Gastrointestinal pathology (1) Flashcards
What is the generic histological structure of the GI tract?
The structure of the GI tract is relatively constant throughout. Which of the 5 histological GI layers varies throughout the GI tract?
Mucosa
Hence, describe the mucosal structure in the following:
- Oesophagus
- Stomach
- Small Intestine
- Colon + rectum
- oesophagus: white stratified squamous (a transit tube)
- stomach: red-brown thick glandular (storage + digestion)
- small intestine: glandular w/ villi (nutrient absorption)
- colon + rectum: glandular w/ crypts (water absorption)
What is gastro-oeseophageal reflux?
- there is regurgitation of acidic gastric contents into lower oesophagus
- acid injures the squamous epithelium lining the oesophagus
- results in inflammation (reflux oesophagitis)
What are the risk factors for developing GORD?
- obesity + pregnancy (inc intra-abdo pressure)
- smoking, alcohol, coffee consumption (lowers oesophageal sphincter tone)
- hiatus hernia
What is a hiatus hernia?
- protrusion (or herniation) of the upper part of stomach
- into the thoracic cavity
- thought to be due to combo of diaphragmatic weakening + inc intra-abdo pressure
- the major clinical effect = weakening of lower oesophageal sphincter mechanism
What is the presentation + associated complications of GORD?
- Heartburn (major feature) relieved by antacids
- Regurgitation -> waterbrash
- Belching
- Oeseophagitis
- Stricture (progressive dysphagia)
- Bleeding (haematemesis, melaena)
- Barrett’s oesophagus
- Nocturnal asthma + chronic cough
A complication of GORD is Barrett’s oeseophagus (10%). What is Barrett’s oesophagus?
- when normal oeseophageal squamous epithelium replaced
- by metaplastic columnar mucosa
- form segment of ‘columnar-lined oeseophagus’
- an adaptive response to prolonged injury caused by GORD
- asymptomatic - most cases identified when pts undergo OGD (for GORD/dyspepsia)
What % of those with Barrett’s Oesophagus progress to oeseophageal cancer?
- 0.1-0.4%
What does metaplasia do to the squamous mucosa lining in the oesophagus?
Metaplasia in Barrett’s Oesophagus:
- Normal squamous mucosa replaced with glandular (columnar) mucosa
- Due to reflux of gastric acid (as the insult)
What may the metaplastic columnar epithelium progress to next?
- Dysplasia (occurs in 2% of those with Barrett’s)
- And then into an invasive adenocarcinoma
- This is known as the metaplasia-dysplasia-carcinoma sequence
Why and how is dysplasia identified and managed in patients?
- Bc development of oesophageal adenocarcinoma (malignant) is preceded by a phase of dysplasia (pre-malignant)
- some gastroenterologists perform surveillance endoscopy w/ biopsies at 3-5yr intervals to look for dysplasia
- if dysplasia identified, intervention (eg radiofrequency ablation or endoscopic mucosal resection) is advised
What is characteristic of the adenocarcinoma that the dysplasia doesn’t demonstrate?
Invasion through the basement membrane
Who is oesophageal cancer common in?
- 50-70yr age group
- M > F
How does oesophageal cancer present?
- Progressive dysphagia (of solids first then liquids too)
- Weight loss
- Anorexia
- Lymphadenopathy
What are the key investigations?
- endoscopy
-
biopsy
- type of cancer
- grade
What is the most common type of oesophageal cancer in the UK?
- adenocarcinoma (70% of all new OCa diagnoses)
- marked rise in incidence in western world in last 30ys
- usually arises from Barrett’s mucosa in lower oesophagus
- remember that progression from Barrett’s -> cancer is not inevitable
- in fact, risk of dying from oesophageal adenocarcinoma in a pt with Barrett’s is 2% over 10 years (less than the risk of dying from ischaemic heart disease!)
What is the second most common type of oesophageal cancer in the UK?
- squamous cell carcinoma
- most common type in other parts of world eg. china, japan
- oesophageal squamous cell carcinoma arises from native oesophageal squamous epithelium
- important risk factors for its development = smoking + alcohol
How is oesophageal cancer staged?
- TNM system
- performed using range of techniques
- eg. EUS, chest/abdo CT, laparoscopy
What is discussed at an MDT meeting for oesophageal cancer?
- decide on most appropriate treatment
- curative intent (surgery with/without neoadjuvant therapy)
- palliative intent (eg. dilatation, stenting, radiotherapy etc)
What is the prognosis for oesophageal cancer?
- 5-10% survival at 5 years
- this is mainly bc tumor is usually at high stage on presentation
What is gastritis?
- strictly speaking, refers to inflammation in stomach
- however, in clinical practice it is often used to describe any redness of the gastric mucosa seen at endoscopy
What are 2 important causes of gastritis?
- NSAIDs
- Helicobacter Pylori infection
What is H. Pylori and how does it survive?
- gram negative bacteria that colonises stomach
- spread by oral-oral or faecal-oral transmission
- it lives in the thick mucus layer on mucosal surface
- H. pylori synthesises urease, which catalyses conversion of urea to ammonia. The ammonia neutralises the gastric acid and thus improves survival of the bacteria
Gastric H. Pylori is associated with a range of consequences, such as?
- > 80% of pts have an asymptomatic mild chronic gastritis
- a minority of pts develop symptomatic gastritis
- a minority of pts develop a peptic ulcer
- a small minority of pts develop gastric carcinoma
- a v small minority of pts develop gastric lymphoma
What is a peptic ulcer?
- breach in mucosa of the lower oesophagus, stomach or duodenum, extends through full thickness of mucosa and in addition may extend into the submucosa or deeper layers of wall
- fails to heal over a reasonable period of time
- most comonly located in the gastric antrum or proximal duodenum
What is the commonest cause of gastric and duodenal peptic ulcers?
- H pylori gastritis
- NSAIDs
- also: alcohol, smoking + stress
What is a Curling (stress) ulcer?
- seen in pts with massive trauma, extensive burns, sepsis, raised intracranial pressure or shock
- thought to arise as a consequence of mucosal ischaemia leading to inc susceptibility to acid pepsin injury
What is the commonest cause of oesophageal peptic ulcers?
Gastro-oesophageal reflux
Are peptic ulcers due to cancer?
No, they are a good example of chronic inflammation
How are peptic ulcers a good example of chronic inflammation?
there is simultaneous:
- persistent tissue injury + destruction at surface
- on-going inflammatory response to limit damage
- the main inflammatory cells are macrophages, lymphocytes and plasma cells
- attempts to organise and heal by fibrosis (scarring)
What is the pathogenesis of peptic ulceration?
- mucosal surfaces normally coming into contact w/ gastric acid + pepsin have evolved a # of defence mechanisms
- surface-adherent mucus/bicarb layer, epithelial cell defences + mucosal blood flow
- surface-adherent mucus/bicarb layer, epithelial cell defences + mucosal blood flow
- peptic ulcers can occur by weakening of these defence mechs or by increased acid attack
- surface mucus is significantly disrupted by H pylori
- epithelial cell defences are undermined by the cytotoxic effects of H pylori and NSAIDs
- mucosal blood flow alterations probs more important in acute ulcers occurring in clinical states of shock
What is Zollinger-Ellison syndrome + how does it lead to peptic ulceration?
- tumours from pancreas, stomach or duodenum secrete large amounts of gastrin (gastrinomas)
- cause excess gastric acid secretion
- therefore increased acid attack -> weakened defence system against peptic ulcer
What are complications of peptic ulcers?
- bleeding
- perforation
- stricture formation
- malignant change
How do acute bleeds of peptic ulcers present?
- when an ulcer erodes wall of a large vessel, tend to be large
- presents with melaena or haematemesis
How does chronic bleeding from peptic ulcers present?
- typically multiple smaller bleeds (compared to acute)
- over a long period of time
- may present as anaemia
What is the term used to describe when a peptic ulcer erodes through all the layers of the wall? How does this present?
- perforation
- present as peritonitis
How might stricture formation due to peptic ulcer present?
- due to healing of the ulcer by fibrosis
- may present as obstruction
Is the development of carcinoma a common complication of peptic ulcers?
- No, it’s rare
- in fact, it’s now believed that reports of malignant transformation in peptic ulcers probably represents cases in which a lesion thought to be a chronic peptic ulcer was actually an ulcerated carcinoma from start
- ulcerated gastric carcinomas typically have a rolled edge
What investigation should be done from any suspected peptic ulcer in the oesophagus or stomach to rule out that it isn’t actually an ulcerated cancer?
Biopsy
NB. Dudoenal cancer is v rare and so chance of duodenal cancer masquerading as a peptic ulcer is remote. Hence duodenal ulcers do not need to be biopsied to exclude malignancy unless there are worrying endoscopic features.
Who is gastric cancer common in? Has the incidence changed?
- peak incidence in over 50yr age group
- M > F
- incidence has fallen in west over last 50yrs
- reduction due to falling prevalence of H pylori infection and an improved diet
What are important risk factors for developing gastric cancer?
- H Pylori infection (but remember, most ppl w H Pylori infection will not develop cancer)
- cigarette smoking
- alcohol
- diet: food w/ nitrates/nitrite components; salt-based preservatives
- autoimmune gastritis
How might gastric cancer present?
- history of new-onset dyspepsia (esp in a pt >55y)
- unintended weight loss
- progressive dysphagia
- vomiting
- Virchow’s node palpable (left supraclavicular fossa) - Troiser’s sign
What kind of cancer are gastric cancers?
- adenocarcinomas
- arising from glandular mucosa
What are the 2 main types of gastric adenocarcinoma and how do they differ?
- intestinal-type adenocarcinomas - show gland formation, lined by mucus-secreting cells. Better prognosis than diffuse-type (but still poor 5 year survival). Tend to occur in older individuals.
- diffuse-type adenocarcinomas - consist of ‘signet-ring’ cells, with a diffuse pattern of infiltration. Very aggressive -> v bad prognosis. Tends to occur in a younger age group.
They key investigation for gastric cancer is endoscopy and biopsy. What important info does biopsy give us?
- type of cancer (usually squamous cell carcinoma or adenocarcinoma)
- the grade - well, moderately or poorly differentiated
How is gastric cancer staged?
- TNM system
- performed using a range of techniques
- eg. chest/abdo CT, staging laproscopy
All pts with gastric cancer are discussed at the MDT meeting to decide on most appropriate treatment: curative or palliative. What is the prognosis of gastric cancer?
- very poor prognosis
- around 5% survival at 5 years
- mainly bc tumour is usually at high stage on presentation
How much of the adult Western population develop gallstones?
- 10-15%
- Each year approx 2-4% of ppl with gallstones develop symptoms, in other words most people are asymptomatic
What is the pathogenesis of gall stones?
Normally cholesterol is solubilised in bile as a micelle with bile salts.
An imbalance between the proportions of cholesterol and bile salts lead to precipitation of the excess component as gallstones.
What are the 3 types of gallstones?
- cholesterol stones (20%) - large, yellow
- billirubinate stones (5%) - small, pigmented (dark)
- mixed stones (75%) - Ca salts, bile pigment + cholesterol
What are the risk factors for cholesterol gallstone formation?
- female sex
- obesity
- middle-age
- family history
all are associated w inc levels of cholesterol -> results in imbalance between cholesterol + bile salts and the precipitation of gallstones
What link does Crohn’s disease have to gallstones?
- Crohn’s predisposes to development of gallstones
- Due to malabsorption of bile salts from terminal ileum
- Affected individual becomes depleted in bile salts
- They do not have enough bile to maintain the cholesterol dissolved in bile
- Thus cholesterol stones form
What can cause bilirubinate gallstones?
- Haemolytic anaemias
- Cause inc bilirubin production (bc of XS breakdown of Hb)
- Results in an imbalance between cholesterol + bile salts
- Thus, the bile salts precipitate as gallstone
What investigations can be done for gallstones?
- Ultrasound of gallbladder -> identify 90% of gallstones
- Liver function tests to assess liver fxn
What ducts meet to form the common bile duct?
- Cystic duct from gallbladder
- Common hepatic duct (from R + R hepatic ducts)
- Come together to form common bile duct (outside the liver)
Remember, most patients with gallstones are asymptomatic. How might patients with symptomatic gallstones present?
- Biliary colic or cholecystitis (>90% of symptomatic presentations)
- Jaundice +/- ascending cholangitis
- Acute pancreatitis
- Gallstone ‘ileus’
How does a biliary colic come about and how does this present?
- if a gallstone impacts in + obstructs the cystic duct
- the gallbladder will contract against the acutely obstructed duct
- resulting in symptoms of biliary colic:
- upper abdo/RUQ pain, may radiate to back/tip of scapula, often nausea + vomiting
How does acute cholecystitis develop from a gallstone?
- if the impacted stone occludes cystic duct for a prolonged period of time
- it will rub + damage the mucosal lining
- thereby inciting an acute inflammatory response in gallbladder wall
- there is development of acute cholecystitis
- presence of fever indicates acute cholecystitis (or cholangitis)
What is acute acalculous cholecystitis?
- acute cholecystitis without gallstones
- thought to result from ischaemia
- the cystic artery is an end artery w/ no collateral circulation
- it occurs in pts who are hospitalised for conditions unrelated to gallbladder eg. hypotension + multiorgan failure; major trauma/burns; infections
- clinical symptoms tend to be insidious since they are obscured by underlying condition
- a high % of pts have no symptoms referable to gallbladder; diagnosis therefore rests on a high index of suspicion
- as a result of either delay in dx or disease itself, incidence of gangrene + perforation is much higher in acalculous cholecystitis than cholecystitis due to gallstones
What is chronic cholecystitis?
- repeated episodes of biliary colic + acute cholecystitis
- results in chronic inflammation w/ healing by fibrosis
- as a consequence, gallbladder wall becomes thickened + the gallbladder shrinks in size
How do gallstones cause jaundice?
- if a gallstone impacts + obstructs the common bile duct (choledocholithasis), it will cause obstructive jaundice
- the jaundice develops bc bile is unable to drain into the duodenum for excretion
A serious complication of a gallstone obstructing the common bile duct is the development of ascending cholangitis. What is this?
- inflammation of common bile duct
- the biliary obstruction causes stasis
- predisposes to superimposed infection: gut bacteria (usually gram negative eg. E coli, Klebsiella) gain entry to biliary tree via ampulla of Vater
How does ascending chlangitis typically present clinically?
- Charcot’s triad
- jaundice, fever (usually w rigors) + RUQ pain
What happens if ascending cholangitis is left untreated?
- infection may ascend up to the liver
- causing abscesses
- and/or cause sepsis
- serious condition if left untreated has a high mortality
Gallstones are the commonest cause of acute pancreatitis. How do gallstones cause acute pancreatitis?
- if gallstone passes down common bile duct
- obstructs Ampulla of Vater
- results in pancreatitis
- there is reflux of pancreatic secretions back up the pancreatic duct -> pancreatic autodigestion -> pancreatitis
What is the other major cause of pancreatitis apart from gallstones?
alcohol
What is gallstone ‘ileus’?
- When a large gallstone causes small bowel obstruction
- Stone erodes through gallbladder into duodenum; then obstructs terminal ileum
- Gallstone enters the small bowel via a fistula, which forms between the inflamed wall of GB and a loop of small bowel
Why is gallstone ‘ileus’ a misnomer?
- Ileus is characterised by cessation of normal peristaltic movements of bowel, typically a rxn of the bowel to any form of irritation around it (eg. post-op, peritonitis)
- If a gallstone obstructs the small bowel, the small bowel proximal to the obstruction will attempt to overcome the blocokage by vigorous peristalsis
Hence, the term gallstone ‘ileus’ is incorrect
What is the clinical presentation of gallstone ileus?
Cardinal features of bowel obstruction
- colicky abdo pain
- vomiting
- abdominal distension
- absolute constipation
What does Courvoiser’s Law state and why?
“In a jaundiced patient, the presence of a palpable gallbladder means that the jaundice is unlikely to be due to gallstones impacted in the biliary system”
- bc a pt w/ jaundice due to gallstone in the common bile duct is likely to have a fibrotic shrunken gallbladder bc of repeated episodes of biliary colic + acute cholecystitis - as a consequence, the gallbladder is impalpable
- a patient w/ jaundice due to another cause may have a palpable gallbladder
What is another cause of a palpable gallbladder, unrelated to gallstones?
Often (but not necessarily) cancer of the head of the pancreas
What are the two broad functions of the pancreas?
- Exocrine - secreting digestive enzymes into the pancreatic duct system
- Endocrine - secreting hormones such as insulin and glucagon directly into the blood
What is the most common type of pancreatic cancer?
- Adenocarcinoma
- Arises from glandular duct cells that line ducts of exocrine system
Who is pancreatic adenocarcinoma common in?
- Elderly males
- Very little is known about underlying cause
- Smoking is only well recognised risk factor
Most pancreatic adenocarcinomas involve the head of the pancreas. What do they present with?
-
Obstructive jaundice
- tumour compresses common bile duct as it passes through the head of pancreas so that bile is unable to drain into duodenum
- other features: weight loss, mid-epigastric pain (often radiating to back)
What is the treatment for majority of pancreatic carcinoma patients?
- 80% of pts with pancreatic carcinoma have advanced disease (high stage) at time of dx
- treatment is palliative
- palliative treatment options:
- chemotherapy
- stenting the common bile duct to relieve jaundice
- optimising symptom control
A minority of pancreatic carcinoma patients (20%) are suitable for curative surgery - Why are they suitable? What is the procedure called?
- bc tumour appears to be confined to pancreas and lymph nodes are not involved
- Whipple’s procedure
What happens in a Whipple’s procedure?
The distal stomach, gallbladder, common bile duct, head of pancreas, duodenum, proximal jejunum and regional lymph nodes are resected.
Reconstruction restores intestinal fxn by re-establishing flow of pancreatic juices, bile and food along GI tract.
What is the 5 year survival following a) curative surgery (Whipple’s) and b) overall survival for pancreatic cancer?
A) Whipple’s - 20-40%
B) 5% (incl majority of pts who have advanced disease)
How common is Coeliac disease?
Affects ~ 1% of UK population
What is Coeliac disease?
- intolerance to gluten
- in particular, gliadin, the alcohol-free fraction of gluten, is the disease-producing component
- gluten is found in wheat, barley and rye
What is the brief pathogenesis of coeliac disease?
- not fully understood
- thought that gliadin triggers inappropriate activation
- of intestinal T cells
- in genetically susceptible individuals (ppl w/ HLA-DQ2 and HLA-DQ8 haplotypes)
- resulting in damage to epithelial cells
Now explain in more detail what happens in patients with coeliac when gluten is digested in comparison to a healthy individual?
- gluten digested by luminal and brush-border enzymes in small intestine
- into aino acids + peptides, incl 33AA gliadin peptide
- gliadin is deamidated in mucosa by tissue transglutaminases (tTG)
- in those w/ HLA-DQ2 and HLA-DQ8 haplotypes, deamidated gliadin closely fits the MHC II grooves
- gliadin presented to T helper cells by antigen presenting cells
- initiates a Th2-predominant immune response
- generates cytotoxic T cells against gliadin
- cytotoxic T cells migrate into intestinal epithelium, visible on biopsy as intraepithelial lymphocytes
- the T cells damage + destroy epithelial cells resulting in progressive villous atrophy
- as a result, crypts become hyperplastic to compensate for cell loss
- loss of normal small bowel fxn -> malabsorption
- also a humoral immune response w/ generation of antigliadin, antiendoymysial and antiTTG antibodies - useful antibodies diagnostically
What is the clinical presentation of coeliac disease?
- at any age, most commonly in childhood or middle age
- symptoms of malabsorption (diarrhoea, steatorrhoea, weight loss, lethargy, bloating, abdo pain)
- non-specific symptoms: eg. anaemia (usually iron def), irritable bowel syndrome-like symptoms, altered bowel habit, abdo pain
- in children, coeliac disease is an important cause of failure to thrive and delayed puberty
- an intensely itchy and blistering rash over elbows + buttocks - dermatitis herpetiformis
- some pts are asymptomatic and diagnosis is discovered incidentally
How is coeliac disease diagnosed?
- history and examination
- gluten-containing diet better to be consumed during diagnostic process
- serology tests: total IgA and IgA tissue transglutaminase antibodies are currently the preferred first line test (owing to its high sensitivity and negative predictive value)
- IgA anti-endomysial (EMA) antibodies can be used if IgA tTG is weakly positive
- gold standard ix: endoscopy and duodenal biopsy
What does tissue biopsy for positive coeliac show?
- villous atrophy
- crypt hyperplasia
- prominent intraepithelial lymphocytes
Generally agreed that duodenal biopsy should be performed on all adult patients to confirm the diagnosis
What is the treatment for coeliac?
- Life-long gluten-free diet
- Those with coeliac disease (+ fam members, carers) should be given sources of info on the disease, including a national and local specialist coeliac groups and dietiticans with a specialist knowledge of coeliac disease
What are complications of coeliac disease?
- Malabsorption (-> anaemia + deficiencies)
- Osteopenia/osteoporosis
- Dermatitis herpetiformis
- Lymphoma
Why do patients with coeliac develop osteopenia/osteoporosis? How can this be investigated and treated?
- most pts w/ coeliac disease are osteopenic (reduced bone density)
- bc they fail to reach their peak bone mass during young adult life
- due to malabsorption of calcium
- reduction in bone density is usually mild, most pts are only osteopenic
- however, some are actually osteoporotic w/ associated risk of fracture
- at dx, pts given lifestyle advice + basline DEXA scan to assess bone mineral density
- pts should maintian adequate calcium and vit D intake
- a gluten-free diet should prevent further bone loss and may improve bone density
Why do coeliac patients develop dermatitis herpetiformis?
- intensely itchy chronic blistering skin condition
- typically occurs symmetrically on extensor surfaces (buttocks, back of neck, knees, elbows etc)
- it’s not related to herpes virus
- rather, associated w/ coeliac disease although exact mechanism not fully understood
- may be due to autoantibodies to epidermal transglutaminase
