Case 2 - Stomach ulcer Flashcards
Where is most of the gastric juice secreted from?
Gastric glands, which open up from the gastric pits (in rugae)
What cell types are present in gastric glands and what do they produce?
Chief cells: pepsinogen and lipase
Parietal cells: HCl and intrinsic factor
Endocrine cells: gastrin and ghrelin
Mucous neck cells: mucin in acidic fluid
Surface mucous cells: mucin in alkaline fluid
D cells: somatostatin
What are some modifications the stomach has for its functions?
- Rugae = mucosal longitudinal folds so when it gets full the walls can expand out, and when its empty it gets smaller
- 3 muscle layers = extra layer of SM to help churn food; inner oblique, middle circular and outer longitudinal
What are the roles of each phase of gastric secretion?
Phase 1 - cephalic: secretes 1/3 of secretion before food enters the stomach
Phase 2 - gastric: secretes 2/3 of secretion when food reaches the stomach (due to distention and peptones)
Phase 3 - intestinal: mechanical and chemical digestion of food
How is phase 1 / cephalic secretion stimulated?
1: the sight, smell, thought and taste of food signals to the dorsal nucleus of vagus in the medulla
2: stimulates parietal and chief cells to increase HCL and pepsinogen secretion
What inhibits phase 1/ cephalic secretions?
Sympathetic nervous system, i.e. stress or emotional upset = via greater splanchnic nerve (opposes actions of vagal so decreases HCl and pepsinogen)
How is phase 2/ gastric secretion stimulated by stretch receptors?
Stretch receptors in the submucosa and muscularis externa, when stimulated:
- Stimulate vagus nerve to increase HCl and pepsin (vago-vagal reflex) = long-arc
- Stimulate submucosal plexus = short reflex arc (enteric NS)
How does the vagus nerve lead to increased HCl and pepsin?
Vagus nerve releases acetylcholine, which:
- inhibits D cells via CCK-2 receptor, to decrease somatostatin (which is inhibitory)
- stimulates G cells via M3 receptor, to increase H+ and pepsin via gastrin
How is phase 2/ gastric secretion stimulated by peptones?
Peptones (partially digested proteins) stimulate enteroendocrine G cells in antrum of stomach to release gastrin, which binds to:
- CCK2 receptors on parietal cells to increase HCl
- CCK1 receptors on chief cells to increase pepsinogen
When can pepsinogen be converted to pepsin?
When pH is 1.8-3.5, thus relies on HCl concentration
What is the negative feedback mechanism of peptones?
They act as buffers to mop up H+, when pH rises this stimulates gastric secretion and subsequent HCl release to digest proteins
What inhibits phase 2/ gastric secretion?
Sympathetic nervous system, and somatostatin:
- Antral D cells (chemoreceptors) detect low pH = release somatostatin
- Somatostatin inhibits G cells from releasing gastrin, to decrease pepsin and HCL
How does phase 3 begin?
Stomach contracts, and the peristaltic wave starts at the cardia, moves down the fundus, body and antrum and ends at the pylorus (most powerful here). Contraction of muscularis externa leads to retropulsion of chyme, i.e. around 27ml is pushed back towards the body, then around 3ml enters the duodenum (start of phase 3).
What 2 factors stimulate intestinal (phase 3) secretion?
- Intestinal gastrin: released when duodenal G cells detect high peptones in the chyme, which stimulates parietal and chief cells to release HCl and pepsinogen
- Entero-oxynctin: released when endocrine cells detect high peptones, it stimulates parietal cells for HCl production
List the inhibitors of intestinal secretion (phase 3)
Secretin
Cholecystokinin (CCK)
Gastrin inhibitory peptide (GIP)
Neurotensin and peptide YY
When is secretin released and what is its role in intestinal (phase 3) secretion?
Released by S-cells in duodenum in response to high H+ and fatty acids in the chyme:
- Inhibits antral G-cells to inhibit gastrin release, thereby decreasing HCl production
- Binds to receptors on the liver to stimualte hepatocytes to convert cholesterol to bile acids (increased bile synthesis - released into duodenum) to help emulsify FA
- Binds to receptors on pancreatic ducts to increase bicarbonate to neutralise protons
When is CCK released and what is its role in intestinal (Phase 3) secretion?
Released by enteroendocrine I cells in the duodenum in response to high H+ and peptones, and to a hyperosmolar chyme:
- Inhibits parietal cells to decrease HCl
- Potentiates secretin to increase bile synthesis
- stimulates gall bladder to contract and sphincter of Oddi to relax = release of bile
- binds to pancreatic acinar cells for exocytosis of pancreatic precursors, e.g. proteases, lipases, amylases
What is the role of peptide YY and neurotensin?
Act on parietal cells to decrease HCl production, to inhibit excessive release of acidic chyme into duodenum
When is gastric inhibitory peptide released and what is its role in intestinal secretion (phase 3)?
Released by K-cells in response to high oligosaccharides and FA:
- Binds to parietal cells to reduce HCL
- Binds to B-cells to increase insulin production, to stimulate glucose and FA uptake
What control mechanisms are in place if the chyme is very acidic?
Chemoreceptors detect high H+ and inhibit the vagal nerve to decrease stimulation of parietal cells (lowers HCl). Simultaneously, the SNS (via thoracic splanchnic nerve) acts on a1-adrenoceptors to contract the pyloric sphincter = prevents chyme entering duodenum
How is acid formed in the stomach?
- In the parietal cell, H2O and CO2 combine to form H2CO3, then dissociated into H+ and HCO3-
- H+ is pumped into stomach lumen via H+-K+ ATPase, using ATP
- HCO3- is pumped into blood via anion exchanger with Cl-
- Cl- then flows from parietal cell into the stomach lumen by chloride channels
- H+ and Cl- in the stomach lumen combines to form HCl
Where are H+/K+ ATPases found at rest?
At rest, minimal numbers are found on the cell membrane of parietal cells, and the remaining are in tubulovesicles
What can increase acid production in the stomach and how?
- Acetylcholine from vagus nerve during cephalic phase (i.e. sight of food) or gastric phase (stomach distention)
- Gastrin from G-cells, release stimulated by vagus nerve or peptones. Binds to CCK-2 on parietal cells to increase calcium = vesicular fusion
- Histamine: enterochromaffin-like cells secrete H in response to ACh and gastrin, which binds to H2 receptors on parietal cells to increase fusion of vesicles by cAMP
How do protein meals affect stomach pH?
They act as buffers (mop up H+) = raises pH after ingestion. Later, acid secretion increases for digestion (lowering pH)
What food types can increase acid reflux and how?
- Chocolate: relaxes LES so food refluxes up
- Coffee: thought to induce gastrin release which increases acid production, may also relax LES
- Citrus fruit and juices: acidic food contributing to an already acidic environment
What are the 3 main mechanisms behind gastric emptying?
- Peristaltic waves: from cardia, fundus, antrum to pylorus
- Systolic contractions of the antrum
- Reduction in the size of the stomach
Compare receptive and adaptive relaxation
Receptive relaxation: during cephalic phase, NO is released to relax SM of the stomach
Adaptive relaxation: when food enters the stomach, distention triggers local reflex of NO to relax the stomach to increase intragastric volume. This can be augmented if the bolus is high in peptones = gastrin release = more SM relaxation
Other than receptive and adaptive relaxation processes, what else contributes to relaxation of the stomach?
Chyme entering the duodenum leads to CCK, secretin and GIP release. these relax the stomach so food is held there more
What is the enterogastric reflex?
Distention of the duodenum activates the sympathetic NS, which sitmulates the pyloric sphincter. this prevents more release of substances into the duodenum from the stomach
What happens to stomach motility during fasting/ interdigestive states?
Motilin is released, which stimulates the migrating motor complex (MMC). This is a peristaltic wave that moves down the stomach to empty contents into the duodenum, and can empty those >2mm
What is a gastric ulcer?
Break in the muscosa of the stomach >5mm in diameter and penetrating to the muscularis mucosa
How might a gastric ulcer appear histologically?
Can see an ulcer base with clear margins deep into muscularis mucosa layer. The submucosa also willl have fibrosis and thickened blood vessels
Where are gastric and duodenal ulcers most common?
Gastric = lesser curvature
Duodenal = first part, just after pyloric sphincter (most common GI ulcer)
What is often seen histologically with duodenal ulcers?
Same as gastric but also get Brunner gland hypertrophy, as the body attempts to secrete more HCO3- rich mucus to compensate
What are the 3 main complications of gastric or duodenal ulcers?
1- Bleeding, if erosion is deep can rupture blood vessels
2- Perforation, leaking GI contents into peritoneal space
3- Obstruction of gastric contents, rare but occurs with oedema or scarring
What blood vessels are at highest risk of rupture with GI ulcers?
Left gastric artery - from ulcers in lesser curvature
Gastroduodenal artery - from ulcers in proximal duodenum
If a patient presents with symptoms of an ulcer with referred shoulder pain, where is the ulcer likely to be located and why?
Duodenal ulcer on the anterior wall, perforation of the ulcer can lead to air to collect under the diaphragm which irritates phrenic nerve = referred pain to shoulder
What are the symptoms of a gastric ulcer?
- Epigastric pain: burning or aching in upper abdomen
- Bloating
- Early satiety
- Nausea and vomiting
What is a red flag of a gastric ulcer?
Black stools - indicates upper GI bleed
How do symptoms vary between gastric and duodenal ulcers?
Gastric ulcers have increased pain while eating (and increased HCl), so are associated with weight loss
Duodenal ulcers have less pain while eating, so is associated with weight gain
What contributes to gastric mucosa protection?
Prostaglandins, mucous, growth factors and adequate blood flow
How do prostaglandins affect the mucosa?
Stimulate mucus and HCO3- release, vasodilate nearby blood vessels for blood flow (protective)
What are some risk factors for peptic ulcers?
- Smoking
- Alcohol – can erode the mucous lining of the stomach and increase HCl production
- Untreated stress
- Spicy food
- NSAIDs, i.e. ibuprofen, aspirin: 4x increase in risk compared to people who don’t use NSAIDs
- Male sex
How does H.pylori contribute to gastric ulcers?
Gram-negative bacteria colonises the mucosa, releases:
- Adhesions = attach to foveolar cells, i.e. SabA and BabA (glucan binding proteins)
- Proteases = damage mucosal cells
- Ureases = production of ammonia
Causes inflammation and gastritis, overall damaging antral somatostatin release and increasing gastrin secretion, thus acid secretion also increases
How can you test for H.pylori infections?
- Stool antigen test: stop PPI for 2 weeks prior and no antibiotics for 4 weeks
- 13 urea breath test
- Serology (but cannot distinguish past from active infections)
- CLO test (biopsy during gastroscopy)
How can NSAIDs cause gastric ulcers?
Inhibit COX-1 enzyme = decreases prostaglandins synthesis. This means less HCO3- is secreted and there is reduced blood flow (mild ischaemia). Makes the gastric mucosa more suceptible to damage, leading to ulcers
How does Zollinger-Ellison syndrome contribtue to gastric ulcers?
Gastrinoma (neuroendocrine tumour) in the duodenal wall or pancreas secretes abnormal amounts of gastrin. This stimulates parietal cells to increase HCl production.
What investigations may be done to check for a stomach ulcer?
Oesophago-Gastro-Duodenoscopy (OGD) - also known as a gastroscopy or endoscopy. It looks at the upper part of the gut with a narrow flexible tube called a gastroscope. A biopsy can also be done to check for malignant cells
How would a stomach ulcer be treated if it was associated with NSAID use? Compare to if it wasnt
Proton pump inhibitors, i.e. omeprazole, or a histamine-2 receptor antagonist for 8 weeks. Then prescribe first-line eradication therapy
If not NSAID related, then go into first-line eradication therapy
What is the first-line H.pylori eradication regimen?
7 day triple therapy of:
- PPI 2x daily
- Amoxicillin 1g 2x daily
- Clarithromycin 500mg 2x daily or metromidazole 400mg 2x daily
If penicillin allergic, use both clarithromycin and metromidazole instead of amoxicillin
What is the follow-up after an ulcer treatment?
Review 6-8 weeks after starting eradication therapy, re-test for H.pylori and repeat endoscopy to check ulcer is healing
What are some alarm symptoms that would indicate need for an urgent OGD?
- Unintentional weight loss
- 50 years +
- Bleeding
- Nausea and vomiting
What is the MOA of omeprazole?
Reduces HCl secretion by binding to the alpha subunit of H+/ K+ ATPase pump on parietal cells, inhibiting it.
What is the MOA of clarithromycin?
inhibits 50S ribosomal subunit of bacteria to inhibit bacterial protein synthesis
What is the MOA of amoxicillin?
Binds to penicillin binding proteins to inhibit cell wall synthesis
Why is it important statin drugs are stopped during treatment of a stomach ulcer?
Combining simvastatin and clarithromycin can significantly increase blood levels of simvastatin, which can increase risk of liver damage and Rhabdomyolysis.
How is the parietal and visceral peritoneum innervated?
Parietal (lining walls of abdominal cavity) is innervated by somatic innervation. Extensions of peripheral spinal nerves innervate it so has noxious pain sensation
Visceral (covering organs) is innervated by autonomic innervation. Pain fibres in the viscera are transmitted by C fibres
How do somatic and autonomic innervation differ?
Somatic = sensitive to pressure, pain, temperature and laceration. Pain is well localised.
Visceral = insensitive to touch, temp and laceration, but stimulated by stretch and chemical irritation. Pain is poorly localised
Give examples of somatic and visceral pain
Somatic - bumping your knee, cutting your lip
Visceral - period cramps, IBS
What is peritonitis and where is it felt?
Irritation of peritoneal lining of abdominal cavity, usually with inflammation infection, i.e. from perforated ulcers, inflammation of gall bladder.
It usually leads to irritation of the diaphragm, so pain is referred to the right shoulder via C3, C4, C5
How is fat absorbed in the SI?
1- large fat globules are emulsified by bile salts in the duodenum
2- pancreatic lipase yeilds free FA and monoglycerides, which then form micelles
3- FA and monoglycerides leave micelles and enter epithelial cells by diffusion
4- taken up into chylomicrons which enter lacteals, where they’re carried away from the intestine in lymph
What drug may be given for weight loss and how does it work?
Orlistat - inhibits pancreatic lipase from breaking down fat
What is gastric banding?
Puts a sleeve around stomach and inflates it with saline – cuts off part of the stomach (not surgically altering but functionally changes size of stomach)
What is a gastric bypass?
Uses a smaller stomach pouch and shortening of intestine, without removal of intestine
What is a biliopancreatic diversion?
Removal of portion of the stomach, and diversion of bile and pancreatic juices
What mucins are present in the stomach and intestine?
Stomach = MUC 5AC and 6
Rest of the intestine = MUC 2
What are mucins?
Glycoprotein polymers, covered in short-chain sugars. They are an essential component for the mucus barrier
How does the presence of mucins affect the mucus barrier?
Mucins swell up in solution, therefore::
Little amounts = watery, i.e. saliva
Lots of mucins = thicker, i.e. in gut
How do mucins protect against pathogens?
- ‘sugar coated cells’ = glycocalyx, the tight sugar coat acts as a defence
- Bind pathogens and act as decoys
Which adhesin genes can make glycan-binding proteins and therefore increase colonisation of H.pylori?
SabA gene and BabA gene
What gene can disable the epithelial tight junction and therefore increase pathogenesis of H.pylori?
CagA gene
Which mucin has glycans that can act as a decoy receptor for H.pylori?
MUC6
What is a succession splash?
Obstruction in the outlet of a patients stomach, so food and fluid collects in the stomach. Succession splash is when you listen to the patients stomach while moving them from side to side- can hear the splash of fluid in their stomach
What is Virchow’s node?
Node (bulge) in the left supraclavicular fossa, a sign of advanced cancer
When would a barium meal investigation be done?
When suspecting issues with motility or obstructions, i.e. dismotility of oesophagus, delayed gastric emptying
When would a BRAVO capsule be used?
Attach a capsule to your oesophagus so you can recall the amount of acid being refluxed - would be used if a patient cannot tolerate a probe in the nose to check for pH
What investigations may be done if you suspect a malignant GI pathology?
- Blood tests: full count, LFTs, iron studies
- Endoscopy/ OGD: gold-standard for diagnosing GI cancer
- CT scan: assess where the cancer is and whether it has spread
- Laparoscopy: key hole approach to see if any small deposits are present
What genetic mutation increases risk of malignancy in the stomach?
Hereditary diffuse gastric cancer (HDCG) CDH1 mutation, carries a high risk even under age of 50
Which mucin inhibits cell wall synthesis of H.pylori?
MUC6
Which mucin is shed when H.pylori binds?
MUC1
What type drug may be given to reduce acid in the stomach for a patient with a peptic ulcer?
H2 receptor antagonist - i.e. cimetidine, ranatidine (all end in ‘dine’), as histamine increases acid production from parietal cells
What proportion of gastric secretion occurs in each of the 3 stages?
Cephalic = 40%
Gastric= 50%
Intestinal = 10%
What is the role of prostaglandin E2 with regards to the stomach?
Stimulates mucin production, and inhibits stomach acid secretion via Gi.
