GI tract Flashcards
1
Q
Congenital abnormalities of the GIT include…
oesophagus, hernias, ectopia, small bowel
A
Atresia, commonly near tracheal bifurcation, sometimes with fistula to bronchi. Stenosis can also occur.
Diaphragmatic hernia, omphalocele and gastroschisis.
Ectopic gastric tissue most commonly occurs in the oesophagus. Ectopic pancreatic tissue occurs more rarely.
Pyloric stenosis.
Meckel’s diverticulum.
2
Q
The rule of 2s for Meckel’s diverticulum.
A
2% of population, within 2 ft of ileocaecal valve, 2” long, twice as common in males, and if symptomatic, are symptomatic by age 2. Only 4% (2 squared) are ever symptomatic.
3
Q
Cause of Meckel’s diverticulum
A
Failed involution of the vitelline duct.
4
Q
Varieties of Meckel’s diverticulum
A
Normal, or with ectopic pancreatic or gastric tissue, the latter of which can cause ulceration.
All forms are a true diverticulum, involving all 3 layers of the bowel wall.
5
Q
Frequency of congenital hypertrophic pyloric stenosis.
A
1 in 300-900 live births. 3-5 times more common in males.
6
Q
Factors associated with increased risk of pyloric stenosis at birth
A
Erythromycin exposure in first two weeks of life
Turner’s syndrome, trisomy 18.
7
Q
Presentation of congenital hypertrophic pyloric stenosis
A
3-6 weeks, projectile non-bilious vomiting and demands for refeeding.
8
Q
Congenital hypertrophic pyloric stenosis on examination
A
Firm ovoid 1-2 cm abdo mass.
9
Q
What can increase narrowing of congenital hypertrophic pyloric stenosis?
A
Edema and inflammatory changes.
10
Q
What causes acquired pyloric stenosis?
A
Antral gastritis, peptic ulcers in pyloric region, carcinoma of stomach or pancreas.
11
Q
Epidemiology of Hirschsprung disease.
A
1/5000 live births, 10% occur in Down’s syndrome and 5% with other neurological deficits.
12
Q
What is Hirschsprung disease?
A
Problem with neural crest migration from caecum to rectum, or with death of ganglion cells; distal intestinal segment has aganglionosis.
Lacks peristalsis; functional obstruction occurs; congenital aganglionic megacolon.
13
Q
Mechanism causing loss of neural crest migration in Hirschsprung disease.
A
Not fully understood. Most familial cases involve receptor tyrosine kinase RET. Penetrance is incomplete, and other genes are also thought to contribute.
14
Q
Clinical features of Hirschsprung disease.
A
Failure to pass meconium.
Obstruction and constipation; occasional passage of stool may occur if only a few cm are involved.
15
Q
Threats to life of Hirschsprung disease.
A
Enterocolites
Fluid and electrolyte imbalances
Perforation
Peritonitis.
16
Q
Causes of acquired megacolon disease
A
Chagas’ disease, obstruction due to neoplasm or inflammatory stricture, UC causing toxic megacolon, visceral myopathy or functional psychosomatic disorders.
17
Q
What are the three forms of oesophageal dysmotility?
A
Nutcracker oesophagus, diffuse oesophageal spasm, lower oesophageal sphincter dysfunction.
18
Q
What is nutcracker oesophagus?
A
High amplitude contractions of the distal oesophagus due to loss of normal coordination between muscle layers.
19
Q
Main effect of oesophageal dysmotility.
A
Formation of small diverticulae.
20
Q
What types of oesophageal obstruction are there?
A
Functional and mechanical
21
Q
Common causes of mechanical oesophageal dysfunction.
A
Strictures or cancer.
22
Q
How does mechanical oesophageal obstruction classically present?
A
With progressive dysphagia, starting with solids and moving to liquids.
23
Q
Common cause of benign oesophageal stenosis
A
GORD, irradiation or caustic injury.
24
Q
What is the triad associated characterising achalasia?
A
Incomplete lower oesophageal sphincter (LES) relaxation,
increased LES tone and aperistalsis of the oesophagus.
25
Symptoms of achalasia.
Dysphagia, difficulty belching, chest pain.
26
Cause of primary achalasia.
Distal oesophageal inhibitory neuronal degeneration (increases tone).
27
Secondary causes of achalasia (1 true, 5 achalasia-like)
Chagas disease (trypanosoma cruzi infection).
Achalasia-like disease can occur in
DM autonomic neuropathy,
infiltrative diseases (malig., amyloidosis,etc),
lesions of dorsal nuclei (polio, surgery),
with Down syndrome,
in Allgrove syndrome.
28
Treatments for achalasia
Laparoscopic myotomy, pneumatic balloon dilatation, botox.
29
Types of oesophageal laceration.
Mallory-Weiss tears, Boerhaave syndrome
30
Which type of oesophageal tear is transmural, and involve rupture of the distal oesophagus?
Boerhaave syndrome.
31
Inflammation of the oesophagus can be caused by what?
Alcohol, corrosive acids or alkalis, very hot fluids, heavy smoking. Some pills.
32
Symptoms of oesophagitis.
Odynophagia, haemorrhage, stricture or perforation.
33
How do you confirm a diagnosis of Hirschsprungs disease?
Using intraoperative frozen section analysis of presence of ganglion cells at the anastomotic margin.
34
Iatrogenic causes of oesophagitis.
Cytotoxic chemotherapy, radiation therapy, graft vs host disease.
35
Causes of oesophageal infections.
Usually in immunosuppressed. HSV (most common), CMV or candidiasis.
36
Morphology of oesophagitis.
Dense neutrophilic infiltrate, or necrosis.
37
Morphology of eosophageal irradiation.
Intimal proliferation and luminal narrowing of blood vessels.
38
Advanced candidiasis morphology
Adherent grey-white pseudomembrane across oesophageal mucosa.
39
Morphology of HSV oesophagitis.
Punched out ulcers.
40
Morphology of graft-vs-host disease in oesophagus.
Basal epithelial cell apoptosis, mucosal atrophy and submucosal fibrosis without acut inflammatory infiltrates.
41
Most frequent cause of oesophagitis.
GORD
42
Cause of GORD.
Transient lower oesophageal spincter relaxation, mediated via vagal pathways.
43
Triggers of LES relaxation causing GORD.
Gastric distension, moild pharyngeal stimulation, abrupt increase in intra-abdominal pressure.
44
Conditions that contribute to GORD.
Alcohol and tobacco use, obesity, CNS depressants, pregnancy, and hiatus hernia.
45
Morphology of GORD
Simple hyperaemia. In more significant disease there may be eosinophilia and basal zone hyperplasia.
46
What is eosinophilic oesophagitis?
A condition like GORD in children, but with food impaction and dysphagia in adults, which can occur in atopic individuals.
47
What proportion of patients with cirrhosis get varices? And variceal bleeding?
Half have varices, and about a quarter get variceal bleeding.
48
What is Barrett's oesphagus?
A complication of chronic GORD characterised by intestinal metaplasia within the eosophageal squamous mucosa.
49
How often is Barrett's oesophagus thought to occur in patients with symptomatic GORD?
10%. Presents most commonly in white males between 40 and 60.
50
What is the greatest concern in Barrett's oesophagus?
An increased risk of oesophageal carcinoma. It shares mutations with this, and is considered a precursor lesion to cancer. Most people with Barrett's oesophagus do not develop oesophageal adenocarcinoma, however.
51
Morphology of Barrett oesophagus.
Tongues of velvety red metaplastic mucosa extend up from the gastroesophageal junction. Long segment is greater than 3 cm.
52
Morphology in diagnosis of Barrett oesophagus.
Can only be identified by endoscopy and biopsy. Endoscopic evidence of metaplastic columnar mucosa above gastro-oesophageal junction. Intestinal-type metaplasia is seen as replacem ent of the squamous eosophageal epithelium with goblet cells.
53
What are the 2 main types of eosophageal cancers?
Adenocarcinoma (esp in west) and squamous cell carcinoma (more common worldwide).
54
Risk factors for oesophageal adenocarcinoma.
Barrett oesophagus. Tobacco. Radiation.
| Negative risk factors include diet high in veg and fruit, and some types of H. pylori (due to gastric atrophy).
55
Mutations in oesophageal adenocarcinoma.
Early stages: TP53, down regulation of CDKN2A (p16/INK4a).
| Late stages: amplification of EGFR, ERBB2, MET, cyclins D and E.
56
Morphology of eosophageal adenocarcinoma.
Distal 1/3 of oesophagus. Initially flat, may form large masses of 5cm diameter, or ulcerate and invade deeply. Often produce mucin and form glands.
57
Key risk factors for eosophageal squamous cell carcinomas.
Alcohol and tobacco. Nutritional deficiencies. Mutagenic compounds in food.
58
Molecular pathogenesis of squamous cell oesophageal carcinoma.
Amplification of SOX2. Overexpression of cyclin D1. LOF of TP53, E-cadherin and NOTCH1.
59
Morphology of squamous cell carcinoma.
Half occur in middle 1/3 of the oesophagus, starting with squamous dysplasia. Can be ulcerative or diffusely infiltrative.
60
Which lymph nodes do squamous cell oesophageal carcinomas invade to?
In upper third, cervical lymph nodes. In middle third, mediastinal, paratracheal and tracheobronchial lymph nodes. In lower third, gastric and coeliac lymph nodes.
61
Parts of the stomach
Cardia, fundus, body and antrum
62
What is the difference between gastropathy and gastritis?
Both are mucosal inflammatory processes, but in gastritis neutrophils are present, and in gastropathy they are rare or absent entirely.
63
Key agents causing gastropathy
NSAIDs, alcohol, bile and stress induced injury.
Acute mucosal erosion or haemorrhage.
Hypertrophic gastropathies.
64
Normal damaging factors to the gastric mucosa.
Gastric acidity, peptic enzymes.
65
Damaging factors causing injury to gastric mucosa.
H. pylori infection, NSAIDs, Tobacco, alcohol, gastric hyperacidity, duodenal-gastric reflux.
66
Normal protective factors to the gastric mucosa.
```
Surface mucus secretion, bicarbonate secretion into mucus,
mucosal blood flow
epithelial barrier function,
epithelial regenerative capacity,
elaboration of the prostaglandins.
```
67
Things damaging normal protective factors to the gastric mucosa.
Ischaemia, shock, NSAIDs.
| Some cancer chemotherapies.
68
How do NSAIDs damage the gastric mucosa?
By preventing prostaglandin synthesis, which stimulates nearly all the defence mechanisms. Although COX-1 plays larger role than COX-2, the latter does have some role.
69
What are the ulcers caused by stress related mucosal injury (physiological stress) called?
In proximal duodenum, associated with sever burns or trauma, they are called Curling ulcers.
Gastric, duodenal and oesophageal ulcers associated with patients with intracranial disease are called Cushing ulcers.
70
What is the risk with Cushing ulcers?
Perforation.
71
What is the pathogenesis of Cushing ulcers?
Systemic hypotension or stress induced splanchnic vasoconstriction cause local ischaemia.
Upregulation of inducible NO synthase and release of vasoconstrictor endothelin 1 also contribute to ischaemia.
72
What is the pathogenesis of Curling ulcers?
Direct stimulation of vagal nuclei, and possibly systemic acidosis.
73
What is a Dieulafoy lesion?
An extra large submucosal artery due to failure to branch properly, which with erosion of the epithelium, can bleed copiously.
74
What is gastric antral vascular ectasia?
Erythematous stripes caused by ectatic mucosal vessels. Usually idiopathic.
75
Endoscopic appearance of gastric antral vascular ectasia.
Longitudinal strips of edematous erythematous mucosa alternating with pale strips of less injured mucosa.
76
What is the most common cause of chronic gastritis?
H. pylori infection.
77
What is the most common cause of diffuse atrophic gastritis?
Autoimmune gastritis.
78
How does H. pylori infection usually present?
Antral gastritis with normal or increased acid production.
79
Which pattern of H. pylori infection is associated with increased risk of gastric adenocarcinoma?
Multifocal atrophic gastritis.
80
Which H. pylori gene is particularly associated with gastric cancer risk?
CagA.
81
Morphology of H. pylori gastritis.
Neutrophils in lamina propria, and some in gastric pits. Superficial lamina propria contains plasma cells. Lymphoid aggregates are common.
82
Site of autoimmune gastritis.
Usually spares the anturm; is associated with hypergastrinaemia.
83
5 characteristics of autoimmune gastritis.
```
Abs to parietal cells and intrinsic.
Reduced serum pepsinogen I conc.
Endocrine cell hyperplasia.
Vit B12 deficiency.
Defective gastric acid secretion.
```
84
What is the inflammatory infiltrate in autoimmune gastritis?
Lymphocytes and macrophages.
85
Principle agents of damage in autoimmune gastritis.
CD4+ T cells directed against parietal cell components including H+,K+ ATPase.
Autoantibodies to parietal cell components and intrinsic factor are present 80% of patients.
86
Morphology of autoimmune gastritis.
Diffuse mucoase damage of oxyntic mucosa within the body and fundus.
87
Associations of autoimmune gastritis with other diseases.
Pernicious anemia, Hashimoto thyroiditis, T1DM, Addison's and other autoimmune diseases.
88
Uncommon forms of gastritis
Eosinophilic gastritis, usually caused by an allergic reaction.
Lymphocytic gastritis usually affects women, and is associated with celiac disease.
Granulomatous gastritis, caused by Crohn disease, sarcoidosis and infections.
89
Complications of chronic gastritis.
PUD
Mucosal atrophy and intestinal metaplasia.
Dysplasia
Gastritis cystica.
90
Peptic ulcer disease associations
H pylori infections, NSAID use, cigarette smoking.
91
Site of gastritis caused by H pylori
Antrum.
92
What is a gastric lesion with a sharply punched out lesion likely to be?
A peptic ulcer
93
What is a gastric lesion with a heaped up margin likely to be?
A cancer.
94
Presenting features of peptic ulcers.
Epigastric burning or aching pain.
| Iron deficiency anaemia, haemorrhage or perforation.
95
What is hypertrophic gastropathy?
A group of uncommon diseases characterised by giant cerebriform enlargement of the rugal folds due to epithelial hyperplasia without inflammation.
96
Name the rare hypertrophic gastropathies.
```
Menetrier disease (associated with TGF-a hypersecretion)
Zollinger-Ellison syndrome (caused by gastrin secreting tumours in small intestine or pancreas)
```
97
Inflammatory and hyperplastic polyps. Cause and treatment
Caused by chronic inflammation; may regress with H pylori eradication. If larger than 1.5 cm, resect.
98
Fundic gland polyps: population affected
Familial adenomatous polyposis sufferers, especially those on PPIs. Does not involve inflammation.
99
Gastric adenomas: people affected.
Almost always on background of chronic gastritis with atrophy and intestinal metaplasia. Increased incidence in people with FAP.
100
Gastric adenocarcinoma: types
Intestinal type (bulky masses) and diffuse type (diffusely thickens wall, composed of signet ring cells)
101
Gastric adenocarcinoma: epidemiology.
Common in Japan, Chile, Costa Rica and Eastern Europe. Associated with poverty. Environmental factors are important. Generally falling in the West, except for those associated with GORD - cancers of the gastric cardia.
102
Key genetic changes in pathogenesis of gastric adenocarcinoma diffuse type.
Loss of E-cadherin.
103
Key genetic changes in pathogenesis of gastric adenocarcinoma intestinal type.
Increased signalling in Wnt pathway including loss of APC adn gain in B-catenins. FAP patients at risk.
104
Morphology of intestinal type gastric adenocarcinomas.
Exophytic mass or ulcerated tumour. Neoplastic cells contain apical mucin vacuoles
105
Morphology of diffuse type of gastric adenocarcinomas.
Composed of discohesive cells with large mucin vacuoles causing signet cell morphology.
Desmoplastic reaction may stiffen gastric wall. If there is a large area of infiltration, may cause linitis plastica.
106
Pathogenesis of MALT lymphoma
Chronic gastritis induces MALT lymphoma; H. pylori eradication usually is followed by durable remission.
107
Morphology of MALT lymphoma
Neoplastic lymphocytes infiltrate gastric glands to create diagnostic lymphoepithelial lesions. Express B cell markers CD19 and CD20.
108
Well differentiated neuroendocrine tumours - common sites
Most common is the intestine, followed by tracheobronchial tree and lungs.
109
Diseases associated with gastric well differentiated neuroendocrine tumours.
Endocrine cell hyperplasia, autoimmune chronic atrophic gastritis, MEN-1 and Zollinger-Ellison syndrome.
110
Gross morphology of well differentiated neuroendocrine tumours (carcinoid tumours)
Intramural or submucosal masses that ccreate small polypoid lesion. May involve mesentary. Yellow or tan in colour and are very firm.
111
Histological morphology of well differentiated neuroendocrine tumours (carcinoid tumours)
Composed of islands, trabeculae, strands, gland or sheets of uniform cells.
Positive for synaptophysin and chromogranin A (endogrine granule markers).
112
Characteristics of carcinoid syndrome associated with ileal carcinoid tumours.
Cutaneous flushing, sweating, bronchospasm, colicky abdo pain, diarrhoea, right sided cardiac valvular fibrosis.
113
Prognosis for foregut carcinoid tumours
Usually cured by resection, esp if associated with atrophic gastritis.
114
Prognosis for midgut carcinoid tumours.
Usually multiple and aggressive. Poor prognostic factors include deep local invasion, large size, necrosis and mitoses.
115
Prognosis for hindgut carcinoid tumours.
Almost always benign.
116
How common are GI stromal tumours?
Very rare, but the most common mesenchymal tumour of the abdomen.
117
Key mutations in GI stromal tumours?
Tyrosine kinase KIT gain of function.
Or
PDGF receptor alpha gain of function.
Mutations of the mitochondiral succinate dehydrogenase complex.
118
Causes of mechanical obstruction of the small intestine.
Hernias, intestinal adhesions, intussusception, volvulus, tumours, infarction, Crohn disease.
119
Most common type of hernia to cause intestinal obstruction.
Inguinal hernias.
120
Pathogenesis of entrapment of intestine in hernia.
Pressure at neck causes impaired venous drainage of entrapped viscus. Stasis and edema in crease bulk of herniated loop, inding to incarceration, strangulation and infarction.
121
Causes of bowel adhesions
Surgery, infection, endometriosis (e.g. causes of peritoneal inflammation).
Rarely, congenital.
122
Complications of adhesions
Internal herniations through the closed loops formed by adhesions, with sequelae including obstruction and strangulation.
123
Order of frequency of bowel likely to form volvulus.
Sigmoid colon, caecum, small bowel, stomach, or rarely, transverse colon.
124
What can you do for an idiopathic intussusception in infants and children?
A contrast enema, which is both diagnostic and therapeutic. Not if there is a mass!
125
What causes a transmural infarction of the intestine?
Acute arterial obstruction - severe atherosclerosis, aortic aneurysm, hypercoag states and etc.
Systemic vasculitides
126
Systemic vasculitides causing intestinal damage.
Polyarteritis nodosa
Henoch-Schonlein purpura
Granulomatosis with polyangiitis.
127
What are the stages of ischaemic injury to the intestine?
Hypoxic injury - limited damage.
| Reperfusion injury - severe damage. Mechanisms unknown, but include leakage of gut bacterial products.
128
Watershed zones in blood supply to the intestines.
```
Splenic flexure (superior and inferior mesenteric)
Rectum (inferior mesenteric, pudendal and iliac)
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129
Gross appearance of mucosal or mural infarction of the bowel.
Patchy infarction, haemorrhagic and possibly ulcerated.
| Bowel wall thickened by edema.
130
Gross appearance of transmural infarction of the bowel
Sharply defined: infarcted bowel is congested and dusky. Later, blood tinged mucus or frank blood in lumen.
Wall becomes edematous.
Coagulative necrosis of muscularis propria in 1-4 days.
Perforation may occure.
131
Microscopic appearance of ischaemic intestine.
Atrophy of surface epithelium.
Hyperproliferative crypts.
Neutrophils present hours after reperfusion.
Chronic may lead to fibrous scarring of lamina propria.
Bacterial superinfection may lead to pseudomembrane formation.
132
Ischaemic disease of the colon. Associations and precipitating factors.
Associations: cardiovascular disease.
| Precipitating factors: therapeutic vasoconstrictors, cocaine, endothelial damage, CMV, E coli.
133
Presentation of acute colonic ischaemia
Sudden onset cramping, left lower abdo pain, desire to defecate, passage of blood.
134
In colonic ischaemia, when should you consider surgical intervention?
Peristaltic sounds diminish, guarding or rebound tenderness develop.
135
What might right sided colonic ischaemia herald?
More severe disease of the superior mesenteric artery; the small intestine may be involved.
136
What can chronic ischaemia of the bowel masquerade as?
Inflammatory bowel disease.
137
How can you differentiate ischaemia of the bowel from radiation enterocolitis?
History of radiation. Presence of 'radiation fibroblasts'.
138
Pathogenesis of angiodysplasia
Mechanical and congenital.
Intermittent occlusion of submucosal veins by normal distension and contraction leads to dilatation and tortuosity of overlying submucosal and mucosal vessels.
139
Why might the caecum be particularly prone to angiodysplasia?
Its large diameter leads to greatest wall tension.
140
Why might angiodysplasia have a developmental aspect?
It is associated with Meckel's diverticulum.
141
Which four phases of nutrient absorption can result in malabsorption if disrupted?
Intraluminal digestion, terminal digestion on the mucosa, transepithelial transport and lymphatic transport.
142
General symptoms of malabsorption
Diarrhoea, flatus, abdominal pain and weight loss.
143
What is dysentery?
Painful, bloody, small volume diarrhoea.
144
What is secretory diarrhoea like?
Isotonic stool which persists during fasting.
145
What is osmotic diarrhoea like?
More concentrated than plasma and abates with fasting.
146
What kind of diarrhoea is caused by lactase deficiency?
Osmotic diarrhoea?
147
What are key features of exudative diarrhoea?
Purulent bloody stools which continue during fasting.
148
What are the GI complications of cystic fibrosis?
Pancreatic intraductal concretions, can begin in utero. Leads to exocrine pancreatic insufficiency.
Occasional intestinal obstruction.
149
What is coeliac disease?
An immune mediated enteropathy triggered by ingestion of gluten-containing foods in genetically predisposed individuals.
150
What part of gluten contains diseases producing components?
Gliadin, the alcohol soluble fraction.
151
How is gliadin involved in the pathogenesis of coeliac disease?
It is resistant to degradation by proteases. Some by induce IL-15, triggering activation of CD8+ lymphocytes have NK cell markers that are receptors for MIC-A, an enterocyte marker for stress.
Gliadin molecules deaminated by tissue transglutaminase interact with APCs to stimulate CD4+ cells.
152
To what degree does the HLA locus determine coeliac disease?
It appears to contribute half the genetic component.
153
Where should you biopsy for suspected coeliac disease?
The second part of the duodenum or the proximal jejunum.
154
What is the histopathology for a coeliac biopsy?
Increased intraepithelial CD8 T cells, crypt hyperplasia and villous atrophy.
155
What causes malabsorption in coeliac disease?
The loss of mucosal and brush border epithelium.
| Increased epithelial turnover may limit differentiation of absorptive enterocytes.
156
How might a coeliac sufferer without GI symptoms present?
Anaemia due to chronic iron and vit malabsorption.
157
Symptoms of paediatric coeliac disease.
6-24 months.
| Irritability, abdo distention, anorexia, chronic diarrhoea, failure to thrive, weight loss and muscle wasting.
158
What dermatological condition is associated with coeliac's disease.
Dermatitis herpetiformis.
159
Sensitive serological tests for coeliac disease.
IgA against tissue transglutaminase.
| Anti-endomysial antibodies can also be present. Absence of HLA-DQ2 and DQ8 are useful for negative predictive value.
160
What malignancies are associated with coeliac disease?
Enteropathy associated T cell lymphoma.
| Small intestinal adenocarcinoma.
161
What are other names for environmental enteropathy?
Tropical sprue or tropical enteropathy.
162
What is autoimmune enteropathy?
An X-linked disorder characterised by severe persistent diarrhoea and autoimmune disease, most often occuring in young children.
163
What does IPEX stand for?
Immune dysregulation, polyendocrinopathy, enteropathy and X-linkage: it is a familial enteropathy caused by a germline mutation in FOXP3
164
What aspects of the immune system are commonly affected in autoimmune enteropathies?
Treg cells.
Abs to enterocytes and goblet cells.
Sometimes increase in intraepithelial lymphocytes.
165
What are the 2 types of lactase deficiency?
Congenital and acquired.
166
Genetic inheritance of congenital lactase deficiency.
Autosomal recessive disorder.
167
Symptoms of congenital lactase deficiency
Explosive diarrhoea with watery, frothy stools and abdo distension on milk ingestion.
168
What causes acquired lactase deficiency?
Downregulation of lactase gene expression following a bacterial or viral infection.
169
Symptoms of acquired lactase deficiency
Abdo fullness, diarrhoea and flatulence.
170
What is abetalipoproteinaemia?
A rare autosomal recessive disease characterised by an inability to secrete triglyceride-rich lipoproteins.
171
What causes abetalipoproteinaemia?
A mutation in MTP.
172
What is the clinical picture of abetalipoproteinaemia?
Presents in infancy with failure to thrive, diarrhoea and steatorrhoea.
Complete absence of all plasma lipoproteins containing apolipoprotein B (not mutated).
Acanthocytic red cells.
173
Vibrio cholerae bacteria
Comma shaped gram -ive.
174
How does cholera toxin have its effect?
B subunit binds GM1 ganglioside. Retrograde transport. Delivery of A subunit by host machinery to cytosol, where it refolds. Interacts with ADP ribosylation factors to activate GsAlpha, stimulating adenylate cyclase. Increase in cAMP opens CFTR, releasing Cl- into lumen.
175
Clinical features of severe cholera.
Abrupt onset of wather diarrhoea and vomiting following incubation period of 1-5 days.
176
What is the most common bacterial enteric pathogen in developed countries?
Campylobacter jejuni.
177
Virulence factors for Campylobacter.
Motility, adherence, toxin production (epithelial damage and cholera toxin like) and invasion (minority; associated with dysentery).
178
Extraintestinal complications of Campylobacter infection
Reactive arthritis in patients with HLA B27.
| Erythema nodosum and Guillain Barre syndrome (molecular mimicry, rare).
179
Morphology of Campylobacter infection.
Comma shaped, flagellated gram negative bacteria.
Mucosal and intraepithelial neutrophil infiltrates.
Crypt architecture preserved.
180
Shigella organism.
Gram -ive unencapsulated non-motile facultative anaerobes of the enterobacteriaceae family.
181
What kind of disease does Shigella infection cause?
Bloody diarrhoea, esp in children.
182
Pathogenesis of Shigella infection.
Resistant to acid. Taken up by M cells. Phagocytosed by macrophages, induce apoptosis, causes inflammation and damages surface epithelium. Allows access to basolateral membranes of colonic epithelial cells. Type III secretion system allows injection of proteins into cytosol.
183
Morphology of Shigella infection
Haemorrhagic and ulcerated mucosa esp in left colon.
184
Clinical course of Shigella infection.
1 week incubation period followed by 1 week diarrhoea, fever and abdo pain. Dysentery occurs in 50% of pts.
Subacute form can mimic UC.
185
Complications of Shigella infection.
Rare: include reactive arthritis, urethritis and conjunctivitis. Hemolyic-uremic syndrome can also follow if Shiga toxin is produced.
186
What can Salmonella infection cause?
Typhoid fever (Salmonella typhi), or salmonellosis (S. enteritidis).
187
Pathogenesis of salmonellosis.
Proteins transferred by type III secretion systems. Activate host RhoGTPases, bacteria grow in endosomes.
Flagellin stimulates inflammatory response via TLR5.
188
Who is likely to be susceptible to salmonella infection?
Those with atrophic gastritis, acid suppressive therapy or genetic defects in Th17.
189
Symptoms of Salmonella infection.
Diarrhoea; ranges from profuse and watery to dysentery. Fever for a couple of days. Antibiotics not recommended.
190
What can S. typhi do that S. enteritidis cannot?
Disseminate viat hte lymphatic and blood vessels.
191
Key morphological features of typhoid fever.
Peyer's patches in terminal ileum enlarge to plateau-like elevations up to 8 cm.
Typhoid nodules form in liver, bone and lymph.
192
Clinical features of typhoid fever.
Anorexia, abdo pain, bloating, nausea, vomitin and bloody diarrhoea.
SHORT BREAK
Bacteraemia and fever with flu-like symptoms. Rose spots.
193
Blood cultures in typhoid fever.
Positive in 90% of patients during febrile phase.
194
Who gets Salmonella osteomyelitis?
Pts with sickle cell disease.
195
Which Yersinia cause GI disease?
Enterocolitica and pseudotuberculosis.
196
Pathogenesis of Yersinia GI disease.
Invade M cells, use adhesins to bind B1 integrins. Iron enhances virulence and systemic dissemination.
197
Where do GI Yersinia infections localise to?
ileum, appendix and right colon.
198
Effect of Yersinia on regional lymph nodes and Peyer patches.
Hyperplasia.
199
Effect of Yersinia on mucosa overlying lymphoid tissue.
Haemorrhage and ulcers. Neutrophil infiltrates.
200
Clinical features of Yersinia GI infection.
Mostly abdo pain, also fever and diarrhoea. Can mimic acute appendicitis.
201
Extraenteric features of Yersinia infection.
Common: pharyngitis, arthralgia and erythema nodosum.
202
What does ETEC cause?
Traveller's diarrhoea
203
What toxins does ETEC use and what are they like?
Labile toxin, like cholera toxin and Stable toxin which activates adenylate cyclase increasing cAMP
204
Where is EPEC a problem?
It is endemic in developing countries.
205
What characterises EPEC?
The ability to cause attaching and effacing lesions encoded by LEE. Proteins include Tir and a type III secretion system.
206
What does EPEC stand for?
Enteropathogenic E. coli.
207
What does EHEC stand for?
Enterohaemorrhagic E coli.
208
What is a common cause of EHEC outbreaks?
Inadequately cooked beef or contaminated milk: cows are a reservoir.
209
What infection is EHEC infection like?
Shigella dysenteriae - it encodes Shiga-like toxins, and also produces bloody diarrhoea and haemolytic uraemic syndrome, though more commonly in the O157:H7 strain.
210
What does EIEC stand for and cause?
Enteroinvasive E. coli, causing acute self limited colitis.
211
What does EAEC stand for?
Enteroaggregative E. coli.
212
What does EAEC cause?
Non-bloody diarrhoea in children and adults.
213
What are other names for pseudomembranous colitis?
Antibiotic associated colitis/diarrhoea.
214
What causes pseudomembranous colitis?
C. difficile after disruption of normal microbiota allows overgrowth.
215
How does C. difficile cause a pseudomembrane in antibiotic associated diarrhoea?
Incompletely understood, probably involving the effects of its toxins with ribosylated small GTPases.
216
What is the histopathology of pseudomembranous colitis?
Surface epithelium denuded, superficial lamina propria has a dense infiltrated of neutrophils.
Crypts distended by mucopurulent exudate.
217
Presentation of pseudomembranous colitis.
In an old person in hospital treated with antibiotics. Causes fever, leukocytosis, abdo pain, cramps, watery pain, diarrhoea and dehydration.
218
Treatment for pseudomembranous colitis.
Usually metronidazole or vancomycine are effective, but there can be resistance.
219
Features of Whipple's disease
Malabsorption, lymphadenopathy and arthritis.
220
Microbe causing Whipple's disease.
A gram positive actinomycete called tropheryma whippelii.
221
How does Tropheryma whippelii cause diarrhoea?
It obstructs lymphatic transport.
222
What is the morphological hallmark of Whipple disease?
Dense accumulation of distended foamy macrophages in the small intestinal lamina propria.
Villous expansion caused by dense macrophage infiltrate.
Bacteria accumulate in mesenteric lymph nodes, synovial membranes of affected joints, cardiac valves and the brain.
223
Presentation of Whipple disease.
Diarrhoea, weight loss and arthralgia in people with occupational exposure to soil or animals.
224
How common is norovirus infection?
It causes half of all gastroenteritis outbreaks worldwide.
225
Symptoms of norovirus infection.
Nausea, vomiting, watery diarrhoea and abdo pain.
226
When is norovirus chronic?
In the immunosuppressed.
227
What does rotavirus cause?
Severe childhood diarrhoea; a common cause of diarrhoeal mortality worldwide.
228
What ages are particularly susceptible to rotavirus?
6-24 months, except in Asia and Africa, where under 6 month infection is common.
229
What causes enterocyte damage in diarrhoea?
NSP4 which induces epithelial cell death.
230
What population does adenovirus cause diarrhoea in?
Children and the immunosuppressed.
231
Names of intestinal parasites.
```
Ascaris
Strongyloides
Necator
Enterobius vermicularis
Trichuris trichiura
Intestinal cestodes
```
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Ascaris
Nematode. Ingested eggs hatch in intestine, migrate via lungs.
233
Strongyloides
Larvae live in soil, penetrate skin, migrate through lungs. Does not need stage outside body; can autoinfect.
234
Necator (hookworm)
Larval penetration of skin. suck blood.
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Enterobius vermicularis
Pinworm. Intraluminal. Eggs cause irritation to perianal area.
236
Trichuris trichiura
Whipworms. Do not penetrate mucosa, but heavy infection can cause bloody diarrhoea and rectal prolapse.
237
Intestinal cestodes
Tapeworms. Can grow very large.
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Giardia lambia
Flagellated protozoa present in contaminated water (resistant to chlorine).
239
Effects of Giardia infection (microscopic)
Decreased expression of brush border enzymes including lactase.
240
Clinical effects of Giardia infection.
Acute or chronic diarrhoea, malabsorption and weight loss.
241
Disease caused by cryptosporidium.
Chronic diarrhoea in AIDS patients, and acute self limited disease in immunologically normal cases.
242
What kills cryptosporidium oocysts?
Not chlorine.
| Freezing (not present in Antarctica).
243
Where is the cryptosporidium parasite in the intestine?
In the endocytic vacuole in enterocytes in the microvilli.
244
Characteristics of IBS
Chronic relapsing abdo pain, bloating and changes to bowel habits.
245
Morphology of IBS
Gross and microscopic evaluation is normal.
246
Pathogenesis of IBS
Poorly defined interplay between psychological stressors, diet, microbiome disruption, abnormal motility and increased enteric responses to GI stimuli.
Possible defective brain-gut axis signalling.
247
Genes that may be linked to IBS
Serotonin reuptake transporters
Cannaboid receptors
TNF related inflammatory mediators.
248
Treatment of diarrhoea-predominant IBS
Opioid and psychoactive anti-cholinergic effects.
249
Criteria for diagnosis of IBS
Abdo pain or discomfort for at least 3 days/month for 3 months, improvement after defecation.
Change in stool frequency.
250
What is IBD?
A chronic condition resulting from inappropriate mucosal immune activation. Comprised of UC and Crohn disease.
251
Where is UC?
Limited to the colon and rectum and extends only into mucosa and submucosa.
252
Where is Crohn disease?
Typically transmural, anywhere in GI tract.
253
Epidemiology of IBD
Usually presents in young adults. Common in caucasians, but on the rise worldwide.
254
Pathogenesis of IBD
Alterations in host interactions with microbiota, altered composition of microbiome, epithelial dysfunction and aberrant mucosal responses.
255
Genetic contribution to IBD
More dominant in Crohn disease. Several involve genes which are involved in the response to mycobacteria. Each gene only has a small effect, but key genes includ NOD2, ATG16L1 and IRGM.
256
Arms of the mucosal immune response involved in IBD
T helper cells in Crohn
Th17 cells - certian polymophisms in IL23 which is involved in their development are protective.
Proinflammatory cytokines.
257
Epithelial defects described in Crohn and UC.
Defects in intestinal tight junction barriers in Crohn. Associated with NOD2 polymorphisms.
Some matrix metalloproteinase polymorphisms are associated with UC, not Crohn.
258
Involvement of the microbiota in IBD
Abs against flagellin common in Crohn disease, not UC.
| Microbial transfer studies induce and reduce IBD in animals, and fecal transplanst may benefit IBD patients.
259
Good model for IBD pathogenesis.
Transepithelial flux of luminal bacterial components activate immune responses. Subsequent release of cytokines leads to increase in tight junction permeability so cycle escalates.
260
Gross morphology of Crohn disease - key features.
Skip lesions. The earlies is the aphthous ulcer, which can progress and spread leading to a cobblestone appearance. Development of fissures through a thickened rubbery intestinal wall. Mesenteric fat extends around the serosal surface.
261
Microscopic morphology of Crohn disease.
Abundant neutrophilia. Crypts filled with neutrophils, distortion of mucosal architecture (crypts not parallel).
Epithelial metaplasia may occure, and paneth cell metaplasia can occur in left colon.
Noncaseating granulomas are a hallmark and cutaneous granulomas form called 'metastatic' Crohn disease.
262
Clinical features of Crohn disease
Intermittent attacks of mild diarrhoea, fever and abdo pain. 20% may present acutely with RLQ, fever and bloody diarrhoea.
263
Gi complications of Crohn disease
Iron def anaemia (colonic)
Serum protein loss and hypoalbuminaemia or malabsorption of vit B12 (small intestine)
Fibrosing strictures may need resection.
Fistulae and perforations common.
264
Extraintestinal manifestations of Crohn disease.
Uveitis, polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum and clubbing.
Colonic adenocarcinoma.
265
Extraintestinal manifestations of UC
Polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin lesions. Primary sclerosis cholangitis.
266
Gross morphology of UC
Always involves rectum, extending proximally.
Extensive broad based ulcers, with abrupt transition between diseased and uninvolved colon. Regenerating mucoas may form pseudopolyps, which fuse to form mucosal bridges.
Mucosal atrophy may occur in chronic disease.
NO mural thickening, strictures or changes to serosal surface.
267
Histological morphology of UC
Inflammatory infiltrates, crypt distortion and abscesses. Inflammation diffuse and limited to mucosa and superficial submucosa. NO granulomas.
268
Clinical features of UC
Attacks of bloody diarrhoea with mucus, lower abdo pain, and cramps relieved by defecation
269
Risk factors for dysplasia following colitis.
Duration of disease
Extent of disease
Nature of inflammatory response.
Cancers include carcinomas and adenomas.
270
What is the precursor to colitis-associated carcinoma?
Dysplastic epithelium.
271
What is high-grade IBD associated dysplasia associated with?
Invasive carcinoma at the same site or elsewhere in colon. Prompts colectomy.
272
Non-IBD causes of chronic colitis
```
Diversion colitis post surgery.
Microscopic colitis (collagenous and lymphocytic)
```
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Key features of diversion colitis
Mucosal erythema and friability.
| Numerous mucosal lymphoid follicles.
274
Key feature of collagenous colitis
Dense subepithelial collagen layer, increased subepithelial lymphocytes
275
Key feature of lymphocytic colitis.
Normal subepithelial collagen layer, increase in intraepithelial lymphocytes, especially T lymphocytes. Strong association with coeliac and autoimmune diseases.
276
What is sigmoid diverticular disease?
Acquired pseudodiverticular outpouching of the colonic mucosa and submucosa.
277
Epidemiology of sigmoid diverticular disease.
Rare in young, very common in over 60s.
278
Pathogenesis of colonic diverticula
Focal discontinuities of the muscle wall are formed where nerves and vasa recta penetrate the inner muscle coat. This is not reinforced by longitudinal muscle as that is gathered into the taeniae coli.
Exaggerated peristaltic contractions (prob due to low fibre) leads to high intraluminal pressure.
279
Morphology of colonic diverticula
Outpouchings 0.5-1.0 cm in diameter. Thin walled, with flattened or atrophic mucosa, compressed submucosa and absent muscularis propria.
280
Proportion of people with diverticular disease who get symptoms
20%
281
Symptoms of diverticular disease.
Intermittent cramping, lower abdo discomfort, constipation, distention or sensation of never being able to empty rectum.
282
Ways to define polyps
Sessile or pedunculated.
| Non-neoplastic (inflammatory, hamartomatous or hyperplastic) or neoplastic.
283
Key point abut colonic hyperplastic polyps
Need to be differentiated from sessile serrated adenomas (malignant potential)
284
Pathogenesis of hyperplastic polyps
Decreased epithelial cell turnover and delayed shedding leads to piling up of goblet cells and absorptive cells.
285
Morphology of hyperplastic polyps
Smooth nodular protrusions of mucosa, composed of goblet and absorptive cells. Commonly found in left colon.
286
Solitary rectal ulcer syndrome triad
Rectal bleeding, mucus discharge and inflammatory lesion of anterior rectal wall.
287
Cause of solitary rectal ulcer syndrome.
Impaired relaxation of anorectal sphincter creates sharp angle of anterior rectal shelf which is recurrently abraded. This causes a polyp to form, which can become entrapped.
288
Causes of hamartomous polyps.
Sporadic, or due to various genetically determined or acquired syndromes. Can be considered as premalignant in many cases.
289
How do juvenile polyps present?
Usually with rectal bleeding.
290
What is Peutz-Jeghers Syndrome?
A rare autosomal dominant syndrome presenting at a median age of 11 with multiple GI hamartomatous pollyps and mucocutaneous hyperpigmentation.
291
Importance of Peutz-Jeghers syndrome.
Associated with marked increased risk of several malignancies, requiring surveillance from birth.
292
Pathogenesis of Peutz-Jeghers syndrome
Germline heterozygous loss of function of the tumour suppressor gene STK11.
293
Adenomas in GI tract - appearance
Intraepithelial neoplasms that range from small often pedunculated polyps to large sessile lesions.
294
What is a colonic adenoma a precursor to?
Colonic adenocarcinoma.
295
What characterises colorectal adenomas?
Epithelial dysplasia; they are precursor lesions, but not all progress.
296
Histological hallmarks of epithelial dysplasia
Nuclear hyperchromasia
| elongation and stratification. Can be seen on adenomas.
297
Classifications of adenomas
Tubular, tubulovillous or villous.
298
Sessile serrated adenomas histology
Overlaps with hyperplastic polyps, but more common in right colon.
Malignant potential, but frequently lack cytological features of dysplasia.
299
Definition of intramucosal carcinoma
When dysplastic epithelial cells invade lamina propria or muscularis mucosa.
300
Prognosis for intramucosal carcinoma.
Little risk of metastasis: polypectomy is usually curative.
301
What is the most important factor that suggests an adenoma may harbor an invasive cancer?
Size.
| Also high grade dysplasia.
302
How many untreated FAP patients get colorectal adeoncarcionoma?
100%
303
What is the standard prophylactic therapy for FAP patients?
Prophylactic colectomy. However, risk from neoplasm at other sites remains.
304
Extraintestinal manifestations of FAP
Congenital hypertrophy of the the retinal pigment epithelium.
305
What is the mutation, other than APC loss, that can give polyposis.
Bi-allelic mutation of the base-excision repair gene MYH. It is autosomal recessive, unlike APC loss.
306
What is the phenotype of MYH associated polyposis?
Similar to attenuated FAP, with fewer polyps (fewer than 100), and delayed onset of colon cancer.
307
What is Lynch syndrome?
Hereditary nonpolyposis colorectal cancer.
308
How common is HNPCC
The most common syndromic form of colon cancer; it accounts for 2-4% of all colorectal cancers.
309
Phenotype of HNPCC
Colon cancers occur in younger patients than sporadic cancers, and are often in the right colon.
310
What are the genes involved in HNPCC
Genes for proteins responsible for detection, excision and repair of errors in DNA replication.
311
Epidemiology of adenocarcinoma of the colon.
1.2 million and 600, 000 associated deaths worldwide; 10% of cancer deaths. More common in Western lifestyles and Japan.
312
Risk factors for adenocarcinoma of the colon.
Dietary factors: low intake of vegetable fibre, high in refined carbs and fat.
313
How low fibre diet causes adenocarcinoma of the colon.
Theory:
Decreased stool bulk + changed microbiota results in potentially toxic oxidative by-products of bacterial metabolism.
High fat increases hepatic synthesis of cholesterol and bile salts, which are converted to carcinogens by bacteria.
314
Pharmacological chemoprevention of colonic adenocarcinoma.
NSAIDS and aspirin may have a protective effect. Also cause polyp regression in FAP patients. Probably mediated by COX2 inhibition which is highly expressed in colorectal carcinomas and promotes epithelial proliferation.
315
Two genetic pathways involved in colorectal carcinogenesis.
APC and B-catenin pathway.
| Microsatelite instability pathway.
316
Earliest mutationin sporadic colon tumours.
80% have mutation of APC gene early.
317
Earliest mutationin sporadic colon tumours.
Typically have mutation of APC gene early. Both copies have to be functionally inactive. If not, usually have B-catenin mutation allowing avoidance of APC function.
318
APC function
Binds to and increases degradation of B-catenin.
319
B-catenin function
Accumulates - translocates to nucleus - binds transcripion factor TCF - activates transcription of MYC and cylin D1 - proliferation.
320
Late genetic events in colonic carcinoma development.
KRAS - promotes growth, prevents apoptosis. Mostly present in large adenomas and carcinomas.
Loss of SMAD2 and 4 which effect TGF-B signalling for inhibition of cell cycle.
TP53 - common in cancers, rare in adenomas.
321
Which genes are commonly affected in people with DNA mismatch repair deficiency?
Mutations occur in microsatellite repeats leading to microsatellite repair instability. Affects TGF-B receptor (inhibition cell cycle) and BAX (apoptosis)
322
Colon cancers that don't show either APC or DNA mismatch repair mutation genotypes
Often have CG island hypermethylation. MLH1 promoter region often hypermethylated if this is with microsatellite instability, and KRAS mutations if no MSI.
323
Gross morphology of tumours in proximal colon.
Tend to be polypoid exophytic masses.
324
Gross morphology of carcinomas of the distal colon
Annular lesions.
325
Microscopic morphology of carcinomas
Tend to be composed of tall columnar cells resembling dysplastic epithelium. Strong stromal response due to invasiveness. Some have glands.
326
Presentation of right sided colon cancers
Fatigue and weakness due to iron deficiency anaemia.
327
Presentation of left sided colon cancers
Change in bowel habit, cramping, left lower quadrant pain and occult bleeding.
328
How is the anal canal divided?
Into thirds - the upper zone is columnar rectal epithelium, the middle third is transitional epithelium and the lower third is stratified columnar epithelium.
329
What are tumours like in the rectal canal?
Upper third; glandular
Lower third; squamous.
Also; basaloid if tumour populated by immature cells derived from the basal layer of transitional epithelium. Hyperchromatic.
330
Association of pure squamous cell carcinoma of the anal canal
HPV.
331
Physiological cause of haemorrhoids
Persistently elevated venous pressure within haemorrhoidal plexus.
332
Predisposing influences on development of haemorrhoids.
Constipation causing straining at defecation, venous stasis at pregnancy, portal hypertension.
333
Presentation of haemorroids
Pain and rectal bleeding in people over 30 ad pregnant women.
334
Where do external haemorroids come form?
The inferior haemorrhoidal plexus below the anorectal line.
335
Where do internal haemorroids come form?
dilation of the superior haemorrhoidal plexus in the distal rectum.
336
Pathogenesis of appendicitis.
Progressive increases in intraluminal pressure compromise venous outflow. Associated with overt luminal obstruction e.g. by stool, gallstone, tumour or mass of worms. Stasis promotes bacterial proliferation, triggers ischaemia and inflammatory responses. Tissue necrosis and neutrophilic infiltration of lumen, muscular wall and periappendiceal soft tissues.
337
Commonest tumour of the appendix
Well-differentiated neuroendocrine tumour.
338
What causes sterile peritonitis?
Leakage of bile or pancreatic enzymes
339
What causes a highly irritating peritonitis with bacterial superinfection.
Perforation or rupture of biliary system.
340
What is the result of acute haemorrhagic pancreatitis?
Peritonitis with fat necrosis, and bacterial spread if there is damage to the bowel wall.
341
Common bacteria in bacterial peritonitis
E. coli, streptococci, S. aureus, enterococci and C. perfringens.
