of liver injury: Rapid progression to
liver failure occurs because the patient is immunosuppressed for a given reason
 Ie immune response is low as illustrated below
o Most common in liver transplant recipients with recurrent hepatitis B
o High levels of HBV; therefore high levels of the following detected:
 sAg
 DNA
 eAg
-
Summary of HBV:
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12/12/13: Liver structure and function: Heather Lewis
Los (from booklet):
Lecture 14 Liver structure and function Heather Lewis
be able to describe the key functions of the liver
Notes:
-
Summary / preview:
o Liver buffers blood glucose
o Important in de- and transamination of amino acids
o Can metabolise fat, synthesise cholesterol, lipoproteins, phospholipid
o Produces bile- digestion and excretion
o Can store nutrients and vitamins
o Protects body from gut bacteria
-
Liver disease mortality is increasing (esp in Scotland)
-
Liver structure and overview [strong overlap here with the anatomy course]
o The 2 corners of the liver are 1.25 cm below each nipple and at the 10th rib on the
right side
o ‘Anatomical’ lobes based on the attachment of the mesenteries
o Boundary between the territories of the left and right branches of the hepatic artery
is important
o This puts the small lobes (caudate and quadrate) in with the functional left lobe
o 8 functionally independent segments
 Numbered clockwise
 Caudate lobe (segment 1) posteriorly; then numbered clockwise when
viewing from front
 This is schematic- anatomical variants frequently occur
 Each segment can be resected without damaging those remaining Centrally
positioned: portal vein, hepatic artery and bile duct
 Peripherally positioned: hepatic vein
o Blood Supply of the Liver
 Rich blood supply- 25% of resting cardiac output
 Dual blood supply:
 20% arterial blood from the hepatic artery (left and right branches)
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
o
o
o
o
80% venous blood draining from the gut through the hepatic portal
vein (HPV) - rich in absorbed nutrients which must pass through liver
The liver and biliary system share a common origin with the ventral pancreas at the
beginning of the midgut [see image below]
NB anatomical lobe vs functional lobe vs segments vs acinus vs lobules:
 Lobule
 Histological (morphological unit)
 Easily identified
 Hepatic vein at centre
 Acinus
 Functional unit
 Less clearly identified
 Unit of hepatocytes aligned around hepatic arterioles and portal
venules
 Acinus divided into zones dependent on proximity to arterial blood
supply
Cell types in the liver
 Hepatocytes
 c.80%
 Endothelial cells
 Lining blood vessels and sinusoids
 Cholangiocytes
 Lining biliary structures
 Kupffer cells
 Fixed phagocytes (liver macrophages)
 Hepatic stellate cells
 Vitamin A storage cells (Ito cells), may be activated to a fibrogenic
myofibroblastic phenotype [ie then role in fibrosis/cirrhosis]
Liver Function
 Digestion
 Biosynthesis
 Energy metabolism
 Degradation/detoxification
 All functions are carried out by the hepatocytes except for the breakdown
and recycling of red cells, which is carried out by fixed macrophages (Kupffer
cells) in the endothelial lining of the blood sinusoids
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Glucose metabolism
o Important to control blood glucose (cf. endocrine)
o After a meal:
 blood glucose 
 taken up by tissues
 stored as glycogen (muscle and liver)
o Between meals:
 breakdown of liver glycogen maintains blood glucose concentration
between meals (also occurs in muscle but muscle cannot release glucose to
blood for use in rest of the body)
o 24h fast:
 will exhaust liver glycogen (80g) - then Gluconeogenesis; The process of
synthesising glucose from non-carbohydrate sources.
 1) From lactate [NB cori cycle]
o
Lactate  Pyruvate  Glucose


-
2) From amino acids via deamination:
o
e.g. Alanine  Pyruvate  Glucose
3) From Triglycerides :
o
TG  Fatty acids and Glycerol  Glucose
Protein metabolism
o Synthesis 90% of plasma proteins (remainder are -globulins).
 Makes 15-50 g/day.
 Importance of plasma proteins: binding/carrier function, plasma COP
[colloid osmotic pressure re oedema]
o Synthesis of blood clotting factors
o Synthesis of dietary “non-essential” amino acids by transamination.
 Start with appropriate -keto acid precursor
 Exchange of an amine group and ketone group
 Glutamic acid: common intermediate
 Eg AA + -ketoglutaric acid  -keto acid + glutamic acid [THEN:]
 Eg Pyruvic Acid + Glutamic Acid  Alanine + alpha-ketoglutaric Acid
 Essential amino acids:
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 lys, met, val, leu, thr, phe, ile, tyr,
 do not have appropriate keto acid precursors.
o Deamination
 Prior to use as an energy source
 Primarily glutamic acid as the end product of transamination reactions
 amino acid + ketone  keto acid + ammonia
 eg Glutamic acid + NAD+ + H2O  NADH + H+ + NH3 + -ketoglutaric
acid
 Urea:
 Metabolism of -NH2 leads formation NH3
 NH3 is toxic - particularly to CNS
 Liver converts NH3 to urea
 Urea very water soluble, metabolically inert, non-toxic. Excreted in
urine
 2NH3 + CO2  UREA + H2O
Fat metabolism
o Main energy store: =100x glycogen.
o In adipose and liver
o Lipogenesis of glucose and amino acids to fat
 Generates Cholesterol, phospholipids, triglycerides
 Phospholipid: fatty acid, phosphate and a nitrogen-containing base
 Cholesterol: synthesis of sterol nucleus from AcetylCoA .
o Used in synthesis of steroid hormones/bile salts
 Phospholipids and cholesterol important role in membranes of cells
and organelles
 Lipoproteins used for transport: contain triglyceride, cholesterol,
phospholipid and a protein coat (apolipoprotein)
 Various types depending on composition and specific gravity: [chylomicrons: mainly TGs: are lipoprotein particles that consist of
triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%),
and proteins (1-2%)]
 VLDL - lot of triglycerides
o The form exported by the liver
 LDL - high cholesterol & phospholipid. “Bad cholesterol”
o atherosclerosis
 HDL - high protein content. “Good cholesterol”
o Metabolises fats as energy source:
 FA’s to AcetylCoA  TCA cycle in liver
 OR: 2AcetylCoA  acetoacetic acid [transported in blood]  2AcetylCoA
[reformed at tissues for use as energy source]
Bile production
o Continually secreted by liver
 Cholesterol + addition of carboxyl and hydroxyl groups  (Chenodeoxy)
cholic acid (primary bile acids)
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
-
primary bile acids + conjugation with taurine or glycine  Bile acid
conjugates / “bile salts”  release to gall bladder
o Stored and concentrated in gall bladder (15-60ml)
o Major components:

bile salts (50% dry weight)

cholesterol

phospholipids (lecithin)

bile pigments (bilirubin, biliverdin)

bicarbonate ions and water
o Separately, some components would be insoluble, but together, bile is stable
 conjugation step changes the pKs of bile acids and causes them to become
much more water soluble
o Bile Functions
 digestion/absorption of fats
 Lipids are poorly soluble in water, which makes digestion more
complex
 Four stage process in the small intestine
o Secretion of bile and lipases
o Emulsification [amphipathic nature of bile salts is utilised]
o Enzymatic hydrolysis of ester linkages
o Solubilization of lipolytic products in bile salt micelles
[amphipathic nature of bile salts is utilised]
 excretion of a variety of substances via GI tract
 Liver breaks down/inactivates steroid and peptide hormones.
Secreted into bile for excretion
 Also performs similar role with variety of “foreign” compounds usually drugs
 Excretory route for excess cholesterol: lecithin allows more
cholesterol in micelles.
o Too much cholesterol  gall stones
 Excretion of bile pigments.
o Bilirubin : old RBC breakdown of haem; 15% from other
proteins [nb Iron: removed in spleen and conserved]
o Porphyrin group is reduced to bilirubin, conjugated to
glucoronic acid
o Liver disease can result: bile pigment gallstones
 neutralises acid chyme from stomach
 ?signalling
Other functions
o Larder Functions of Liver:
 Storage of fat soluble vitamins (A,D,E,K): Stores sufficient 6-12 month
except Vit K (blood clotting) where store is small.
 Storage of iron as ferritin:
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
o
o
Free iron in gut binds to apoferritin [apoprotein capable of storing
iron in bodily cells] and is transported across the basolateral
membrane into the blood.
 In the circulation, iron is bound to a b-globulin called transferrin,
which transports it from the small intestine to storage sites in the
liver where it will again be stored as a complex with apoferritin]
 From the liver, iron is transported to the bone marrow [prob via
transferrin], where it is released and utilized in the synthesis of
haemoglobin: Available for erythropoeisis
 Storage Vit B12 :
 pernicious anaemia, nerve demyelination [see pukka explanation]
 Glycogen and fat store
Protection:
 macrophages (Kupffer cells) in sinusoids prevent bacteria crossing to blood
from gut.
2+
Ca metabolism :
 UV light converts cholesterol to preVitamin D; then Requires 2x
hydroxylation to activate it:
 First is in the liver [therefore Rickets from liver disease in children;
adults get Osteomalacia]
 Second in the kidneys
 active form of vitamin D: 1,25-dihydroxycholecalciferol
 promotes Ca2 absorption from the small intestine by inducing the
synthesis of vitamin D–dependent Ca2 -binding protein (calbindin D28K) in intestinal epithelial cells
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12/12/13: Pathophysiology of Portal hypertension /
Cirrhosis and portal hypertension: Ameet Dhar
Los (from booklet):
Notes:
-
Conclusions / preview:
- Chronic liver disease is common and increasing
- Despite new therapies patients continue to die from the complications of portal
hypertension
- Current understanding of the pathophysiology of portal hypertension suggests
numerous avenues for further exploration.
-
Hepatic haemodynamics
o Liver blood flow:
 Portal vein: 1.2L/min (75% total blood flow)
 Hepatic artery : 400ml/min (total blood flow 25%)
 Hepatic vein: 1.6L/min
o 100% of portal blood flow is recoverable from hepatic veins in healthy liver
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o
Portal circulation is obstructed - collateral circulation develops to carry portal blood
into the systemic veins (porto-systemic shunting)
-
Causes of end stage liver disease:
o Alcohol and HepB/C are the main causes:
-
What is cirrhosis?
o End result of a number of chronic liver diseases
o Results from Hepatic fibrosis [fibrosis is a less severe form of cirrhosis]
 Normally tissue damage  inflam  repair
 Critical role of stellate cells in fibrosis:
 become activated due to inflammatory factors then give
fibrogenesis:
o With repeated damage fibrosis occurs instead or repair;
directly due to stellate cell action: give inc ECM: (type 1
collagen , fibronectin, proteoglycans)
 Other stellate cell actions:
o Proliferation
o Chemotaxis
o White blood cell chemo-attraction
o Contractility: impedes blood flow
o Matrix degradation: via matrix proteases: ie doesn’t just
synth ECM but is a balance: In cirrhosis collagen formation is
greater than breakdown due to the action of tissue
inhibitors of matrix metalloproteinases (TIMPS)
o Nodular regeneration of the liver
o Disruption of liver architecture
o Compensated versus decompensated
 Compensated cirrhosis [1% 1 yr mortality]
 No Ascites
 No Varices
 Decompensated cirrhosis: [each step down chain is associated with a jump
in mortality rate]:
 No Ascites, Varices
o Ascites +/- Varices
 Ascites +/- Bleeding [57% 1 yr mortality]
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o
o
Clinical features of decompensated cirrhosis:
 Encephalopathy
 Jaundice
 Ascites
 Liver flap
 Peripheral oedema
 -pulmonary hypertension [coexistence of portal and pulmonary
hypertension]
 In portal hypertension, blood will shunt from portal to systemic
circulation, bypassing the liver. This leaves unmetabolized
substances to reach and attack the pulmonary circulation. Ie liver
would otherwise change the levels of such substances
 Serotonin, normally metabolized by the liver, is returned to the lung
instead where it mediates a smooth muscle hyperplasia and
hypertrophy.
 hepatopulmonary syndrome: [syndrome of shortness of breath and
hypoxemia (low oxygen levels in the blood of the arteries) caused by
vasodilation (broadening of the blood vessels) in the lungs of patients with
liver disease]
 In portal hypertension, blood will shunt from portal to systemic
circulation, bypassing the liver. This leaves unmetabolized
substances to reach and attack the pulmonary circulation.
 The mechanism is unknown but is thought to be due to increased
hepatic production or decreased hepatic clearance of vasodilators,
possibly involving nitric oxide
 The endothelin-1 vasoconstrictor is often found elevated in cirrhotic
and portal hypertensive people etc
Cirrhosis: complications
 Poor synthetic function
 Heptocellular carcinoma
 Portal Hypertension
 PHT = pathological increase in the heptic venous pressure gradient
(pressure difference between the portal vein and the inferior vena
cava)
 Can arise from any condition interfering with blood flow at any level
within the portal system
 Cirrhosis is by far the most common cause of portal hypertension
(90%) [can largely be considered equivalent]: two factors contribute:
o Increased blood flow TO the liver
 Splanchnic vasodilation mediated by circulating NO,
PG12, CO, endocabinoids, Glucagon, etc
 On top of the vasodilation itself in the splanchnic
region, it will also cause a fall in systemic MAP
causing renal vasoconstriction and thus inc flow to
the liver
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
o
Lung vasoconstriction as mentioned above will
contribute to in flow to portal system too
 Splanchic angiogenesis contributes too
Increased resistance to flow THROUGH the liver
 The Primary factor in development of PHT
 Mechanical: architectural disturbances [nodule
formation, etc], fibrosis and vascular occulusion
 Dynamic: Endothelial dysfunction gives increase to
vascular tone
 Active contraction of portal/septal
myofibroblasts



-
Activated hepatic stellate cells/vascular
smooth muscle cells: which then contract
Increased vasoconstrictors in cirrhosis and
response of hepatic vasc bed
o Endothelin
o Angiotensin
o Nor-adrenaline
o Leucotrienes/thromboxane A2
Decreased Vasodilators and defective
response to vasodilators
o Nitric oxide: dec eNOS activity and
inc NO scavenging
portal hypertension in detail:
o How do we measure portal pressure?
 Hepatic Venous Pressure Gradient (HVPG) = (WHVP- FHVP)
 Normal HVPG= 1-5 mmHg
 Clinical significant PHT: HVPG> 10 mmHg
 5-9 mmHg = pre-clinical portal hypertension
 Wedged hepatic venous pressure= WHVP (balloon occlusion in HV) =
pressure in portal venules which is a surrogate for PV pressure
 Free Hepatic Venous Pressure= FHVP (catheter withdrawn into HV)
o Subtypes:
 Prehepatic :



PVT: portal vein thrombosis
 Normal Wedge and Free Hepatic venous pressures (FHVP)
Intrahepatic :
 Cirrhosis: (Liver disease)
 Increased Wedge pressure and FHVP
Post hepatic:

Budd-Chiari (Hepatic venous outflow obstruction due to

thrombus)
Increased Wedge pressure and FHVP
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o
o
Clinical manifestations: other organs
 Heart: ↑ baseline CO, impaired contractility to stimuli
 Brain: changes in cerebral blood flow, vasc reactivity- contributes to
encephalopathy
 Blood:
 low plats/Hb, WCC (pancytopaenia)
o - splenomegaly/”hyperplenism”
o - Reduced thrombopoietin production (plats)
 Skin: bounding pulses, palmar erythema, spider naevi
Complications
 Varices and variceal bleeding
 Portal hypertension leads to formation of collaterals
 Portal blood flows through these channels in an attempt to
circumvent the resistance of the liver
 Examples of these collaterals are
o Oesophageal varices
o Caput medusae
o Spleno -renal shunts
o Many others
 Small varices get larger (12%/year) and bleed (12% at 2 years)
 Risk of bleeding proportionate to +/- red signs and clinical condition
of the patient
 Mortality of first bleed remains high (10-30%) despite numerous
therapies
 Principles of treatment of varices:
o
Vasoactive Drugs [eg somatostatin or octreotide
[mimics natural somatostatin
pharmacologically] cause vasoconstriction in the
o
blood vessels but reduce portal vessel pressures in bleeding
varices]: Rationale:
 Drugs which lower portal pressure may arrest
haemorrhage
 Endoscopic expertise may not be available
 Re-bleeding and subsequent mortality may be
reduced
 Drugs may make endoscopic therapy more effective
Terlipressin (also a vasoactive drug)
 Synthetic vasopressin analogue Tri-glycyl-lysine
vasopressin
 Slow breakdown in vivo to Vasopressin
 Intrinsic vasoconstrictor activity
 Reduced hepatorenal syndrome, dec splanchnic
vasodilation, inc kidney perfusion; Maintains hepatic
blood flow [prob is not the problem; hepatic
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o
perfusion is high] whilst decreasing portal pressure
(selective splanchnic vasoconstrictor)
 Increased collateral resistance
 Terlipressin decreases mortality if given early
Endoscopy
 Endoscopic rubber band ligation: band to tie off the
varices
 Injection of sclerosing agent: glue to block off the
veins
o Transjugular Intrahepatic Portosystemic
Stent Shunting (TIPS)

o

Formation of a tract between the HV and the
intrahepatic segment of the PV
 Therefore reducing IR
 Aim to reduce HVPG <12
 Technically successful in >90%
 Controls acute haemorrhage >95%
 Encephalopathy in 25%
 Diastolic dysfunction on ECHO implies poor
prognosis
Novel future targets
 COX derived vasconstrictor prostanoids: TXA2/PGH2
 COX-1 enzyme derived PGs promote ↑
intrahepatic resistance/resistance to portal
inflow
 NO donors/NO-hepatic delivery
 Statins:
 enhance endothelial cell NO production
 reduce stellate cell contraction
Ascites
 Definition: pathological accumulation of fluid within peritoneal
cavity.
 Ascitic fluid accumulation = excess of total body sodium and water
o May leak
o May get a hydrothorax
 Pathophysiology: 3 proposed theories
o Underfilling theory
o Overflow theory
o Arterial vasodilatation theory
 most widely accepted theory of ascites
accumulation
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

Secondary reduction in effective arterial blood
volume due to: [ie the reasons for inc flow to
splanchnic region]
 - Splanchnic vascular bed vasodilatation
 - Peripheral arterial vasodilation (e.g. NO)
 Increase in vascular resistance: [ie the blood cannot
escape so builds up]
 - portal hypertension
 - increase in filtration/lymph formation
  Ascites
 Treatment of ascites
o Bed rest and Na+ restriction:
 Upright posture
 Increase net Na+ loss by reducing intake
o Diuretic therapy:
 ↑ urinary Na+ excretion (reducing renal tubular Na+
reabsorption)
 - Aldosterone antagonist - spironolactone
 (mineralocorticoid rec in collecting tubular
epithelial cells)
 - Loop diuretics - frusemide
 (inhibition of Na+-K+-2Cl- co transporter at
loop of henle)
o Paracentesis:
 is a procedure in which a needle or catheter is
inserted into the peritoneal cavity to obtain ascitic
fluid for diagnostic or therapeutic purposes
o Liver transplant
Encephalopathy
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Summary
- The gastrointestinal tract is innervated by both the parasympathetic and sympathetic
nervous systems, which converge on the intrinsic nervous system in the myenteric and
submucosal plexuses.
- Gastrointestinal peptides are secreted by cells of the gastrointestinal tract and include the
hormones gastrin, CCK, secretin, and GIP, which are released into the circulation; the
paracrines somatostatin and histamine, which act locally; and neurocrines, which are
released from nerves.
- Slow waves in gastrointestinal smooth muscle cells are spontaneous depolarizations and
repolarizations of the membrane potential. Action potentials are fired if the membrane
potential reaches threshold as a result of a slow wave. Thus, the n of slow waves
determines the frequency of action potentials and, consequently, the frequency of
contractions.
- Gastric motility includes mixing and grinding of ingested food. Small intestinal motility
includes segmentation contractions, which mix chyme with digestive enzymes, and
peristaltic contractions, which move the chyme in the caudad direction. In the large
intestine, mass movements push the fecal material over long distances and eventually into
the rectum, where it is stored until defecation occurs.
- Salivary secretion is utilized for buffering and dilution of foods and for initial digestion of
starch and lipids. Saliva is hypotonic and is produced by a two-step process involving
formation of an initial saliva by acinar cells and its modification by ductal epithelial cells.
- Pancreatic secretion contains HCO3 for the neutralization of H from the stomach and
enzymes for digestion of carbohydrates, proteins, and lipids. Pancreatic juice is isotonic and
is produced by a two-step process. The acinar cells secrete the enzymatic component,
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centroacinar and ductal epithelial cells secrete the aqueous HCO3-containing component,
and ductal cells modify the secretion.
Bile salts, the major constituents of bile, are used for emulsification and solubilization of
lipids, aiding in their digestion and absorption. Bile is produced by hepatocytes, stored in the
gallbladder, and secreted into the intestine when the gallbladder contracts. Bile salts
solubilize and form micelleswith the products of lipid digestion. Approximately 95% of bile
acids are recirculated to the liver via the enterohepatic circulation.
Carbohydrates must be digested to monosaccharides for absorption. The digestive steps are
carried out by salivary and pancreatic amylases and disaccharidases in the intestinal brush
border. Glucose and galactose are absorbed by intestinal epithelial cells by Na -dependent
cotransporters, and fructose is absorbed by facilitated diffusion.
Proteins are digested to amino acids, dipeptides, and tripeptides for absorption. The
digestive steps are carried out by pepsin, trypsin, and other pancreatic and brush-border
proteases. Amino acids, dipeptides, and tripeptides are absorbed by intestinal epithelial cells
by Na or H-dependent cotransporters.
Lipids are digested to monoglycerides, fatty acids, cholesterol, and lysolecithin by pancreatic
enzymes. The products of lipid digestion are solubilized in micelles with bile acids. At the
apical membrane of intestinal epithelial cells, the lipids are released from the micelles and
diffuse into the cells. Within the cells, they are packaged in chylomicrons and transferred
into lymph vessels by exocytosis.
Approximately 9 L of fluid is absorbed daily by the gastrointestinal tract. The volume of fluid
absorbed is approximately equal to the sum of the volume ingested and the volume
secreted in salivary, gastric, pancreatic, and intestinal juices. Diarrhea results if absorption is
decreased or if secretion is increased.
Gastric glands: is the general term; the order down the gland given below but as is known
not all the cells will coexist in a single gland; ie pyloric and oxynitic glands differ: [‘true’
gastric glands are in the central stomach areas but mainly used as a general term for any
stomach glands]
Location Name
Description
Secretion
Staining
In gastric pits.
mucus gel layer
Clear
Isthmus
Mucous neck
cells
Neck
Between the chief cells and
thebasement membrane, larger oval
cells, which stain deeply with eosin, are
gastric
parietal (oxyntic) found; these cells are studded
acidand intrinsic
cells
throughout the tube at intervals, giving
factor
it a beaded or varicoseappearance.
These are known as the parietal
cells or oxyntic cells, and they are
Acidophilic
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connected with thelumen by fine
channels which run into their
substance.
Base
At the point where they open into the
duct, which is termed the neck,
the epithelium alters, and consists of
short columnar or polyhedral, granular
chief
cells, which almost fill the tube, so that
pepsinogen,rennin Basophilic
(zymogenic) cells the lumen becomes suddenly
constricted and is continued down as a
very fine channel. They are known as
thechief cells or central cells of the
glands.
Base
G cells are a type of enteroendocrine
cell that secrete the hormone gastrin
enteroendocrine (gastrin promotes the secretion of
(APUD) cells
pepsinogen (by chief cells) and HCl (by
parietal cells) and promotes gastric
contractions to mix contents).
hormones
-
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