GIT high and low Flashcards

Question 1

Q

Describe the features of the oral cavity

Answer

A

Muscles of the oral cavity
- walls of the oral cavity are comprised of the buccinator, which holds the cheek against the alveolar arches
- the floor is comprised of the mylohyoid and geniohyoid, which together help depress the mandible to open the mouth

Question 2

Q

Describe the features of the pharynx

Answer

A

Pharynx
- the common pathway for food via the oesophagus, and air via the trachea
- spans base of skull to C6
- food is blocked
- from nasal cavity by soft palate
- from larynx by epiglottis

![[Pasted image 20240430084725.png]]

The pharynx is made of striated muscles:
- constrictors (superior middle and inferior) - the external layer, contracts sequentially to push food bolus down to oesophagus for swallowing
- superior attaches to pterygomandibular ligament: site for administration of inferior alveolar nerve block
- longitudinal muscles/internal layer: palat0/salpingo/stylopharyngeus, elevate the pharynx
- salpingo: eustachian tube and constrictors
![[Pasted image 20240430084743.png]]
![[Pasted image 20240430084753.png]]

Question 3

Q

Describe the features of the oesophagus

strictures and sig, musculature, anatomical rels

also blood veins nerves lymphatics

Answer

A

Oesophagus
The oesophagus has three constrictions, as it passes various anatomical structures:
- at junction with pharynx i.e. upper sphincter - cervical C6/7
- crossing with aortic arch and L main bronchus - T3/4 / bronchoaortic
- passing oesophageal hiatus: diaphragmatic - T10/11

Clinical significance:
- common site of damage
- foreign bodies
- passing endoscope
- estimating distance of nasogastric tube

There are three parts to the oesophagus:
- cervical: C6 to jugular notch
- thoracic: jugular notch to oesophageal hiatus, longest portion
- abdominal: hiatus to cardia, shortest portion

Anatomical relationships:
- cervical: posterior to the trachea, lateral: carotid sheath (Artery, IJ vein, vagus n.)
- thoracic: in posterior mediastinum i.e. posterior to the heart, left atrium; anterior and right to aorta

The regions of the oesophagus have unique musculature, blood supply and lymphatics:
- upper third is striated muscle
- middle third is a mix
- lower third is smooth muscle

Note these thirds do not relate directly to the divisions above

Arteries
- upper third of the oesophagus is supplied by inferior thyroid arteries (branch of thyrocervical trunk, branch of subclavian)
- middle third is supplied by oesophageal arteries (2-5 unpaired), branches of the thoracic aorta
- lower third is supplied by left gastric artery (branch of coeliac trunk, branch of abdominal aorta)

Veins
- upper third is drained by inferior thyroid veins, which drain into brachiocephalic veins and SVC
- middle third is drained by oesophageal veins, which drain into azygos vein and into SVC
- lower third is drained by left gastric vein, which drains into portal vein
- note that oesophageal and left gastric vein anastomose

NOTE ALSO: portal hypertension and oesophageal varices (As a consequence of anastomoses)

Lymph drainage
- upper third drained by deep cervical nodes
- middle third drained by superior and posterior mediastinal nodes
- lower third drained by left gastric nodes and coeliac nodes

clinical significance: cancer of the lower third often spreads to coeliac nodes and all regions that drain into the coeliac nodes i.e. stomach, duodenum, spleen, omenta

see also block 6

Innervation
Two main sources of innervation
- oesophageal plexus
- vagal trunks (vagus nerve – parasympathetic, and somatic motor in upper oesophagus)
- cervical and thoracic sympathetic trunks (sympathetic)
- enteric nervous system, see [[Anatomy B5 - Lecture 2]]
note: upper portion receives somatic innervation from recurrent laryngeal n

Question 11

Q

List the branches of the coeliac trunk

Answer

A

celiac trunk
- left gastric artery
- splenic artery (tortuous to accommodate for stomach movement inferior to it)
  - pancreatic
  - L gastroepiploic/gastro-omental (anastomoses with R counterpart) - note R and Ls serve greater curvature of stomach
  - short gastrics (fundus and upper portion of greater curvature)
common hepatic artery
- right gastric
- proper hepatic
- gastroduodenal (R omental)

Superior mesenteric
- midgut: duodenum, jejunum, ileum, large intestine to transverse colon
- several branches
- jujunal
- ileal
- vasa recta–> arterial arcades
- ileocolic
- colic branch
- anterior and posterior caecal
- appendicular
- right colic
- middle colic
- inferior pancreaticoduodenal

Inferior mesenteric
- hindgut: part of transverse, descending and sigmoid colon, rectum
- branches include:
- left colic
- asc and desc branches
- sigmodial aa
- superior rectal

Question 12

Q

What are the main tributaries to the portal vein?

Answer

A

‘special K’: Portal vein, into which drains
- SMV (continuous with portal vein)
- Splenic vein, which enters SMV
- IMV, which drains into splenic, into SMV, ultimately into portal vein
Note also pancreaticoduodenal, gastric, pancreatic veins

Question 13

Q

Draw the bile and pancreatic pathways to the duodenal exits/describe the biliary tree

Answer

A

from hepatocytes
- biliary canaliculi
- interlobular bile duct
- R and L hepatic ducts
- common hepatic duct (into which drains cystic duct)
- common bile duct (into which drains pancreatic duct) through head of pancreas
- ampulla of Vater, surrounded by sphincter of Oddi
- inserts into greater duodenal papilla

Question 14

Q

Describe the blood supply fo the hwole GIT, and venous drainage

Answer

A

Arterial supply
- celiac trunk
- left gastric artery
- splenic artery (tortuous to accommodate for stomach movement inferior to it)
- pancreatic
- L gastroepiploic/gastro-omental (anastomoses with R counterpart) - note R and Ls serve greater curvature of stomach
- short gastrics (fundus and upper portion of greater curvature)
- common hepatic artery
- right gastric
- proper hepatic
- gastroduodenal (R omental)

Veins of GIT
- ‘special K’: Portal vein, into which drains
- SMV (continuous with portal vein)
- Splenic vein, which enters SMV
- IMV, which drains into splenic, into SMV, ultimately into portal vein
- Note also pancreaticoduodenal, gastric, pancreatic veins

Superior mesenteric
- midgut: duodenum, jejunum, ileum, large intestine to transverse colon
- several branches
- jujunal
- ileal
- vasa recta–> arterial arcades
- ileocolic
- colic branch
- anterior and posterior caecal
- appendicular
- right colic
- middle colic
- inferior pancreaticoduodenal

Inferior mesenteric
- hindgut: part of transverse, descending and sigmoid colon, rectum
- branches include:
- left colic
- asc and desc branches
- sigmodial aa
- superior rectal

Veins of GIT
(See [[Anatomy B5 - Lecture 1]])
- note also L gastric straight to portal
- g omental v into inferior mesenteric V

Question 15

Q

Distinguish between the features of the jejunum and ileum

Answer

A

Jejunum and ileum
- jejunum mainly occupies upper quadrants
- ileum mainly occupies lower quadrants
- jejunum has longer vasa recta
- ileum has larger arterial arcades
- jejunum has thicker mucosa/submucosa: smaller lumen
- ileum has aggregated lymphoid nodules, jujunum does not

Jejunum vs ileum
![[Pasted image 20240430120824.png]]
- jejunum is deeper red, ileum is paler pink
- calibre is similar: 2-4 vs 2-3 cm
- wall is thick and heavy vs thin and light
- vascularity is greater vs less
- vasa recta is long vs short
- arcades: few short loops vs many short loops
- less mesenteric fat vs more
- circular folds are large, tall, and closely packed vs low distal and sparse – completely absent in distal part
- few lymphoid nodules or Peyer’s patches vs many

Question 16

Q

Describe the features of the liver

Answer

A

Liver

Position
- the diaphragmatic surface fits under the dome of the diaphragm
- ascends with expiration, descends with inspiration
- occupies both of right hypogastric and epigastric regions
### Anterior surface
- irregular, wedge-like shape
- covered by peritoneum
- diaphragmatic i.e. superior anterior surface, is convex, fits under the dome of the diaphragm
- key features include:
- diaphragm
- coronary ligament
- L triangular ligament
- falciform ligament
- R and L lobes
- round ligament, recall left-over from fetal circulation ([[Embryology B3 - Lecture 1]])

Visceral surface
- has four margins: anterior, posterior, left and right
- portia hepatis
- hepatic artery proper
- hepatic portal vein
- hepatic ducts
- key features include:
- R and L lobes
- caudate lobe
- quadrate lobe
- IVC
- bare area - uncovered by peritoneum, rougher texture
- portia hepatis: cystic duct, hepatic artery proper, hepatic portal vein
- R triangular ligament

Question 17

Q

17.describe the features of the appendix

Answer

A

Appendix\

*Appendix arises from the
caecum and is lined by large
intestine mucosa
* Abundant lymphoid tissue
in lamina propria and
submucosa

end of appendix can sit in several positions including
- preileal
- postileal
- prececal
- retrocecal
- subcecal
- pelvic
- promonteric
clinical significance: size and position can vary — influences where pain is perceived

Question 18

Q

Describe the embryology of the foregut

Answer

A

Foregut
- Function: transport and storage primarily, although the duodenum is, of course, involved in absorption. Stomach secretes acid and digestive enzymes, both sterilizing the food and initiating digestion.
- Derived structures: branchial structures (thymus, thyroid, parathyroid), lungs, esophagus, stomach, first part duodenum. Liver, gallbladder, pancreas.
- Local growth and differential growth create a large capacity part of the gut called the stomach. Differential growth causes it to rotate so that the left vagus comes to lie anteriorly, and the right posteriorly.
- Endodermal buds from the duodenum:
- Grow into the septum transversum to create the bile ducts and to interact with mesenchyme of septum transversum to form the liver (i.e. develops in ventral mesentery).
- Grow ventrally and dorsally to form pancreatic buds. Differential growth brings both buds together as pancreatic ducts on the left of the retroperitoneum. Generally, the two ducts fuse to form a single pancreatic duct, supplying a left-pointing retroperitoneal pancreas. The pancreatic head, uncinate process and its duct are the remains of the ventral duct and pancreatic bud. The dorsal duct forms the rest of the pancreas.
- The main blood supply of the foregut is the coeliac axis.

Foregut
Derived structures: branchial structures, lungs, esophagus.
- Six branchial arches e.g. hyoid, malleus, incus, stapedis, thyroid, thymus… (of which 1 is vestigial) form around developing pharynx.
- Mesoderm-derived. Endodermal coverings form thyroid, thymus, parathyroid, etc.
- Important in head and neck development.
- Lung formation
- laryngo-tracheal groove separates from oesophagus by end of wk 4 to make lung buds
- by day 20 neurenteric canal closes and notochord forms

“H” TOF - an issue: persistent connections between trachea and oesophagus, or interruption of oesophagus where distal oesophagus is continuous with trachea

Foregut
Local growth and differential growth create a large capacity part of the gut called the stomach. Differential growth causes it to rotate so that the left vagus comes to lie anteriorly (ventrally), and the right posteriorly.
- Ventral, becomes right-sided.
- Dorsal, becomes left-sided.

Foregut
Solid cord stage of gut development: 6 – 8 weeks.
- huge proliferation of tissue in duodenum
- dudodenum becomes solid
- lumen re-develops by 8 weeks
Foregut mal-development:
- Duodenal atresia - solid stage persists
- Thought to be a failure of recanalization of the solid cord stage
- Why? Local Wnt or Hox gene defect?
- Assoc with Down syndrome (~40%)

day 30: early bile duct and pancreas development

Question 19

Q

Describe the embryology of the midgut

Answer

A

Function: absorption of food.
Derived structures: small bowel from the second part duodenum to the ileo-caecal valve and colon to mid transverse. Vermiform appendix. Pathologically, may include Meckel’s diverticulum.
The main job of the small bowel is nutrient absorption, and to do this job properly given humans complex diet, we need length. During the first trimester, the midgut elongates greatly, protruding out from the abdominal cavity into the umbilical cord making the “physiological hernia”. Towards the end of the first trimester, the abdominal cavity grows to re-engulf the midgut, and as the midgut re-enters the abdominal cavity, it rotates around the axis of its artery 270° anticlockwise. This is the normal midgut rotation. It is surprisingly important.
The main blood supply around which the midgut rotates is the superior mesenteric artery.

Question 20

Q

Describe the embryology o fthe hindgut

Answer

A

Hindgut.
- 12 weeks: ganglion cell migration reaches the anus – enteric nervous system
- Function: salt and water reabsorption. Faecal storage until release is convenient.
- Derived structures: Mid transverse colon to the bottom of the rectum.
Sigmoid and rectum involved in storage pending defaecation.
- Bladder and urethra are endodermal derived, the urogenital sinus being divided from the rectum by the uro-rectal septum.
- Bladder originally drains into the allantois.
- The main hindgut blood supply is the inferior mesenteric artery.

Hindgut: cloacal region
The hindgut is progressively separated from the primitive urogenital sinus by an ingrowing fold – the uro-rectal septum, which grows from cranial to caudal to reach the cloacal membrane which then breaks down.
NB. Urogenital sinus also lined by endoderm.

Question 21

Q

Describe the innervation fo the GIT

Answer

A

Innervation of GIT
- sympathetic: thoracic splanchnic nerves
- parasympathetic: vagal trunks: anterior and posterior
- enteric

Innervation
- sympathetic which inhibits contraction muscle excitability
- PSY which enhances muscle excitability
- head, neck, thorax and body wall: paravertebral ganglia (Sympathetic trunk)
- abdomen and pelvis: paravertebral ganglia, coeliac, SMG, IMG

Sympathetic
- greater splanchnic nerve
- celiac ganglian
- stomach, liver, ?intestine, adrenal glands and kidneys
- lesser
- superior mesenteric ganglion
- small intestine
- lumbar splanchnic
- inferior mesenteric ganglion
- large intestine

Enteric nervous system
- System: mechanical and chemical receptors –> enteric reflex
- myenteric plexus: muscle motility
- submucous plexus: secretion and absorption

Question 22

Q

Describe the underlying genetic of Gilbert’s

Answer

A

Gilbert’s Syndrome
- Common: 3-7%
- Defect (extra TATA sequence) in promoter of bilirubin UDP-glucuronosyl transferase (BR-GT)
- Life-long, mild (BR rarely exceeds 50 µmol/L)
- Worse with fasting, stress
- No bilirubinuria; other LFTs normal
- No symptoms (minimal jaundice)

Question 23

Q

Describe the underlying gnetics of CRC

Answer

A

Familial adenomatous polyposis (FAP)
-mutations in the tumour suppressor gene, adenopolyposis coli (APC)
-APC degrades beta-catenin and inhibits cellular proliferation
-adenomas require inactivation of both APC alleles, but mutates for “second” hit
-autosomal dominant with near-complete penetrance of colonic manifestations (polyps) but
incomplete penetrance of extra-colonic manifestations (retinal pigment)

MUTYH associated polyposis (MAP)
-Autosomal recessive, result of germline mutation
-Phenotype resembles FAP
-mutation in base excision repair gene (mutY
homolog)
Hereditary non-polyposis colon cancer (HNPCC)
-Also known as lynch syndrome.
-Autosomal dominant disorder caused by germline
mutation in DNA mismatch repair genes
-2-3% of colon cancer cases and 2% of
endometrial cancers.
Diagnosis – 3-2-1 rule →
Abnormal function of mismatch repair enzymes resulting from germline mutation in allele +
inactivation of second by mutation, or epigenetic silencing by methylation leading to inactivation of
enzyme function

HNPCC – feature is microsatellite instability from abnormal gene
repair, often occurring in genes that control cell growth or apoptosis.
Immunohistochemistry available for visualising the expression of
mismatch repair enzymes.
Relevance – Treatment of CRC will be determined by underlying
genetic changes

Question 24

Q

Describe the genetics of lactose intolerance. Of lactose persistence/ Describe how lactose intolerancecan be diagnosed

Answer

A

Lactose Intolerance

Lactose

Disaccharide – glucose and galactose
- Main source of calories from milk of all mammals
Lactase: Brush-border enzyme hydrolyzing lactose
It peaks at birth, then starts to decline (lactase non-
persistence) following weaning in most human
populations, except for

Lactase Persistence Trait

Descendants of cattle domestication populations
Frequency varies across populations:
- High in northern European populations
- Intermediate in southern Europe and the Middle East
- Low in Asia and most of Africa
- Common in pastoralist populations from Africa
Lactase persistence is inherited as an autosomal dominant Mendelian trai

Genetics of Lactase (LCT) Persistence

Adult expression of lactase gene (LCT, 2q21) regulated by cis-acting elements
Variants associated with lactase persistence:
- C/T-13910
- G/A-22018
- within introns upstream of LCT
Multiple variants in different populations: T-13910 allele is ~86%–98% associated with lactase persistence in
other European populations

There are several lactase gene single SNVs in other populations.
People bearing these variants do NOT down-regulate lactase upon weaning
unlike the majority of the world’s population.
Lactase persistence developed independently in different areas of the world.
Multiple independent variants allowed various human populations to modify
LCT expression and have been conserved in adult milk-consuming populations,
emphasizing the importance of regulatory mutations in recent human evolution.

Diagnosing Lactose Intolerance

Classical history
Disaccharidase assays of small bowel biopsies - definitive test - includes lactase
- by endoscopy
Genetic studies (rarely necessary)
- genetic predisposition for lactose intolerance
- lactose tolerance test less used

Types of Lactose Malabsorption

Primary lactose malabsorption
- Racial or ethnic lactose malabsorption (as above)
- Developmental lactase deficiency - prematurity associated
- Generally result of prematurity
- Congenital lactase deficiency
  - Rare autosomal recessive disorder mainly in Finland
  - ~ 40 cases reported
Secondary lactose malabsorption

Due to intestinal disease e.g. coeliac disease, Crohn’s disease,
bacterial overgrowth

Question 25

Q

What is the role of APC gene and what do mutations APC predispose to?

Answer

A

Familial adenomatous polyposis (FAP)
-mutations in the tumour suppressor gene, adenopolyposis coli (APC)
-APC degrades beta-catenin and inhibits cellular proliferation
-adenomas require inactivation of both APC alleles, but mutates for “second” hit
-autosomal dominant with near-complete penetrance of colonic manifestations (polyps) but
incomplete penetrance of extra-colonic manifestations (retinal pigment)

Question 26

Q

The gut plays a role in the immune system. Describe in detail the three main protective mechanisms of the gut

Answer

A

Protective Mechanisms in the Gut
- Non-immunological defence mechanisms represent an important line of intestinal defence in addition to humoral and cellular immunity, and include:
- Microbiological defences (i.e., normal gut flora)
- Physical defences
- Chemical defences

Physical Defence Mechanisms
A single layer of intestinal epithelial cells (IECs) provides a physical barrier between the lamina propria (internal milieu) and the intestinal lumen, which contains normal gut flora and pathogens.

Physical Defences: Tight Junctions
- Intestinal epithelial cells are held together (cell-to-cell adhesion) by tight junctions, which form a seal against the external environment.
- Primary barrier to the diffusion of solutes and traversal of pathogens through the intercellular space, creating a boundary between the apical and the basolateral plasma membrane domains.
- Infection occurs only when a pathogen can colonize or cross through these barriers.
- Tight junction:
- ‘Kissing points’.
- No intracellular space.
- Adherens junction & Desmosomes:
- Opposing membranes are 15-20 nm apart.

Physical Defences: Epithelial Cell Turnover and Peristalsis
- Intestinal epithelial cell (IEC) turnover is constant (every 4-5 days) and involves:
1. Shedding of cells damaged by microbial infection or stresses.
2. Replenishment by intestinal stem cells.
- IEC turnover and peristalsis contractions help expel colonized pathogens and prevent overgrowth of normal gut flora.

Chemical Defence Mechanisms
- Often the first line of defence against infection.
- Certain chemicals are produced by the host to protect against infections by GIT pathogens:
- Bile: produced in liver, helps with digestion, antibacterial.
- Enzymes:
- Pepsin: produced in stomach, helps with digestion, antibacterial.
- Trypsin/chymotrypsin/lipase: produced in pancreas, help with digestion, antibacterial.
- Lysozyme: produced in upper intestinal tract, antibacterial.
- Gastric acid: produced in stomach, helps with digestion antibacterial.
- Mucus; viscous, antibacterial

Chemical Defences: Mucus
- Highly viscous, hydrophobic gel that covers mucosal surfaces and protects epithelial cells against chemical and microbial insult. For example:
- Microbes coated in mucus may be prevented from adhering to the epithelium.
- Mucus retains dimeric IgA to maximize exclusion of pathogens from gut epithelium
- Mucin glycoproteins are a major component of mucus and responsible for the viscosity of the mucus layer.
- Mucus layers range in thickness: 10 μm in the eye and trachea, 300 μm in the stomach, 700 μm in the intestine.
- Mucus layer is not static but moves to clear trapped material. For example:
- In GIT, the outer mucus layer is continually removed by peristalsis.

Chemical Defences: Mucus-Secreting Cells in the GIT
In the stomach:
- Surface mucus cells (within gastric pit).
- Neck mucus cells (within gastric gland).

In the small and large intestine:
- Brunner’s glands (within submucosa):
- Localized to the duodenum.
- Also produce alkaline fluids.
- Goblet cells (within epithelium).

Chemical Defences: Gastric Mucus Layer
- HCl (acid) produced by parietal cells in the human stomach is concentrated enough to digest the stomach itself, yet gastric epithelium remains undamaged because it is acid-resistant.
- Gastric mucus forms a protective layer over the gastric epithelium and acts as a diffusion barrier by secreting bicarbonate ions that remain trapped in the mucus gel, establishing a gradient: from pH 1-2 at the lumen, to pH 6-7 at the cell surface.

Chemical Defences: Intestinal Mucus Layer
- In the small intestine, the mucus forms a diffusion barrier containing antibacterial products that limit penetration by bacteria.
- In the colon, bacteria are compartmentalized to the outer loose mucus layer; the inner mucus layer, which is attached to the epithelium, is almost free of bacteria and protects the epithelium (because outer layer has trapped microbes).

How Can Pathogens Overcome the Mucus Barrier?
- Several pathogens have developed mechanisms to subvert mucosal defensive measures, colonize the GIT, and cause infection. Examples include:
- Helicobacter pylori (H. pylori) can swim through gastric mucus in the stomach and attach to epithelial cells beneath, where it can cause inflammation over the course of a lifelong infection. for more see [[Microbiology B5 - Lecture 2]]
- Enterohaemorrhagic Escherichia coli (EHEC) produce proteins that specifically degrade mucin to gain access to the intestinal epithelium.
- Defective mucus release, resulting in defective mucous layers and stagnation.

The Mucosal Immune System
- Immunological defence mechanisms represent an important line of intestinal defence in addition to non-immunological defence mechanisms that can be breached relatively easily.
- These defence mechanisms are referred to as the mucosal immune system and are specifically adapted to generate a response to antigens encountered in:
- Upper and lower respiratory tract.
- Urogenital tract.
- GIT.
- And exocrine glands associated with these organs, e.g., pancreas, salivary glands, etc.

As such, the mucosal immune system forms the largest part of the human body’s immune tissue.

Location of Immune Cells in the GIT
- Lymphocytes (Bs, Ts) and other immune-system cells (e.g., macrophages, dendritic cells) are found throughout the GIT, in organized tissues, and scattered throughout the surface epithelium of the mucosa and lamina propria.

Question 27

Q

Describe what gut-associated lymphoid tissue (GALT) is, its location and the cells involved

Answer

A

Gut-Associated Lymphoid Tissue (GALT)
- Organized lymphoid tissues in the gut are known as the gut-associated lymphoid tissue (GALT), for example:
- Peyer’s patches.
- Solitary lymphoid follicles of the intestine.
- Mesenteric lymph nodes.
- Appendix.
- Tonsils/adenoids

Peyer’s Patches
- Found in the small intestine (rich within the ileum), see also [[Anatomy B5 - Lecture 2]].
- Consists of many B-cell follicles with germinal centers, and smaller T-cell areas.
- Subepithelial dome (SED) is rich in dendritic cells, T cells, and B cells.
- Overlying the lymphoid tissue and separating them from the gut lumen is a layer of follicle-associated epithelium containing:
1. Conventional intestinal epithelial cells (enterocytes).
2. Specialized epithelial cells (microfold or M cells).

Question 28

Q

What immunoglobulin is associated with mucosal immune defences? What is the function of this?

Answer

A

The dominant class of antibody in the mucosal immune system is (dimeric) IgA.
To generate an IgA-mediated response to antigen, naïve B cells are activated by antigen as IgM-producing B cells in Peyer’s Patches and mesenteric lymph nodes, undergo isotype switching to IgA-producing B cells, and are then redistributed in the intestinal immune system.
Once in the lamina propria, plasma cells synthesize and secrete IgA into the subepithelial space.
To reach its target antigens in the gut lumen, IgA has to be transported across the epithelium, in a process known as transcytosis.

Translocation/Transcytosis of IgA
- Translocation of IgA across the IEC barrier is mediated through a process called transcytosis.
- IgA dimers are secreted by plasma cells in the lamina propria and bind to the polymeric immunoglobulin receptor (pIgR) on the IEC basolateral surface.
- The IgA-pIgR complex is endocytosed and transported to the apical surface for release to the intestinal mucus layer and intestinal lumen.
- Secreted IgA, together with the secretory component (SC; a proteolytic cleavage product of pIgR that remains associated with dimeric IgA), is known as secretory IgA (sIgA), which is important for neutralizing extracellular pathogens.

IgA Functions
Murphy et al. (2008)
- secreted IgA on gut surface can bind and neutralise pathogens and toxins
- IgA is able to bind and neutralise antigens internalised in endosomes
- IgA can export toxins and pathogens from the lamina propria while being secreted i.e. opsonisation
—

CD4+ T Cell Response
- To generate a T cell response, naïve T cells must be activated and redistributed in the intestinal immune system.
- Pathogens that penetrate the epithelium activate dendritic cells, to give strong co-stimulatory signals so that when they present antigen to naïve CD4 T cells in the lamina propria, effector TH1 and TH2 cells are generated to stimulate an active immune response.
- CD4 TH1 cells produce macrophage-activating cytokines.
- CD4 TH2 cells produce cytokines that stimulate B cells to produce antibodies.

CD8+ T Cell Response
- Peptides from invasive organisms bound to major histocompatibility complex (MHC) class I molecules on infected epithelial cells are recognized by intraepithelial lymphocytes (mainly CD8+ T cells loaded with antimicrobial proteins).
- CD8+ T cells then release antimicrobial proteins/cytotoxic signs, inducing death of infected cells eg by perforin/granzyme, Fas/FasL pathways. ^[recall also against tumour cells]

Question 29

Q

Describe the two mechanisms of direct antigen uptake in the gut

Answer

A

Mechanisms of Antigen Uptake
- Antigens present at mucosal surfaces must be transported across the epithelial barrier before they can stimulate the mucosal immune system.
- The intestine has distinct routes and mechanisms of antigen uptake:
- Uptake by Peyer’s patches, mediated by M cells.
- Direct uptake by dendritic cells.
- Both routes lead to T cell activation.

Antigen Uptake by M-Cells
- Microfold cells (M cells) mediate the transport of luminal antigens and bacteria across the epithelial barrier (transcytosis).
- M cells are localized to Peyer’s Patch lymphoid tissue.
- Antigens that are transported across the epithelial barrier are taken up by dendritic cells within Peyer’s Patches to facilitate antigen presentation to naïve T cells.

Antigen Uptake by Dendritic Cells
- Dendritic cells can extend processes across the epithelial layer to capture antigen from the lumen of the gut.
- This allows dendritic cells to acquire antigens across the intact epithelial barrier without the need for M cells.
- After antigen uptake, dendritic cells transport them to T cell areas eg Peyers, patches, or mesenteric lymph nodes via lymphatics that drain the intestinal wall.

Question 30

Q

Discuss immunological tolerance

Answer

A

Control of the Immune Response
- The majority of antigens encountered by the intestinal immune system are not derived from pathogens, but come from food and normal gut flora.
- As such, the intestinal immune system has evolved means to distinguish harmful pathogens from antigens in food and natural gut flora by:
- Producing strong effector responses to pathogens.
- Remaining unresponsive to foods and commensals.

Is the Normal Flora Ignored?
- Generally normal flora are unable to penetrate the epithelium
- The inability of normal flora to penetrate the epithelium as well as the downregulation of TLRs/NODs on the apical surface of epithelial cells means that they have a reduced ability to induce a localized epithelial cell-mediated inflammatory response.
- Even after their direct uptake by dendritic cells, there is production of TGF-β, thymic stromal lymphopoietin (TSLP), and prostaglandin E2 (PGE2) by gut epithelial cells, which maintain dendritic cells in a quiet state with low levels of co-stimulatory molecules, producing TH3 and Treg cells, which have a more immunomodulatory function.
- However, lack of tolerance to these bacteria in the systemic immune system means that **it will be able to generate protective immunity to them if they do enter other parts of the body and bloodstream.

Does the Normal Flora Overcome Immune Tolerance?
YES. For example:
- Massive influx of commensal bacteria overcomes these homeostatic mechanisms, resulting in full activation of the immune response eg C difficile (See [[Microbiology B5 - Lecture 1]], [[Microbiology B5 - Lecture 4]]).
- Or if regulatory mechanisms fail, unrestricted immune responses to normal flora can lead to inflammatory bowel diseases.

Immunological Tolerance to Food
- Food is not digested completely in the intestine, with significant amounts being absorbed into the body.
- Absorbed food is then taken up by mucosal dendritic cells that give weak co-stimulatory signals so that when they present antigen to naïve CD4 T cells, anti-inflammatory (TH3) or regulatory T cells (Treg) are generated.
- CD4+ TH3 cells produce transforming growth factor-beta (TGF-β) that has many immunosuppressive properties.
- CD4+ Treg cells produce the anti-inflammatory cytokine interleukin-10 (IL-10).

This lack of an inflammatory response in the intestine induces an active form of immunotolerance characterized by a state of long-lasting and antigen-specific unresponsiveness.
Breakdown of immunotolerance is believed to occur in celiac disease, where effector T cells generate a response against gluten found in wheat, resulting in inflammation that destroys the upper small intestine. ^[see also [[Gastroenterology - Lecture 1]]]

Question 31

Q

What are the presentations of a patient with coeliac disease

Answer

A

GI manifestations
* Vomiting
* Abdominal bloating
* Abdominal pain
* Variable bowel habit (both loose bowel motions and constipation)
* steatorrhea
* Iron deficiency anaemia

Question 32

Q

What are some extra-intestinal presentations

Answer

A

on-GI manifestations
* Lethargy, weakness
* Altered bowel habit
* Failure to thrive
* Recurrent or persistent iron deficiency anaemia
* Dental enamel defects
* Low vitamin D
* Delayed puberty and infertility
* Aphthous ulcers
* Raised transaminases
* Dermatitis herpetiformis

Question 33

Q

What is the pathology of coeliac

Answer

A

Pathogenesis
* Usually responds to strict exclusion of gluten
* Requires a specific genetic background (HLA DQ2 or HLA DQ8)
* Patients have circulating IgA autoantibodies to tissue transglutaminase (tTG) a ubiquitous enzyme that
catalyses deamination from a glutamine to lysine residue - increases afffinity for HLA
* 30-50% amino acids in gluten are glutamine
* A 33 amino acid peptide from alpha-2 gliadin, the main fraction of gluten binds to HLA class II DQ2 > DQ8
* These class II antigens loaded with peptide stimulate antigen-specific CD4 T cells and trigger an
inflammatory response and antibodies directed against tTG
* Only 1/50 of those who are HLA DQ2 or DQ8 positive develop coeliac disease with other genetic and/or
environmental factors contributing to development of the disease
* A number of non-HLA genes identified as conferring predisposition to coeliac disease

Diarrhoea related to villous atrophy i.e. flattening in the
small intestine resulting in mucosal
malabsorption (steatorrhoea) and lactase
deficiency, fluid hypersecretion from crypt
epithelia secondary to crypt hyperplasia

v
### Histology and pathology
* Macroscopic clues on endoscopy
* loss of folds, modularity, fissuring
* Multiple biopsies of the duodenum required
* duodenal bulb and second part of the duodenum
* Biopsies need to be performed while the individual is on a gluten-containing diet
* Histological diagnosis based on the classification of Marsh, Marsh modified or Corazza
classification

Increased HLA Class II and
cytokine expression precedes
abnormal histology
Intraepithelial lymphocytes
Crypt hyperplasia
Villous atrophy
Patchy involvement so multiple
biopsies required

Question 34

Q

What antibodies are involved? in coeliac

Answer

A

Requires a specific genetic background (HLA DQ2 or HLA DQ8)
Patients have circulating IgA autoantibodies to tissue transglutaminase (tTG) a ubiquitous enzyme that
catalyses deamination from a glutamine to lysine residue - increases afffinity for HLA
Serum IgA levels and tissue transglutaminase IgA antibodies or
tissue transglutaminase IgA antibodies and deaminated gliadin peptide IgG
(DGP - IgG)
IgA endomyseal antibodies (performed in limited laboratories)
Where tTG-IgA and/or DGP IgG positive refer for confirmatory small intestinal
biopsy

Question 35

Q

What tests are conducted for coeliac disease

Answer

A

Testing

Serology
* Firstly confirm that the patient is consuming a normal, gluten-containing diet
* Serum IgA levels and tissue transglutaminase IgA antibodies or
* tissue transglutaminase IgA antibodies and deaminated gliadin peptide IgG
(DGP - IgG)
* IgA endomyseal antibodies (performed in limited laboratories)
* Where tTG-IgA and/or DGP IgG positive refer for confirmatory small intestinal
biopsy

Genotyping
* HLA DQ2 and HLA DQ8 found in 99% of patients with coeliac disease
* 40-50% of the Australian community so most people with these genes will not
develop coeliac disease
* Main use of HLA DQ2/DQ8 genotyping to exclude a diagnosis of coeliac
disease

Question 36

Q

List causes of sepsis by abdominal region

Answer

A

Clinical Classification
- RUQ:
- Cholecystitis
- Liver pathology
- RLL pneumonia
- RLQ:
- Appendicitis
- Ovarian pathology
- Pyelonephritis
- Right sided diverticulitis
- Epigastric:
- Peptic ulcer disease
- Pancreatitis (usually radiates to back)
- Inferior myocardial infarct
- LLQ:
- Diverticulitis
- Ovarian pathology
- Pyelonephritis
- LUQ rare

Question 37

Q

Describe possibel presentaiton fo intra abdominal sepsis

Question 38

Q

Distinguish between UC and Crohn’s

Question 39

Q

List types of diahhoea and relevant history questions, and investigations for diarrhoa

Answer

A

inflammtory, secretory, osmotic; malabsorption/digestion; motility related fucntinal disease

Investigations:
- history: systemic disease; iatrogenic eg drugs radiation surgery; onset; pattern; duration; epidemiology; stool characteristic; abdominal pain and weight loss; aggrevating, mitigating – fasting improves osmotic

Question 40

Q

List questions on history diarrhia

Question 41

Q

Name causes of liver cirrhosis and describe the pathophysiology of 2 of these.

Answer

A

Mechanisms of Liver Fibrosis
- Generally restricted to conditions causing chronic liver damage.
- Options for liver after Irreversible liver cell damage and loss:
1. Regeneration (mitotic replication of adjacent hepatocytes) – unfortunately with time replicative senescence occurs.
2. Scarring and fibrosis.
—
#### Liver Scarring and Fibrosis
- Involves a complex process of stellate cell activation/proliferation ➔ stellate cells become myofibroblastic ➔ collagen synthesis.
—
### Cirrhosis
- The end-stage of many types of chronic liver disease/injury.
- Not all end-stage liver diseases are cirrhotic.
- Potential for reversal of fibrosis in future?
- Reflects significant liver damage with scarring/fibrosis and functional/vascular derangements.
- Consequences:
- Liver dysfunction/failure.
- Portal hypertension (bleeding).
- Risk of hepatocellular carcinoma.

Fatty Liver Disease
- Identical histologic findings in both alcoholic and non-alcoholic forms (Clinical History !!!).
- Histologic Findings:
1. Evidence of excess fat in hepatocytes (steatosis):
- Macrovesicular (one large droplet) > microvesicular (multiple small droplets).
2. Evidence of damage to hepatocytes (steatohepatitis):
- Ballooning degeneration.
- Mallory-Denk bodies (degenerate intermediate filaments complexed with ubiquitin)., can be surrounded on neurtophils
- Neutrophilic infiltrates.
3. +/- Fibrosis (begins “pericellular”).–progresses

VIRAL HEPATITIS

Viral Hepatitis
- Infiltration by lymphocytes with any combination of:
- Portal tract inflammation.
- Interface hepatitis.
- Lobular hepatitis (death of hepatocytes).
- Variable degrees of fibrosis.
- Viral serology is essential.

Chronic viral hepatitis
- dominated by lymphocytes
- occurs in lobules, around portal tract, at interface

Hepatitis B
- ground glass hepatocytes: cytoplasmic inclusions
- accumulation fo surface antigen - HepBsAg
- can be seen on HE and on IHC

Hepatitis C
- often prominent lymphoid follicles
- bile duct damage may be present
- often steatosis

note CLD can also be wilson, haemochrom, alpha 1 antitryspin

Question 42

Q

Describe the stigmata of liver disease and the underlying cause of each

Answer

A

nonspecfic: anorexia weight los swkness fatigue
decompensation: jaundice, pruritus, upper GIT bleed, abdminal distention, confusion
physical exam: jaundice, spider naevi, gynaecomastia, ascites, heaptosplenomagely and hypersplenism, palmar eryhtema, clubbing, asterixis, bleeding and bruidsing easilt, decreased BP, caput medusae, portal hypertension

Question 43

Q

Ascites is a complication of liver disease. Describe the pathophysiology of this
Describe hoe ascites are treated

Answer

A

Liver Failure with Portal Hypertension
- Ascites
- Dilated abdominal wall veins
- Muscle wasting (check shoulders, buttocks, thighs)
- Fullness left flank (splenomegaly)

Ascites Pathophysiology
- Cirrhosis
- Low albumin
- Low colloid oncotic pressure -
- High portal pressure
- Increased capillary hydrostatic pressure
- High aldosterone and ADH
- Na+, water retention

Inevitably leading to
- Fluid transudation
- ascites

Sodium restrictionis an important consideration in the management of ascites, and educating patients about appropriate dietary modifications is essential. Salt substitutes are not recommended, and drugs that cause sodium retention (eg non-steroidal anti-inflammatory drugs [NSAIDs]) or contain relatively large amounts of sodium (eg antacids, effervescent preparations and some antibiotics) should be avoided.

Treatment: Diuretics (see block 2 for specific information about each) and in refractory caseslarge-volume paracentesis (drainage);reduction of portal pressure by percutaneous insertion of a shunt between the hepatic and portal veins (transjugular intrahepatic portosystemic shunt [TIPS]).

Question 44

Q

Describe complications of liver disease

Answer

A

Complications of Cirrhosis
- Portal hypertension
- Portal hypertensive gastropathy (vascular ectasia - oozy lining of stomach, vessels markedly dilated)
- Oesophago-gastric varices (catastrophic upper gastrointestinal bleeding)
- Thrombocytopenia (TPO down)
- Ascites/ hepatic encephalopathy
- Bacterial infection – impaired immunity (reduced complement synthesis), especially spontaneous bacterial peritonitis, septicaemia, pneumonia

Complications of Cirrhosis - a complex conundrum

Metabolic Defects
- Hypoglycemia
- Gluconeogenesis, glucose intolerance, diabetes
- Impaired drug clearance (CYP-mediated metabolism, hepatic blood flow)

Circulatory Disorders
- renal failure - hepatorenal syndrome (renin-angiotensin-aldosterone, ADH activation)
- hepatopulmonary syndrome (NO–> hypoxia, clubbing, pulmonary hypertension)

Hepatocellular Carcinoma (HCC) Complicates Cirrhosis

HCC
- 2nd most common cause of cancer death worldwide
- Incidence trebled in Australia and USA last 3 decades
- Regard as a complication of cirrhosis (>90% of cases)
- Most common in chronic viral hepatitis (B, C, B+C)
- … and longstanding cirrhosis, especially males, HBV/HCV, alcohol, fatty liver (NASH)
- Cholangiocarcinoma – less common; different associations e.g., primary sclerosing cholangitis, schistosomiasis

Question 45

Q

Describe the presentation and clinical importance of alcohol related and non-alcoholic fatty liver (physical examination and investigation findings

Answer

A

before= asymptomatic, mainly fatidue, third, dull or sharp aching abdo pian, thirst, sleep disrtbances, blaoting
cirr or end stage: nausea vomit, jaundice, pruritus, hepatomegaly, acites, memory imp, blled, oss of appetiet

clinical = can progress to steatohepatitis and cirrhosis

Question 46

Q

How can you differentiate alcohol related and non-alcohol related fatty liver disease histologically?

Answer

A

You cannot

Question 47

Q

Describe the disease course of fatty liver disease and its association with metabolic disorders and cardiovascular disease

Answer

A

Spectrum
- Healthy liver
- Fatty liver (Steatosis) >5% vol - at this stage, <1d/d women, <2 in men
- Steatohepatitis (N/MASH)
- Cirrhosis - irreversible step
- HCC either from MASH, or cirrhosis
- Alcohol-like liver histology in persons who don’t drink significant amounts of alcohol.

Fatty Liver - Spectrum

Lobular inflammation
Ballooning degeneration
Perivenular fibrosis

N/MAFLD - Why Bother?
- 30%
- Advanced liver disease in a subgroup [age >45, obesity, diabetes].- screen
- Co-factor for other liver diseases.
- Increased cardiovascular risk^[significant contributor to mortality], diabetes mellitus.
- HCC risk.

mAFLD - Pathogenesis
- Main underlying mechanism: insulin resistance.
- mAFLD is the hepatic manifestation of the metabolic syndrome.
- Other important processes: lipotoxicity, oxidative stress, adipocytokines, mitochondrial defects, genetic factors.

Clinical Presentation
- Asymptomatic
- Abnormal ultrasound, liver tests
- ALT > AST
- Enlarged, soft liver
- Advanced liver disease not common
- Look for metabolic syndrome: hypertension, type 2 diabetes, central obesity

mAFLD - Natural History
- Overall, 5% of mAFLD develop cirrhosis, 1.7% die of cirrhosis complications (mean follow-up 7 years).
- Simple steatosis: benign outcome.
- mASH: One-third will progress (fibrosis).
- Cirrhosis 5%-10% over 5 years.
- Poor outcome of mASH-related cirrhosis.

Question 48

Q

Describe how you would manage a patient with non-alcohol related fatty liver disease and alcohol-related liver disease

Answer

A

Principles of Treatment
- lifestyle modification- aerobic and resistance exercise, eg Med diet; engaging personal trainer/dietitian/family support
- targeting MetS components
- liver-directed pharmacotherapy- only one recent drug, not mainstay
- managing complications of cirrhosis

Impact of Weight Loss on Improving Fatty Liver
- steatosis 35-100 - w/ weight loss >=103
- ballooning/inflammation 41-100 - w/ weight loss >=5
- NASH resolution in 64-90% - w/ weight loss >=7
- fibrosis in 45% - w/ weight loss >=10

Other treatments for MAFLD
- bariatric sg when done for other metabolic disease
- semaglutide no effect on fibrosis, steatosis; only in context of diabetes
- other drugs not licensed except resmeritrom (thyroid hormone b-receptor), pioglitazone, vitamin E

–

Principles of Treatment
- No alcohol.
- Nutritional supplements: thiamine, B12, folate
- Corticosteroids (in severe alcoholic hepatitis).- only s-term, first 4 weeks therapy. Long-term does not improve outcomes
- Managing cirrhosis complications (AFP, liver ultrasound, endoscopy- looking for varices).
- Liver transplant (abstinence > 6 months, good social support demonstrated).

Alcohol and Liver Disease
- Safe limits important but liver risk variable.
- Clinical spectrum: asymptomatic, big liver, “hepatitis”, cirrhosis/liver failure.
- Suspicion important: MCV, AST > ALT.
- Fatty liver reversible, hepatitis can progress, cirrhosis can progress.
- Treatment: stop drinking, supplements, steroids, rarely liver transplant.

Question 49

Q

What are common symptoms of reflux?

Answer

A

Heartburn:
- substernal discomfort
- radiation of pain toward mouth
- precipitation by meals and recumbency
- amelioration with antacid use

Symptoms
- oesophageal
- heartburn
- retrosternal burning pain, can radiate into neck, typically after meals or laying down
- regurgitation
- retrograde movement of acidic gastric contents into the mouth or pharynx
- chest pain

extraoesophageal
- cough
- asthma
- laryngitis
- hoarse voice
- dental erosions
- globus sensation - feeling of something stuck in throat around sternal notch

Oeso vs extra symptoms
- extra- symptoms not as responsive to therapeutics
- heartburn 50-70% will experience symptom relief from PPI
- chest pain if positive pH study up to 80%
- chronic cough, asthma, hoarse voice and pH negative chest pain , less than 25% will improve, some may get worse

Question 50

Q

Describe the pathophysiology of common symptoms of reflux

Answer

A

Pathophysiology

Lower (o)esophageal sphincter – LOS/LES tone
Anatomical disruption on LOS
Oesophageal mucosal defences
Motility

Sphincter
- 3-4 cm, tonically contracted, smooth muscle
- crural diaphragm provides an extra layer of protection
- LOS and crural diaphragm together constitute the barrier
- most of the time LOS is closed and opens in response to food in the oesophagus
- transient LOS relaxations account for 50-70% of reflux events

TLOSR
- where teh LOS relaxes and intragastric pressure exceeds that of LOS, allowing for reflux of gastric contents into oesophagus
- many factors decrease LOS tone
- gastric distention e.g. large meal size
- chocolate
- caffeine
- smoking
- pregnancy
- meds: nitrates, CCBs

Anatomical disruptions
- hiatus hernia is most common - pulls above diaphragm
- LOS is shorter and weaker due to loss of support of crural diaphragm, leading to increased TLOSR
- makes reflux more likely
- can increase severity of erosive disease due to nocturnal reflux
- volume reflux

–
Oesophageal mucosal defences
- pre-epithelial:
- thin water layer with limited buffering capacity due to salivary bicarbonate
- secretions from oesophageal submucosal glands
- epithelial defences
- cell membranes and the intercellular junctional complex limit the rate of hydrogen ion penetration into the intracellular space or cell cytosol
- cellular and intracellular buffers (HCO3, proteins, phos) that neutralise back-diffusing luminal acid
- cell membrane ion transports remove acid from the cytosol when intracellular pH falls to acidic levels

Breaching mucosal defences
- high luminal acidity, alcohol , heat causing caustic injury, smoke derived chemicals
- acid attacks and damages intracellular junctions
- increased paracellular permeability ie non-erosive reflux
- acidification of intracellular space by back diffusion of luminal acid
- cell oedema and necrosis
- poor epithelial repair due to reduced salivary epidermal GFs
- erosive reflux disease

Oesophageal and gastric motility
- reduced acid clearance by impaired oesophageal peristalsis
- ineffective oesophageal motility present in about 50% of cases of acid reflux referred for manometry and pH studies - direction of causality unknown
- swallowing of saliva which contains bicarbonate is essential to clear oesophageal acid and restoring oesophageal pH
- primary oesophageal peristalsis is initiated by swallowing ~60/h
- secondary peristalsis is not initiated by swallowing and can be triggered by luminal content and acid
- re-reflux can occur when refluxate is cleared but trapped in a hernia sack increases oesophageal acid exposure time

Question 51

Q

What are red flag symptoms associated with reflux?

Answer

A

Red flags
- dysphagia
- especially progressive from solids to liquids
- weight loss
- haematemesis or melaena
- sudden change in reflux symptoms

Question 52

Q

Describe potential complications of reflux

Answer

A

Complications

Barrett’s oesophagus
- the normal stratified squamous epithelium in the lower oesophagus is replaced wiht metaplastic columnar epithelium with both gastric and intestinal features
- develops as a consequence of chronic GORD
- other RFs include obesity, family Hx, smoking
- increased risk of oesophageal adenocarcinoma: <1% /y
- prevalence: 1.3-1.6/1000 endoscopies

Oesophageal cancer
- 60% Ad, 40% SCC in Au
- SCC predominates in developing nations
- Poor prognosis, 1700/y, 23% 5ys

Surgery for GORD
- especially if refractory disease

fundoplication: stomach wrapped around lower oesophagus
reinforces LOS
different types: 180, 270, 360
surgery may also be done to fix hernia

Question 53

Q

Describe the pathophysiology of Barrett’s oesophagus and how it can lead to cancer

Answer

A

**
* Barrett’s oesophagus / adenocarcinoma
- metaplasia (Squamous to glandular epithelium), goblet cells
- biggest RF is untreated chronic reflux
- can become dysplastic i.e. malignant potential, cytological features of malignancy, +/- BM invasion
- if resected – big section, implications for morbidity

**

Follows dysplasia-carcinoma sequence
– therefore suitable for surveillance
– anticipated decline in population treated with PPI’s

Barrett’s esophagus - stratified squamous epithelium is replaced by metaplastic columnar epithelium which in turn predisposes to the development of adenocarcinoma of the oesophagus.
Endoscopically it appears as salmon pink tongues of mucosa extending above the gastro-oesophageal junction (GOJ) and into the tubular oesophagus, replacing the stratified squamous epithelium that normally lines the distal oesophagus.

Barrett’s oesophagus – squamous mucosa is
replaced by glands with intestinal metaplasia,
(numerous goblet cells)

Dysplasia in Barrett’s
intracytoplasmic mucin droplets of varying sizes , nuclei are pleomorphic, darker, larger and disorganised with multiple layers indicating dysplastic change.

Question 54

Q

Describe the common investigation modalities used to investigate suspected gastro-oesophageal reflux disease

Answer

A

oesophageal physiologic evaluation i.e.
- endoscopy (structural overview of oesophageal and stomach - see LA grades)
- ambulatory pH monitoring
adjunctive approach

Ambulatory monitoring
- wireless - Bravo capsule
- attached endoscopically 3-5 cm above GOJ
- wireless pH recording for up to 48h
- capsule detaches spontaneously
- attachment can cause chest pain and discomfort in some people
- advantages: wireless, 48h
- disadvantages: requires endoscopic insertion, possibility of chest pain post attachment, early capsule detachment, acid exposure time only (nothing else measured - look to see if pH dips below 4)

wired - 24 h pH
- catheter based system
- inserted while patient is awake therefore no anaesthetic risk
- multiple catheter options
- impedance capacity
- advantages: multiple catheter option (Single or dual pH sensor +/- impedance i.e. flow across oesophagus- helps to assess response to treatment, disringuish GERD from NERD), inserted in clinic setting i.e. no endoscopy, simple reinsertion if catheter dislodged, no pain
- disadvantages: unable to pass catheter nasally e.g. due to previous ENT surgery or anatomical abnormalities, if unable to tolerate catheter insertion, attached to box for 24h -can’t have shower

Question 55

Q

Describe management strategies for GORD

Answer

A

Anti-secretory medication
- H2 receptor blockers e.g. ranitidine, famotidine, nizatidine
- PPIs e.g. omeprazole, esomperazole
- P-CAB e.g. vonoprazan

MoAs
- H2Rbs
- competitive antagonists that bind to histamine receptor in parietal cell, blocking the binding of histamine
- gastrin stimulates release of histamine from enterochromaffin-like cell sin response to food which then bind to H2 receptor on partieal cells stimulatinf acid secretion
- onet of action 1 h
- laasts 4-6 hours

PPIs
- irreversibly bind to and inhibit HK ATPase transporter on teh luminal membrnae of parietal cells
- accumulate in the secretory canaliculus of the parietal cell where the active drug forms a disulphide bond with the external surface of the HK ATPase transporter
- onset 30-60 m
- takes 3-5 days to reach steady state
PCAB
- competitive, reversible blockade of K binding site of the HK ATPase transporter on the luminal membrane of parietal cells
- onset of action 30m
- lasts 21 h
PPI> H2RB
- unless under specific circumstances e.g. younger, or younger with functional
- vonoprazan not funded by PBS
- recommendation: 8-12 wks of once daily standard dose
- only advised in patients with typical reflux symptoms e.g. heartburn, regurgitation and/or chest pain
- note: dose between PPIs means different potency
lifestyle and acid modification
- reduce foods and drinks that trigger TLOSR
  - coffee, alcohol and spicy foods
- stop smoking: cigarette smoking increases TLOSR
- weight loss
  - central obesity increases intra-abdominal pressure and reduces gastric compliance
sleep with head of bed elevated

Question 56

Q

What are the top 3 non-indetermined causes of acute liver failure?
not cirrhosis, viral, etc

Answer

A

paracetamol, drugs, no4

Question 57

Q

Distinguish between intrinsic and indiosyncratic hepatotoxicity.

Answer

A

Intrinsic or idiosyncratic drug-induced hepatotoxicity.
- Intrinsic: Hepatotoxicity is predictable if dose is high enough.
- Idiosyncratic: Hepatotoxicity results at therapeutic dose of drug. Often fatal if drug use continued - but not always: isoniazid induced liver injury can disappear even with continued use. Dose can still play a role by increasing the likelihood of injury

Question 58

Q

What are the six mechanisms of hepatocyte injury?

Answer

A

Disrupted Ca2+ homeostasis -> blebbing -> cell death.
Disruption of actin filaments next to canaliculus, inhibition of transporters eg of bile.
Covalent binding of drug to cytP-450 - adducts.
Adducts migrate to plasma membrane - immune response.
Apoptosis - loss of nuclear chromatin.
Inhibition of mitochondrial function (loss of ATP and increase in ROS and build-up of fatty acids).

Note also: bile duct epithelium can be damaged by toxic metabolites

Question 59

Q

How does paracetamol induced liver damage occur and how can it be prevented in overdose?

Answer

A

Paracetamol Metabolism
Mainly synthesised by phase II conjugation. Will switch to PHS/P450 systems. which generates NAPQI. Usually converted to not harmful metabolite with incorporation of glutathione.

Pathways become saturated and deplete glutathione stores. If glutathione levels drop below 30% normal, NAPQI levels rise and cause damage. Prostaglandin H synthase is a minor pathway. NAC “replaces” glutathione. Is an analog of cysteine.

(Golan et al. Principles of Pharmacology - 2nd edition).

Mechanism of Toxicity
At least 17 hepatic enzymes are known to be inhibited by NAPQI, likely more.
- Microsomes (1)
- Cytosol (10)
- Mitochondria (4)
- Cell membrane (2)
14 others bind directly to paracetamol but are not yet shown to be inhibited. Cell death likely due to multiple parallel events rather than a single mechanism.

3 major Mechanism of Toxicity
- Uncouples mitochondria - GDH inhibited, inability to produce ATP
- Depletes glutathione further, inhibits glutamylcysteine synhtetase
- Disrupts Ca2+ homeostasis (Park et al. Annu Rev Pharmacol. Toxicol (2005) 45:177-202).
Overall resultsin susceptibility to additional damage.

Altering gene expression, production of TFs, altered gene expression, protein activity and expression, in addition to…
Toxic metabolites, GSH depletion, and oxidative stress probably render hepatocytes more susceptible to the innate immune system (Kaplowitz Nature Reviews - Drug Discovery (2005) 4:489-499).
genetic susceptibility (either increased or decreased) identified in animal model KO studies
#### Risk Factors for Paracetamol-induced Hepatotoxicity
Chronic alcoholism (more than 50g/day)
- alcohol is usually metabolised by CYP450
- induces increased expression of CYP450 nad migration to membrnae
- ethanol out-competes paracetamol hence NAPQI initially low
- as ethanol is metabolised, and there is more P450, hence more NAPQI
Prolonged fasting
Other medications (inducers of cytP450 2E1 and 3A4) e.g., isoniazid, rifampicin, carbamazepine. Stimulated cytP450 enzymes & reduced glutathione levels in the liver increase the risk.
Enzyme inducers can enhance hepatotoxicity, not just ethanol: smoking, phenytoin, phenobarbital.

Question 60

Q

List RFs for paracetamol induced hepatotoxicity

Answer

A

Risk Factors for Paracetamol-induced Hepatotoxicity
- Chronic alcoholism (more than 50g/day)
- alcohol is usually metabolised by CYP450
- induces increased expression of CYP450 nad migration to membrnae
- ethanol out-competes paracetamol hence NAPQI initially low
- as ethanol is metabolised, and there is more P450, hence more NAPQI
- Prolonged fasting
- Other medications (inducers of cytP450 2E1 and 3A4) e.g., isoniazid, rifampicin, carbamazepine. Stimulated cytP450 enzymes & reduced glutathione levels in the liver increase the risk.
- Enzyme inducers can enhance hepatotoxicity, not just ethanol: smoking, phenytoin, phenobarbital.

Question 61

Q

What is one reason so many drugs are withdrawn from the market or are never released?

Answer

A

New Drugs and Hepatotoxicity
Hepatotoxicity is the reason why many new drugs never reach the market and is a major reason why drugs are withdrawn from the market. Examples include Bromfenac (NSAID) and Troglitazone (used in type 2 diabetes).

Question 62

Q

Which herbal remedies have been associated with hepatoxicity.

Answer

A

Herbal Remedies
Some herbal remedies can cause severe hepatotoxicity, including Kava-Kava, Chaparral, Germander, Valerian root, Skullcap, Mistletoe, Senna, and Comfrey.

Question 63

Q

List biomarkers of cirrhosis

aka FBC, UEC, LFT

Answer

A

ALT and AST is moderately elevated
AST is more often elevated than ALT
ALP- less than 2-3 times elevated
May be higher if cirrhosis is related to primary sclerosing cholangitis or primary biliary cirrhosis.
GGT is non specific but correlated to cirrhosis when alcohol associated.
Bilirubin may be normal in compensated and rise as disease progresses.
Albumin level falls are synthetic liver function declines. Albumin can be used to help grade disease

PT: this is the first clotting time to increase because of the short half life of FVII. Worsening coagulopathy correlates with severeity of hepatic dysfunction
Important to remember this does not always mean more bleeding as the liver also synthesizes bodies natural anticoagulants (protein S, C)
Hyponatremia: decrease ability to excrete free water
Thrombocytopenia: due to decrease production of thrombopoietin and platelet sequestration in the spleen (main culprit).
Anemia: mulifactoral, could be related to blood loss, folate deficiency, bone marrow suppression of anemia of chronic disease.

Question 64

Q

What is the classification of IBS

Answer

A

C, D, M, U
Changes in motility, vsiceral hypersense, gastro perm alteration
> 6 mo since onset: recurrent abdo pain > 1d/week un past 3 months, abdo pain relates to def, change in stooll freq or appearance –> 2 of 3

Answer 61

A

Multifactorial: psychoscial, environmental, physiological

Answer 62

A

Fits criteria, to the exclusion of others eg UC
Non pharm: diet, triggers, low FODMAP, lifestyle: activity, stress, psychobehaviiural therapy
Lopearmide, movical, antispasmodics for abdo pain

Answer 63

A

see tree
- induce remission
- maintain remission
- 5ASA mainstay of UC to oinduce and maintain
- use oral CCS if severe or not responsive
- escalate to immods like AZA if severe
- or monoAb vedo, infliximab
- if acute and severe may try IV CCS

For Crohns
- mild mod oral CCS
- severe Iv then oral CCS
- maintenance: AZA/6MP, MTX-> inflix ada ustekin,m vedo

Antibs: metronidazole or cipro if perianal fistula or abscess foramtion

Answer 64

A

A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by 2 or more of the following occurring within 12 mo

The severity of the disorder will be graded by the number of criteria the person meets. If it’s 0 to 1, no diagnosis is made. From 2 to 3 criteria, the diagnosis is mild; 4 to 5, moderate; and 6 or more, severe.

Answer 65

A

Epi/RUQ pain
fever
nausea and vomiting
SIRS

Answer 66

A

Pancreas is usually protected from autodigestion by mucus.

In autodigestion protease breaks down muscle, lipase breaks down cell wall and amylase leads to membrane integrity loss.

Answer 67

A

alcohol, ERCP, gallstones

associateions with obesity diabetes and smoking

Answer 68

A

endo vs exo insufficiency

Answer 69

A

interstitial»>necrosis

Answer 70

A

assess for fluid loss organ failure SIRS
fluid replacemnt in 24-48h
prophylactic if extrapanc
pain control - fluid management woudl help, potential opioids
close monoting and nutoronal support
progress to drain/debridement

Answer 71

A

Anorexia
Confusion - enceph
Dark urine - bilirubin
Scratch marks
Liver tenderness
Black stools - depends, eg yes if varices
Peripheral stigmata: high sensitivity, spider naevi from SVC: nipple line to head

Answer 72

A

Cholestasis
- Impaired bile flow
- Jaundice common
- Dark urine: bilirubinuria
- Pale stools
- Malabsorption - long chain fatty acids,
fat-soluble vitamins (impaired coagulation)
- Pruritus

Cholestasis does NOT (always) mean biliary obstruction!
There are many causes, the most common of which is due to mechanical obstruction of CBD
- gallstones: pain, fever, jaundice (triad)
- malignancy: pancreatic head, bile duct, other
- scarring: primary or secondary sclerosing cholangitis
- infection eg cholangitis, parasites
Some molecular (“medical”) causes
- Drug-induced cholestasis (eg amoxycillin/clavulanic acid)
- Cholestasis of pregnancy
- Primary biliary cholangitis (PBC, formerly known as PB cirrhosis)

Answer 73

A

alcohol
metabolic syndrome

lifestyle changes

Answer 74

A

Iron Homeostasis

Essential for life, involved in heme proteins, drug and steroid metabolism, and immune system
Total body iron: men 5 g, premenopausal women 3.5 g
Iron absorption occurs mainly from red meat; daily requirements small
Daily requirements small – replace losses
Recommended daily intake (RDI):
– Males and post-menopausal females 8 mg/day: absorb 10-15% (~1 mg/day)
– Pre-menopausal females 16 mg/d, pregnant females 24 mg/d
Richest dietary source is red meat: vegetarians are at risk of iron deficiency
### Key Proteins of Iron Metabolism

Hepcidin: Iron Regulatory Hormone

Blocks ferroportin, the cellular iron exporter
Predominant negative regulator of iron absorption from the intestine and iron transport out of macrophages
Synthesis stimulated by iron and inflammation

Answer 75

A

Hereditary Hemochromatosis (HFE)

Single gene disorder, near HLA loci on chromosome 6p
Autosomal recessive disorder
Mutations in the HFE gene (C282Y, H63D) change HFE structure and function
other variants outdated, irrelevant
associated with iron overload: homozygous C282Y - 90% of genetic haemochromatosis in Au, compound C/H mild phenotype usually only shows up after taking excessive iron medication
- homozygous H63D has no phenotype
HFE allele frequency is 8% in caucasian –> pseudo-dominant inheritance ie one parent homozygous recessive x heterozygous
Penetrance of HFE mutations is low (~30%)

Answer 76

A

Hereditary Hemochromatosis (HFE)

Single gene disorder, near HLA loci on chromosome 6p
Autosomal recessive disorder
Mutations in the HFE gene (C282Y, H63D) change HFE structure and function
other variants outdated, irrelevant
associated with iron overload: homozygous C282Y - 90% of genetic haemochromatosis in Au, compound C/H mild phenotype usually only shows up after taking excessive iron medication
- homozygous H63D has no phenotype
HFE allele frequency is 8% in caucasian –> pseudo-dominant inheritance ie one parent homozygous recessive x heterozygous
Penetrance of HFE mutations is low (~30%)

Penetrance of Hemochromatosis

Penetrance refers to the proportion of individuals with a disease-causing mutation who exhibit clinical effects.- thus phenotype:genotype 1:1
Clinical penetrance of genetic hemochromatosis (GH), particularly C282Y homozygosity, is low.
- Approximately 28% of males and 1.2% of females with C282Y homozygosity had iron overload-related disease.
Factors influencing penetrance include environmental (blood donation; physiological blood loss due to pregnancy or menstruation; diet vegetarian) and genetic factors, with recent studies suggesting genetic factors are more significant.

Answer 77

A

Serum iron concentrations fluctuate; not a useful test
Transferrin saturation is a better indicator
- Normal: 20 - 44%
- Hemochromatosis: >50%, can be >90%
- Iron deficiency <20%

Answer 78

A

Diagnosis of Hemochromatosis

Diagnosis is based on evidence of increased body iron stores, typically indicated by raised serum ferritin and transferrin saturation.
HFE gene testing is essential for family screening.
Liver stiffness measurement and liver ultrasonography are performed for diagnosis and surveillance.
Other tests not necessary eg MR quantitation of liver iron, or not done eg quantitative phlebotomy, and liver biopsy

Answer 79

A

Interactive Liver Toxicity

Excessive alcohol consumption most important factor contributing to cirrhosis
Excessive alcohol consumption synergistically interacts with iron overload, contributing to cirrhosis. - recommend NHMRC safe drinking ([[Gastroenterology - Lecture 6]])
Obesity and type 2 diabetes further exacerbate liver disease, diabetes risk in patients with hemochromatosis.
Alcohol + obesity/T2D is double jeopardy
Alcohol + obesity/T2D + iron overload is triple jeopardy
Control of comorbidities ie alcohol and obesity is essential to prevent liver complications AND NOT JUST IN HAEMOCHROMATOSIS.

Answer 80

A

Discuss with patients the importance of alcohol and weight moderation (diabetes, cirrhosis, liver cancer)
Venesection is recommended for patients with hemochromatosis (eg genetically proven) and evidence of iron overload (raised serum ferritin and transferrin).
Referral to specialized services is needed for difficult cases.

Answer 81

A

Common causes of intra-abdominal sepsis
- Appendicitis
- Cholecystitis
- Pancreatitis
- Diverticulitis
- Perforated ulcer
- Ischaemic bowel

atomical Classification: Oesophagus-Stomach-Duodenum
- Perforated peptic ulcer (mild until perforated = severe)
- Gastric
- Duodenal
- Boerhaave’s syndrome
- Spontaneous oesophageal rupture - severe and high mortality, rare
- Iatrogenic injury
- Gastroscopy
- ERCP
- PEG tube
- Trauma

Anatomical Classification: Liver / Gallbladder / Pancreas
- Liver abscess - uncommon, pyogenic or non
- Biliary colic – cholecystitis
- Cholangitis (jaundice, fever, RUQ)
- Gallstone ileus
- Bile duct injury or bile leak after cholecystectomy
- Acute pancreatitis - usu due to gall stones or alcohol

Anatomical Classification: Small bowel
- Meckel’s diverticulitis
- Small bowel obstruction- usu due to adhesions
- Acute mesenteric ischaemia- uncommon
- Inflammatory bowel disease eg Crohn’s
- Hernia involving small bowel

Anatomical Classification: Colon, rectum and appendix
- Appendicitis
- Diverticulitis
- Right side
- Sigmoid
- Inflammatory bowel disease
- Infectious or ischaemic colitis
- Volvulus
- Sigmoid
- Caecal

Anatomical Classification: Other
- Kidneys, ureter, bladder
- Renal colic
- Pyelonephritis
- Renal abscess
- Cystitis
- Female reproductive organs
- Pelvic inflammatory disease

Answer 82

A

Cholecystitis
Clinical presentation:
- History of biliary colic, worse with food
- Persistent RUQ pain
- Nausea, vomiting, loss of appetite, fever
- Murphy’s positive - push RUQ take a breath – sharp pain

Diagnosis:
- Ultrasound (thickened wall, increased vascularity, pericholecystic fluid, tenderness to probe)
- Assess LFTs to determine likelihood of choledocholithiasis
- Ensure Lipase is not elevated - differential for pancreatitis

Cholecystitis
Management of sepsis:
- Antibiotics - triple
- Surgery - depends septic or no

Answer 83

A

Appendicitis
Clinical presentation:
- Migratory abdominal pain (periumbilical –>RLQ)
- Loss of appetite, nausea/vomiting
- common young
- Fever
- RLQ peritonitis
- Rovsing’s (push on left - pain on right), obturator positive/psoas (lift right leg elicits pain)

Diagnosis:
- Clinical diagnosis (Especially in young, men)
- Suspicious raised by elevated inflammatory markers
- If doubt about diagnosis, imaging:
- US vs CT

Management of sepsis:
- Triple antibiotics (metronidazole, ampicillin, gentamicin)
- Surgery - timing depends on patient stability

Answer 84

A

haemic bowel
End of the line result for a number of pathologies
- Mesenteric ischaemia - eg atrial fibrillation and embolism, chronic ischaemia with thrombosis/stricture
- Strangulated hernia - venous congestion, arterial insufficiency
- Closed loop adhesional small bowel obstruction

Clinical presentation:
- Non-specific abdominal pain (may or may not localise, various regions)
- Pain out of proportion to examination
- Can be difficult to diagnose, needs high degree of suspicion

Diagnosis:
- CT (may see thickened wall, free fluid)
- Lactate sometimes elevated (not always)

Ischaemic bowel
Management of sepsis:
- Antibiotics
- Surgery

Answer 85

A

Pancreatitis
Clinical presentation:
- Epigastric pain radiating to back
- Nausea, vomiting, loss of appetite
- Fever

Diagnosis:
- 2/3 of:
- Clinically typical symptoms
- Elevated lipase >3x upper limit normal
- CT findings consistent with pancreatitis
- Identify cause:
- Biliary ultrasound - gstones
- Screen for secondary causes (Lipids, Igg4 subclasses, Ca 19.9, MRCP)

classification mild moderate severe depending on local complications, organ failure and timeline of failure

Pancreatitis
Management of SIRS:
- No antibiotics
- Supportive care
- Prevent further episodes
- Cholecystectomy prior to discharge if gallstones are the cause
- Treat complications of pancreatitis
- Avoid surgery (mostly)

Answer 86

A

Diverticulitis
Clinical presentation:
- LLQ pain
- Fever
- Diarrhoea or constipation
- LLQ or suprapubic peritonitis

Diagnosis:
- Elevated inflammatory markers
- CT diagnosis
- CT also used to assess severity

Diverticulitis
Management of sepsis:
- Antibiotics
- Control of sepsis
- Abscess -> drainage
- Purulent or faeculant peritonitis -> surgery

Answer 87

A

rforated ulcer
Clinical presentation:
- Sudden onset upper abdominal pain
- Fever, nausea
- History of NSAIDs without PPI, smoking, untreated helicobacter pylori
- Peritonitis in upper abdomen

Diagnosis:
- CT showing free gas and free fluid in upper abdomen; lipase normal

Perforated ulcer
Management of sepsis:
- Antibiotics (triple)
- Surgery

Answer 88

A

Acute hepatitis (hepatocellular necrosis)
- Anorexia (profound), nausea, vomiting
- Lethargy
- Jaundice common
- Scleral icterus especially in people of colour

Acute hepatitis (hepatocellular necrosis)
- also:
- Dark urine: bilirubin-uria
- Tender (soft) liver
- Acute liver failure - not making clotting factors hence bruising/bleeding,
prolonged coagulation time (not corrected by vitamin K injection)
- Liver biochemistry: ALT >10 fold increased;
changes in BR, GGT, ALP less specific

Answer 89

A

What are Parasites?
- Protozoa – single-celled eukaryotes
- Metazoa – multi-celled eukaryotes
- Helminths - worms
- Arthropods – insects; cause disease or serve as vectors
(Murray et al. 2002)

Answer 90

A

Parasite Hosts
- Host specificity
- range of different hosts in which a parasite can mature
- can be fairly specific to a particular host species

Definitive Host: parasites mature into adult form; Adult undergoes sexual reproduction;
Incidental Host: Parasite develops but does not mature sexually; may undergo asexual reproduction
also paratenic: parasite alive and infective but no development
incidental: intermediate; does not allow transmission to another host
Humans may serve as
- Definitive
- Intermediate
- Incidental/Dead end

e.g. humans as definitive host for tapeworm:
- eat cyst or larval form in pork
- adult tapeworm develops in intestine
- eggs excreted in faeces

e.g. humans as intermediate host for tapeworm:
- eat egg in contaminated food or water
- larvae released and migrates to various tissues and encysts
- will only complete lifecycle if another human eats tissue with cysts

Answer 91

A

Giardia
- G. lamblia =
- G. intestinalis =
- G. duodenalis
- Giardia has a wide host range in which it can complete its entire lifecycle
- Common
- Transmission from contaminated water or directly such as in childcare centres

Pathophysiology of Giardia infection
- Excystation occurs in response to exposure to stomach acid, releasing four trophozoites (TZ)
- TZ colonise the small intestine
- TZ undergo rapid asexual reproduction
- Encystation occurs as TZ transit through the large intestine

Pathophysiology of Giardia infection – Encystation
- Flattening of the villi and inflammation of the mucosa is observed
- Pathophysiological mechanisms potentially including
- Direct damage to the intestinal brush border and mucosa
- Alteration of absorption
- Alteration of small intestinal function
- Induction of a host immune response resulting in secretion of fluid and damage to the gut

Symptoms
- range from
- asymptomatic
- chronic diarrhoea
- epigastric pain
- nausea and vomiting
- bloating and flatulence
- malabsorption
- weight loss
- symptoms: 6-15 days after exposure
- usually last several days but are self limiting

Treatment of Giardiasis
- Treatment
- Metronidazole
- Tinidazole

Answer 92

A

Cryptosporidium
- thick walled oocyst ingested, sporulated thick walled oocyst excreted, contaminates water and food
- Note – resistant to chlorination. Outbreaks can be associated with water supply, swimming pools

Pathophysiology of Cryptosporidium infection
- goes through several lifecycle stages
- asexual and sexual cycles
Cryptosporidium Infections - Symptoms
- Immunocompetent adults - self-limiting gastroenteritis lasting 1-2 weeks most commonly characterized by watery diarrhea
- Immunocompromised populations – potentially disseminated disease and/or life threatening symptoms
- Cholera-like illness
- Chronic diarrheal illness
- Intermittent diarrheal illness
- Transient diarrheal illness

Extremely difficult to treat
- Nitazoxanide – need to import to Australia under special access scheme

Answer 93

A

worldwide distribution
young children
asymptomatic
perianal itching
sleep disruption
migration into vagina
abdominal pain
appendicitis

Answer 94

A

Strongy hook scabies Tvaginalis

Answer 95

A

Salmonella: General Characteristics
- Motile, Gram-negative rods
- Facultative anaerobes
- Resistant to bile salts, although poor resistance to acids ^[contrast with [[#Shigella General Characteristics]]]
- Non-lactose fermenting, but do ferment xylose
- XLD agar can be used to differentiate Salmonella from Shigella
- Grow within a wide temperature range (≤54°C)
- Grows optimally at 37°C
- *Psychrotrophs (2-4°C)

Salmonella: Taxonomy
- Taxonomy based on genomic relatedness show that there are two Salmonella species:
- S. bongori
- S. enterica
- S. enterica has a further 6 subspecies:
- S. enterica subspp. arizonae
- S. enterica subspp. diarizonae
- S. enterica subspp. enterica
- S. enterica subspp. houtenae
- S. enterica subspp. indica
- S. enterica subspp. salamae
- There are >2500 serovars/serotypes for S. enterica.
- Most of the pathogenic Salmonella serovars are found within S. enterica subspp. enterica
- e.g., S. enterica subspp. enterica serovar Typhimurium generally shortened to S. enterica serovar Typhimurium, and Salmonella paratyphi ?.

Salmonella: Classification
- Non-typhoidal: Cause acute gastroenteritis
- Most infections caused by S. enterica serovar Typhimurium and S. enterica serovar Enteritidis.
- Large animal reservoir, transmitted to humans via food in developing and developed countries.
- Typhoidal: Cause enteric (typhoid/paratyphoid) fever
- Most infections caused by S. enterica serovar Typhi and S. enterica serovar Paratyphi.
- S. enterica serovar Typhi associated with asymptomatic carriage (gall bladder usually the reservoir).
- Infect humans only, common in developing countries/areas of poor sanitation, faecal-oral route of transmission.

Salmonellosis: Gastroenteritis
- Most common form of salmonellosis in developed countries, typically associated with low mortality.
- High infectious dose (~10^5 cells)
- Incubation: 2-7 days, Duration: 2-7 days
- Symptoms: vomiting, fever (more with Typhi), abdominal cramps, watery diarrhoea with PMNs
- Inflammatory diarrhoea: due to invasion
- Osmotic diarrhoea: due to loss of absorptive surface - similar mix to shigellosis diarrhoea
- Usually self-limiting, antibiotics not prescribed unless:
- Extraintestinal disease develops (typically bloodstream infection)
- Severe gastroenteritis * * * *
- Infants and immunosuppressed individuals

Typical Sources of Non-Typhoidal Salmonella
- Commensals in birds (and other animals)
- Poultry meat and eggs are common sources of infection

Salmonellosis: Enteric Fever
- In Australia, most cases are acquired overseas i.e. returned travellers
- Low infectious dose (10–100 organisms)
- Incubation: 7–28 days (Typhi), 1–15 days (Paratyphi)
- Symptoms: Prolonged fever, vomiting, abdominal cramps, diarrhoea with PMNs, headache, myalgia, nausea, (+/-) rash of flat rose-coloured spots.
- Inflammatory + Osmotic diarrhoea
- Humans are the only hosts for these species
- Transmission: Faecal-oral route and person-to-person spread by chronic carrier
- After infection, people can carry the organisms for months to years

## Treatment Of Typhoidal Salmonellosis
- Antibiotics should be started as soon as enteric fever has been confirmed.
- Identify and treat carriers of S. enterica serovar Typhi and S. enterica serovar Paratyphi:
- Antibiotics
- Or cholecystectomy (if antibiotics fail); sometimes patients will elect to do this
- Ideally, Typhoid carriers should be excluded from jobs involving food handling and preparation.

Salmonella: Virulence Strategies
- Invasiveness:
- Intracellular survival and multiplication in intestinal epithelium and macrophages.
- Type III secretion system and effector proteins (SPI-1) required for initial invasion into intestinal epithelium.
- Type III secretion system and effector proteins (SPI-2) required for replication in intestinal epithelium and macrophages.
- LT-like toxin and other enterotoxins.
- Capsule (S. enterica serovar Typhi only).

Typhoidal Salmonella: Systemic Infections (I)
- Organism is consumed.
- Enter lamina propria via M cells.
- Taken up by macrophages.
- Migrate in macrophages to mesenteric lymph nodes and multiply.
- Released into the bloodstream (1° bacteraemia, low level, typically asymptomatic).
- Removed from blood by macrophages in spleen, bone marrow, liver; multiply and re-enter bloodstream (2° bacteraemia, onset of symptoms i.e. headache, malaise, fever).
- Re-enter GIT via gall bladder, replicates asymptomically but enters GIT and sheds, or causes bouts of typhoid fever

Answer 96

A

EIEC and Shigella are genotypically nearly identical.
- Have same virulence factors and strategies
- Cause a syndrome identical to Shigellosis
EIEC can be differentiated from Shigella only by a very limited number of tests based on utilisation of different nutrients, including utilisation of serine, xylose and/or sodium acetate, and mucate fermentation
- EIEC isolates may be positive for one or more of the tests but Shigella are generally negative
- Do not fit the full definition for the “genus” Shigella

Answer 97

A

Shigella: General Characteristics
- Non-motile, Gram-negative rod
- Facultative anaerobes
- Resistant to gastric acid and bile salts
- Non-lactose/xylose fermenting
- Inability to ferment xylose can be used to distinguish Shigella spp. from Salmonella spp. (black colonies) from clinical samples and from food using Xylose Lysine Desoxycholate (XLD) agar (red colonies)

Shigella spp.
- Four species:
- Shigella sonnei (most infections: mild form of disease)
- Shigella flexnerii (more severe form of the disease)
- Shigella boydii (more severe form of the disease)
- Shigella dysenteriae (most serious form of the disease)
- Human pathogens exclusively – no animal reservoirs.
- No environmental reservoirs.
- Faecal-oral spread, contaminated foods, *flies act as mechanical vectors.

Shigellosis
- Primarily a paediatric disease in developing countries.
- Acute onset: Incubation 1–4 days, Duration 2–3 days.
- Small infective dose (10-100 organisms).
- Epidemics occur due to overcrowding and insufficient sanitation.
- Refugee camps, nurseries, day-care centres and other residential facilities
- Symptoms:
- Spectrum: Mild to severe depending on the species (As well as host factors)
- (+/-) Fever, abdominal cramps, severe and bloody diarrhoea - especially with dysentery, often with pus (PMNs) and mucus ^[stool MCS shows leucocytes]
- Inflammatory diarrhoea: due to invasion
- Osmotic diarrhoea: due to loss of absorptive surface

Shigella: Virulence Strategies
- Invasiveness:
- Intracellular survival, multiplication, and intercellular spread
- Shigella can lyse the phagocytic vacuole (phagosome) and replicate in the cytoplasm
- in this way it can escape host defences
- Type III secretion system and effector proteins required for invasion and escape from the vacuole
- AB5 exotoxin (Shiga toxin) and other toxins (e.g., SigA)
- IcsA autotransporter:
- Outer membrane protein
- Localised at pole of bacterium
- Facilitates host-actin polymerisation, brings pathogen closer to epithelial cell, thereby faciltiating intracellular spread【Sansoneh (2004)】

Answer 98

A

Motile, Gram-positive rod.
Widespread among animals and the environment.
- Found in plants, soil, and surface water samples in addition to being in sewage, food, and human/animal faeces.
Outbreaks associated with high-risk foods:
- Unpasteurised milk, soft-serve ice-creams, and soft cheeses (brie, camembert, ricotta), raw vegetables, cold deli meats, raw seafood.
Infectious dose (<1000 organisms).
**Grow optimally at 37°C, but Psychrotroph**: 2–4°C.
Infections most common in immunocompromised individuals, pregnant women, neonates, and the elderly <65.

Listeriosis
- Symptoms:
- In healthy adults it is usually asymptomatic.
- Flu-like illness and/or Gastroenteritis: nausea, vomiting, fever, diarrhoea + PMNs.
- Inflammatory and osmotic diarrhoea.
- In 5 - 10% of the population, L. monocytogenes is present in the intestinal tract.
- In at-risk populations: bloodstream infection, sepsis, chorioamnionitis, meningo-encephalitis
- One of the few bacterium that can cross both the placental and blood-brain barrier.
- Treatment: IV benzylpenicillin ^[higher doses may be required i.e. for CNS infections]

L. monocytogenes: Virulence Strategies
- Adhesion:
- Listeria adhesion protein (LAP)
- Fibronectin binding protein A (FbpA)
- Invasion:
- Invasion A (InlA)
- Invasion B (InlB)
- Vacuolar Rupture:
- Listeriolysin O (LLO)
- Phospholipase A (PlcA)
- Phospholipase B (PlcB)
- Intracellular Spread:
- Actin-assembly-inducing protein (ActA)【Radoshevich & Cossart (2018)】

Answer 99

A

Motile, Gram-negative “comma-shaped” rods.
Microaerophilic (5-7% O2).
Most species grow well at 42°C (thermophilic).
Taxonomically classified in the same order as Helicobacter ^[when first characterised H pylori was called ‘Campylobacter sthng’].
Campylobacter jejuni and Campylobacter coli are the species most commonly implicated in human GIT infections.

Campylobacteriosis
- Gastroenteritis, can lead to Guillain-Barré syndrome.
- Low-Medium infective dose (~500 organisms)
- Incubation period of 2 – 11 days.
- Duration: 3 days – 3 weeks, relapses take place in 15 – 25% cases.
- Symptoms include abdominal cramps and fever, vomiting rare, bloody diarrhoea + PMNs (inflammatory and osmotic diarrhoea).
- Rare complication- GBS (see also [[Immunology B4 - Lecture 3]])
- Organism is excreted for several weeks unless treated with antibiotics (erythromycin), but typically self-limiting.

Sources Of Campylobacter
- Common GIT commensal of chickens and other animals (cattle, pigs, dogs, wild birds, etc.).
- Common cause of foodborne illness in developed countries (particularly contaminated chicken and unpasteurised milk).
- While invasive, mechanism not well understood.
- Infrequently causes invasive/extraintestinal disease esp. if host is immunocompromised
- Inflammatory process consistent with invasion of intestinal epithelium, M-cell uptake, and with the production of bloody diarrhoea + PMNs.

Campylobacter: Virulence Strategies
- Invasiveness:
- Intracellular survival and multiplication.
- Surface structures:
- Capsule important for virulence, epithelial cell adherence, and invasion.
- Lipooligosaccharide (LOS) required for epithelial cell adherence and invasion.
- LOS structures of C. jejuni can display molecular mimicry of neuronal gangliosides (linked to Guillain–Barré syndrome).
- Flagellum required for colonization, virulence and epithelial cell invasion, and also acts as a secretion apparatus for invasion antigens.
- Cytolethal distending toxin:
- Causes DNA damage promoting inflammation and cell death.

Answer 100

A

(Osmotic) Diarrhoea
- Caused by an excess amount of poorly absorbed nutrients (i.e., malabsorption) that remain in the intestinal lumen
- Examples include lactulose and magnesium
- Causes retention of water in the lumen through osmotic effects
- Attaching/Effacing (A/E) lesions:
- Result from destruction of intestinal microvilli and induction of cytoskeletal rearrangements directly beneath intimately attached EHEC organisms
- Mediated by Intimin and Tir
- Decreases surface area for nutrient absorption, causing the intestinal contents to increase in osmolarity, leading to secondary osmotic diarrhoea

Secretory diarrhoea
- Through increased secretion or decreased absorption of fluids and electrolytes
- e.g. Vibrio cholerae, ETEC - disease is mediated by exotoxins in the gut

Inflammatory diarrhoea
- Through inflammation causing damage to host tissues resulting in fluid exudation
- e.g. C. difficile - mediated by direct damage to the IEC barrier and disruption of tight junctions

Answer 101

A

Bacterial Exotoxin: Soluble proteins secreted into extracellular environment by some species of Gram-positive and Gram-negative bacteria.
- Toxins can attack different cell types:
  - Enterotoxins
  - Neurotoxins
  - Leukotoxins
  - Cytotoxins
- Can act through specific mechanisms:
  - Botulinum toxin (Clostridium botulinum): blocks neurotransmitter release leading to paralysis (botulism)
  - Streptolysin O (Streptococcus pyogenes): haemolysis
  - Pertussis toxin (Bordetella pertussis): alters cell function leading to cell death

Bacterial Endotoxin: LPS (lipopolysaccharide) present in Gram-negative bacteria. An intrinsic feature of the bacterium

Answer 102

A

Intoxication
- Results when a host ingests pre-formed exotoxin
- Ingested enterotoxins directly cause disease
- Presence of a replicating pathogen is not required for disease
- often requires shorter incubation time eg hours, as pre-made toxin is cause of symptoms

Infection
- Results when a pathogen colonises a part of the body and subsequently causes disease
- Often pathogens will then synthesise toxin which causes toxin-mediated disease
- often slightly longer incubation time eg 1-2 days compared with intoxication (hours)

Answer 103

A

Vibrio cholerae
- Gram-negative, facultative anaerobe, highly motile bacillus with a single polar flagellum (locomotion organelle).
- Persists in natural aquatic reservoirs and infects human host via consumption of contaminated water/food.
- People with access to adequately treated water typically not exposed.
- Areas without adequate water treatment still suffer from epidemic infection.
- Causative agent of cholera, an acute diarrhoeal disease which can be fatal without treatment.
- A type of secretory diarrhoea
- Estimated 3–5 million cases and 100,000–120,000 deaths due to cholera every year.

Cholera: Clinical Features and Treatment
Clinical features
- Acute profuse watery diarrhoea with severe dehydration (can lead to hypovolaemic shock and death if untreated)

Treatment
- Cholera is a readily treatable disease
- Up to 80% of infected people can be treated successfully with prompt administration of oral rehydration solution
- Severely dehydrated patients require administration of intravenous fluids
- May also require adjunctive antibiotics to attenuate duration of diarrhoea, reduce volume of rehydration fluids needed, and shorten duration of V. cholerae excretion

V. cholerae Colonisation Factors
- Colonisation is dependent on production of a type IV pilus, toxin coregulated pilus (TCP), which is essential for adhesion to the small intestine.
- N-acetylglucosamine-binding protein A (GbpA) is also required (mediates binding to intestinal mucin).
- Colonisation of the gut is a pre-requisite for the subsequent production of toxins which are directly responsible for the profuse diarrhoea.
- V. cholerae causes toxin-mediated disease

V. cholerae Toxins
- V. cholerae has 7 different toxins that together result in a particularly severe diarrhoea.
- Cholera toxin (CT), accessory cholera toxin (ACE), NAG-stable toxin, and V. cholerae cytolysin (VCC): affect ion secretion into the intestinal lumen.
- Haemagglutinin/protease (HA/P), repeats in toxin (RXT), and zonula occludens toxin (Zot): promote the loss of barrier function.

Cholera Toxin Structure
- Consists of an A subunit bound to a pentameric ring of B subunits, where the B subunits are responsible for delivery of the A subunit into the host cell.

Cholera Toxin Function
- CT (A subunit): causes Cl− secretion and Na+ absorption, leading to an increase in NaCl levels in the intestinal lumen.
- CT (A subunit): activates adenylate cyclase: catalyses conversion of ATP to cAMP.
- cAMP: increases activity of the chloride (CFTR) transporter.
- cAMP: decreases activity of sodium (NHE2/NHE3) transporters.
- Modulation of both receptors causes elevated concentrations of Na+ and Cl– ions in small intestinal lumen which becomes hyperosmotic compared to cells lining the intestines.
- Causes osmosis of large volumes of water into the intestinal lumen from the cells and ultimately from the bloodstream.
- Water exits the body in form of diarrhoea, resulting in dehydration.

Enterotoxigenic Escherichia coli (ETEC)
- Gram-negative, facultative anaerobe, motile bacillus.
- Infects human host via consumption of contaminated food/water.
- Causative agent of traveller’s (abundant watery) diarrhoea in developing countries.
- Also secretory diarrhoea (along with V.cholerae )
- Responsible for an estimated 300,000 -

500,000 deaths annually in children aged <5 years.
- Clinical features and treatment are similar to cholera (emphasis on rehydration and electrolyte replenishment).

ETEC Colonisation Factors
- Colonisation of the small intestine is essential for ETEC infection
- A variety of different structures are required for adhesion:
- Fimbriae (e.g. CFA/I)
- Pili (e.g. ECP)
- Non-fimbrial adhesins (e.g. Tia, TibA)
- Colonisation of the gut is a pre-requisite for production of toxins that are directly responsible for causing the watery diarrhea
- ETEC causes toxin-mediated disease

ETEC Toxin Structure and Function
Heat labile toxin (LT)
- Similar to CT in structure (AB5) and function

Heat stable toxin (ST)
- Small cysteine-rich peptide
- Binds to receptor (guanylyl cyclase C) on surface of small intestinal epithelium: catalyses conversion of GTP to cGMP:
- cGMP: increases activity of chloride (CFTR) transporter
- cGMP: decreases activity of sodium (NHE3) transporter
- Causes Cl– secretion and Na+ absorption, leading to an increase in NaCl levels in the intestinal lumen
—
Enterohaemorrhagic Escherichia coli (EHEC)
- Gram-negative, facultative anaerobe, motile bacillus
- Infects human host via consumption of contaminated food/water
- Primary sources of EHEC outbreaks are raw or undercooked ground meat products, unpasteurised milk, and faecal contamination of vegetables or drinking water
- Causative agent of diarrhoea, haemorrhagic colitis (HC), and haemolytic uraemic syndrome (HUS) ^[anemia, thrombocytopenia, and renal failure] in developing and developed settings - a type of osmotic diarrhoea
- Common cause of renal failure in young children

Symptoms:
- Diarrhoea which can be bloody

Treatment:
- Rehydration and renal-supportive therapy
- Antibiotics are not recommended due to increased risk of HUS

EHEC Colonisation Factors
- Colonisation of the large intestine is essential for EHEC infection
- A variety of different structures are required for adhesion:
- Intimin and Tir
- Long polar fimbriae (Lpf)
- Haemorrhagic coli pilus (type IV pilus)
- Non-fimbrial adhesins (e.g., OmpA, Efa1, Iha)
- EHEC colonisation of the gut is a pre-requisite for production of toxins which contribute to the diarrhoea

Attaching/Effacing Lesion-Mediated (Osmotic) Diarrhoea
- Caused by an excess amount of poorly absorbed nutrients (i.e., malabsorption) that remain in the intestinal lumen
- Examples include lactulose and magnesium
- Causes retention of water in the lumen through osmotic effects
- Attaching/Effacing (A/E) lesions:
- Result from destruction of intestinal microvilli and induction of cytoskeletal rearrangements directly beneath intimately attached EHEC organisms
- Mediated by Intimin and Tir
- Decreases surface area for nutrient absorption, causing the intestinal contents to increase in osmolarity, leading to secondary osmotic diarrhoea

Shiga Toxin-mediated Diarrhoea
- Shiga toxins (Stx) 1 and 2:
- Antigenically distinct AB5 toxins responsible for the progression to HUS (bind to renal cells)
- Stx A subunit inactivates host ribosomes, thereby inhibiting protein synthesis (translation)
- Both Stx1 and Stx2 inhibit intestinal absorption of water, causing luminal fluid accumulation which exits the body as diarrhoea

Clostridioides difficile
- See notes from “Normal Gut Flora” Lecture
- Gram-positive bacillus, obligate anaerobe, spore-forming
- Part of the normal gut flora
- Leading cause of healthcare-associated infectious diarrhoea, with spectrum of disease ranging from:
- Uncomplicated diarrhoea, inflammatory type
- Systemic toxic effects leading to significant colonic inflammation, sepsis, and death
- A hospital “superbug” due to the difficulties in treatment and the propensity to spread in nosocomial settings
- Economic burden of C. difficile infection estimated at $800 million annually in the US

C. difficile Infection
- Most important risk factor for C. difficile infection (CDI) is the recent administration of broad-spectrum antibiotics which cause gut dysbiosis
- CDI can also occur when environmental spores are ingested and then reach the large intestine
- Spores comprised of several heat/chemical-resistant layers, allowing them to survive acidic environment of the stomach
- Bile salts within the small intestine trigger germination of spores into vegetative cells in the large intestine

C. difficile Transmission
- Stopping transmission of C. difficile to other individuals is important and challenging.
- C. difficile can easily spread by direct or indirect exposure to a patient or the patient’s environment:
- Exposure to contaminated care equipment or high-touch surfaces in patients’ room/bathroom
- Transfer of bacterial spores to patients via hands of healthcare workers
- Oral vancomycin and metronidazole are used as treatment, however these antibiotics do not kill spores.
- Bleach should be used to clean contaminated surfaces as normal cleaning products may be ineffective against spores.
- Hand-washing preferred over handrubs for hygiene

C. difficile Clinical Features and Treatment
Clinical features:
- Diarrhoea (can range from mild self-limiting to severe haematochezia, abdominal cramps, and abdominal pain)
- Pseudomembranous colitis (inflammation of the colon)- so named because C diff overgrowth forms layers resembling membranes
- Toxic megacolon (acute toxic colitis with dilation of colon) which can result in perforation of the colon, sepsis, and death

Treatments:
- Antibiotics including vancomycin (oral), metronidazole (oral or IV), fidaxomicin (oral)
- Faecal microbiota transplant (FMT) – disease remission in up to 92% of cases
- Surgical removal of colon (for severe toxic megacolon)

C. difficile Colonisation Factors
- Colonisation (and overgrowth) within the large intestine is essential for C. difficile infection
- A variety of different structures are required for adhesion:
- S-layer proteins
- Cell wall proteins (e.g., Cwp66)
- Fbp68 fibronectin-binding protein
- FliC-FliD components of flagella
- Colonisation of the colon is a pre-requisite for production of toxins that are directly and indirectly responsible for causing the (inflammatory) diarrhoea
- Inflammatory diarrhoea is characterised by bloody stools, small-volume mucous stools, and fever

C. difficile Toxins
Toxin A (TcdA)
- 308 kDa, binds to receptor (glycoprotein gp96) on the apical surface of colonic epithelial cells
- Causes direct alterations in barrier function

Toxin B (TcdB)
- 270 kDa, gains access to basolateral surface of colonic epithelial cells after tight junction disruption, binding to an unidentified receptor

Binary toxin (CDT)
- 147 kDa, actin-specific ADP ribosyltransferase that destabilises the cytoskeleton and potentiates toxicity of TcdA and TcdB, contributing to the severity of infection

## TdcA/B can be detected by PCR in stool, part of diagnostic toolkit for C. diff

C. difficile TcdA and TcdB Toxins
- Potent cytotoxic enzymes that specifically glycosylate small GTPase protein Rho, leading to disruption of cytoskeletal integrity and cytotoxicity.
- Trigger an extensive inflammatory cascade resulting in damage to host tissue and release of inflammatory exudative fluid into the colonic lumen (appears mucous-y due to presence of WCCs).
- Activate enteric nerves and (Toxin A) promote the release of neuropeptides, which elicit Cl– secretion from intestinal epithelial cells (therefore diarrhoea also has a secretory component)

TcdA/TcdB-mediated inflammation (inflammasome activation)
- TcdA and B are potent cytotoxic enzymes that specfically glycosylate small GTPase RHo, leading to disruption fo cytoskeletal integrity and cytotoxocoty
- triggers an extensive inflammatory cascade resulting in damage to host tissue and release inflammatory exudative fluid into the colonic lumen
- activate enteric nerves and toxin A promotes release of neuropeptides, which elicit Cl- secretion from intestinal epithelial cells
- hence diarrhoea has a secretory component but it is by and large inflammatory

Pathogenesis of C. difficile-associated Diarrhoea
- Toxin-induced inflammation damages tight junctions and the IEC barrier resulting in fluid exudation (inflammatory diarrhoea)
- Part of the inflammatory response includes neutrophils which release an adenosine precursor that activates CFTR thereby promoting Cl– secretion (secretory diarrhoea)
- Continual destruction of intestinal epithelium from inflammation results in:
- Exudation of blood and serum into the lumen (bloody diarrhoea)- note may not be so bloody in mild disease
- Destruction of absorptive epithelium (osmotic diarrhoea)

Answer 104

A

Rota paeds, noro epidemic

Answer 105

A

General features
- Small, but very tough
- Non-enveloped
- Resistant to drying
- Hard to disinfect
- Rapid disease course
- Incubation down to 24 hr
- Symptoms from 24 hr to 7 days
- Spectacular replication
- Low minimal infectious dose, ≤ 10 infectious units
- Massive yield, up to 1010 infectious doses excreted

Viruses that cause gastroenteritis
- Rotavirus
- Pediatric diarrhoea
- Norovirus
- Epidemic gastro
- Adenovirus
- Serotypes 40 and 41 (less frequent)
- Astrovirus
- Not discussed

Answer 106

A

Rotavirus vaccines
- Multiple infections with rotavirus are possible
- BUT these are often with different serotype
- AND are generally much less severe
These suggest that a vaccine might work
- Live attenuated vaccines best explored
- Single genotype (attenuated human rotavirus)
- Rotarix (GlaxoSmithKline) G1P1[8]
- Mixtures of reassortant viruses
- RotaShield (withdrawn after a single year in 1999, long story…)
- RotaTeq (CSL/Merck) G1, 2, 3, 4 P1[8]
- Rotarix and RotaTeq in the National Immunisation Program as of 2007
- Given at 2 and 4 (R’rix) or 2, 4 and 6 months (R’Teq)

Multivalent rotavirus vaccines (e.g. RotaTeq)
- Reassortants have different gene segments from different viruses; on attenuated bovine rotavirus backbone
- rotateq has 4 G-types and one human P-type in its collecton

Rotavirus in Australia 2008 vs 2014
- Hospitalisations and Emergency department visits reduced by 71% for under 5s
- 7000 admissions avoided
Source: Immunise Australia website

Impact on mortality
- Data on mortality from Mexico
- decreased significantly

Richardson V et al. N Engl J Med 2011;365:772-773.

Does the vaccine drive serotype change?
- In Australia different states use different vaccines
- Rotarix (G1, P8) states (inc NSW and ACT)
- RotaTeq (G1,2,3,4, P8) states (inc Vic, Qld, SA)
- short answer: yes, selecting for those with different serotype, but does not seem to confer resistance
- no data suggesting reduced efficacy of vaccines
- may be down to steady P serotype

Roczo-Farkas et al. Communicable Diseases Intelligence Volume 40 No 4 – December 2016

Answer 107

A

Rotavirus vaccine and intussusception
- There is a small increase in risk of intussusception, especially within a week of the first dose - data is suspect

TGA, 2011
Minimise risk:
- Stick to schedule (esp. upper age limit)
- Don’t vaccinate risk groups (immunocompromised or ill)
- Vigilance, advise parents (severe colic, fever, bloody stool, drawing legs up)

Answer 108

A

Original strain was Norwalk Virus
- An outbreak of gastro occurred at a Norwalk school
- A rectal swab taken and a bacteria-free sample made
- Fed to adult volunteers, their stool collected
- Serially passaged to other volunteers
- Virus identified by immune electron microscopy
  - Volunteers needed for serum and virus samples
- Similar viruses were called Norwalk-like viruses
  - AKA small round structured viruses

Studying noroviruses is very hard
- Human norovirus cannot be grown in culture
- Only host is human
- Only source of norovirus is human poo
- Only way to test virus viability is to feed it to humans

Volunteers have contributed greatly…
- A mouse norovirus is the only one that grows well in culture; one other calicivirus genus can be grown

Lots of extrapolation required…
- With enough virus, the genome can be sequenced
- Individual proteins can be expressed and studied

Answer 109

A

**Molecular biology **
- Norovirus is a member of the calicivirus family

Calici from calyx, Latin for cup
- Discovered in ’60s by EM
Characteristics
- - sense, linear, ssRNA genome, ~7.5 kb -> straight to ribisome
  - - or positive = genome same sense as mRNA
- Non-enveloped virion: bleach and water/soap
- Replicates in the cytoplasm
Other caliciviruses
- Saporovirus (GI disease in humans)
- Rabbit calicivirus used as biological control agent

Noroviruses are relatively simple
- Capsid composed of one major and one minor protein
- Major capsid protein (VP1) forms virus-like particles
- The genome is a single strand of + sense RNA
- has three open reading frames

ORF1 makes a polyprotein
- A common trick used by viruses
- Cleaved into individual proteins by the viral proteinase
- A total of 8 proteins including the 2 capsid proteins
- Approximately 2500 amino acids in total
- Many mammalian proteins are bigger!

Answer 110

A

Rotavirus disease and pathogenesis
- Typical disease course
- 3 days of vomiting that starts first
- 5 days of diarrhoea that overlaps the vomiting
- Most emphasis is on the cause of diarrhoea
- Direct viral damage to enterocytes at the tips of villi
- Shortening of villi, malabsorption and secretion before, after, during
- BUT diarrhoea does not entirely correlate with damage
- Work in animal models suggests it’s more complex

Incubation from ½ to 2 days
Disease course
- Acute symptoms generally last ½ to 2½ days
- Rapid disease almost diagnostic:
  - Kaplan’s criteria for identifying norovirus outbreaks

Answer 111

A

Adenoviruses
- Adenoviruses (AdV)
- Adeno from adenoid
- Found in 50s using cell culture
- Originally associated with human respiratory disease
- Human AdV has 6 species (A-F) and 51 serotypes
- Characteristics
- Linear, dsDNA genome ~35 kb
- Non-enveloped virion- survives stomach to cause disease there and elsewhere
- Replicates in the nucleus
- Other adenoviruses
- Adenoviruses infect fish, reptiles, birds and mammals

Adenoviruses do lots of nasty things
TROPISM dependent
- Disease
- Upper respiratory infections
- Pneumonia
- Epidemic keratoconjunctavitis
- Gastroenteritis
- Menigoencephalitis
- Hepatitis (kids with transplants)
- Myocarditis
- Acute haemorrhagic cystitis

Answer 112

A

Normal flora
- Synonymous with microbiota, indigenous microbial population, microflora, commensal flora.
A collection of microbial species found on tissue surfaces of normal healthy individuals.
Coexist with the host in a non-disease-inducing manner, and are beneficial to the host.
Includes those that can become opportunistic pathogens .
- Normally harmless organisms that can cause infection/disease when host immune system is compromised or natural barrier defences are breached
Microbial communities that colonise the human gastrointestinal tract (GIT):
- GIT is organ site of largest microbial biomass
  - Comprising 1012 -1013 bacteria in colon.
  - Of at least 500-1,000 bacterial species.
  - Composition of community varies within different parts of the GIT and between individuals.
  - Plays a pivotal role in health and disease.
BUT ALSO INCLUDES:
- Fungi (mostly Candida yeast e.g. Candida albicans).
- Protozoa (controversial but include Blastocystis and Entamoeba).
- Eukaryotic viruses
- Prokaryotic viruses (including bacteriophages/phages)

Answer 113

A

Microbial Dysbiosis

Altered or imbalanced normal gut flora can result in dysbiosis, which is associated with several human diseases.
This imbalance can mean 3 things:
1. Loss of beneficial microbial organisms in our gut.
2. Expansion of potentially harmful microorganisms.
3. Loss of microbial diversity.

These are not mutually exclusive and can
occur at the same time.

Microbial Dysbiosis: Causes & Disease

Dysbiosis can be caused by various factors including deterioration of health, old age, malnutrition, diet, stress, genetics, infection, and antibiotic usage.
- Antibiotic usage – kills large numbers of normal gut flora, offering an ecological niche to bacteria that would not otherwise be able to compete.
- multiple consequences: asthma, coeliac, RA, obesity, NASH, NAFLD, stress

Microbial dysbiosis and chronic intestinal disease
- While specific causality is unclear, there is a link between microbial dysbiosis and:
- Irritable bowel syndrome (IBS)
Ø Increased Firmicutes:Bacteroidetes ratio, decreased Bifidobacterium
- Inflammatory bowel disease
Ø Increased bacterial numbers in mucosa, decreased bacterial diversity
- Colorectal cancer
Ø Increased Fusobacterium spp., E. coli
- Obesity
Ø Increased Firmicutes:Bacteroidetes ratio, decreased bacterial diversity

Gut virome in human disease
huge diversity, also play role in disease

Answer 114

A

Normal gut flora can also cause disease by known means, such as antibiotic-induced dysbiosis leading to infection with opportunistic pathogens (C. difficile), or upon escaping their natural habitat into abdomen/bloodstream when intestinal mucosa is compromised (e.g. when intestinal integrity disrupted, Bacteroides fragilis).

C. difficile infection

Gram-positive spore-forming, anaerobic bacillus considered a member of the normal gut flora (~5% of population).
Loss of normal gut flora barrier effect following broad spectrum antibiotics allows C. difficile to colonize and overgrow in the colon.
- egs beta lactams (ceftriaxone, piperacillin-tazobactam), clindamycin, fluoroquinolones eg ciprofloxacin
spectrum of disease from diarrhoea and abdominal pain to pseudomembranous colitis, to toxic megacolon and death
Interaction of C. difficile with intestine leads to toxin release causing various symptoms.
- Mild diarrhoea
- Pseudomembranous colitis (inflammation of the colon)
- Toxic megacolon (acute toxic colitis with colon dilation)
- Death
C. difficile secretes toxins that are internalised by host cells through receptor-mediated endocytosis.
Toxins cause disruption to cytoskeletal architecture, which leads to cell death.
Toxin-mediated cell death results in the loss of intestinal barrier integrity and the translocation of bacteria into underlying/deeper tissues including bloodstream.
Toxin-mediated damage to the epithelium activates the host inflammatory immune response.
An overly robust inflammatory response can be damaging to the host and contribute to disease pathology.

B. fragilis infection

Gram-negative, anaerobic bacillus and prevalent member of the normal gut flora.
Highly beneficial to the host (breaksdown complex carbohydrates, releases anri-inflammatory cytokines)
Probiotic to treat a range of disorders characterised by up-regulation of pro-inflammatory cytokines (e.g. IBS, multiple sclerosis, autism, etc.)
When intestinal integrity is disrupted, B. fragilis can escape into peritoneum, causing abscesses or peritonitis; or in blood causing bacteraemia and sepsis
Treatment includes antibiotics targeted against B fragilis, reconstitution of gut flora, surgical procedures to drain pus and remove necrotic tissue if necessary

Answer 115

A

Age
- Health (comorbidities eg cancer, stress, hormones, immunity)
- Lifestyle & physical activity
- Geographical location
- Diet & nutrition
- Genetics
- Medication eg antibiotics, PPIs
- Mode of birth
- Infant feeding type

Answer 116

A

§ Prebiotics:
Ø Nutritional compounds used to promote growth of beneficial gut flora.
§ Probiotics:
Ø Bacterial cultures that restore the population of beneficial gut flora.
§ Faecal microbial transplantation (FMT):
Ø Isolation of beneficial bacteria from the faecal matter of healthy donor to
replace disrupted populations in diseased individuals.
Ø FMT is successful in treating C. difficile infection, with disease remission in
up to 92% of cases.
Ø FMT has promising results in the treatment of post-infectious IBS and and
various other gut microbiome imbalances (e.g. ulcerative colitis).
§ Antimicrobials (other than classical antibiotics):
Ø Eliminate pathogens or manipulate the normal gut flora to benefit the host.

Answer 117

A

CAUSES OF PEPTIC ULCER DISEASE:

Helicobacter pylori
NSAIDs
The rest:
- Cancer especially if of a certain age
- Other drugs
- Zollinger-Ellison syndrome (Gastrinoma)
In 1983, Warren and Marshall described an ‘unidentified curved bacillus on gastric epithelium in active chronic gastritis’ Lancet 1 (8336): 1273-75.
Successfully cultured under microaerophilic conditions, on chocolate agar, at 37°C
Gram-negative
Initially thought to be Campylobacter, now known as Helicobacter pylori (Hp)

KOCH’S POSTULATES

Heinrich Hermann Robert Koch

Criteria used to establish a causative relationship between a microbe and a disease

The microorganism must be present in every case of the disease but absent from healthy individuals
The suspected microorganism must be isolated and grown in pure culture
The same disease must (should) result when the isolated microorganism is inoculated into a healthy host
The same microorganism must be isolated again from the diseased host

OUTCOME OF HUMAN EXPERIMENTS

Marshall developed transient gastritis (MJA 142;436 1985)
Morris developed persistent gastritis which resolved after sequential therapy with doxycycline and bismuth subsalicylate (Am J Gastroenterol 82:192 1987)

Answer 118

A

TREATMENT

Triple therapy, most commonly used in Australia, involves:
- Proton pump inhibitor (PPI) with
- Two antibiotics:
  - Most commonly used – clarithromycin and amoxicillin
  - Also – metronidazole, tinidazole, tetracycline, azithromycin, levofloxacin
Quadruple therapy may also be used – includes bismuth compound

HIGH INCIDENCE OF ANTIBIOTIC RESISTANCE IN DEVELOPING COUNTRIES

CHOICE OF ANTIBIOTICS

Choose two antibiotics with different modes of action:
- Amoxicillin - for peptidoglycan;
- Tetracycline
- Clarithromycin
- Azithromycin
  - for the ribosomes

Answer 119

A

cagA (cytotoxin-associated gene A), a 128-140 kDa protein that is co-expressed with;
VacA (vacuolating cytotoxin) that causes cell injury
85-100% of patients with DU have cagA+ strains, compared to 30-60% of infected patients who do not develop ulcers
Host genetic factors (sensitivity to gastrin, higher parietal cell mass – cells that secrete HCl)
Environmental factors: smoking (73 vs 27%), NSAID use (61 times more likely if colonized by Hp), alcohol usage

HOW DO HP SURVIVE IN THE STOMACH?

Hp use urea present in gastric juice
- Urease enzyme produced by every strain to combat the acidic environment of the stomach by producing ammonia
- Breaks down urea into NH3,which neutralises acid, and CO2
Cytosolic urease can constitute up to 10% of bacterial protein
Basis of the urease breath test
2-6 sheathed unipolar flagellae for motility through the mucus layer
Chemotaxis: sensors will be on the lookout for bicarbonate or neutral compounds
Lipopolysaccharide (LPS) and outer membrane proteins for adherence to host cells
vacA (exotoxin) and secretory enzymes (mucinase, lipase, protease) cause gastric mucosal injury (Acute and chronic inflammation)
Type IV secretion system for injecting effectors
cagA (effector) causes actin remodeling, IL-8 induction, inhibits apoptosis and T-cell activation and proliferation

HP TYPE IV SECRETION SYSTEM AND CAGA

cagA encoded on a pathogenicity-associated island (PAI)- e.g. antibiotic resistance genes
More commonly associated with symptomatic disease and cancer
PAIs, in general:
- Encode genes involved in virulence
- Large segments of DNA encode numerous genes
- Acquired through horizontal gene transfer
- A pathogenic strain may have more than one PAI

Answer 120

A

DIAGNOSTICS – HP TESTING

Urease breath test – detection of C14 labelled urea
Endoscopy and biopsy – histology or CLO test - to check out complications or confirm healing
Blood test – antibody test
Stool antigen test

DISADVANTAGES

Urease breath test:
- False-negative results possible in the presence of PPIs and recent antibiotic or bismuth compound use. Less sensitive than biopsy test. Considerable resources and personnel required to carry out test. Not widely available.
CLO test (biopsy test):
- Invasive ie needs endoscopy. Expensive.
Antibody test:
- Cannot confirm whether it is a past or present infection. Not recommended for confirming eradication.
Stool test:
- False-negative results possible in the presence of PPIs and recent antibiotic or bismuth compound use. Stool collection may be considered distasteful to the patient.

ADVANTAGES

Urease breath test:
- Provides rapid results (when available). Excellent specificity and very good sensitivity.
CLO test (biopsy):
- Allows culture and therefore determination of antibiotic resistance profiles. -
Blood antibody test:
- Inexpensive, widely available, very good NPV.
Stool test:
- Identifies active Hp infection. Excellent PPV and NPV regardless of Hp prevalence. Useful before and after therapy.

CONFIRMATORY TESTS FOR HP ERADICATION:

In patients treated for Hp, eradication of infection should be confirmed four or more weeks after the completion of therapy.
PPIs should be withheld for one to two weeks prior to repeat testing to reduce false-negative results.
Serologic testing should not be performed to confirm eradication as patients will continue to have antibodies after eradication.

Answer 121

A

Gastrointestinal tract Histology
* Mucosa
* Submucosa
* Muscularis propria
* Adventitia/Serosa

**Mucosa

◼ epithelium
◼ lamina propria
◼ muscularis mucosae

Submucosa
loose collagenous
tissue containing
blood vessels,
lymphatics, nerve
submucosal plexuses
(meissner’s) and
lymphoid aggregates

Muscularis Propria

generally two layers
of smooth muscle
(inner circular and
outer longitudinal) to
allow for peristalsis,
and nerve plexuses
(myenteric)

Adventitia
loose supporting
tissue containing
blood vessels and
nerves

Serosa
Mesothelial lining
covering the outer
most aspect of
gastrointestinal
tract

Adventitia vs serosa
Adventitia – found all parts
of GIT, lies between
muscularis propria and
serosa (in some parts of
bowel minimal to non-
existent)

Serosa – outer most lining
of those parts of GIT found
within abdomen (similar to
pleura of lungs)

Answer 122

A

Functions of GIT mucosa
* Protection - barrier to external environment
* Secretion - and synthesis of various substances
(e.g digestive enzymes, mucus, antibodies,
hormones)
* Absorption - products of digestion, water,
electrolytes
* Immunological functions - containing lymphoid tissue

Oesophagus

Lumen is lined by
protective stratified
squamous epithelium
Primary function is to
transfer ingested food
and fluids from mouth
to stomach
Thin lamina propria
contains lymphoid
tissue –> immune role

Stomach mucosa

Stomach mucosa – cell types
* Fundus and body consist of
straight tubular glands
(formed by simple columnar
epithelium)
- note surface cells are low columnar or cuboidal
* Contains large mucinogen
granules which maintain the
thick mucus sheet protecting
epithelium
* Surface mucous cells
secrete bicarbonate, helps to
protect epithelium from
acidic gastric juices

Parietal cells: secrete
gastric acid and
intrinsic factor
(needed to absorb
vitamin B12 in
terminal ileum), stain
pink (many
mitochondria)
Chief cells: secrete
pepsin, stain blue
(many ribosomes)
http://www.lab.anhb.uwa.edu.au/mb140/default.htm

Gastric glands – cell types
* Neuroendocrine cells
– secrete hormones
such as serotonin and
gastrin
* Stem cells – can
differentiate into any
of other cells as
required —> constant turnover of cells

Found in antrum

villous
mucosa
lined by
columnar
mucosa with
goblet cells
of duodenum

Simple columnar
epithelium
Enterocytes:
absorptive cells with
microvilli, cover villi
and crypts
Goblet cells:
scattered along
epithelium and
produce mucus
http://www.siumed.edu/~dking2/erg/GI125b.htm

Small intestine epithelium
* Paneth cells: base of crypts,
contain secretory granules of
lysozymes, can phagocytose
some bacteria and protozoa
* Neuroendocrine cells:
produce hormones such as
secretin (important for
digestion- regulates pH)
* Stem cells: at base of crypts – regeneration and high cell turnover
- Intraepithelial lymphocytes:
mainly T cells
\
\
Mucosa with
crypts lined by
columnar mucosa
with goblet cells
of large intestine

Large Intestine mucosa
* Simple columnar
epithelium which forms
tubular glands (crypts)
* Enterocyte, - absorptive
cell - microvilli (most
common cell type)
* Goblet cells produce
mucus, needed to
lubricate intestine and
allow for passage of
bowel contents
* Stem cells found at base
of crypts
http://www.kumc.edu/instruction/medicine/anatomy/histoweb/gitract/gitract.htm

stratified
squamous
epithelium
of anus

Answer 123

A

Stomach mucosa – cell types
* Fundus and body consist of
straight tubular glands
(formed by simple columnar
epithelium)
- note surface cells are low columnar or cuboidal
* Contains large mucinogen
granules which maintain the
thick mucus sheet protecting
epithelium
* Surface mucous cells
secrete bicarbonate, helps to
protect epithelium from
acidic gastric juices

Gastric glands – cell types
* Parietal cells: secrete
gastric acid and
intrinsic factor
(needed to absorb
vitamin B12 in
terminal ileum), stain
pink (many
mitochondria)
* Chief cells: secrete
pepsin, stain blue
(many ribosomes)
http://www.lab.anhb.uwa.edu.au/mb140/default.htm

Gastric glands – cell types
* Neuroendocrine cells
– secrete hormones
such as serotonin and
gastrin
* Stem cells – can
differentiate into any
of other cells as
required —> constant turnover of cells

Answer 124

A

Oesophageal-gastric junction
(usually called gastro-oesophageal junction)

stratified
squamous
epithelium
of
oesophagus
columnar
epithelium
of stomach

Gastro-duodenal junction

Cell types are the same but the structure of the epithelium changes.

Simple
columnar
epithelium
of stomach

vs

villous
mucosa
lined by
columnar
mucosa with
goblet cells
of duodenum

Ileo-caecal junction

lined by
columnar
mucosa with
goblet cells and
Paneth cells of
ileum

vs

Mucosa with
crypts lined by
columnar mucosa
with goblet cells
of large intestine

Recto-anal junction
glandular mucosa of rectum

vs

stratified
squamous
epithelium
of anus

Answer 125

A

2nd most common across sexes.
Age-specific rates, generally low until 50.
Steadily rises after 50 with slight male predominance, then drops over time.
Incidence and mortality are falling over time.

5YS: Improved to 70%.

Colon Cancer: Lifetime Risk
- male 1/10 if lives to 85
- female 1/15

Colon Cancer Risk from Age 50-84
- 1/10 in males, 1/15 in females
- hence >50 y cut off for screening

Risk Factors for Colon Cancer
- Age (as shown in age specific rate graphs)
- Family history
- Personal history of CRC or “at-risk” polyps
- Inflammatory bowel disease

–
Genetic Causes of CRC
- ~1-5% of CRC is associated with germline mutations
- - ~75% of CRC is sporadic - no family history is apparent

Epidemiological Risk Factors for CRC
- Diabetes mellitus
- Alcohol
- Obesity
- Acromegaly

Controversial Associations
- Smoking
- Coronary artery disease
- Ingestion of red meat

Role of the microbiome

Risk Factors for Early-Onset CRC
- males
- Caucasian
- family history
- obesity and hyperlipidaemia– may explain high rates
- NOT smoking
- but alcohol does

Protective Factors: Drugs
- Aspirin
- Other NSAIDs (e.g., sulindac)
- Statins (controversial)
- Hormone replacement therapy (HRT)
- Antioxidants (controversial)
- Green tea

Protective Factors: Uncertain
- Physical activity
- Diet – fruit and vegetables
- Fibre intake
- Resistant starch
- Folic acid
- Vitamin B6 (pyridoxine)
- Calcium
- Vitamin D
- Magnesium
- Garlic
- Fish consumption

Clinical Features
- Abdominal pain (site of neoplasm dictates location of pain and pattern e.g. periumbilical and colicky if near ileo-caecal valve, bilateral lower abdomen if in left side of colon)
- Obstruction
- Perforation
- Localized spread (especially rectal cancers)
- Peritoneal spread
- Change in bowel habit esp if sigmoid/rectum, unlikely if right-sided
- Bleeding (= ulceration)
- Visible/identifiable blood per rectum (overt)
- Occult (covert) bleeding leading to iron deficiency anaemia
- Anaemia (Fe deficient, fairly common presentation)
- Weakness
- Weight loss

Right-Sided vs Left-Sided Cancers

Right-Sided
- Liquid stool
- Iron deficiency anaemia without other symptoms (falling Hb and MCV even if still in normal range)

Left-Sided
- Formed stool
- Abdominal pain
- Change in bowel habit
- Rectal bleeding

Metastatic Disease
- Anorexia, vomiting, early satiety
- Fatigue
- Weight loss
- Abnormal liver tests
- Abdominal distension (ascites or hepatomegaly)
- Spread most commonly to draining lymph nodes and liver but also to lungs, bone, brain, skin (nodules)

Symptoms and Prognosis
- Asymptomatic cancers (picked up by screening) generally have a better prognosis
- Acute surgical presentations (bowel obstruction or perforation), likely to have peritoneal seeding, and have a poor prognosis
- Presence of metastatic disease (20% of cases) indicates a poor prognosis

Diagnosis
- Symptoms (see above)
- Asymptomatic (population screening)
- Examination
- Abdominal mass - liver, RIF mass
- Lymphadenopathy
- Hepatomegaly or ascites
- Rectal mass eg on DRE - rare
- Supportive blood tests
- Iron deficiency anaemia (in appropriate age group)
- Abnormal liver tests (possible metastatic disease)
- Diagnostic tests
- Colonoscopy - definitive test
- Barium enema
- CT colonography

Answer 126

A

Commonest mesenchymal tumour of GI tract
Extraintestinal examples eg. mesentery
Recapitulate Interstitial Cells of Cajal (ICC) – “pacemaker” cells of gut, neural and myoid features – can have neural and myoid appearance
Cause célèbre of targeted therapy
Most (85%) GISTS in kids lack C-KIT or PDGFR muts , and more commonly have succinate dehydrogenase muts (adults will almost always have these)
Sporadic vs. Inherited
– NF1 (SI), Carney Triad (Paraganglioma, GIST, pulmonary chondroma), Carney Stratakis syndrome (Paraganglioma, GIST, SDH muts), Familial GIST Syndrome (KIT muts)

Molecular genetics GIST
* Majority of GIST (80-85%) have KIT mutations
– Usually gain-of-function; exon 11, also 9, 13, 17
– Results in abnormal activation of gene, “switches on” cell proliferation and survival pathways
* Most others are wild type (10-12%) or have PDGFRα mutations (5-7%)
– PDGFR mutations are associated with myxoid and epithelioid phenotype and gastric location
– Exons 12, 18
* Kit and PDGFR mutations apparently mutually exclusive
- BUT those with PDGFR mutations often still express CD117 protein

GIST demographics
* Sporadic – commonest in 40-60 group; slight male preponderance
* Syndromic/special types:
– Carney’s triad (GIST, pulmonary chondroma, paraganglioma)
– Familial GIST
* rare, autosomal dominant; germline kit or PDGFR mutation
* multiple tumours, ICC hyperplasia
– Paediatric GIST
* Median age 12, 75% female, 70% epithelioid
– NF1-associated
* Usually spindled, CD117 negative
* Usually intestinal, often multiple
* Often Imatinib-resistant
– Other associations: tuberous sclerosis, others

GIST histology
- macroscopy: dumbbell shape
* Spindled, elongated cells and nuclei
* Epithelioid
* Other variants (signet ring, oncocytic, rhabdoid, small cell, …)
* Majority express CD117, CD34, DOG-1 – pathognomic
* May express neural and/or myoid markers

Behaviour
* Histology is an imperfect predictor of behaviour: size, mitotic rate, necrosis
* Varies with site:
– Oesophageal: rare, most are malignant
– Gastric: commonest, fundic more often malignant than antral
– Small bowel: less often malignant
– Colorectal: less common but 50% malignant,
often aggressive
* Mets to liver/peritoneum; other sites rare
* Molecular genetics relevant

Answer 127

A

Gastric carcinoma demographics
* Second most common tumour worldwide
* Predominantly disease of developing
countries + Japan; less common in Aus
* Highly lethal
– tends to present late (except in Japan!)
– limited treatment options

GC RFs
ENVIRONMENT:
* (atrophic gatsritis with intestinal metaplasia)
– Helicobacter pylori infection
– Autoimmune gastritis
* Diet: nitrosamines, salty foods, low consumption of fresh fruit and vegetables/fibre
* Tobacco, smoking
* Radiation
* Gastroenterostomy, ?bariatric surgery
* Obesity
* Low SES
* Viruses, e.g. EBV?

GENETICS:
– Susceptibility to H pylori
– Familial gastric cancer: e-cadherin (CDH1) mutation (herieditary Diffuse Gastric Cancer)
– HNPCC/Lynch. Peutz-Jeghers, BRCA, AD Fundic Gland Polyposis, Cowden’s Syndrome

GC: histology
* Adenocarcinoma: “intestinal” or “diffuse”
– Many shared genetic aberrations eg p53
– Diffuse type: e-cadherin mutation
– Intestinal type: genes implicated in
colorectal cancer eg. APC, TGFB
* Gastritis -> intestinal metaplasia -> dysplasia -> intramucosal carcinoma -> invasive cancer

The intestinal-type of Gastric Carcinoma is related to many of the risk factors previously alluded to: often occurs on the background of chronic gastritis → atrophy → intestinal metaplasia → dysplasia → adenocarcinoma

The diffuse-type of gastric carcinoma is NOT related to many of the risk factors
previously alluded to except hereditary diffuse gastric carcinoma

Diffuse type:
Diffusely infiltrating small groups and single cells (often signet-ring cells). E- Cadherin loss or mutation means that cells cannot adhere/stick to each other → diffuse pattern, no glands

-
## Treatment and behaviour

Surgery is mainstay for curative intent
Chemo
Herceptin for cases with HER2 overexpression
Pattern of metastases:
– Intestinal type (distal stomach, men) -> liver
– Diffuse type (premenopausal women) -> ovaries (“Krukenberg tumour”)
– Both -> peritoneal spread
5-year survival Stage I = 95%; Stage IV = 7%

Answer 128

A

Adenocarcinoma of oesophagus
* Typically arise at gastro-oesphageal junction, may be difficult to distinguish from proximal gastric cancer
* But usually arises in Barrett’s mucosa
* Follows dysplasia-carcinoma sequence
– therefore suitable for surveillance
– anticipated decline in population treated with PPI’s

Barrett’s esophagus - stratified squamous epithelium is replaced by metaplastic columnar epithelium which in turn predisposes to the development of adenocarcinoma of the oesophagus.
Endoscopically it appears as salmon pink tongues of mucosa extending above the gastro-oesophageal junction (GOJ) and into the tubular oesophagus, replacing the stratified squamous epithelium that normally lines the distal oesophagus.

Barrett’s oesophagus – squamous mucosa is
replaced by glands with intestinal metaplasia,
(numerous goblet cells)

Dysplasia in Barrett’s
intracytoplasmic mucin droplets of varying sizes , nuclei are pleomorphic, darker, larger and disorganised with multiple layers indicating dysplastic change.

Diagnosis: endoscopy and histology appearance

Well differentiated invasive adenocarcinoma

Architectural changes – invasive glandular pattern, very poorly formed and disorderly glands with a cribriform pattern. In a background of desmoplastic stroma. + Cytological features of malignancy

Poorly differentiated
Marked nuclear and cytoplasmic pleomorphism, very no recognizable glandular structures. Adenocarcinoma is diagnosable in this instance due to the **presence of
intracytoplasmic mucin vacuoles which have a clear appearance, often appearing as signet rings with a squashed, indented nucleus pushed to one side

Adenocarcinomas in summary
* MAKE GLANDULAR STRUCTURES WITH LUMINA
* +/OR PRODUCE MUCIN
* INTRACYTOPLASMIC
* EXTRACELLULAR

Answer 129

A

Simple columnar
epithelium
Enterocytes:
absorptive cells with
microvilli, cover villi
and crypts
Goblet cells:
scattered along
epithelium and
produce mucus
http://www.siumed.edu/~dking2/erg/GI125b.htm

Small intestine epithelium
* Paneth cells: base of crypts,
contain secretory granules of
lysozymes, can phagocytose
some bacteria and protozoa
* Neuroendocrine cells:
produce hormones such as
secretin (important for
digestion- regulates pH)
* Stem cells: at base of crypts – regeneration and high cell turnover
- Intraepithelial lymphocytes:
mainly T cells

Small intestine submucosa
Submucosa of
duodenum can be
distinguished by
presence of
submucosal mucus
producing glands,
Brunner’s glands
lymphoid tissue
H+E: duodenum x50
www.technion.ac.i
l/~mdcourse/2742
03/lect10.html
H+E: duodenum x100

Answer 130

A

PPI
MoA
- irreeversibly inactivate theHK ATPase system or proton pump, on parietal cells
- termainal step in acid secretory pathway (suppression is more complete than H2 receptor antagonists)
- suppressing both stimulated and basal acid secretion (regardless of stimulus - histamine, gastrin, Ach)
- when PPIs are stopped, acid secretion is restored by synthesis of new HK ATPase

PPIs are pro-drugs converted to active metabolites by acids in the canaliculus ofthe gastric parietal cell

Adverse effects:

generally well tolerated
serious toxicity rare but includes; anaphylaxis, hepatitisandinterstitial nephritis
Possible increased risk (associated with prolonged therapy):
- C. difficile-associated colitis
- community-acquired pneumonia
- hip fracture (high doses > 1 y)
- decrease vitamin/mineral absorption such as B12 and Mg

Answer 131

A

5- Aminosalicylates (5-ASA)
Steroid (prednisone, prednisolone, budesonide)
immunosuppression (azathioprine/methotrexate)
- cyclosporin
Anti-TNF (infliximab) or other biological agents including vedolizumab

Crohn’s disease:

steroid (prednisone, prednisolone, budesonide) together with
immunosuppression (azathioprine/6-mercaptopurine /methotrexate)
Anti-TNF (infliximab) or other biological agentsincluding vedolizumab and ustekinumab
5-ASAhas a limited role

5-ASA

MoA
5-ASA is an agonist for peroxisome proliferator activated receptor gene-γ (PPARγ) ->stimulation of PPARγ decreasesinflammation in the bowel mucosa.

Indications
The mainstay of maintaining remission in UC (can also be used to induce remission in mild disease).

The active agent, 5-ASA, is delivered to the site of action in various formulations:

Sulfasalazine (5-ASAconjugated to sulfapyridine)
mesalazine (5-ASA)
olsalazine (5-ASA dimer linked by a bond that is hydrolysed by colonic bacteria)
balsalazide (pro-drug of 5-ASA and released following hydrolysis)

A combination of oral and topical 5-ASA compounds brings patients into remission more quickly than oral therapy alone

Adverse effects
- headache, nausea, epigastric pain, skin rashes, interstitial nephritis, blood dyscrasias and hepatitis.
- reversible male infertility (sulfasalazine)

Contraindications

Other information

Administration
- 5-ASA is absorbed when administered orally so various formulations are used to deliver the active drug (to prevent absorption) to the colonic mucosa topically so that it can reach the site of action. This can be done a few different ways eg:
- combining 5-ASA with a carrier molecule (e.g. sulfapyridine to form sulfasalazine)
- creating a dimer (eg olsalazine) to prevent its absorption in the small intestine.
- These combination molecules are linked by a diazo ( -N=N- ) bond which is broken down by colonic bacteria to release 5-ASA.
- using formulations which release 5-ASA in the distal small bowel and colon by a pH-dependent mechanism (e.g. mesalazine).
- The choice of formulation for rectal administration of 5-ASA depends on the extent of active disease involvement:
- suppositories can be used for limited proctitis;
- foam preparations for disease extending to the sigmoid colon;
- enemas for disease extending to the descending colon and splenic flexure.

Answer 132

A

MoA
Corticosteroids are used for anti-inflammatory properties. They regulate gene expression, which results in:

glucocorticoid effects, e.g. gluconeogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses
mineralocorticoid effects, e.g. hypertension, sodium and water retention, potassium loss.

Rapid suppression of inflammation and symptoms usually within days(weighed against the significant side effect profile)

Steroids can also be given topically: the formulation (suppository, foam or enema) depends on the extent of active disease as for 5-ASA.
Indications
Patients with acute flares who are either too sick for or don’t respond/tolerate 5-ASA therapy oral steroids are considered.

Used for moderate to severe UC

NOT effective for maintenance therapy

Crohn’s
For ileocaecal disease, oralbudesonide, particularly for patients with a history of adverse reactions to systemic corticosteroids may be used.

For mild to moderate disease oral therapy is usually adequate, however induction for severe disease may require intravenous therapy for a period.

Adverse effects
Side effects: MANY! Less with topical compared with systematic steroids.
- psychological effects
- sleep disturbance
- weight gain and fat redistribution
- skin atrophy
- immunosuppresssion
- metabolic effects
- osteoporosis
- GI effects
- myopathy
- HPA suppression
- hypertension
- sodium retention

Contraindications

Other information
Budesonide is more active topically in the bowel (compared to it’s systemic effect) when given orally and may offer benefit over other corticosteroids.

Therapy usually requiresstep-down and tapering.

Answer 133

A

MTX
MoA
Folic acid analogue which binds to and inhibits DHFR activity.
MTX impairs cell division and induces apoptosis as folic acid is essential to DNA synthesis.

Indications

Adverse effects

Contraindications

Other information
Folic acid should be co-administered - though not on the same day, to reduce GI adverse effects and hepatotoxicity

Note for thiopurines or MTX
- Much more evidence for the use of thiopurines and are therefore the class of choice.
- Started when disease is severe at onset
- steroid-dependent
- a second course of steroid for relapse is required within 12 months
- patient has important reason to avoid steroids.

Answer 134

A

TNF-alpha inhibitors (infliximab and adalimumab)
- Effective and approved for both CD and UC

TNFa-i
MoA
TNF-alpha antagonists (infliximab, adalimumab and golimumab).
Appear to be effective with 60-70% improvement.

Indications
Effective and approved for both CD and UC

Adverse effects

Contraindications

Other information
Precautions

_Infection:_Contraindicated in serious or untreated infection, e.g. sepsis, abscess, hepatitisB, active TB (before completing TB treatment). May reactivate inactive hepatitisB and latent TB (begin TB treatment before starting a TNF-alpha antagonist).
Demyelinating disorders: e.g. MS — contraindicated; TNF-alpha antagonists may increase disease activity.
Psoriasis and other skin reactions: up to 20% of patients on anti-TNF agents develop skin reactions including psoriasis and eczema.
_Heart failure:_contraindicated in moderate or severe heart failure (NYHA classIII–IV) and left ventricular ejection fraction <50%; use cautiously in mild disease as TNF-alpha antagonists may worsen heart failure.
_Treatment with other immunosuppressants:_increases risk of infection;
_History of blood dyscrasias:_rare cases of serious blood dyscrasias (some fatal) have been reported; monitor complete blood count regularly.
_Respiratory disease:_may be at increased risk of interstitial lung disease with TNF-alpha antagonists
_Antibodies against double-stranded DNA (eg lupus):_TNF-alpha antagonists are associated with the formation of autoantibodies to ds-DNA. These mayworsen or induce a lupus-like syndrome.
Malignancy:Contraindicated if there is a history of lymphoproliferative disease within the last 5years. TNF-alpha affects cellular immune response and its inhibition may affect development of malignancies.
_Surgery_: Consider the risk of infection.

Answer 135

A

Anti-integrin antibodies
eg vedolizumab

MoA
- Gut-specific, recombinant, humanised IgG1 monoclonal antibody against alpha4-beta7-integrin present on the surface of leucocytes, including Tlymphocytes.
- Inhibits adhesion of Tlymphocytes to mucosal addressin-cell adhesion molecule‑1 (MAdCAM‑1) expressed in the GIT and prevents lymphocyte migration into intestinal tissue.
- Slower onset of action compared with anti-TNF

Indications
Approved for both UD and DC, gut-specific targeted. Longer onset of action than anti-TNF

Adverse effects
- Favourable due to GIT selectivity
- Arthralgia, headache, cough, infections, hypersensitivity reactions (may be significant)
Contraindications

Other information

Answer 136

A

MoA
Recombinant human immunoglobulin monoclonal antibody that targets the p40 subunit on IL-12 and IL-23 inhibiting their activity.
Indications
Indicated for moderate to severe CD; well tolerated
Adverse effects
Similar Adverse effects as the other biological classes (listed above)
Contraindications

Other information

Answer 137

A

reserved for “medical rescue” when severe disease is non-responsive to high-dose intravenous corticosteroids
Not discussed here - covered in block 6 as used for other indications

Answer 138

A

MoA
Blocks D2 receptors inthe chemoreceptor trigger zone (CTZ)

At high doses is 5HT-3 blocker (may also block histamine and muscarinic receptors)

Prokinetic (increased gastric emptying) effects on upper GIT

Indications
Commonly used antiemetic class

Adverse effects
- can cause acute dystonias/Parkinsonism and tardive dyskinesia or extrapyramidal side effects
-
Contraindications
- avoid in PD (domperidone is a D2 antagonist, and prokinetic, that does NOT cross BBB and may be suitable in some PD patients)

Answer 139

A

Serotonin antagonists
5HT receptors occur peripherally in the GIT on the vagus nerve and centrally in the vomiting centre and the CTZ

Useful in most causes of nausea and vomiting such as post-op, chemotherapy, etc

Commonly used antiemetic class

Side effects: Well tolerated, can prolong the QT interval

Answer 140

A

H1 antagonists
Block histamine from activating the H1 receptor

Cause drowsiness - less commonly used in practice due to drowsiness

Indicated for postoperative nausea and vomiting, motion sickness and radiation-induced nausea and vomiting

eg promethazine cyclizine

Muscarinic antagonists
Competitively blocks acetylcholine receptor (M1) in vestibular and vomiting centre

Mostly used for motion sickness

Anticholinergic side effects - limits use in practice, but are used if abdominal cramps are problematic

hyoscine

Answer 141

A

eg aprepitant)

Act on NK 1 receptors located through CNS and involved in pain and emetic pathways

Used to treat chemotherapy-induced nausea and vomiting (usually in combination with other agents)

**Relatively new agents and place in therapy is evolving

Answer 142

A

**
### GCs and benzodiazepines
### (usually dexamethasone)

Used as part of combination therapy in oncology-related nausea and vomiting (and per-operative refractory emesis)

Indicated for nausea and vomiting associated with cerebral swelling and CNS tumors

usually lorazepam)

Sedation and anxiolytic properties

Used in anticipatory vomiting (particularly in oncological setting)

Prucalopride/5HT-4
A 5HT4receptor agonist that increases GI motility (prokinetic) used in chronic idiopathic constipation, when other regular laxatives are inadequate.

Onset of laxative effect generally occurs within the first few weeks (not fast acting!)

nOTE; the usual stepwise approach to treating functional constipation in adults is as follows: bulk forming, osmotic, stimulant, prokinetic

Answer 143

A

Loperamide
MoA’
Activates opioid receptors in the gut wall (no central effects)

↓ secretions and inhibit propulsive movements in the gut
Slow the passage of intestinal contents
Allow reabsorption of water & electrolytes
↓ stool frequency
Indications
Short term treatment
Diarrhoea
Intestinal stoma (to reduce frequency and fluidity of motions)
Adverse effects
Abdominal pain and bloating, nausea, vomiting, constipation
Contraindications

Extra information

Codeine
MoA’
Natural occurring opioid (a pro-drug of morphine - 10% is converted to morphine in the liver) .

Agonist at mu receptors in the GIT causing inhibition of peristalsis -> constipation

Does also work centrally and therefore can have opioid related side effects such as drowsiness and nausea.
Indications

Adverse effects

Contraindications

Extra information

Diphenoxylate

MoA’
- Inhibits intestinal propulsive motility
- Acts directly on mu (μ) opioid receptors on intestinal smooth muscle
- The addition of atropine acts as an anticholinergic and also to discourage abuse
Indications

Adverse effects
Abdominal pain, nausea, vomiting, constipation, rash, dizziness and drowsiness, anticholinergic side effects (due to atropine)

Answer 144

A

Antacids
Symptomatic based relief of excessive gastric acid secretion (directly neutralise acid)

Most antacids use a combination of magnesium and aluminium salts

Magnesium salts cause diarrhoea
Aluminium salts cause constipation

Antacids are faster acting when given in a fasting state

Liquid and powder dosing forms tend to be more effective than tablets

Antacids can reduce the effect of a number of other medicines taken by mouth. The best way to avoid a problem is to separate taking antacids and other medicines by at least 2hours

Most available without prescription (and even in the supermarket)

Examples include
- MgOH
- - forms magnesium chloride in stomach
- no systemic effects as Mg2+ is poorly absorbed from the gut .˙. local action
- diarrhoea
- AlOH
- Forms aluminium chloride in stomach
- Raises gastric juice pH to ~4
- constipation
- Alginates
- sometimes added to antacids
- ↑ viscosity and adherence to mucus
- forms protective barrier
- Simethicone
- sometimes added to antacids
- anti-foaming agent
- relieves bloating and flatulence

Mucosal protective agents
Rarely used in practice

Sucralfate: aluminium salt – forms protective barrier at ulcer site resistant to acid, bile and pepsin

Misoprostol: prostaglandin E1 (PGE1) analogue; stimulates secretion of gastric mucus and bicarbonate in the duodenum and decrease in gastric acid secretion by parietal cells

Bismuth subcitrate: no longer marketed in Australia. Forms an acid‑ and pepsin-resistant protective coating at the ulcer site; also has an antibacterial effect against_H.pylori_

Answer 145

A

Varices - Why Are They Important?
- Most (80%) cirrhotics will develop varices.
- Main cause of upper GI bleeding in cirrhosis (peptic ulcer, other causes less often).
- High mortality from bleed and rebleed (SCREEN ALL CIRRHOTICS).
- use platelet count, liver stiffness measurements i.e. fibroscan to screen

Management Plan
- Prevent: Prevent bleeding through banding or drugs that lower portal pressure (propranolol, carvedilol - beta blocker with alpha blocking action, may be useful in liver specifically). ^[avoid non-selective drugs in asthmatics]
- Bleeding: Treat bleeding with banding + drugs that lower portal pressure (octreotide IV/infusion - somatostatin analog).
- Prevent Re-Bleeding: Prevent re-bleeding through banding.

Managing Acute Bleeding
- Bleeding can be SEVERE.
- Protect airway e.g. intubation, aim for Hb 80 g/L.
- Administer antibiotics and lactulose.
- SBP (Spontaneous Bacterial Peritonitis) and encephalopathy are common after a bleed.
- Antibiotics also reduce rebleeding risk.
- Start octreotide (reduces splanchnic flow).
- Endoscopy
##### Endoscopic Variceal Ligation (EVL)
- EVL is 90% effective for control of acute bleeding.- done monthly until all variceal columns targeted

Alternatives to Endoscopy
- If endoscopy fails:
- Balloon Tamponade: Sengstaken-Blakemore tube – OCCLUDE varices.
- Transjugular Intrahepatic Portosystemic Shunt (TIPS): DIVERT BLOOD.
- Surgery: Very rare now.

Answer 146

A

Hepatic Encephalopathy
- Impaired neuropsychiatric syndrome due to acute or chronic liver disease

Hepatic encephalopathy in essence: ammonia intoxication as a result of portal shunting to brain, altering mental state
- ammonia end-product of protein metabolism in intestine, due to bacteria
- shunted to liver, normal de-toxxed to urea and excreted
- Grades I (mild confusion, non-specific, poor sleep, ‘night watchman- awake at night, asleep in day’) to IV (coma)
  - FLAP/Asterixis - more prominent in GII/III - unlikely in GI
  - neuropsychiatric symptoms worsens in III
- STROOP TEST/psychometric number connection tests (timed test)
  - can be used to check response to treatment
Remember!
- There are other causes of confusion: SDH, sedating drugs and meds, hyponatremia, hypoglycaemia, withdrawal delirium from alcohol or Wernicke’s

Hepatic Encephalopathy - Management
- Treat precipitating factors (infection, drugs, constipation, hypokalaemia, GI bleeding) -> helps improve encephalopathy
- Lactulose (MAIN STAY)
- How does it work?
- Acidifies gut (reduces ammonia)
- Inhibits ammonia-forming bacteria
- Acts as a laxative
- Antibiotics: Sterilize gut - if not responsive to lactulose
- Rifaximin
- Metronidazole
- Neomycin (historical)
- combination of lactulose and antibiotics may be useful, eg if lactulose poorly tolerated ie patient becomes bloating

Answer 147

A

**CYP enzymes
- CYP enzymes responsible for Phase 1 (functionalisation) metabolism
- CYP enzymes found in the smooth endoplasmic reticulum
- Abundant in hepatocytes
- More than 50 varieties. Three main families
- Genetic polymorphisms occur altering clearance of particular medications
- Responsible for many drug interactions
- Liver disease can effect the performance of these enzymes

Hepatic clearance
- Depends on hepatic blood flow (Q) and extraction ratio (EH)

Hepatic extraction ratio (EH):
- the fraction of drug entering the liver in the blood that is irreversibly removed by metabolism on each pass through the liver. (0.7 = 70% removed)
Hepatic clearance (Cl)= Q. EH
Hepatic clearance can be:
- low extraction:
  - clearance capacity by limited by liver enzymes to clear drug (clearance is independent of blood flow)
- high extraction
  - clearance capacity limited by delivery of drug to the liver (blood flow)

Answer 148

A

Mastication (Chewing):
- Breaks up large pieces of food
- Mixes food particles with saliva to form a bolus, to facilitate swallowing and digestion
- Optimal number of chews: 20 - 25
Swallowing:
- Note oesophageal sphincter closes; epiglottis goes up, uvula goes down to ensure food goes the right way
Primary peristalsis initiated by act of swallowing
- Secondary peristalsis initiated by distension of oesophagus - flush out any potential reflux
- On average, bolus takes 10 s to reach stomach

Answer 149

A

Stomach
Gastric functions & secretions
- Motor function:
- Regulate food intake
- Mixing with secretions
- Reduction in particle size by grinding
- Empties chyme into duodenum
- Liquids - proximal part
- Solids - antral part
- Secretions:
- Acid
- Pepsinogen
- Mucus
- Bicarbonate
- Intrinsic factor
- H2O

Gastric Filling
- Three types of stomach relaxations:
1. Receptive relaxation - triggered by swallowing
2. Adaptive relaxation - distension (filling)
3. Feedback relaxation - triggered by nutrients in small intestine - ensure all food making its way out
- ENS is the primary regulator of gastric accommodation
- Vagus nerve plays a modulatory role
- note: Increase in intragastric volume without increase in pressure - accommodates more food
- as pressure builds: satiety
- hence Gastric Banding, see also [[Gastroenterology - Lecture 19]]

Gastric Emptying:
- Saline and water empty first
- Acidic and caloric fluids more slowly
- Fatty material even slower
- Solids must be reduced to less than ~ 2 mm - hence lag for solids
- Three distinct phases: Propulsion, Grinding, Retropulsion
- propulsion: gastric contractions propel food towards antrum (initiated by gastric pacemaker). Pyloric valve is closed
- grinding: chyme is churned in the antrum by propulsion. Pyloric valve is closed - helps to slam food, breaking down particles
- retropulsion: most of chyme will not go through and is returned to stomach. Pyloric valve is slightly open
- process cycles

Delaying Gastric Emptying
- Volume of liquid in stomach is of primary importance (emptying rate proportional to volume i.e. bigger volume quicker empty)
- Receptors in small intestine and duodenum monitor the fluid leaving the stomach.
- Low **pH
- High **caloric content
- **Lipid
- Some **amino acids
- **Osmolarity
- all of the above Trigger a delay in gastric emptying via neural & hormonal signals (listed below):

This happens by: Fundic relaxation, Decrease in antral motor activity, Contraction of pyloric sphincter, Altered intestinal motor activity
via:
Vagus nerve
Secretin
Cholecystokinin
Gastric inhibitory peptide

Answer 150

A

Carbohydrate Digestion
- Substrate is dietary CH2 O (starch from plants, glycogen from animals)
- Amylase hydrolyzes α1,4 glycosidic linkages in polysaccharides
- Cellulose is a polysaccharide (poly-glucose) but joined in β1,4 links. No animal enzyme can cleave them. (Bacterial cellulase in ruminants)
- Result is a mixture of trisaccharide (maltotriose) + disaccharide (maltose) α-limit dextrin (branched oligosaccharide with α1,6 bonds)
-
- Salivary amylase may hydrolyze up to 25% of total starch in diet.

Carbohydrate Digestion - 2

Following digestion by salivary and pancreatic amylase, there is a mixture of oligo- and di-saccharides. These are metabolized by disaccharidases located in the brush borders of the intestinal enterocytes. The end result is the production of monosaccharides, which can be absorbed by the intestinal mucosa. For persons on a normal diet, glucose accounts for approximately 80% of the final monosaccharides available for absorption.
![[Pasted image 20240501084654.png]]
- lactose —> glucose and galactose
- maltose –> 2 glucose
- sucrose —> glucose and fructose

Glucose is absorbed in association with sodium (3Na/2K, makes intracellular environment more negative, which drives passive Na/glucose symporter – which also transports galactose. Absorbed into blood by glucose/fructose transporters). See also [[Physiology B5 - Lecture 4]]
Firstly sodium is transported from the intestinal epithelial cell into the blood.
Secondly, in response to reduced epithelial cell sodium, sodium is absorbed from the intestine by facilitated diffusion, bound to a transport protein.
This transport protein will not move into the cell without glucose.
Galactose is absorbed in similar fashion to glucose.

Fructose is absorbed by facilitated diffusion via a sodium-
independent process.

Carbohydrates

Only
glucose,
galactose and
fructose are well absorbed
(mostly in duodenum and proximal jejunum)
Intestine has the capacity to transport 3.6 kg glucose/day

Monosaccharide transporters
- SGLT1 AND GLUT5 for Na/glucose/galactose, fructose respectively on apical surface, GLUT2 on basolateral membrane
- gradient driven by 3Na 2K ATPase
-

Carbohydrate malabsoprtion syndromes
Most are a result of a deficiency in carbohydrate digestion
(e.g. lactose intolerance)
But not all..
Glucose-galactose malabsorption syndrome
(very rare hereditary disorder)
Missense mutation in SGLT1

Answer 151

A

Lipid Digestion (1)

90% of dietary fat is triglyceride (TG), with the remainder being cholesterol, cholesterol ester, phospholipid, and free fatty acids (FFA).
The primary site of lipid digestion is in the duodenum, requiring fat to be highly emulsified with bile salts and lecithin.
(TAG) Lipase released from the pancreas hydrolyzes TG to monoglycerides and FFA, requiring co-lipase for activity.
Co-lipase binds to water-lipid interface (on globule surface, of micelle) and simultaneously activates lipase

Lipid Absorption

Absorption occurs in the jejunum, where micelles deliver lipid digest to the brush border.
FFA eg glycerol and 2-mono-acylglyceride (MAG) are taken up into enterocytes by diffusion because they are lipid-soluble.
- 2MAG used for re-synthesis of TAGs, by fatty acid CoA ligase, using long chain fatty acids
Within enterocytes, absorbed FFA are converted predominantly to triglycerides, which are released into thoracic duct lymph as chylomicrons – for long chain FAs.
Some short chain fatty acids are absorbed directly into portal blood

Lymphatics

The lymphatics drain excess fluid and secretions from the interstitial spaces.
Especially important is the ability to carry proteins, large molecules, and particulate matter from tissue spaces.
Lymphatic drainage from the gut empties into the thoracic duct, which drains into the left internal jugular vein at the junction with the left subclavian vein.

Lipid entry into the unstirred layer
- Small fatty acids penetrate unstirred water layer and are absorbed
- Effective concentration of long chain fatty acids adjacent to brush border is increased by a factor of 0.1 - 1 million by micellar solubilisation
### Lipid absorption
- TAGs are emulsified and form micelles
- pancreatic lipase and colipase results in monoglycerides and FFAs mainly by diffusion, some facilitated diffusion or active transport
- cholesterol is transported, but some diffused
- TAGs reconstituted in cells, fats and cholesterol and proteins to form chylomicrons which go to lymph to vena cava (Too big to enter capillaries)
- note choelsterol is ‘kicked out’ by some channels

Answer 152

A

Protein Digestion - 1

The total protein load in the gastrointestinal tract per day is:
- Dietary: 70 - 100 g per day (adult)
- Endogenous: 35 – 200 g (enzymes, other proteins, cell turnover).
Digestion is efficient, usually resulting in only 6-12 g of protein in feces.
Two types of proteolysis are described:
- Trypsin and chymotrypsin split proteins into smaller peptides.
- Carboxypeptidase cleaves proteins to individual amino acids.
The net end products are amino acids, di- and tri-peptides.
Sites of action of the peptidases are very specific e.g. chemotrypsin and hydrophobic pocket (Phe), trypsin and salt bridges (Lys), elastase small hydrophobic pocket (Gly)

Protein Digestion - 2

Proteases (peptidases) are generally secreted into the lumen in an inactive form.
The active form is produced either by a pH change (e.g., pepsinogen B) or by HCl itself (pepsinogen A) in the stomach. Pancreatic trypsinogen needs duodenal entero-peptidase or (-kinase).
Trypsin’s central role is the activation of other pancreatic peptidases. (See also [[Gastroenterology - Lecture 10]]
Notably, trypsin inhibitor is secreted in the pancreas in concert.
HCO3– is important for optimal protease activity.
Membrane-bound endopeptidases, dipeptidases, and aminopeptidases convert peptides to amino acids.
Absorption of amino acids by very specific carriers (similar in renal tubular epithelium).

Proteins are generally digested into peptides
and amino acids before they are absorbed
Six major amino acid transporters in small intestine
(transport the L in preference to the D forms)

Amino acid and peptide transporters
- H/di and tripeptides, Na/AA and endocytosis
- dipeptide transport most efficient
- Na co transport most common

Answer 153

A

**
- Endocrine (Islets of Langerhans)
- Exocrine (acini in lobules-> interlobular ducts into main duct) which drain into the duodenum at ampulla of Vater and the accessory duct
- inactive forms of enzymes stored into zymogen granules in acinar cells
- duct epithelial cells release HCO3, electrolytes; lots of mitochondria

Answer 154

A

Carbohydrate regulation
- Fed: BSL high. Insulin release. Stimulates glycolysis, glycogenesis, down-regulates gluconeogenesis.
- Fasted: BSL low. Glucagon release. Stimulates glycogenolysis, gluconeogenesis, down-regulates glycolysis, switches off glycogenesis.

Answer 155

A

Environment:
- Drugs active in hydrophobic environments like tissues, cells, and membranes. Excretion is hydrophilic in bile or urine.
Detoxification Phases:
- Phase 1: Oxidation, usually by Cytochrome P450.
- Phase 2: Conjugation, including glucuronidation and sulfation.
Influences:
- Genetic polymorphisms- leading to variability in expression
- enzyme induction, age, disease, competition.

Answer 156

A

The tract is as follows:

Bile acid synthesis occurs in liver cells, which synthesize primary bile acids (cholic acid and chenodeoxycholic acid in humans) via cytochrome P450-mediated oxidation of cholesterol in a multi-step process.

 Bile canaliculi >> Canals of Hering >> intrahepatic bile ductule (in portal tracts / triads) >> interlobular bile ducts >> left and right hepatic ducts[4]
These merge to form the common hepatic duct[4]
The common hepatic duct exits the liver and joins with the cystic duct from gall bladder[4]
Together these form the common bile duct which joins the pancreatic duct[4]
These pass through the ampulla of Vater and enter the duodenum[4]

Answer 157

A

Immune cells in the liver: Kupffer cells
(macrophages). Phagocytose. Remove antigen-
antibody complexes.
Liver NK/T cells: non-specific cell killing, anti-
tumour effects

Theory that non-specific (MHCI) presentation in
the liver leads to tolerance.. (? – theories being developed

Answer 158

A

Motility/Motor Activity
- Musculature: Two layers of smooth muscles, circular and longitudinal
- Motor Activity: Peristaltic contractions (propulsive), Segmental contraction (mixes food, no propulsion), Sphincter control (retains contents in stomach and large intestine)
- all are achieved by smooth muscles

Answer 159

A

Tonic and Rhythmic Contractions:
- Tonic: Sustained contractions
- Rhythmic: Alternating contraction and relaxation - slow wave activity; cycles of depolarisation and repolarisation
  - Function of Vm: Intrinsic slow-wave activity (-65 to -45 mV), Action Potential (increase in muscle tension)
  - key channels in slow wave: VGCC(K moves out – hyperpolarisation – closes VGCC – Ca decreases – K channels close, depolarising, VGCC opens, and K channel (iCa-dependent)

Answer 160

A

Mastication & Swallowing
- Mastication (Chewing):
- Breaks up large pieces of food
- Mixes food particles with saliva to form a bolus, to facilitate swallowing and digestion
- Optimal number of chews: 20 - 25

Answer 161

A

Swallowing:
- Note osophageal sphincter closes, epiglottis goes up, uvula goes down to ensure food goes the right way
Primary peristalsis initiated by act of swallowing
- Secondary peristalsis initiated by distension of oesophagus - flush out any potential reflux
- On average, bolus takes 10 s to reach stomach

Esophageal Sphincters
- Upper Esophageal Sphincter:
- Striated muscle - potential to gain control
- Highest resting pressure of all sphincters in GI tract
- Under control of swallowing centre in medulla

Lower Esophageal Sphincter
- Smooth muscle
- Opens when swallowing begins - synchronous
- Tonically active (prevents reflux) but relaxes upon swallowing
- Under control of the vagus nerve (contract) and intrinsic properties of smooth muscle (release of NO and VIP causes relaxation).

Swallowing
- Contraction is strongest and fastest during oropharyneal phase
- UES and LES relax simultaneously
- LES contracts after UES contraction i.e. stays relaxed until food has passed
- Vomiting - anti-peristalsis

Answer 162

A

Secretions:**
- Acid
- Pepsinogen
- Mucus
- Bicarbonate
- Intrinsic factor
- H2O

Answer 163

A

Gastric Filling
- Three types of stomach relaxations:
1. Receptive relaxation - triggered by swallowing
2. Adaptive relaxation - distension (filling)
3. Feedback relaxation - triggered by nutrients in small intestine - ensure all food making its way out
- ENS is the primary regulator of gastric accommodation
- Vagus nerve plays a modulatory role
- note: Increase in intragastric volume without increase in pressure - accommodates more food
- as pressure builds: satiety
- hence Gastric Banding

Answer 164

A

Delaying Gastric Emptying
- Volume of liquid in stomach is of primary importance (emptying rate proportional to volume i.e. bigger volume quicker empty)
- Receptors in small intestine and duodenum monitor the fluid leaving the stomach.
- Low pH
- High caloric content
- Lipid
- Some amino acids
- Osmolarity
- all of the above Trigger a delay in gastric emptying via neural & hormonal signals:

This happens by: Fundic relaxation, Decrease in antral motor activity, Contraction of pyloric sphincter, Altered intestinal motor activity
via:
- Vagus nerve
Secretin
Cholecystokinin
Gastric inhibitory peptide

see gastric acid secretionand regulation for part a

Answer 165

A

Secretin: secreted by S cells in mucosa of duodenum in response to pH, Inhibitory effect on motility of most of GI tract, Stimulates secretion of bicarb from pancreas and liver.

Answer 166

A

Cholecystokinin (CCK): Secreted by I cells in mucosa of duodenum and jejunum mainly in response to fat breakdown products, Moderately inhibits stomach motility, **Potently increases contraction of gallbladder.

Answer 167

A

Gastric inhibitory peptide (GIP): Secreted by K cells in mucosa of the proximal small intestine in response to macromolecules i.e.. fatty acids, AAs, and carbohydrates; Moderately inhibits stomach motility, Prevents overloading of small intestine.

Answer 168

A

Electrolytes**
- Na and Cl are net absorbed by SI and LI
- K is secreted by LI and absorbed by SI (net)
- HCO3 is net secreted by SI and LI

Na+ Absorption**
- Na+/nutrient cotransport
- primary mechanism
- Na is transported by either Na/glucose or Na/AA symporters
- gradient/absorption is by 3Na-2K-ATPase
- mechanism is electrogenic
- primarily occurs in jejunum, moderate amount in ileum
- Na+/H+ exchange
- Na/H exchangers 2 and 3 on apical surface (amiloride works here in mM doses)
- another exchanger NHE1 helps to regulate pH of cell
- 3Na-2K-Atpase imports Na/helps establish gradient
- Na/H exchanger activity stimulated by luminal alkalinity
- mechanism is electroneutral
- mainly occurs in jejunum, moderate amount in duodenum
- Na+/H+ & Cl-/HCO3- exchange
- NHE and Cl/HCO3 exchanger on apical surface
- CO2 diffuses into cell, with water
- water splits into H and OH
- H is exchanged for Na
- OH combines with CO2 catalysed by CA to form HCO3, which is secreted out
- Cl leaks out via transporters
- 3 Na/2K ATPase helps establish gradient
- this is Primary mechanism of Na+ absorption between meals
- Results in electroneutral absorption of NaCl
- Diminished activity results in diarrhea
- happens in both ileum and proximal colon
- Epithelial Na+ channels
- ENaC on apical surface, 3Na-2K-ATPase on basal surface
- occurs in distal colon
- electrogenic Na absorption
- amiloride acts here in uM doses

Cl- Absorption
- Passive
- Occurs paracellularly
- Small intestine
- jejunum and ileum
- facilitated by electrogenic Na process (nutrient co-transport)
- Large intestine
- distal colon
- facilitated by electrogenic Na process (ENaC)
- Cl-/HCO3- exchange
- same process as Na/H/Cl/HCO3 – with Na/H on basolateral membrane (transporting H from splitting water)
-
- NHE and Cl/HCO3 exchanger on apical surface
- CO2 diffuses into cell, with water
- water splits into H and OH
- H is exchanged for Na
- OH combines with CO2 catalysed by CA to form HCO3, which is secreted out
- Cl leaks out via transporters
- 3 Na/2K ATPase helps establish gradient
- this is Primary mechanism of Na+ absorption between meals
- Results in electroneutral absorption of NaCl
- Diminished activity results in diarrhea
- happens in both ileum and proximal colon
- mainly proximal colon, also ileum and distal colon
- Na+/H+ & Cl-/HCO3- exchange
- see above
- proximal colon and ileum

Cl- Secretion
- Involved in the pathophysiology of many types of diarrhea (bacterial enterotoxins, certain intestinal tumors (↑ VIP production), laxatives)
- occurs all along SI and LI
- insertion of pre/made Cl channel at apical surface
- cAMP nad Ca enhance this process
- also encourages Cl channels to be more open, increases 2 types of K channels at basolateral surface, driving 3Na-2K-ATPase, making Na concentration low in the cell, driving NA/K/2CL ATPase driving Cl out to lumen

K+ Secretion/Absorption
- Intestines have capacity for K+ absorption and secretion
- Net absorption in small intestine
- Net secretion in large intestine
### Passive K+ transport
- absorption occurs via solvent drag i.e. paracellularly
- jujunum and ileum
- secretion
- paracellular
- main pathway responsible for net K secretion in colon
- net negative charge in lumen generated by Na movement through Na channel (3Na 2K ATPase)
- distal colon mainly, also proximal colon

Active K+ transport
- absorption
- H/K exchanger, gradient driven by 3Na 2K ATPase
- leaves into blood by K channels on basolateral surface
- distal colon
- secretion
- same as Cl secretion process
- K leaves via channels on apical surface
- 3Na-2K-ATPase, making Na concentration low in the cell, driving NA/K/2CL ATPase driving Cl out to lumen
- mainly proximal colon, also distal colon

Answer 169

A

Oral Rehydration Solution (ORS)
- Takes advantage of sodium and glucose transport in small intestine.
- Water is taken up osmotically after sodium entry.
- Potassium is then absorbed via solvent drag (paracellular).
- Sodium concentration can be varied depending on degree of dehydration.

Answer 170

A

Cl- Secretion
- Involved in the pathophysiology of many types of diarrhea (bacterial enterotoxins, certain intestinal tumors (↑ VIP production), laxatives)
- occurs all along SI and LI
- insertion of pre/made Cl channel at apical surface
- cAMP nad Ca enhance this process
- also encourages Cl channels to be more open, increases 2 types of K channels at basolateral surface, driving 3Na-2K-ATPase, making Na concentration low in the cell, driving NA/K/2CL ATPase driving Cl out to lumen

Answer 171

A

**
- Approximately 1.5 L secreted/day (pH 7 (basal) - pH 8 (stimulated i.e. when eating))
- Contains two digestive enzymes: lingual lipase (glands on tongue ) and salivary amylase (Salivary glands)
- Also contains mucins to lubricate food and facilitate swallowing, lysozyme which breaks down bacterial cell wall, lactoferrin binds iron and is bacteriostatic, and proline-rich proteins - protect teeth and bind tannins
- Acts as a solvent and lubricant, facilitating taste and speech respectively

Position of Salivary Glands
- Parotid glands (25% watery secretion)
- Submandibular glands (70% mixed secretion: mucous and water)
- Sublingual glands (5% viscous secretion)

Answer 172

A

salivon unit that secretes
- acinus secreted into
- divided by intercalated duct
- straited duct carries out into mouth - can change content of saliva along length eg more water, K HCO3, less Na Cl
serous cell: watery secretion - electrolytes and salivary amylase
mucuous cell: mucin

Salivary-duct transporters
![[Pasted image 20240430205551.png]]
- key transporters include - in duct not acinus:
- H/K ATP-ase - K out, H in - regulated by iCa and M3 (Ach)
- CL/HCO3 exchanger - REABSORB cL - reabsorbed via Cl channels, HCO3 secretion
- NA- h atpase -> Na/K ATPase (reabsorb Na)

note lumen is impermeable to water

Electrolyte composition of saliva
- osmolarity increases with rate of secretion
- Na, HCO CL up
- k GOES DOWN
- not enough time for Na Cl to be absorbed
- HCO3 going up to bring pH up ?

Answer 173

A

Acid Secretion
- Mediated by HK ATPase: P-TYPE ATPases (H swapped for K, from splitting water, so OH and Co2 makes HCO3 swapped out for Cl; Cl goes into lumen along gradient; K along gradient in or out)
- juice: Cl and H increases with secretory rate; K (related to pump) and Na goes down
Acid secretion regulation
- Regulated by three secretagogues: acetylcholine, gastrin, and histamine
- Ach and gastrin act directly and indirectly
- Histamine acts directly
- Ach binds M3- induces histamine release from ECL cells to promote H, and Ach binding M3 directly induces H from parietal cells
- Gastrin promotes Histamine release from ECL cells and H directly from parietal cells
- note omeprazole directly binds HK ATPase
- antihistamines can bind H2 to reduce acid secretion
- Somatostatin acts as a major inhibitory mechanism
- made by D cells in corpus and antrum
- 2 forms, SS-14 and 28
- Direct pathway: binds SS receptors on parietal cells to inhibit the stimulatory effect of histamine; acts endocrine via D CELLS OF ANTRUM OR paracrine via D cells in corpus
- Indirect pathway: Paracrine; acts in corpus to reduce histamine release from ECL cells, and in antrum reduces gastrin release from G cells

Phases of Gastric Acid Secretion
- Acid secretion follows basal state and three phases during a meal: cephalic, gastric, and intestinal

Basal state: Inter-digestive phase, H+ secretion takes place 24/7
- follows circadian rhythm: lowest in morning highest in evening
- H+ secretion is associated with parietal cell number
- high varaibility in basal state pH (3-7)
Cephalic phase: Activated by sight, smell, taste, thought, and swallowing of food. Vagus plays main role. 30% of acid secretion
- starts happening before food reches stomach
- four distinct phases
  - Direct stimulation of parietal cells(acetylcholine mediated)
  - Release of histamine from ECL cells(acetylcholine mediated)
  - Release of gastrin from G-cells(gastrin-releasing peptide mediated)
  - Decrease in somatostatin release from D-cells (acetylcholine mediated)
Gastric phase: Stimulated by distention of gastric wall and partially digested proteins. Gastrin release in main role. 50-60% of acid secretion
- Entry of food in stomach causes two stimuli for H+ secretion
  - Distention of gastric wall (corpus and antrum)
    - Activates Vagovagal reflex(same response as that seen in cephalic phase)
    - Activates local ENS reflex (Ach mediated activation of parietal cells)
  - Partially digested proteins (peptones) stimulate G-cells in antrum to release more gastrin
Intestinal phase: Stimulated by peptones and amino acids in proximal small intestine. 5-10% of acid secretion
- Peptones stimulate G-cells in duodenum - gastrin release
- An ‘entero-oxyntin’ stimulates parietal cells
- Absorbed amino acids stimulate acid secretion by an unknown mechanism
  -

Answer 174

A

Vitamin B12 Absorption**
- vitamin B12 ingested in food
- salivary glands secrete haptocorrin
- acid in stomach releases vitamin B12 from food
- haptocorrin binds released vitamin B12 in stomach
- stomach parietal cells secrete intrinsic factor
- pancreatic proteases digest haptocorrin in small intestine releasing B12
- vitamin B12 binds to intrinsic factor in the small intestine
- vitamin B12 intrinsic factor complex is absorbed in the terminal ileum

Answer 175

A

Pepsinogen Secretion
- Multiple pepsinogens are secreted by Chief cells
- Initiate protein digestion as aspartic proteases
- Released as zymogens by ‘compound exocytosis’ (i.e. vesicles fuse and then exocytose)

secretin and other compounds act via cAMP
Ach, gastrin/CCK act via increased intracellular Ca concentration

Pepsin Activation
- Small N-terminal fragment needs to be cleaved to become active
- pH < 5 - note at lower pepsin catalyses reaction to make more pepsin
- Optimal activity pH: 1.8 - 3.5
- pH > 7.2 irreversibly inactivates the enzyme - a protective feature to ensure SI cells are protected from degradation

Answer 176

A

Intestinal Factors Reducing H+ Secretion
Intestinal chyme during gastric phase inhibits gastric acid secretion- Reverse Enterogastric Reflex
- Purpose is to slow down release of chyme from stomach
1. Transmitted through ENS and Vagus nerve
- Initiated by: stretch, pH, peptones
2. Mediated by intestinal hormones
- Initiated by: pH, fat, peptones & osmolarity
- Mainly Secretin but also GIP, VIP, and SS

-

Answer 177

A

Pancreas
- Anatomy
- Endocrine (Islets of Langerhans)
- Exocrine (acini in lobules-> interlobular ducts into main duct) which drain into the duodenum at ampulla of Vater and the accessory duct
- inactive forms of enzymes stored into zymogen granules in acinar cells
- duct epithelial cells release HCO3, electrolytes; lots of mitochondria
- Secretions
- Water, electrolytes and bicarbonate to neutralize the acid secretions from the stomach
- Enzymes to metabolize protein, carbohydrate and fat

Pancreatic Secretion
- Signals for release of pancreatic contents are primarily:
- Secretin: Secreted when food, esp. acid, enters duodenum
- from duodenal and jejunal mucosa
- Secretin stimulates pancreatic ductal epithelium to secrete large quantities of water and sodium bicarbonate to neutralize gastric acid
- Cholecystokinin (CCK): Secreted when food (fat and amino acids) enters duodenum
- from duodenal and jejunal mucosa
- CCK stimulates pancreatic acinar cells to secrete digestive enzymes
- Note: Pancreatic secretion is also mediated by vagal stimulation: releases enzymes into acini

Control of pancreatic enzyme activation
and autodigestion in acinar cells
* Proteins exist as proenzymes or zymogens
* Proteins sequestered in secretory granules – membrane is impermeable to proteins - avoid digestion of intracellular contents
* Proteins stored with inhibitors
* Conditions in secretory pathway inhibit enzyme activity

Answer 178

A

BD - Crohn’s vs Coeliac vs UC
Irritable bowel syndrome (IBS) - recurrent abdominal pain 1+ days per week in the last 3 months
associated with one of the following 1) related to defecation, 2) stool frequency change
(constipation or diarrhoea) 3) stool consistency change.
Lecturer– alternating constipation/diarrhoea. Lower abdominal cramping. Bloating/distension.
Passage of mucous. Can often be controlled with diet, stress management and medications
IBD – encompasses many other conditions - below
CROHN’S DISEASE
Can affect any area of GIT (unlike UC)
Immune related – immune system triggered by foreign pathogen in
GIT. Unregulated/dysfunctional inflammation response results in
tissue destruction.
Thought to be genetic (NOD2 gene frameshift mutation)
Histopathology – granuloma, ulcer formation
Transmural inflammation (during entire depth of intestinal wall,
mucosa -> serosa). Scattered areas of inflammation (not
continuous).
Symptoms – diarrhoea (loss of ability to absorb water) + blood in
stool. If SI affected, malabsorption issues.
Treatment – anti-inflammatory medications and antibiotics (control gut bacteria and reduce
immune response). Severe symptoms -> immunosuppressants.
Removal doesn’t cure.
ULCERATIVE COLLITIS
Forms ulcers along inner surface of large intestine, including both colon and rectum
Only affects mucosa and submucosa (not deeper layers)
Autoimmune in origin – caused by T cell destroying walls of large intestine, leaving behind ulcers.
Precise mechanism/reason unknown.
Inflammation is circumferential and continuous
Symptoms – left lower quadrant pain, diarrhoea (can’t absorb water, can be with or without blood)
Diagnosis requires colonoscopy.
Treatment depends on symptoms – anti-inflammatory (mesalamine), immunosuppressants,
biologics as last resort. Colectomy as very very last resort.

Answer 179

A

Bilirubin is a waste product produced by the breakdown of red blood cells. Bilirubin is the end-product of heme metabolism; the liver is the site for bilirubin metabolism.

Hemoglobin is broken down into heme, which is converted to biliverdin, and finally into unconjugated bilirubin (which is not water-soluble). In the bloodstream, unconjugated bilirubin binds with serum proteins—most commonly albumin. The unconjugated bilirubin is then taken up by the liver.

In the liver, the unconjugated bilirubin is bound to glucuronide by the enzyme uridine 5’-diphospho-glucuronosyltransferase (UDP) and becomes conjugated bilirubin. Conjugated bilirubin is then excreted in bile.

In the intestines, bacterial enzymes hydrolyze conjugated bilirubin to release free, unconjugated bilirubin, which is reduced to urobilinogen. Urobilinogen, bound to albumin, is then excreted in urine.

In the intestines, some urobilinogen is converted to stercobilinogen and excreted in the stool. Thus, in normal urine, only urobilinogen is present; in normal stool, only stercobilinogen is present.

Answer 180

A

biliary canaliculi draining into branches of bile ducts
heaptic arteriole coming from brnach of hepatic artery
barin of heaptic portal vein draining into central venule or central vien

Answer 181

A

AE enterl
BCD blood serum bodily including vertical transmission

Answer 182

A

**IgM-anti-HAV
- **HBsAg
- **Anti-HCV

Answer 183

A

note some PR indications: altered bowel, lower abdo pelvic pain or acute abdo, PR bleeding + malaena, anal pain, external rectal lesions, male lower urinary symptoms, prostatic sumptoms, rectal cancer

Answer 184

A

fever
anorexia
unexplained weight loss
per rectal bleeding
flamily hsitory
(chronic t course…)

Answer 185

A

ASUC or fulminant colitis, toxic megacolon
perinanal: fissuere, absecess, fistulae; malabsorption, nutrition; colorectal cnancer

Answer 186

A

average risk every 2 years, 50-74
only 3% of positives
IfFOBT
colonoiscpy for surveillance: family hsitory, familial conditions, previous cancer or polyps/symptoms

Answer 187

A

- age over 65
IHD
shock on admssion
CLD
ascites
continued bleeding or rebleeding
anaemia (Hb< 8)

not alcoholism, PUD, NSAIDs, hepatomegaly

mgmt by resus, assesemtn of risk, fbc clot X match, EUC, ECG, ENDO, MED THERAPY, SURG – also ascites

Answer 188

A

upper Gi most fcommon: peptic ulver then oeso, varices, gastroduodenal erosion
jujunal ileeal diverticulae rare
large borwel: andiodysplasia= diverticular disease, then carcioma/polp, Ibd each 5%