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MD1 Revision > Gastrointestinal > Flashcards

Gastrointestinal Flashcards

1
Q

How doe diarrhoea kill children?

A

Fluid and electrolyte imbalance - immediate

Malnutrition - delayed

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2
Q

What is the association between diarrhoea and malnutrition?

A 
Increased energy loss
- Diarrhoea and vomiting
- Increased metabolic needs
Reduced energy intake
- Malabsorption
- Withholding of food
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3
Q

How do the proportions of infective causes of diarrhoea vary between developing and developed countries?

A

More bacterial and parasitic diarrhoea in developing countries
More viral diarrhoea in developed countries

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4
Q

What is dysentery and what is it caused by?

A

Presence of blood, pus, and mucus in faeces
Caused by
- Shigella = enteroinvasive E coli (EIEC)
- Amoeba
- Non-infectious sources

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5
Q

What are the aetiological agents of foodborne diarrhoea (food poisoning)?

A 
Staphylococcus aureus - pre-formed toxin ingested
Salmonella
Clostridium perfringens
Bacillus
Vibrio cholerae
Listeria - associated with soft cheese
Viruses
- Rotavirus
- Norovirus
Ciguatoxin
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6
Q

What organism causes antibiotic-associated colitis?

A

Clostridium difficile

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7
Q

How does haemorrhagic colitis differ from dysentery? What is it caused by?

A

Blood present, but no pus in faeces

Caused by enterohaemorrhagic E coli (EHEC)

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8
Q

What is the cause of cholera-like diarrhoea which is not caused by V cholerae?

A

Enterotoxic E coli (ETEC)

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9
Q

What are the types of diarrhoea producing E coli, and what diseases do they produce?

A

ETEC = watery diarrhoea
- Colony factor Ags allow for adhesion to brush border
- Produces enterotoxins
Enteropathogenic E coli (EPEC) = non-specific gastroenteritis
- Adhesins: intimin, Bfp
- Produces T3S effectors
EHEC = blood diarrhoea = haemorrhagic colitis
- Causes haemolytic uraemic syndrome (HUS)
- Evolved in EPEC
- Adhesins: intimin, Efa
- Produces Shiga toxins
EIEC = dysentery
- Doesn’t cause HUS because doesn’t produce Shiga toxin
- Adhesin: IpaC
- Produces Sen toxin
Enteroaggregative E coli (EAEC) = watery diarrhoea
- Adhesin: AAF
- Produces Pet and EAST

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10
Q

Which diarrhoea-causing bacteria are adhesive enterotoxigenic?

A

Cholera

ETEC

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11
Q

Which diarrhoea-causing bacteria are adhesive with brush border damage?

A

EPEC

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12
Q

Which diarrhoea-causing bacteria have invasion restricted to the mucosa?

A

Shigella

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13
Q

Which diarrhoea-causing bacteria invade the submucosa?

A

Salmonella

Campylobacter

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14
Q

Which diarrrhoea-causing bacteria systemically invade?

A

Salmonella

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15
Q

Why can Salmonella typhi cause enteric fever?

A

Can survive in macrophages, especially in immunocompromised people

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16
Q

What are the virulence determinants of diarrhoea causing agents?

A

Adhesins
Invasive ability
Exotoxins
Ability to resist killing

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17
Q

How is laboratory diagnosis of diarrhoea causing agents made?

A

Macroscopic appearance
Miscroscopy
Culture for bacteria only
Ag detection used mainly for viruses and parasites
Detection of nucleic acid for viruses, bacteria, and protozoa

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18
Q

What is the treatment of diarrhoea?

A 
Replace fluid and electrolytes
Reduce fluid loss
- Anti-diarrhoeals
   - Anti-motility agents
   - Anti-secretory agents
   - Binding agents
- Antibiotics
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19
Q

What are the common structural features of the gastrointestinal tract (GIT)?

A

Mucosa
Submucosa
Muscularis externa
Serosa/adventitia

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20
Q

Describe the subcomponents of the mucosa

A 
Mucosa = innermost layer
Sensing and responding to contents
Epithelium
- Columnar enterocytes/stratified squamous epithelium
- May also include endocrine cells
- Renewed every 5-6 days
Lamina propria
- loose connective tissue containing
   - Nerves
   - Blood vessels
   - Immune cells
Muscularis mucosae
- Thin layer of smooth muscle 
- Forms boundary of mucosa
- Facilitates mixing
Most diverse layer of GIT
Varies from region to region
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21
Q

Describe the subcomponents of the submucosa

A 
Dense irregular connective tissue - gives structural strength and elasticity
Contains
- nerves
- Ganglia
- Blood vessels
Sometimes contains
- Glands
- Immune cells
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22
Q

Describe the subcomponents of the muscularis externa

A 
Responsible for gut movement
Usually has 2 layers of smooth muscle - except for stomach
- Inner circular
- Myenteric plexus between 2 layers
- Outer longitudinal
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23
Q

What is the difference between serosa and adventitia?

A

Serosa secretes fluid from simple squamous epithelium > allows organ movement
- Contains thin layer of connective tissue
Adventitia = connective tissue joining GIT with surrounding structures
- Present in parts of oesophagus and rectum
- Doesn’t secrete fluid

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24
Q

What does the enteric nervous system regulate?

A

Absorption and secretion regulated by submucosa ganglia

Smooth muscle activity regulated by myenteric ganglia

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25
Q

Describe the histology of the oesophagus

A 
Non-keratinising squamous epithelium
Submucosal glands
- Secrete mucus to lubricate movement
2 muscle types
- Top = striated
- Bottom = smooth
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26
Q

Describe the structure of the gastric glands

A 
Vary between cardia, corpus, and pylorus
Mucous cells
- Secrete mucus
- In isthmus and neck
Parietal cells
- Secrete HCl
- In isthmus, neck, and base
Chief cells
- Secrete pepsinogen
- In base
Enteroendocrine cells
- Secrete gastrin
- In neck and base
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27
Q

Describe the histology of the small intestine

A

Villi = finger-like extensions of mucosa
- Covered by simple columnar epithelium
- Each epithelial cell has microvilli
Very folded surface = plicae circulares - maximise surface area for absorption

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28
Q

What are the absorptive and secretory zones of the small intestine?

A

At level of villus, tubular glands > secrete fluid and mucus into lumen between villi
Glands = crypts of Lieberkuhn
Absorption through microvilli on enterocyte surface of villi

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29
Q

What are the epithelial cells of the small intestine?

A 
Enterocytes = fluid transport and absorption
Goblet cells = mucus secretion
Enteroendocrine cells = hormones
Paneth cells = secrete anti-microbial peptides - deep in glands
Stem cells = renew epithelium
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30
Q

What are the distinctive features of the duodenum?

A

Brunner’s glands in submucosa
- Release alkaline mucus to inactivate stomach enzymes and neutralise acid from stomach
Low plicae circulares
Long villi

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31
Q

What are the distinctive features of the ileum?

A

Peyer’s patches = massive lymphoid follicles
- Very basophilic
Short villi
More goblet cells

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32
Q

What is distinctive about the large intestine’s muscularis externa?

A

3 bundles of longitudinal muscle form taeniae coli

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33
Q

How do the large intestinal glands differ from those of the small intestine?

A

No villi
Straight tubular glands, compared to coiled Brunner’s glands
Columnar epithelium

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34
Q

Why do the large intestine and rectum contain more goblet cells?

A

Lubrication for increasingly solid material in lumen

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35
Q

How do the types of epithelium in the large intestine differ from the types in the small intestine?

A

In large intestine

  • Paneth chells rare
  • Higher proportion of goblet cells
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36
Q

What are the key regulatory functions of the GIT?

A

Control contractions of intestinal smooth muscle
Regulate secretion of digestive enzymes and solvents needed for their proper function
Control reabsorption of water from lumen to prevent dehydration
Coordinate widely separated regions to ensure proper function

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37
Q

What are the local control systems of the gut?

A 
Enteric nervous system
- Controls contractile activity
- Controls secretion of water and salt
- Control over mm-cm = local action
Interstitial cells of Cajal
- Pacemaker cells > produce rhythmic activity in muscle
- Nervous system operates on top of this
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38
Q

Describe the endocrine control system of the gut

A

Signals from intestinal mucosa to ancillary organs like
- Brain
- Pancreas
- Gall bladder
Essential for secretion of enzymes and solvents into intestinal lumen, and regulating appetite

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39
Q

What do enterochromaffin cells release?

A

Serotonin

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40
Q

What are the mucosal enteroendocrine cells?

A 
Enterochromaffin cells
CCK-secreting cells
Secretin-secreting cells
Somatostatin-secreting cells
GLP-secreting cells
ECL cells release histamine
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41
Q

What are the reflex pathways involved in the GIT?

A

Vago-vagal reflex pathways coordinate movements in upper GIT
- Control of swallowing
- Regulates acid secretion in stomach
- Coordinates contractions of stomach and duodenum
Instestino-intestinal reflexes
- Some mediated by vagus
- Others via dorsal root ganglia and spinal cord
- Viscerofugal neurons have cell bodies in gut wall and project out to pre-vertebral sympathetic ganglia > reflex inhibition of enteric nervous system
CNS control relating to anticipation, mood, and activity

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42
Q

Describe the cephalic phase of digestion

A

Triggered by sight, smell, and taste of food
Causes
- Salivation
- Gastric acid and pepsin secretion
- Relaxation of gastric corpus and fundus
Operates via vagus nerve
Accounts for 30% of acid secretion in stomach
Sets up stomach to store food and begins barrier function of GIT

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43
Q

Describe the general control of acid and pepsin secretion

A

Acetylcholine from enteric neurons excited by vagal efferent neurons stimulates
- ECL cells to release histamine > histamine stimulates parietal cells
- Parietal cells to release H
- G cells to produce gastrin
Acetylcholine inhibits
- D cells from producing somatostain

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44
Q

How is peristalsis controlled in the oesophagus? How does this differ to the rest of the GIT?

A

Entirely under neural control via vagus nerve
As opposed to rest of GIT > under enteric nervous system control
Secondary peristalsis can be activated in oesophagus if vagus nerve fails

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45
Q

What happens when chewed food enters the stomach?

A

Fundus and corpus of stomach relax to accommodate volume of food swallowed > distension activates enteric and vago-vagal reflexes > more acid and pepsin secretion
Due to interstitial cells of Cajal: large pacemaker potentials > strong constrictions > propagate from corpus to pylorus > drive food towards pyloric sphincter
Food enters antrum > reflex inhibition of acid secretion in corpus > continued constriction driving food towards closed sphincter > acid, protease, and mechanical activity separate components of food > liberates fat - floats to top of stomach

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46
Q

What happens to food in the antrum of the stomach?

A

Continual grinding up in presence of protease and water > food becomes dilute paste
Peptide bonds broken
Amylase breaks carbohydrates up
Pylorus opens briefly by relaxing pyloric sphincter due to enteric nervous activity > squirt of food mixed with acid and pepsin enters duodenum

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47
Q

What is the response to acid in the duodenum?

A

Activates D cells in mucosa of duodenum to release somatostatin
- Enters portal circulation to reach stomach
Excites terminals of vagal afferent neurons > triggers vago-vagal reflex > Brunner’s glands release mucus and bicarbonate
Vago-vagal reflex inhibits gastric emptying
Duodenal-pyloro-antral reflex closes pylorus > inhibits gastric emptying

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48
Q

What does the presence of fatty acids and amino acids in the duodenum activate? What is the consequence of this?

A

Release of CCK from I cells
Leads to
- Excitation of terminals of vagal afferent neurons > activates many gastric reflexes > inhibits appetite
- Excitation of intrinsic neurons > stimulates mixing behaviours of bolus of food and enzymes
- Release of digestive enzymes from pancreas
- Contraction of gallbladder > forces bile down common bile duct > duodenum
Amino acids trigger release of secretin from S cells

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49
Q

What is the role of secretin in the duodenum?

A

Triggers secretion of bicarbonate-rich solution from pancreas > neutralises acid in duodenal lumen

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50
Q

What does neutralising acid in the duodenum do?

A

Inactivates pepsin
Stops somatostatin secretion from duodenal D cells
Removes inhibition of gastric emptying by somatostatin-stimulated reflexes

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51
Q

Describe sensing in the intestinal mucosa

A

Sensory information from mechanical stimuli
- Distension stretches mechanoreceptors > activates vagal afferents
- Mucosal deformation
Sensory information from chemical stimuli acting via enterochromaffin and enteroendocrine cells
- Nutrients and other stimuli act on apical surface receptors > mediator release from basolateral surface

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52
Q

How do mucosal cells “taste” the lumen?

A

Enterochromaffin and enteroendocrine cells in intestinal crypts express same taste receptors as those on tongue for bitter and savoury flavours
Tastants cause release of serotonin
L cells express components of sweet taste receptors

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53
Q

What hormones do L cells release? What are their functions?

A 
Release in duodenum and jejunum
- GLP-1
- GLP-2
- PYY
GLP-1 and GLP-2 = carbohydrate absorption and insulin resistance
PYY =  appetite regulation
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54
Q

What are the types of motor patterns of the GIT?

A 
Retropulsion = constrictions running towards pylorus mixes pancreatic juices and bile with food > activates and facilitates digestion
Segmentation = local constrictions alternating with relaxation mix food with digestive enzymes and bile > brings nutrients to epithelium
Peristalsis = propels contents into new regions of intestine
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55
Q

Describe what happens to food as it passes from the jejunum to the colon

A

Absorption of water makes content more viscous > increases resistance to flow
High levels of anaerobic bacteria in colon > feed off and ferment colonic contents > release short-chain fatty acids > stimulate enteric reflexes

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56
Q

What causes defecation?

A

Distension of rectum triggers urge to defecate via sacral primary afferent neurons
Mass movement contractions move faecal matter from colon to rectum
Conscious neural activity relaxes anal sphincter and contracts abdominal muscles for normal defecation

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57
Q

What is the migrating motor complex?

A

Wave of constriction initiated in antrum/upper duodenum
Propagating slowly to ilio-colonic junction
Constriction clears bacterial and cellular debris from otherwise empty lumen

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58
Q

What are the gastric pits lined by?

A

Foveolar epithelium

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59
Q

True or false: there are normally lymphocytes in the gastric lamina propria

A

False

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60
Q

Why does the stomach not digest itself?

A

Gastric mucosal barrier
Contains bicarbonate to neutralise acid
Phospholipid monolayer in direct contact with lumen > prevent water from entering

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61
Q

How may the gastric mucosal barrier be broken down?

A

Organisms that can survive acid
NSAIDs which block prostaglandin synthesis
Bile - refluxes from duodenum and antrum > disrupts surface hydrophobic layer
Alcohol - breaks down permeability barrier

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62
Q

How do prostaglandis prevent and reverse mucosal injury in the stomach?

A

Inhibit acid secretion
Stimulate bicarbonate and mucus secretions
Increase mucosal blood flow
Modify local inflammation

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63
Q

How is inflammation initiated when there is breakdown of the mucosal barrier?

A

HCl can gain access to lamina propria and stimulate mast cells to produce histamine > start inflammatory process

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64
Q

What are the common causes of acute gastritis?

A 
Chemical injury
Alcohol/drugs
Stress
Shock
Burns
Head injury
Septiceamia
Staphylococcal food poisoning
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65
Q

How does acute gastritis heal?

A

Regeneration in 24-48 hrs due to rapid cell turnover in stomach

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66
Q

What is the difference between gastric erosion, acute and chronic peptic ulcers?

A

Erosion = defect above muscularis mucosae
Acute ulcer = defect penetrating muscularis mucosae and submucosa
Chronic ulcer = defect penetrating deeper than submucosa with dense fibrosis at base

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67
Q

What are the main types of causes of chronic gastritis?

A

Autoimmune
Helicobacter-associated
Chemical

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68
Q

Describe the autoimmune cause of chronic gastritis

A

Immune-mediated destruction of acid secreting tubules > atrophy > achlorhydria and loss of intrinsic factor > pernicious anaemia
- Caused by circulating autoAbs to parietal cell membrane H/K ATPase, IF receptor, and gastrin receptor
Confined to gastric corpus mucosa with total loss of parietal cells
Loss of HCl and parietal cells causes hypergastrinaemia > linear and nodular ECL hyperplasia and occasionally carcinoidosis
- Hypergastrinaemia due to lack of stimulation of D cells by HCl

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69
Q

Describe helicobacter-associated chronic gastritis

A

Helicobacter pylori uses its flagella to enter mucosal gel layer > colonises neutral area where it can survive
Secretes urease to increase pH
- Ammonium toxic to cells
Uses adhesins to attach to gastric surface epithelium and intercellular junctions
Neutrophilic gastritis as acute inflammatoryresponse
- Acute foveolitis = damage to gastric pits > replacement with intestinal mucosa = intestinal metaplasia > dysplasia and carcinogenesis
- Soluble Ags/chemoattractants
- IL-8
Infiltration with chronic inflammatory cells at 4 wks
Infection has low clearance rate and generally persists for life when established

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70
Q

Describe chemical chronic gastritis

A

Reflux of bile and alkaline duodenal juice due to
- Altered antro-duodenal motility
- Gastro-jejunostomy
- Long term use of aspirin/NSAIDs
Direct mucosal injury: disruption of mucous layer and gastric barrier > epithelial desquamation
Compensatory foveolar hyperplasia with
- Elongation and tortuosity of gastric pits
- Vasodilation
- Oedema
- Fibromuscular hyperplasia of lamina propria
- Mild inflammatory cell infiltration

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71
Q

Describe the progression from normal mucosa to adenocarcinoma due to chronic H pylori infection

A

Normal mucosa > H pylori infection > chronic gastritis > atrophic gastritis > intestinal metaplasia > dysplasia > adenocarcinoma

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72
Q

What are the longer-term outcomes of gastritis?

A

Chronic gastritis >

  • Antral predominant gastritis > duodenal ulcer (age 20-40)
  • Multifocal atrophic gastritis >
    • Gastric ulcer (age 40-70)
    • Gastric cancer (age >70)
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73
Q

What is another name for multifocal gastritis?

A

Pan-gastritis

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74
Q

What are the two main patterns of H pylori gastritis?

A 
Antrum-predominant
- Chronic inflammation
- Neutrophils
- Increased acid output
- In duodenum
   - Gastric metaplasia
   - Active chronic inflammation
- Duodenal ulcer risk
Pan-gastritis
- Chronic inflammation
- Neutrophils
- Atrophy
- Intestinal metaplasia
- Reduced acid output
- Normal duodenum
- Gastric ulcer risk
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75
Q

How does antrum-dominant H pylori gastritis lead to dudenal ulcers?

A

More acid in D1 section > duodenal mucosa comes to resemble gastric mucosa > H pylori colonises D1 > active chronic duodenitis > duodenal ulcer

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76
Q

What are the diseases associated with H pylori?

A 
Peptic ulcer disease
Gastric adenocarcinoma
Gastric B-cell lymphoma of MALT
Iron-deficiency anaemia
Atrophic gastritis > increase in susceptibility to bacterial gastroenteritis and B12 deficiency
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77
Q

What are the most common sites for peptic ulcer disease?

A

Most common in D1 and antrum
Oesophagus at squamo-columnar junction with gastric cardia/Barrett’s mucosa
Gastro-enterostomy stoma
Meckel’s diverticulum

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78
Q

Describe the chronic ulceration found in peptic ulcer disease

A

Deep, sharply punched out
Destroying all layers through muscularis propria to subserosa
Scarring at base drawing in gastric folds to its margin
Scarring precludes restoration of submucosa and muscularis propria, leaving radial scar on healing with partial restitution of specialised gastric mucosa
- Replaced by intestinal and pyloric gland metaplasia

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79
Q

What are the four histological layers of an ulcer in peptic ulcer disease?

A

Exudate of fibrin, neutrophils, and necrotic debris
Narrow zone of fibrinoid necrosis
Zone of granulation tissue
Zone of fibrosis

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80
Q

What are the possible complications of peptic ulcer disease?

A

Perforation from anteriorly located ulcers > generalised peritonitis
Haemorrhage due to erosion of artery > haematemesis, melaena, anaemia
Penetration as ulcer erodes into adjacent organ > fistula
Stenosis due to contraction of fibrous scar > pyloric canal stenosis/lower end oesophageal stenosis
Development of malignancy

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81
Q

What is coeliac disease?

A

Immune mediated disease in genetically susceptible people, driven by gluten found in wheat, rye, and barley
Results in chronic inflammation of small bowel mucosa
Remission on gluten free diet = hallmark of disease

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82
Q

Describe the process of regeneration of the intestinal epithelium

A

Cells replaced every 2-3 days
Move from zone of proliferation > zone of maturation > incorporated into villous epithelium
Everyvillus surrounded by group of crypts

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83
Q

What happens if the cells of the intestinal epithelium are being sloughed off at a faster rate than normal?

A

Enlargement/elongation of zone of proliferation

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84
Q

Describe the microscopic changes associated with advanced coeliac disease

A

Total villous atrophy with crypt hyperplasia and intraepithelial lymphocytes

  • Submucosa entirely normal
  • Lymphocytes found in lamina propria and at surface - very few in crypts
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85
Q

What are the three stages of coeliac disease?

A

Infiltrative (type I): villus:crypt length normal (4:1) but increase in intraepithelial lymphocytes
Hyperplastic (type II): intraepithelial lymphocytosis, elongation and branching of crypts
Destructive (type III): villi shortened and blunted and villus:crypt ratio <1:4

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86
Q

What are the other causes, aside from coeliac disease, of intraepithelial lymphocytosis and villous atrophy with crypt hyperplasia?

A 
Tropical sprue
Small bowel bacterial overgrowth
Common variable immunodeficiency = deficiency in IgA, IgG, and IgM
Autoimmune enteropathy
Various drugs
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87
Q

What are the typical clinical presentations of coeliac disease?

A 
Gastrointestinal symptoms
- Diarrhoea
- Bloating
- Abdominal cramps
- Flatulence
- Steatorrhoea
Iron-deficiency anaemia
Vitamin deficiency
Malabsorption of nutrients
Infants: failure to thrive
Osteoporosis because of lack of vitamin D
Lethargy
Migraines
Infertility
Mouth ulcers
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88
Q

Outline the role of environment in the development of coeliac disease

A

Breast feeding protective
Timing/amount of gluten introduced to infant diet
- Too much gluten, too soon > increased risk
Infections increase risk

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89
Q

Outline the effect of T cells on coeliac disease

A

CD4 HLA-DQ2/8 restricted T cells - reactive to gluten-specific epitopes
Reside in small bowel mucosa
Cause damage by producing harmful cytokines; eg: IFN-gamma
CD8 T cells accumulate in epithelium and involved in immune response

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90
Q

Why do toxic gluten peptides survive digestion by the gut?

A

High content of proline confers resistance to digestion by proteases

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91
Q

Describe the consequence of gluten peptide deamidation

A 
Deamidated gluten peptides bear negatively charged glutamate instead of glutamine
Bind to HLA-DQ2
CD4 T cells recognise deamidated peptides presented by MHC class II > activated > produce cytokines
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92
Q

Outline the overall pathophysiology of coeliac disease

A

Ingestion of gluten peptides > gluten crosses mucosal epithelium > exposure to tTG > deamidated gluten/ross-links gluten > presentation on DC > presentation of deamidated gluten peptide and/or gluten-tTG complex to CD4 T cell

  • Th1 response > IFN-gamma
    • Secretion of MMPs by fibroblasts > villous flattenning and increased enterocyte death
    • Increased cytotoxicty of CD8 T cells against enterocytes > villous flattenning and increased enterocyte death
      • IL-15 released by CD8 T cells > promotes survival of CD8 T cells > predisposition to T cell lymphoma
  • Th2 response > plasma cells > anti-tTG and anti-gliadin Abs > structural enterocyte change > epithelial damage
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93
Q

How is coeliac disease diagnosed?

A

Serological testing
- Ab to tTG
- Ab to deamidated gliadin peptide (DPG-IgG)
HLA-DQ haplotyping used to rule out diagnosis if HLA-DQ2/8 absent
Small bowel biopsy during gluten exposure = gold standard

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94
Q

What is EATL?

A

Enteropathy-associated T cell lymphoma

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95
Q

What is the predominant class of bacteria found in the body?

A

Gram negative rods

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96
Q

What are the main phyla associated with the human body?

A

Bacteriodetes
Firmicutes
Actinobacteria
Proteobacteria

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97
Q

What is the development of the microbiota?

A

Development finished at about 2.5 years

Usually stable after that but can be modified slightly by various events

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98
Q

What are the general roles of the microbiota?

A

Metabolism
Development
Protection against enteropathogens

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99
Q

What are the factors that influence the gut microbiota?

A 
Mode of delivery
Age
Diet
Antibiotics
Genetics
Environment
Chronic inflammation
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100
Q

What is the effect of diet on the intestinal microbiota?

A

Short term changes in diet can have profound effect on gut microbial composition
Bacteriodes genus decreases when more Western diet introduced

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101
Q

What is the role of microbiota in nutrition?

A

Directly supply nutrients
- Carbohydrate breakdown
- Vitamin production
- Bile acid breakdown
- Amino acid metabolism
Alter metabolic machinery of host cells by changing host genes and maintaining enterocyte differentiation/function
- Bacterial degradation of host glucans > new glycan synthesis; eg: mucus
- Produce short chain fatty acids from indigestible carbohydrates
- Induce changes in host genes > promote angiogenesis

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102
Q

Describe the role of the mucosal immune system in immunity

A

Protects body surfaces
GIT immune system greatest site of Ag challenge as there’s large surface area of small intestine
2 main functions
- Protection from pathogens - IgA
- Tolerance to normal microbiota and food Ags

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103
Q

What are the immune roles of the cells of the villus?

A

Sites for induction of T and B cell activation
Enterocytes secrete TGF-beta, chemokines, and anti-microbial peptides
Goblet cells secrete mucins, lysozyme, and lactoferrin
Lamina propria lymphocytes
Paneth cells at base of crypts secrete defensins

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104
Q

What villous cells are imporant in inducing tolerance?

A

Enterocytes

Intraepithelial lymphocytes

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105
Q

What are the innate defences of the gut?

A 
Peristaltic action
Acid
Mucous layer/glycocalyx = molecular sieve
Enterocytes
- Barrier
- Antimicrobial factors to kill off cells that get through barrier
- Cytokines and chemokines
Innate leukocytes
Mechanisms for controlled Ag access
- M cells
- DCs
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106
Q

What is the significance of IL-22 in the innate gut immune system?

A

Enhances antimicrobial defence and epithelial repair and barrier integrity
Produced by NK cells and intraepithelial lymphocytes

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107
Q

How are macrophages in the gut different from those in the rest of the body?

A

Express lower levels of TLR

Hypo-responsive to TLR signalling

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108
Q

Describe how M cells allow Ag access safely

A

M cells don’t have villi and don’t secrete mucus > microbial access easier
Located over sites of organised lymphoid aggregates and deliver Ags directly to cells in these aggregates
Ags immediately taken up into DCs and macrophages > present to T and B cells

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109
Q

What is the role of dendritic cells in the mucosa?

A

Direct sampling of Ag from intestinal mucosa
Indirect sampling of Ag from intestinal mucosa via goblet cells and M cells
Induce variety of T cell differentiation pathways
- Tregs and Th2 in steady state
- Th1 and Th17 during inflammation
Bias B cell isotype switching to secretory IgA

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110
Q

Describe the fate of T and B cells activated in the gut

A

Activated B cells produce secretory IgA
CD4 T cells have multiple roles depending on their subset
CD8 T cells protect against intracellular infections
Many persist as memory cells

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111
Q

What are the effects of intestinal microflora on the mucous layer and gut epithelium?

A

Block binding sites
Produce bacteriocins
Interact with PRRs on enterocytes
- Stimulates mucin production
- Stimulates proliferation of crypt enterocytes and Paneth cells
- Stimulates release of antimicrobial peptides
- Induces regulatory cytokines
Short chain fatty acids inhibit production of inflammatory cytokines
IL-22 produced after PAMP interaction promotes epithelial barrier integrity

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112
Q

How does the gut immune system respond differently to normal microbiota and pathogens?

A

Normal microbiota induce physiological inflammation via Tregs and Th2 cells
Pathogens induce pathological inflammation via Th1 and Th17 cells

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113
Q

What is the role of the gut microbiota in obesity?

A

High-fat diets/obesity associated with decrease in diversity of microbiota
Low microbial diversity > higher levels of
- Insulin resistane
- Serum triglycerides
- Cholesterol
- Insulin

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114
Q

How may the intestinal microbiota be associated with infectious disease?

A 
Microbiota escapes GIT can cause infections
- Urinary
- Respiratory
- Wound
- Peritoneal
- Bloodstream
Needs abnormality in patient
- Anatomical
- Functional
- Immunocompromised
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115
Q

How may alteration in the intestinal microbiota be a cause of GIT disease?

A

Susceptibility to infection by gastrointestinal pathogens and/or overgrowth of certain commensals

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116
Q

How is pseudomembranous colitis caused? Where is it commonly found and spread?

A

Overgrowth of C difficile, usually due to use of antibiotics/cytotoxic drugs
Commonly found and spread in hospitals

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117
Q

How is antibiotic-resistant pseudomembranous colitis treated?

A

Metronidazole and vancomycin

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118
Q

How is recurrent C difficile treated?

A

Faecal transplant

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119
Q

What is the role of salivary amylase?

A

Alpha-amylase hydrolyses alpha1-4 linkages between glucose molecules

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120
Q

How is salivary amylase inactivated?

A

By acid pH in stomach

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121
Q

How is salivary amylase reactivated?

A

In duodenum when pH returned to neutral

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122
Q

How are carbohydrates digested in the small intestine?

A

Pancreatic alpha-amylase secreted due to CCK release from duodenal mucosa
Mixes with luminal contents by segmentation and retropulsion
Pancreatic amylase can’t break alpha1-6 linkages, leaving some oligosaccharides intact
Remainder of digestion happens at brush border mebrane of mucosal enterocytes
Isomaltase breaks alpha1-6 linkages

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123
Q

How is maltase and sucrase activated?

A

Synthesised as single large glycoprotein

Separated and activated in brush border membrane by pancreatic proteases

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124
Q

How are glucose and galactose transported into intestinal enterocytes at the brush border?

A

Through Na-dependent glucose transporter (SGLT1)

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125
Q

How is fructose transported into intestinal enterocytes at the brush border?

A

Facilitated diffusion through GLUT5

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126
Q

How are monosaccharides absorbed into the bloodstream from intestinal enterocytes?

A

GLUT2

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127
Q

Describe protein digestion in the stomach

A

Pepsinogen secreted from chief cells in stomach
Pepsinogen > pepsin by gastric acid
Pepsin hydrolyses bonds between amino acids > polypeptides
Pepsin inactivated at neutral pH in stomach

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128
Q

Describe protein digestion in the duodenum and jejunum

A

CCK released triggered by amino acids in small intestine
Secretion of pancreatic proteaases as proenzymes
Enterokinase in brush border membrane activates cleavage of trypsinogen > trypsin
Trypsin cascades cleavage of other proenzymes
Peptidases break up polypeptides into mix of short peptides and free amino acids

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129
Q

How are proteins digested at the brush border membrane?

A

So di- and tri-peptides transported directly into enterocytes > broken to free amino acids by enteroyte peptidases
Free amino acids transported into enterocytes via various transport systems

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130
Q

How is lipase secreted?

A

In inactivated form
Activated by colipase
Colipase activated by trypsin

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131
Q

What is the role of gastric lipase?

A

Minor

Produces just enough fatty acid to stimulate duodenal fatty acid receptors to release CCK

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132
Q

How are lipids absorbed?

A

Inside micelles - brought to apical surface of epithelial cells at tips of villi
Contact enterocyte membrane > dissolve in membrane > enter cells
Inside enterocytes, reformed in smooth ER and coated with apolipoproteins > chylomicrons
Chylomicrons secreted into lymphatics by exocytosis

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133
Q

Where, apart from via digestion of fats, are short chain fatty acids produced in the body?

A

Proximal colon by fermentation of dietary fibre
Absorbed in distal small bowel and proximal part of colon via H dependent mechanism
Contribute significantly to total energy intake

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134
Q

Describe the early development of an embryo

A

Egg fertilised in Fallopian tube > moves into uterus, propelled by cilia > cell division continues > blastocyst formation > implants into uterine wall between 5 and 10 days

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135
Q

What is gastrulation?

A

Formation of 3 germ layers by epiblast

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136
Q

What are the derivatives of the ectoderm?

A

Nervous system

Epidermis

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137
Q

What are the derivatives of the mesoderm?

A 
Blood
Heart
Kidneys
Gonads
Most 
- Bones
- Muscles
- Connective tissues
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138
Q

What are the derivatives of the endoderm?

A

Epithelium of gut and associated organs

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139
Q

Describe the formation of the nervous system

A

Notochord induces overlying ectoderm to form neural plate > neural plate folds in on itself to form neural tube > neural crest cells separate from neural tube

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140
Q

What is the most common congenital heart defect?

A

Ventricular septal defect

- From failure to divide single ventricle into left and right ventricles

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141
Q

What is the second most common congenital heart defect?

A

Atrial septal defect

- From failure to close foramen ovale

142
Q

What is hypospadiasis?

A

Partial failure of fusion of urogenital folds to make urethra
Occurs in 1 in 300 males
Easily corrected with surgery

143
Q

Describe the structure of H pylori

A

Gram negative curved rod

144
Q

Describe the process of acid secretion in the stomach

A

Secreted by parietal cell by H/K ATPase
Acetylcholine and gastrin act to increase histamine production from enterochromaffin-like cells > stimulate H/K ATPase to secrete more acid

145
Q

How is the gastric mucosa maintained at neutral pH whilst the stomach contents have a pH of 1-2?

A

Mucous layer containing
- Bicarbonate
PGE2 and PGI2 important in maintaining mucous layer

146
Q

What are the common H/K ATPase inhibitors = proton pump inhibitors (PPIs)?

A

Omeprazole
Esomeprazole
- Better bioavailability

147
Q

How are PPIs used?

A

For about 8 weeks for healing of peptic ulcer
Also used for
- Zollinger-Ellison syndrome
- Reflux oesophagitis

148
Q

What are the common histamine H2 receptor antagonists?

A

Cimetidine
- Causes gynaecomastia in men
Ranitidine

149
Q

What are the common antacids?

A

Magnesium hydroxide
Sodium bicarbonate
- Can interact with other prescription drugs

150
Q

What are the common side effects associated with antacid use?

A 
Magnesium based
- Diarrhoea
Sodium based
- Systemic alkalosis
- Hypertension
Calcium based
- Rebound acidity
151
Q

What are cytoprotective agents?

A

Coat cells and protect from erosion

152
Q

What effect does peptic ulcer disease have on motility? How is this treated?

A

Increased motility

Treated with spasmolytics

153
Q

What are the different types of spasmolytics?

A

Muscarinic receptor antagonists

Direct spasmolytics = anti-spasmodic drugs without anti-cholinergic effect

154
Q

What is the drug class of hyoscine butylbromide?

A

Muscarinic receptor antagonist

155
Q

What is the drug class of mebeverine?

A

Direct spasmolytic

156
Q

How do prostaglandin E analogues work?

A

Increase mucus secretion and mucosal blood flow

Decrease gastric acid secretion

157
Q

What is the drug class of misoprostol?

A

Prostaglandin E analogue

158
Q

Why are prostaglandin E analogues contraindicated in pregnancy?

A

PGE causes uterine contractions at high levels

Analogue may may raise levels high enough to cause miscarriage

159
Q

What are the receptors involved in emesis?

A 
Acts directly on vomiting centre
- Histamine H1 receptors
- Muscarinic receptors
Acts on chemoreceptor trigger zone
- Dopamine D2 reeptors
- Serotonin 5HT3 receptors
Neurokinin-1 (NK1) receptors
160
Q

Where is the vomiting centre located?

A

In dorsolateral reticular formation in floor of medulla

161
Q

Where is the chemoreceptor trigger zone?

A

In medulla but outside BBB

162
Q

What are the common anti-emetic drugs?

A 
Histamine H1 receptor antagonists
- Act directly on vomiting centre
Muscarinic receptor antagonists
- Act directly on vomiting centre
Dopamine D2 receptor antagonists
- Act on chemoreceptor trigger zone
Serotonin 5HT3 receptor antagonists
- Act on chemoreceptor trigger zone
NK1 receptor antagonists
163
Q

What is the drug class of promethazine, and what is a major side effect?

A

Histamine H1 receptor antagonist

Sedative

164
Q

What is the drug class of hyoscine hydrobromide, and what is a major side effect?

A

Muscarinic receptor antagonist

Sedative

165
Q

What is the drug class of metoclopramide?

A

Dopamine D2 receptor antagonist

166
Q

What is the drug class of prochlorperazine?

A

Dopamine D2 receptor antagonist

167
Q

What is the the drug class of ondansetron?

A

Serotonin 5HT3 receptor antagonist

168
Q

Other than at the chemoreceptor trigger zone, where else will ondansetron work?

A

In GIT, where some cytotoxic drugs can trigger release of serotonin

169
Q

Which drug classes are very effective in treating motion sickness?

A

Histamine H1 receptor antagonists

Muscarinic receptor antagonists

170
Q

What are the effects associated with blocking muscarinic receptors?

A

S > dry mouth
L > blurred vision
U > urinary retention
D > constipation

171
Q

What effects are associated with prolonged D2 receptor antagonist use?

A

Tardive dyskinaesia

  • Extra-pyramidal effects
  • Parkinson’s like
  • Repetitive, involuntary, purposeless movements
172
Q

How does metoclopramide work in the gastrointestinal tract?

A

At higher doses acts on 5HT3 receptors in gut as pro-motility drug
- Stimulate gastric emptying
Acts on 5HT4 receptors as agonist
- Stimulates acetylcholine release
- Further stimulate gastric emptying
Doesn’t cause diarrhoea because
- Selective for upper gastrointestinal tract

173
Q

Define a parasite

A

Plant/animal that lives on/in another living organism on which it’s metabolically dependent

174
Q

Define a definitive host

A

Host in which parasite reaches sexual maturity

175
Q

Define an intermediate host

A

Host in which development occurs but parasite doesn’t reach sexual maturity

176
Q

Define a paratenic host

A

Host in which parasite enters body and doesn’t undergo development but remains infective

177
Q

Define a reservoir host

A

Animal which can be normally infected with parasite that also infects people

178
Q

What are ectoparasites?

A

Organisms that gain metabolic benefit and life cycle requirements from cutaneous surface interaction with host

179
Q

What are the principle groups of arthropod parasites?

A 
Insects
- Flies
- Mosquitoes
- Fleas
- Lice
Arachnids
- Mites
- Ticks
180
Q

What are the three main species of human louse?

A 
Pediculus humanis
- Body louse
- Clothing spread
Pediculus capitis
- Head louse
- Spread by contact
Pediculus pubis
- Pubic louse
- Spread by contact
181
Q

Describe the life cycle of lice

A
  1. Egg
    - Diagnostic stage
  2. 1st nymph
  3. 2nd nymph
  4. 3rd nymph
  5. Adults
    - Infective stage
    - Diagnostic stage
182
Q

What are scabies?

A

Sarcoptes scabiei
Itch mites
Form and live in burrows in epidermis

183
Q

How is scabies spread?

A

Female lays eggs around entrance to tunnel

Eggs spread by scratching

184
Q

How can scabies be detected?

A

Under microscope of scrapings/biopsy

185
Q

How is scabies treated?

A

Topical scabicides
Mites can live for short periods of time away from host, so clothes and bedding should be washed with hot water for sterilisation

186
Q

What are the common symptoms of tick infection?

A

Rapid ascending paralysis caused by neurotoxin - starts with local paralysis

187
Q

How is the incidence of disease caused by ticks controlled?

A

Clothing
Repellent
Examination of body surfaces after potential exposure

188
Q

Where do ticks usually live, and how do they infect humans?

A

Usually in long grass

Infect humans via contact

189
Q

Why are protozoa generally not true parasites?

A

Most can live outside host

190
Q

What are the two general forms of a protozoan parasite?

A 
Trophozzoate = active infective form
Cyst = inactive, typically resistant to destruction
191
Q

Describe the illness caused by Entamoeba histolytica

A

Invades tissues in colon

Causes persistent large-volume diarrhoea and/or extra-intestinal infection: liver/brain abscesses

192
Q

What is the main form of disease control for amoebiasis?

A

Clean water and sewage treatment

Treatment of infection = metronidazole and drainage of abscesses if present

193
Q

What is Giardia intestinalis, and how is it transmitted?

A

Flagellated primitive eukaryote

Faecal-oral transmission by zoonoses - commonly possums

194
Q

What is the main disease control for G intestinalis?

A

Cleaning water and sewage treatment

195
Q

How is a diagnosis of G intestinalis made?

A

Presence of cysts in faeces

196
Q

What is Toxoplasma gondii?

A

Obligate intracellular parasite

Reproduces in cats

197
Q

Describe toxoplasmosis

A

Infection with T gondii persists for life, but usually asymptomatic in immunocompetent people
In immunocompromised people - susceptible to more serious symptoms
- Brain lesions
- Disseminated disease
Infection during pregnancy
- Can transfer to foetus

198
Q

What are the main groups of helminths?

A

Roundworms (nematodes)
Flukes
Tapeworms

199
Q

Describe roundworms

A

Tube-like animal covered with cuticle

Most free living

200
Q

Describe flukes

A

All parasitic

Cycle back and forth between human and animal reservoir phases

201
Q

Describe tapeworms

A

All parasitic

Large and consume high amounts of energy

202
Q

Where do helminths develop?

A

Generally eggs develop outside host

Except for strongyloides

203
Q

Describe the life cycle of pinworms = Enterobius vermicularis

A
  1. Eggs on perianal folds
    - Diagnostic stage
  2. Embryonated eggs ingested by humans
    - Infecteive stage
  3. Larvae hatch in small intestine
  4. Adults in lumen of caecum
  5. Pregnant females migrate to perianal region at night to lay eggs
204
Q

Describe transmission of pinworms

A

Highly contagious
Transmitted via perianal/vaginal itch
- Contaminates fingers and sheets
Frequent reinfection

205
Q

What is the life cycle of Ascaris lumbricoides?

A
  1. Adult roundworms mature and live in lumen of small intestine
  2. Eggs passed into faeces
    - Diagnostic stage
  3. Unfertilised eggs can be ingested but not infective. Fertile eggs mature in soil and become infective
  4. Infective eggs swallowed
    - Infective stage
  5. Larvae hatch
  6. Invade intestinal mucosa > portal system > systemic system > lungs
  7. Mature in lungs > penetrate alveolar walls > ascend bronchial tree > swallowed
206
Q

What illnesses can A lumbricoides cause?

A

Pneumonitis in lungs
Intestinall obstruction
- Pancreatitis
- Cholangitis

207
Q

How is A lumbricoides diagnosed?

A

Presence of eggs in faeces
Imaging of obstructions
Can be ruled out if patient has been away from endemic areas for over 2 years

208
Q

Describe the life cycle of Strongyloides stercoralis

A
  1. Rhabditiform larvae in intestine excreted in stool
    - Diagnostic phase
  2. Development into free-living adult worms
  3. Eggs produced by fertilised female worms
  4. Rhabditiform larvae hatch from embryonated eggs
  5. Rhabditiform larvae develop into infective filariform
  6. Infective filariform larvae penetrate intact skin
    - Infective phase
  7. Filariform larvae enter circulatory system > lungs > penetrate alveolar spaces > carried to trachea and pharynx > swallowed > reach small intestine > adults
  8. Adult female worm in intestine
  9. Eggs deposited in intestinal mucosa > hatch > migrate to lumen
  10. Autoinfection: rhabditiform larvae in large intestine > become filariform larvae > penetrate intestinal mucosa/perianal skin > follow normal infective cycle
209
Q

Describe the life cycle of Schistosoma mansonii

A
  1. Eggs in faeces
    - Diagnostic phase
  2. Eggs hatch > miracidia
  3. Miracidia penetrate snail tissue
  4. Sporocysts in snails
  5. Cercariae released by snail in water and free swimming
    - Infective stage
  6. Penetrate skin
  7. Cercariae lose tails during penetration > schistosomulae
  8. Circulation
  9. Migrate to portal blood in liver > mature into adults
  10. Paired adult worms migrate to mesenteric venules of bowel/rectum > lay eggs > eggs circulate to liver > shed in stools
210
Q

What are the three requirements for schistosomiasis?

A

Fresh water supply
Snails
Human contact

211
Q

Where is schistosomiasis mainly found?

A

Africa

Tropical South America

212
Q

What illnesses may be caused by re-infection with S mansonii?

A 
Eggs deposit in various tissues
Cause local inflammation
- Acute hepatitis
- Local itch
- Pulmonary fibrosis
213
Q

Describe the illness caused by Echinococcus granulosus

A

Zoonotic infection
Humans accidental intermediate hosts as they consume infected animals
Larval cysts = hydatid cysts
Cysts can enlarge and compress tissue > pain
Commonly deposit in
- Liver
- Lungs

214
Q

What are the causes of taeniasis?

A

Taenia saginata

Taenia solium

215
Q

What is taeniasis?

A

Humans intermediate host of cestode parasites
Can cause brain cysts
Tapeworm can be up to 10 m long
Infection in humans by ingesting raw/undercooked infected meat

216
Q

What are the primary tissue types in the liveer?

A 
Hepatocytes
Blood vessels and lymphatics
- Capillaries called sinusoids
Connective tissue
Fibrous connective tissue capsule
Serous external surface
217
Q

Outline the process of liver regeneration

A

Existing hepatocytes able to divide and replace lost tissue after injury/disease
Life span = 150 days
After extensive repair, regenerated liver tissue may not have same lobular structure > more fibrous

218
Q

How is liver tissue organised?

A

Hepatocytes organised into lobules around blood vessels
Surrounded by connective tissue for support
- Amount of collagen not very significant

219
Q

Describe the structure of portal triads

A

Branch of hepatic artery
Branch of hepatic portal vein
Bile duct = canaliculi
Lymph vessel

220
Q

Describe the structure of the lobule central vein

A

All blood going away from liver empties into central vein
Carried into hepatic vein
Sinusoids surround each row of hepatocytes and converge on central vein

221
Q

Outline the features of sinusoids

A

Direct, 2-way communication between hepatocytes and bloodstream
Larger than other capillaries with discontinuous lining
Gaps between endothelium and adjacent hepatocytes = spaces of Disse
Microvilli line surface of hepatocytes in contact with sinusoids
Kupffer cells = macrophages present on inner walls of sinusoids

222
Q

What are the three methods of defining the organisation of hepatocytes?

A

Classic lobule model
Portal lobule model
Acinar lobule model

223
Q

How is the classic lobule model organised?

A

Centre of lobule = central vein
Triads in periphery
Focus on direction of blood flow

224
Q

How is the portal lobule model organised?

A

Central of lobule = portal triad
Central veins in periphery
Focus on direction of bile flow

225
Q

How is the acinar lobule model organised?

A 
Different zones have different oxygenation and metabolic function
Zone 1
- High O2
- High in toxins
- High in nutrients
Zone 3
- Low O2
- Low in toxins
- Low in metabolites
226
Q

Describe the histology of the gall bladder

A 
Simple columnar absorptive epithelium
No
- Goblet cells
- Mucous cells
- Endocrine cells
227
Q

Describe the structure of the exocrine pancreas

A

Basal region of cells has high density of rough ER
Luminal surface has numerous zymogen granules containing inactive digestive enzymes
Pancreatic glands formed from acini

228
Q

Describe the structure of the endocrine pancreas

A

Islets of Langerhans

Rich vascular supply because must secrete hormones into blood

229
Q

What parameters are required for approximating energy expenditure?

A

Weight
Height
Age
Activity factor

230
Q

Describe control of appetite from higher centres

A

Weight controlled in hypothalamus

231
Q

How are weight-controlling centres peripherally modulated?

A

Higher cortical centres
Size of fat stores
Presence of food in gut

232
Q

How is leptin trasported into the brain? What does it do there?

A

By receptor on choroid plexus
Signals size of fat stores
Suppresses appetite

233
Q

What is the role of the brain insulin receptor in the control of body weight?

A

Insulin signals to brain that there’s a lot of fat present > appetite suppressed

234
Q

How is glucose a critical physiological regulator of feeding?

A

Glucose metabolism produces acetyl-CoA > LCFA-CoA > inhibits food intake

235
Q

What are the long term inhibitors of food intake?

A

Leptin

Insulin

236
Q

Describe the progression of dysplasia in intraepithelial neoplasia

A 
Benign neoplasm - orderly
Dysplasia
- Mild
- Moderate
- Severe
Carcinoma
- Invasion = malignant cells breach basement membrane to invade underlying stroma
237
Q

What is the tropism of human papilloma virus (HPV) infections?

A 
Low risk types
- Major cause of genital warts
- Mild squamous dysplasia
High risk types = 16 and 18
- Moderate to severe squamous dysplasia
- Major cause of squamous cell carcinoma
238
Q

How does a HPV infection lead to cervical dysplasia?

A

Episomal viral replication
- Latent infection with low level viral replication
- Majority of infections transient with viral clearance
Integration with cellular genome in high risk HPV types
- Integration of viral genome into host DNA > E2 gene disruption
- Overexpression of E6 and E7 oncoproteins
- Loss of p53 and Rb function tumour suppressing function
- Loss of p53 apoptosis function
- Continued cell proliferation > high risk for malignancy

239
Q

What is the key histological hallmark of HPV infection?

A

Koilocytosis = white clearing around nuclei

240
Q

Describe the histological progression of HPV infection to squamous cell carcinoma

A

CIN 1 = increase ink variation in size and increase in mitotic activity of basal cells
CIN 2 = increase in thickness of dysplasia
CIN 3 = dysplasia seen full thickness
Squamous cell carcinoma = invasion into basement membrane

241
Q

How do Pap smear screen for squamous dysplasia?

A

Scraping of cervical transformation zone to visualise cells and nuclei
In high-grade squamous intraepithelial lesions - crowding of cells with high amount of chromatin

242
Q

What is the diagnostic criteria for Barrett’s oesophagus?

A

Endoscopic evidence of columnar lining in oesophagus above gastro-oesophageal junction
Histological evidence of intestinal metaplasia (goblet cells) in biopsies from columnar epithelium

243
Q

Describe the pathogenesis of Barrett’s oesophagus

A

Chronic reflux oesophagitis > repetitive mucosal injury by gastric acid > cellular proliferation, re-epithelialisation by columnar epithelium (tries to secrete bicarbonate) > likely exposure to carcinogens > increased risk for oesophageal adenocarcinoma

244
Q

What are the histological criteria for identifying dysplasia?

A 
Surface maturation of glandular mucosa
Architecture of glands
- Crowding
- Change in shape and complexity
- Gland fusion
Cytology of proliferating cells
- Nuclear atypia
- Loss of polarity
Response to inflammation and erosion/ulcers
- Reactive/regenerative changes vs dysplasia
245
Q

What are the histological changes in reflux oesophagitis?

A

Barrett’s, negative for dysplasia > low dysplasia > high grade dysplasia > intramucosal carcinoma > deep invasive adenocarcinoma

246
Q

What are the types of hiatus hernia?

A 
Sliding
- Common
- Sometimes called reflux symptoms
Rolling
- Volvulus - involves twisting
   - May cause strangulation > purple colour
247
Q

What is achalasia?

A

Lower oesophageal sphincter fails to relax > abnormal peristalsis

248
Q

How are bleeding duodenal ulcers managed?

A

Local injection of adrenaline > local vasoconstriction

Cauterisation to aid process of haemostasis

249
Q

What is the most common reason for small bowel operations?

A

Adhesions in small intestine > small bowel obstruction

- Arise from scar tissue from previous surgery

250
Q

What are the types of herniae?

A 
Ventral
- Usually incisional
- Underlying viscera involved
Groin
- Inguinal - especially in men
   - Direct
   - Indirect
- Femoral - more common in women
251
Q

Describe the hepatitis A virus (HAV)

A 
Non enveloped (+) ssRNA
Resistant to stomach acid
Single serotype globally
252
Q

Outline the life cycle of HAV

A

Can replicate in both liver and intestinal epithelial cells
Contaminated water/food > ingestion > replication in intestinal epithelia > blood > replication in liver > secreted in bile > excreted in faeces

253
Q

What causes pathology in a HAV infection, and how long do symptoms last?

A

Immune mediated cytopathology
Viral clearance
Symptoms for 2-3 weeks

254
Q

Describe the serological response to HAV and hepatitis E virus (HEV)

A

IgM rises then falls
Rising IgG titre confirms acute infection
ALT (liver enzyme) also rises with acute infection

255
Q

What are the clinical features of a HAV infection?

A 
Incubation period = 30 days
Symptoms
- Jaundice
- Vomiting
- Pale faeces
- Dark urine
Symptoms last for 2-3 weeks
256
Q

What are the prevention and treatment options for HAV?

A 
Sanitation
Administration of Ig
- Pre-exposure for travellers
- Post-exposure - within 14 days
   - Intimate contacts
   - Within institutions
Supportive rehydration and nutrition
Inactivated vaccine
257
Q

Describe the hepatitis E virus

A

Non-enveloped (+) ssRNA

More fragile than HAV

258
Q

How does the transmission of HAV and HEV differ?

A

Both transmitted via faecal-oral route

HEV has minimal person-person transmission, whilst HAV highly infectious

259
Q

For which groups of people do HEV infections have a higher risk of more severe outcomes?

A

Pregnant women

Increasing age

260
Q

What are the clinical features of a HEV infection?

A 
Jaundice
Malaise
Anorexia
Abdominal pain
Hepatomegaly
Nausea and vomiting
Fever
Pruritis
261
Q

Describe the pathogenesis of HEV

A

Poorly understood
Entry across intestinal mucosa
Secreted in faeces, 2 weeks before and 1 week after symptoms
Detected ins erum for 2 weeks after onset
Affects Kupffer cells and hepatocytes

262
Q

Outline the typical serological course of a HEV infection

A

Incubation period of 40 days on average
Symptoms start to appear when Abs reach significant level
Diagnosis made on ELISA assays for IgM and IGG

263
Q

Compare and contrast HAV and HEV prevention and treatment

A

Sanitation used for prevention of both
Supportive therapy used as treatment for both
In HEV, administration of serum Ig not effective
No vaccine for HEV

264
Q

What are adenomatous polyps?

A

Dysplastic precursor lesions for colorectal carcinoma

265
Q

What are the type of adenomatous polyps?

A 
Tubular adenoma
- Sessile/pedunculated
Villous adenoma
- Often large and sessile
Tubulovillous adenoma
- Mixed featured
266
Q

What are predictors of increased malignant risk of adenomatous polyps?

A

Increassed polyp size
Villous morphology
High grade dysplasia

267
Q

What are the syndromes which increase the risk of early onset colorectal cancer?

A

Lynch syndrome (HNPCC)
Familial adenomatous polyposis (FAP)
MUTYH-associated polyposis

268
Q

Describe FAP

A 
Autosomal dominant syndrome
APC gene mutation
More than 100 adenomatous polyps in large bowel
Most progress to carcinoma by 30
Attenuated variant
- Less than 100 polyps
- Colorectal carcinoma by 55
269
Q

Describe the histology of an adenomatous polyp

A

Abnormal crypt architecture
Dysplasia
- Crowded cells
- Enlarged, hyperchromatic, pseudostratified nuclei
- Abnormal complexity to glandular architecture
- Fusion of glands in high grade dysplasia
- Goblet cell depletion
- Increased mitotic count
No invasion beyond muscularis mucosae
- No lymphatics in lamina propria > lymphatic spread not possilbe
- Complete excision = curative

270
Q

What are the genetic pathways involved in colorectal cancer?

A

Chromosomal instability; eg: FAP
Microsatellite instability; eg: Lynch sydrnome
CpG island methylator phenotype

271
Q

What are the common genetic changes that occur in the dysplasia-carcinoma sequence?

A 
Loss of APC function > decreased cell adhesion and increase cellular proliferation
Chromosomal instability
Accumulated mutations
- Proto-oncogenes; eg: K-Ras
- Activation of telomerase
272
Q

What is Lynch syndrome?

A

Hereditary non-polyposis colorectal cancer

Most common familial colorectal cancer syndrome

273
Q

What are the histological features of a sessile serrated adenoma?

A

Typically arise in proximal colon
Saw-tooth architecture
More complex branching than in hyperplastic polyp
Dilatation at base of crypts
Elongated, vesicular nuclei, prominent nucleoli
Increased atypia with dysplasia

274
Q

Outline the staging of colorectal cancers

A

Depth of tumour invasion
- Tis (in situ) = carcinoma in situ = adenomatous polyp
- T1/stage 1/Dukes A = invades beyond musularis mucosae
- T2 = invades into muscularis propria
- T3/stage 2/Dukes B = invades beyond muscularis propria into subserosa/pericolic/perirectal fat
- T4 = invades other organs/structures/perforates visceral peritoneum
Lymph node metastases
- N0 = no lymph node metastases
- N1/stage 3/Dukes C = metastases in 1-3 lymph nodes
- N2 = metastases into 4+ lymph nodes
Distant metastases
- Mx = distant metastases can’t be assessed
- M0 = no distant metastases
- M1/stage 4/Dukes D = distant metastases

275
Q

Describe the structure of the hepatitis B virus (HBV)

A

Double-walled structure with outer envelope and inner capsid = fullin infectious
- Incomplete dsDNA
- Viral DNA polymerase
- RNA primer
Incomplete particles containing only envelope proteins = non-infectious

276
Q

Outline the process of HBV replication

A

HBV enters hepatocyte > dsDNA moves into nucleis > repairs gap in incomplete dsDNA > cccDNA transcribed to pre-genome RNA > pre-genomic RNA released into cytoplasm > combines with encoded polymerase > reverse transcription using encoded polymerase > core particle with viral DNA > core particle re-enters nucleus for further amplification of cccDNA/goes to ER to be coated with HbsAg > released as infectious virus

277
Q

Outline the life cycle of HBV

A

Sex, close contact > penetration of mucosal epithelia > blood > replication in liver > blood, semen, secretions

  • Sex, close contact
  • Injection
278
Q

What is the main mode of HBV transmission in endemic countries?

A

Perinatal transmission

Mothers who’re HBeAg psotive much more likely to transmit virus to their offspring then those who aren’t

279
Q

How does age of HBV infection influence clinical outcome?

A

Infected at younger age > less clinical illness but higher likelihood of chronic infection
Infected at older age > increased likelihood of clinical illness but less chance of chronic infection

280
Q

What is a chronic infection with HBV marked by?

A

Persistent high levels of HBsAg and lack of anti-HBs

281
Q

Outline the progression of liver disease

A

Normal > infection > acute/chronic hepatitis B > cirrhosis > hepatocellular carcinoma

282
Q

What is the most common cause of liver cancer?

A

HBV infection

283
Q

What are the serological tests used for diagnosis of hepatitis B infection?

A

HBsAg = general marker of infection
Anti-HBs IgG = recovery and/or immunity to HBV infection, and successful vaccination
Anti-HBc IgM = marker of acute infection
Anti-HBc IgG = marker of past/chronic infection
HBeAg = active replication of virus
Anti-HBe IgG = virus no longer replicating
- May still be positive for HBsAg
HBV-DNA = active replication of virus
- More accurate than HBeAg

284
Q

What are the current HBV antiviral drugs?

A

IFN-alpha
Nucleoside analogues
Nucleotide analogues
New generation drugs targetting cellular receptor NCTP

285
Q

Describe the HBV vaccine

A

Surface protein made from yeast with Alum adjuvant
2-3 doses protects from HBV and HDV
Also can be used for post-exposure vaccination of healthcare workers

286
Q

Describe the structure of the hepatitis D virus (HDV)

A

Depends on coating with HBsAg to be taken into hepatocu=ytes

ssRNA

287
Q

What are the clinical features of HDV?

A

Only infects in conjunction with HBV

  • Co-infection with HBV
    • Severe acute disease
    • Low risk of chronic infection
  • Super-infection of HDV in HBV-positive patients
    • Usually develops chronic HDV infection
    • High risk of severe chronic liver disease
288
Q

What is the association between hepatitis C virus (HCV) infection and intravenous drug use?

A

80% of infectious occur through injecting drug use

289
Q

Why is there no vaccine for HCV?

A

HCV instigates poor immunity and carriers can be superinfected readily with a different strain of HCV

290
Q

Describe the structure of HCV

A

(+) ssRNA
Linear
Enveloped
High mutation rate > international genotype diversity

291
Q

Outline the replication of HCV

A

Associates with lipid receptors and envelope protein receptors > enters via endosome > uncoated, releases RNA into hepatocyte > goes to ER for translation to various viral proteins > production of (-) ssRNA > RNA-dependent RNA polymerase makes (+) ssRNA > translation of new proteins and new viral particles which assemble in membranous web > exocytosis of virus/cell-to-cell transmission to spread virus to other hepatocytes

292
Q

How does HSV evade the immune system?

A

Viral enzymes highly error prone > high levels of mutation

293
Q

What are the sequalae of HCV?

A

70-90% become chronic carriers
Liver fibrosis
Cirrhosis > liver failure
Primary hepatocellular carcinoma

294
Q

What are the treatments for HCV?

A 
IFN-alpha and ribavirin
- Not effective for all
- Significant side-effects
IL-28 gene associated with HCV recovery
New treatments target non-structural proteases
- Viral entry inhibitors
- HCV RNA translation inhibitors
- Post-translational processing inhibitors
- HCV replication inhibitors
- Viral assembly and release inhibitors
295
Q

How does constipation result from use of laxatives?

A

Laxatives empty out a large proportion of bowel

Takes time for faeces to fill descending colon and rectum > patient experiences constipation

296
Q

How do bulking agents work?

A

Hydrophilic colloids containing indigestible vegetable fibre > greater faecal water retention > greater vvolume of intestinal contents > increased normal reflex bowel activity

297
Q

What are common bulking agents?

A

Bran

Psyllium

298
Q

What should bulking agents be taken with?

A

Water

299
Q

How do faecal softeners work?

A

Act as detergents to enhance mixture of water into faeces

300
Q

What are the main groups of osmotic laxatives?

A 
Saline laxatives
Disaccharide hydrophilic colloid
Polyols
Macrogols/polyethylene glycols
Others - usually in suppository form
301
Q

What is the drug class of magnesium sulphate (Epsom salks)?

A

Saline laxatives

302
Q

What is the drug class of lactulose?

A

Disaccharide hydrophilic colloid

303
Q

What is the drug class of sorbitol?

A

Polyols

304
Q

What is the proposed mechanism of action of stimulant laxatives?

A

May

  • Stimulate colonic myenteric nerve plexuses
  • Irritate intestinal mucosa
  • Direct sensory nerve ending irritation
305
Q

What is the most common group of laxatives?

A

Stimulant laxatives

306
Q

What is the drug class of bisacodyl?

A

Stimulant laxatives

307
Q

What is the drug class of senna?

A

Stimulant laxatives

308
Q

What are the common anti-diarrhoeal drugs?

A

Opioids
Musculotropic antispasmodics
Muscarinic receptor antagonists

309
Q

What is the advantage of using loperamide over other opioids?

A

Doesn’t cross BBB > doesn’t produce CNS effects caused by other opioids

310
Q

What is the drug class of mebeverine?

A

Musculotropic antispasmodic

311
Q

What is the drug class of hyoscine hydrobromide?

A

Muscarinic receptor antagonist

312
Q

What is simethicone used for?

A

Flatulence - defoaming polymer > removes gas by changing surface tension of air bubble in GIT

313
Q

What are the three patterns of acute hepatitis?

A

Lobular disarray and apoptosis
Zonal coagulative necrosis
Acute hepatitis with Mallory bodies

314
Q

What can cause lobular disarray and apoptosis in the liver?

A

Acute HAV and HBV

315
Q

Describe the lobular disarray and apoptosis pattern of acute hepatitis

A

Inflammation of entire lobule and portal tracts

Presence of apoptotic hepatocytes = Councilman bodies

316
Q

Describe the zonal coagulative necrosis pattern of acute hepatitis

A

Intrinsic liver toxin causes hepatocellular injury in predictable and dose-dependent way
Liver injury caused by toxic metabolite (NAPQI) which directly injures hepatocytes and causes depletion of glutathione
Coagulative necrosis most commonly seen in zone 3
No inflammatory response in acute phase > macrophages present later

317
Q

What can cause zonal coagulative necrosis in the liver?

A

Paracetamol toxicity

318
Q

Describe acute hepatitis with Mallory bodies

A 
Presents with
- Fever
- Jaundice
- Right upper quadrant tenderness
Presence of fat vacuoles
Presence of neutrophils
Mallory bodies result from massive collapse of hepatocyte cytoskeleton containing keratin
- Form C shaped structures around hepatocyte nucleus
Extreme hepatocellular swelling
Scarring around portal vein
319
Q

What can cause acute hepatitis with Mallory bodies?

A

Alcohol - also called alcoholic hepatitis

320
Q

How is cholestasis identified histologically?

A

Plugs of yellow bile located in dilated biliary canaliculi

321
Q

How is chronic hepatitis defined?

A

Persistence of liver injury with raised serum aminotransferase for >6 months
Not all patients with chronic elevation of liver enzymes have chronic hepatitis

322
Q

What are the main causes of chronic hepatitis?

A

Chronic HBV and HCV infectionss most common
Autoimmune hepatitis
Drug-induced hepatitis

323
Q

How is chronic hepatitis diagnosed histologically?

A

Portal tract densely infiltrated by lymphocytes
Lymphocytes spilling across edge of portal tract into periportal tissue, disturbing interface between portal tract and hepatocellular parenchyma
- Interface not well defined due to spillage
- Degree of interface hepatitis = grade of interface hepatitis - determinant of rate at which fibrosis develops
Apoptotic bodies should be seen in interface and associated with lymphoplasmacytic inflammation
- Apoptosis hallmark feature of acute and chronic hepatitss
Fibrosis in septa
- Radiate in stellate fashion outwards from portal tract
- Stage of chronic hepatitis describes degree of fibrosis and how far liver is on way to cirrhosis

324
Q

Describe the stages of chronic hepatitis

A

Stage 1 = enlarged portal tracts with no septa
Stage 2 = septa but not much linking between portal tracts
Stage 3 = portal-to-portal bridging
Stage 4 = cirrhosis

325
Q

What is non-alcoholic fatty liver disease (NAFLD)?

A

Different categories
Steatosis = accumulation of abnormal amounts of lipid in hepatocytes
- Macrovesicular/large droplet steatosis
- Usually caused by increased triglyceride synthesis/decreased excretion
- Microvesicular/small droplet - very rare
Steatohepatitis and fibrosis (NASH)
- Steatosis = background on which steatohepatitis develops
- Macrovasicular steatosis accompanied by inflammation and hepatocyte injury
- Hallmark = ballooning degeneration
- NASH and alcoholic steatohepatitis can only be distinguished from each other clinically

326
Q

What is the pathogenesis of non-alcoholic steatohepatitis (NASH)?

A

Steatosis = protective mechanism against factors causing excess fatty acid synthesis and levels in circulation
Excess fat stored in liver as lipid droplets
When storage pathway overladed, hepatocellular free fatty acids may be diverted into toxic metabolic pathway > lipotoxic metabolites
Metabolites trigger inflammatory response

327
Q

Whatt substances are exported out of the liver by the bile?

A 
Bilirubin
Cholesterol in lipoproteins
Drugs
Heavy metal ions, especially Cu
IgA Abs
328
Q

How do bile acids act as detergents?

A

Amphipathic > form micelles
Fats aand lipids captured inside micelles
Outer surface of micelles hydrophilic > washed away with water

329
Q

How does cholesterol contribute to gall stones?

A

Bile salts at limit of their ability to keep cholesterrol in micelles
If excess cholesterol, won’t be able to be taken up into micelles > precipitates to form gall stones

330
Q

What are the functions of colipase?

A

Binds to lipase to activate it

Prevents bile acid inhibition of pancreatic lipase

331
Q

What is the enterohepatic circulation?

A

Bile salts in gall bladder > released into duodenum > actively transported out of ileum > enter portal circulation > enters liver > actively transported into gall bladder

332
Q

How does the pancreas protect itself from digestion if trypsinogen is accidentally cleaved to trypsin?

A

Pancreas also makes trypsin inhibitor > binds to any traces of active trypsin present before secreted into intestine
Overwhelmed in case of pancreatitis, causing inflammation and pain

333
Q

What are the two groups of reasons that complicate drug use?

A

Unusual drug behaviour
- Drugs with small therapeutic index
- Need constant monitoring of plasma concentration and therapeutic effect
- Low bioavailability
- Slow distribution
- Peak of curve with slow distribution higher than what would be expected using its volume of distribution
- Drug high enough to saturate elimination process
Inter-patient variability

334
Q

Why must the loading dose f digoxin be divided?

A

Has narrow therapeutic index
Also has long half-life so needed loading dose
If loading dose administered all at once, would produce toxic peak concentration

335
Q

What is the effect of multiple dosing of zero-order elimination drug?

A

Steady state reached due to other elimination mechanisms
Steady state never expected to be reached in theory
Increasing dose rate > disproportionate increase in concentration as same amount eliminated per unit time, not same proportion

336
Q

What are the effects of age on pharmacokinetics?

A

Renal excretion and hepatic metabolism reduced in neonates and elderly
Metabolism reduced in babies because they’re deficient in some drug metabolising enzymes - particularly phase II glucuronate conjugation enzymes
Metabolism reduced in elderly because reduced activity of cytochrome P450

337
Q

What are the genetic factors affecting pharmacokinetics?

A

Polymorphism of metabolising enzymes > fast and slow metabolisers

338
Q

What are the two categories of drug-drug interactions

A

Pharmacodynamic: drug A modifies effect of drug B without affecting its concentration
- Receptor antagonists
- Physiological effects
- May be beneficial
Pharmacokinetic: drug A modifies concentration of drug B at its receptor
- A = drugs affecting gastric emptying rate
- D = drugs displace other drugs from plasma protein binding sites
- M = drugs can induce metabolism of other drugs via induction/inhibition of cytochrome P450
- E = drug alters protein binding/tubular secretion/urine flow/pH

339
Q

Where are the hepatocyte enzymes located?

A 
Membrane
- ALP
- GGT
Cytoplasmic
- ALT
- AST
- LD
Organelle
- Mitochondrial ASL
- Lysosomal SOD
Nucleus
- DNA synthase
340
Q

Describe the mechanism of cell death

A

Disruption of cytoskeleton > disordered molecular transport and disrupted membrane integrity
Mild cell damage > hydropic cell swelling > bleb formation
Severe damage > lysis of cells

341
Q

What are the factors affecting enzyme activity in plasma?

A

Liver enzymes usually released into plasma by blebbing apoptotic cells
- Being turned over physiologially
Enzymes usually cleared by macrophages and Kupffer cells

342
Q

What causes the release of liver enzymes?

A 
Liver necrosis
- Viruses, toxins, anoxia
- Elevations in ALT, AST, LD
- Especially AST with toxins
Biliary disease
- Gall stones, cancer
- ALP, GGT
Inducing drugs
- No cell damage - increased production of GGT and ALP > higher GGT and ALP plasma levels via normal cell turnover
- Alcohol, anticonvulsants
- GGT, ALP
343
Q

Whys is ALT more specific than AST?

A

ALT found in cytoplasm of liver and bone, where it’s involved in Cori cycle
AST found in mitochondria and cytoplasm of any cell that has mitochondria

344
Q

What is the consequence of AST levels being higher than ALT levels?

A

ALT removed at half rate of AST

Therefore higher AST levels indicate acute hepatocellular damage/damage affecting mitochondria

345
Q

What is the consequence of ALT levels being higher than AST levels?

A

Indicates chronic/resolving infection

346
Q

What are the common drugs causing hepatitis?

A 
Flucloxacillin
Amoxicilllin
Statins
Ethanols
Paracetamol
347
Q

Why does mild hepatitis A infection not cause right upper quadrant tenderness and pain?

A

ALT levels are around 250 - need to be >500 for symptoms like tenderness and pain
Only produce vague symptoms like
- Nausea
- Loss of appetite

348
Q

Describe the normal action of GGT

A

Predominantly found in liver and biliary epithelium
Low levels in kidneys
Needed in production of glutathione

349
Q

Describe the normal action of ALP

A 
Adds phosphate groups, involved in transport
Found in
- Bone
- Liver
- Placenta
350
Q

Describe the difference between extra-hepatic and intra-hepatic biliary obstructions

A

Extra-hepatic
- Entire biliary tree obstructed
- Jaundice
- Significant increases in GGT and ALP
Intra-hepatic
- Biliary obstructions only lead to mild obstructions to bile flow, not complete block
- Can be caused by liver enzyme-inducing drugs

351
Q

What is the most common cause of liver enzyme elevation?

A

Obesity
Affects ALT more than AST
Caused by sugar

352
Q

What is included in a liver function test?

A 
Bilirubin
Albumin
PT/INR
Vitamin K
Liver enzymes marker of cell damage and not directly marker of liver function

MD1 Revision (9 decks)

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