GIT high and low Flashcards
Describe the features of the oral cavity
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
Describe the features of the pharynx
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]]
Describe the features of the oesophagus
strictures and sig, musculature, anatomical rels
also blood veins nerves lymphatics
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
Lower oesophageal sphincter
- a high pressure zone between
- the positive pressure of the abdomen
- negative pressure of the thorax
- Both the oesophageal muscle and diaphragm play a a role in LOS to move contents into stomach
- Note the “Z” line at squamo-columnar junction
- Malfunction of LOS: GORD
- No voluntary control as opposed to UOS
Describe the parts of the stomach
Describe the features of the stomach
- is comprised of four parts: cardia, fundus, body or corpus, and pyloric region - which can be further divided into antrum and canal
- two borders: greater and lesser curvature
- two openings: cardial orifice or entrance, pylorus or exit
- three muscle layers from outer surface: longitudinal, circular and oblique - different direction fibres help move in different ways to move food
- longitudinal is more superficial
- followed by circular
- oblique is deepest
List teh parts of the small and large intestines
- The duodenum has a ‘c’ shape and is comprised of four parts: superior, descending, inferior, ascending (in that order)
- ejunum 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 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
Large intestine
- has five parts
- caecum (where ileum opens into)
- appendix - taenia coli can help identify
- colon: taeniae coli (three bands of smooth muscle: omental (only along transverse), mesocolic (posterior) and free(anterior)), haustra, omental appendage
- rectum
- anal canal
TRANSVERSE MESOCOLON AND SIGMOID MESOCOLON
List and describe the salivary glands
Salivary glands
- sublingual and submandibular (sits outside oral cavity floor), innervated by CN VII
- parotid gland, innervated by CN IX
List the strictures of the 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
List and describe the muscles of the tongue and the pharynx and their innervaton
- intrinsic: refers to muscles that originate and insert within the tongue e.g. , work to lengthen and shorten, curl and flatten the tongue
- extrinsic: refers to muscles originating from structures outside the tongue, and insert within the tongue. Includes mylohyoid and geniohyoid as well as…
- styloglossus: retracts tongue
- palatoglossus: elevates back of tongue, moves arches towards midline, depresses soft palate
- hyoglossus: depresses tongue
- genioglossus(most superior): depresses central part and protrudes anterior part
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
Describe the arterial supply, venoys draingae, innervation and lymphatic drainage of the oesophagus
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
List the branches of the coeliac trunk
- 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
- What are the main tributaries to the portal vein?
- ‘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
- Draw the bile and pancreatic pathways to the duodenal exits/describe the biliary tree
- 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
- Describe the blood supply fo the hwole GIT, and venous drainage
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
- Distinguish between the features of the jejunum and ileum
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
- Describe the features of the liver
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
17.describe the features of the appendix
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
Describe the embryology of the foregut
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
Describe the embryology of the midgut
- 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.
Describe the embryology o fthe hindgut
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.
Describe the innervation fo the GIT
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
Describe the underlying genetic of Gilbert’s
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)
Describe the underlying gnetics of CRC
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
Describe the genetics of lactose intolerance. Of lactose persistence/ Describe how lactose intolerancecan be diagnosed
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
- What is the role of APC gene and what do mutations APC predispose to?
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)
- The gut plays a role in the immune system. Describe in detail the three main protective mechanisms of the gut
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.
- Describe what gut-associated lymphoid tissue (GALT) is, its location and the cells involved
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).
- What immunoglobulin is associated with mucosal immune defences? What is the function of this?
- 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]
- Describe the two mechanisms of direct antigen uptake in the gut
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.
Discuss immunological tolerance
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]]]
- What are the presentations of a patient with coeliac disease
GI manifestations
* Vomiting
* Abdominal bloating
* Abdominal pain
* Variable bowel habit (both loose bowel motions and constipation)
* steatorrhea
* Iron deficiency anaemia
- What are some extra-intestinal presentations
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
- What is the pathology of coeliac
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
- What antibodies are involved? in coeliac
- 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
What tests are conducted for coeliac disease
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
List causes of sepsis by abdominal region
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
Describe possibel presentaiton fo intra abdominal sepsis
Distinguish between UC and Crohn’s
List types of diahhoea and relevant history questions, and investigations for diarrhoa
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
List questions on history diarrhia
- Name causes of liver cirrhosis and describe the pathophysiology of 2 of these.
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
- Describe the stigmata of liver disease and the underlying cause of each
- 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
- Ascites is a complication of liver disease. Describe the pathophysiology of this
- Describe hoe ascites are treated
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]).
- Describe complications of liver disease
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
- Describe the presentation and clinical importance of alcohol related and non-alcoholic fatty liver (physical examination and investigation findings
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
- How can you differentiate alcohol related and non-alcohol related fatty liver disease histologically?
You cannot
- Describe the disease course of fatty liver disease and its association with metabolic disorders and cardiovascular disease
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.
- Describe how you would manage a patient with non-alcohol related fatty liver disease and alcohol-related liver disease
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.
What are common symptoms of reflux?
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
- Describe the pathophysiology of common symptoms of reflux
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
What are red flag symptoms associated with reflux?
Red flags
- dysphagia
- especially progressive from solids to liquids
- weight loss
- haematemesis or melaena
- sudden change in reflux symptoms
- Describe potential complications of reflux
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
- Describe the pathophysiology of Barrett’s oesophagus and how it can lead to cancer
**
* 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.
- Describe the common investigation modalities used to investigate suspected gastro-oesophageal reflux disease
- 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
- Describe management strategies for GORD
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
- reduce foods and drinks that trigger TLOSR
- sleep with head of bed elevated
- What are the top 3 non-indetermined causes of acute liver failure?
not cirrhosis, viral, etc
paracetamol, drugs, no4
- Distinguish between intrinsic and indiosyncratic hepatotoxicity.
- 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
- What are the six mechanisms of hepatocyte injury?
- 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
- How does paracetamol induced liver damage occur and how can it be prevented in overdose?
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.
- List RFs for paracetamol induced hepatotoxicity
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.
- What is one reason so many drugs are withdrawn from the market or are never released?
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).
- Which herbal remedies have been associated with hepatoxicity.
Herbal Remedies
Some herbal remedies can cause severe hepatotoxicity, including Kava-Kava, Chaparral, Germander, Valerian root, Skullcap, Mistletoe, Senna, and Comfrey.
- List biomarkers of cirrhosis
aka FBC, UEC, LFT
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.
- What is the classification of IBS
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
- What are the causes of IBS:
Multifactorial: psychoscial, environmental, physiological
- Investigations for IBS?
- Management of IBS?
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
- What are the clinical features of IBD?
- What is the treatment of ulcerative colitis?
- Treatment of Chrons?
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
- Define AUD
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.
- What are some of the clinical signs associated with pancreatitis
Epi/RUQ pain
fever
nausea and vomiting
SIRS
- Explain autodigestion in relation to the pancreas
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.
- What are three common causes of acute pancreatitis
alcohol, ERCP, gallstones
associateions with obesity diabetes and smoking
- Explain the difference between exocrine and endocrine dysfunction in the pancreas, and the disease states each may lead to
endo vs exo insufficiency
- What are the two types of acute pancreatitis and how common is each?
interstitial»>necrosis
- What is the treatment paradigm for acute pancreatitis?
- 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
- What are the signs associated with chronic liver disease
- 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
- Define cholestasis
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)
- Which liver diseases may be prevented and how?
alcohol
metabolic syndrome
lifestyle changes
- Describe the immune function of the liver
- 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
Describe mechanisms of defecation
List liver functions
Describe hepatitis serology
- **IgM-anti-HAV
- **HBsAg
- **Anti-HCV
History questions for abdominal pain
PR bleeding differnetials
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
List some factors which could lead to constipation
