Case 2 Flashcards

Question

what are the types of factors that are continually monitored in the duodenum and that can initiate enterogastric inhibitory reflexes?

Answer 1

1. Degree of distention of the duodenum 2. Degree of irritation of the duodenal mucosa (if any) – especially sensitive to this 3. Degree of acidity of the duodenal enzyme – especially sensitive to this  When the pH of the chyme in the duodenum falls below about 3.5-4, the reflexes frequently block further release of acidic stomach contents into the duodenum until the duodenal chyme has been neutralised by pancreatic and other secretions. 4. Degree of osmolality of the chyme  Hypertonic and hypotonic (especially hypertonic) fluids elicit the inhibitory reflex.  Too rapid flow of non-isotonic fluids into the small intestine is prevented, thereby also preventing rapid changes in electrolyte concentrations in the whole body extracellular fluid during absorption of the intestinal contents. 5. Presence of certain breakdown products in the chyme, especially breakdown products of proteins and perhaps to lesser extent of fats  By slowing the rate of stomach emptying, sufficient time is ensured for adequate protein digestion in the duodenum and small intestine.

Answer 2

fats entering the duodenum, although other foods can increase this hormone release to a lesser extent: o Fats bind to receptors on the duodenal and jejunal epithelium, thus extracting different hormones from the epithelium. o These hormones are then carried by blood to the stomach, where they inhibit the pyloric pump and at the same time increase the strength of contraction pyloric sphincter.

Answer 3

cholecystokinin (CCK)

Answer 4

released from the duodenal and jejunal mucosa in response to fatty substances in the chyme.

Answer 5

• CCK acts as an inhibitor to block increased stomach motility caused by gastrin.

Answer 6

the hormones secretin (opposite - don't secrete chyme) and gastric inhibitory peptide (GIP).

Answer 7

duodenal mucosa (S cells in the crypts of Lieberkuhn).

Answer 8

gastric acid passed from the stomach through the pylorus.

Answer 9

o This has a general but weak effect of decreasing GI motility. o Released from the duodenal and jejunal mucosa. o Released in response to fat in the chyme, but to lesser extent carbohydrates as well. o Although GIP weakly decreases the GI motility, its primary function is to stimulate secretion of insulin by the pancreas.

Answer 10

• Emptying of the stomach is controlled only to a moderate degree by stomach factors such as the degree of filling in the stomach and the excitatory effect of gastrin on stomach peristalsis. • Probably the more important control of stomach emptying resides in inhibitory feedback signals from the duodenum, including both enterogastric inhibitory nervous feedback reflexes and hormonal feedback by CCK. • These feedback inhibitory mechanisms work together to slow the rate of emptying when 1. Too much chyme is already in the small intestine. 2. The chyme is excessively acidic, contains too much unprocessed protein or fat, is hypotonic or hypertonic, or is irritating. • In this way, the rate of stomach emptying is limited to that amount of chyme that the small intestine can process.

Answer 11

Increased stretching of the stomach wall – increased pressure in the stomach Gastrin – enhanced pyloric pump + increased HCl production in parietal cells

Answer 12

Nervous reflexes (via enteric nervous system, extrinsic nerves and vagus nerve) – inhibit pyloric pump + increase pyloric sphincter tone ``` The following factors affect the duodenal mucosa and initiate the nervous reflexes: • Distention • Irritation of mucosa • Acidity of digestive enzymes • Osmolality of chyme (hyper-/hypotonic) • Protein breakdown products ``` Hormonal feedback - inhibit pyloric pump + increase pyloric sphincter tone The hormones are secreted due to the presence of fat in the duodenum. The hormones released are: • Secretin (released from duodenal mucosa in response to gastric acid) – inhibit gastrin, thus lowering acid secretion • Cholecystokinin/ CCK (released from jejunal mucosa in response to fat in chyme) – inhibit gastrin, thus lowering acid secretion • Gastric inhibitory peptide/ GIP(released from jejunal mucosa in response to fat in chyme) – weakly decrease GI motility

Answer 13

1. Oxyntic glands/ Gastric glands  Acid forming glands composed of three types of cells: 1) Mucous neck cells – secrete mucus 2) Peptic (chief) cells – large quantities of pepsinogen 3) Parietal (oxyntic) cells – HCl and intrinsic factor  These are located on the inside surfaces of the body and fundus of the stomach, constituting the proximal 80% of the stomach. 2. Pyloric glands  Secrete mainly mucus for protection of the pyloric mucosa from the stomach acid and they also secrete the hormone gastrin.  These are located in the antral portion of the stomach, the distal 20% of the stomach.

Answer 14

* The parietal (oxyntic) cell contains large branching intracellular canaliculi. * The HCl is formed at the villus-like projections inside these canaliculi and is then conducted through the canaliculi to the secretory end of the cell (the apical end).

Answer 15

 The movement and exchange of ions in and out of parietal cells is primarily powered by ATP from the numerous mitochondria present in the parietal cells. 1) Cl- ions are actively transported from parietal cell cytoplasm into the lumen of the canaliculus via a chloride pump. Na+ ions are actively transported out of the canaliculus into the cytoplasm of the parietal cell via a sodium pump. This creates a negative potential (-40 to -70 mV) in the canaliculus. This causes K+ ions (and some Na+ ions) to enter the canaliculus from the cytoplasm. Thus, in effect, mainly KCl and smaller amounts of NaCl enter the canaliculus. 2) Water dissociates into hydrogen ions (H+) and hydroxyl ions (OH-) in the cytoplasm. H+ ions are actively secreted into the canaliculus in exchange for K+ ions. This is catalysed by the H+/K+ ATPase (proton pump). Also, Na+ ions are ions are actively reabsorbed by a separate sodium pump. Therefore, the Na+ ions and K+ ions that were initially secreted into the canaliculus have ben reabsorbed, whilst H+ ions have been added to the canaliculus. This gives us the HCl in the canaliculus. 3) Water passes into the canaliculus by osmosis because of the increased ionic concentration in the canaliculus. The final secretion from the canaliculus contains water, HCl (conc = 150-160mEq/L), KCl (conc = 15mEq/L) and small amounts of NaCl. 4) OH- combines with CO2 under the influence of carbonic anhydrase to form bicarbonate ions (HCO3-). These diffuse into the extracellular fluid in exchange for Cl- ions.

Answer 16

• Different types of pepsinogen are secreted by the peptic (chief) cells of the gastric/oxyntic gland. • All pepsinogens have the same function:  It has no digestive activity.  As soon as it comes into contact with HCl, it is activated to form active pepsin.  Pepsin functions as an active proteolytic enzyme for protein digestion, in an acid medium.

Answer 17

 Optimum pH is 1.8 - 3.5 but above a pH of 5 it has almost no proteolytic activity and becomes completely inactivated is a short time.

Answer 18

• Regulation of pepsinogen secretion by the peptic cells in the oxyntic glands occurs in response to two types of signals: 1. Stimulation of peptic cells by acetylcholine released from the vagus nerves or from the gastric enteric nervous plexus. 2. Stimulation of peptic cell secretion in response to acid in the stomach.  Acid doesn’t stimulate the peptic cells directly, instead it elicits additional enteric nervous reflexes that support the original nervous signals to the peptic cells.  The rate of pepsinogen secretion is influenced by the amount of acid in the stomach.

Answer 19

the absorption of vitamin B12 in the ileum. (protein that binds to B12 and is required for B12 uptake in the ileum)

Answer 20

parietal (oxyntic) cells along with the secretion of HCl.

Answer 21

• When the acid-producing parietal cells of the stomach are destroyed, which frequently occurs in chronic gastritis, the person develops not only achlorhydria (lack of stomach acid secretion) but often also pernicious anemia because of failure of maturation of the red blood cells in the absence of vitamin B12 stimulation of the bone marrow.

Answer 22

increase by histamine, ACh, gastrin decrease by somatostatin, GIP, prostaglandin, secretin

Answer 23

- mucosal cells (stomach, duodenum, salivary glands, pancreas) and Brunner's glands (duodenum) - neutralises acid - increase pancreatic and biliary secretion with secretin - HCO3- is trapped in mucus that covers the gastric epithelium

Answer 24

* The pyloric cells are structurally similar to oxyntic glands but contain few peptic cells and almost no parietal cells. * Instead, they contain mainly mucous cells that are identical with the mucous neck cells of the oxyntic glands. • These cells secrete:  Small amounts of pepsinogen.  Large amounts of thin mucus that helps lubricate food movement, as well as to protect the stomach wall from digestion by the gastric enzymes.

Answer 25

* The entire surface of the stomach mucosa between glands has a continuous layer of a special type of mucous cells called simply “surface mucous cells.” * They secrete large quantities of viscid mucus that coats the stomach mucosa, thus providing protection for the stomach and lubrication. * This mucus is alkaline (presence of bicarbonate ions), therefore, the normal underlying stomach wall is not directly exposed to highly acidic, proteolytic stomach secretion. * Even the slightest contact with food or any irritation of the mucosa directly stimulates the surface mucous cells to secrete additional quantities of this thick, alkaline, viscid mucus.

Answer 26

parietal cells

Answer 27

enterochromaffin-like cell (ECL cell)  ECL cells secrete histamine which binds to H2 histamine receptors on parietal cells.  This activates the parietal cells to form and secrete HCl.  Rate of formation and secretion of HCl is dependent on the amount of histamine secreted by ECL cells.

Answer 28

1. Gastrin – when G-cells of the antral mucosa come into contact with amino acids, they pass gastrin to ECL cells through the digestive juices, which in turn secrete histamine. 2. Acetylcholine – this is released from stomach vagal nerve endings. 3. Hormonal substances secreted by the enteric nervous system of the stomach wall.

Answer 29

by gastrin cells (G-cells) located in the antral mucsoa (pyloric glands).

Answer 30

a. G-34 = this contains 34 amino acids | b. G-17 = this contains 17 amino acids (and is more abundant)

Answer 31

* When amino acids reach the antral end of the stomach, they have a stimulatory effects on the G-cells in the pyloric gland. * This causes release of gastrin into the digestive juices of the stomach. * The vigorous mixing of the digestive juices transports the gastrin rapidly to the ECL cells in the body of the stomach, causing release of histamine directly into the deep oxyntic glands, which stimulates the parietal cells to form and secrete HCl.

Answer 32

1. Cephalic phase 2. Gastric phase 3. Intestinal phase

Answer 33

* This occurs before food enters the stomach, especially whilst in the mouth. * It results from the sight, smell, thought, or taste of food. * The greater the appetite, the more intense the stimulation. * Neuronal signals from appetite centres of the amygdala and hypothalamus are transmitted through the dorsal motor nuclei of the vagi through the vagus nerves to the stomach.

Answer 34

• This phase has stimulatory effects on HCl secretion:  It stimulates the vagus nerve to release more ACh, thus activating more ECL and parietal cells.  It stimulates the vagus nerve to activate gastrin-releasing-peptide (GRP), which increases the secretion of gastrin, thus activating parietal cells. • This phase accounts for about 20% of gastric secretion associated with eating a meal.

Answer 35

• This occurs once food has entered the stomach. • This phase has both stimulatory and inhibitory effects: Stimulatory effects on HCl secretion:  It stimulates the vagus nerve to release more ACh, thus activating more ECL and parietal cells.  It stimulates the vagus nerve to activate gastrin-releasing-peptide (GRP), which increases the secretion of gastrin, thus activating parietal cells.  It increases the pH of the food, thus causing an increase in gastrin secretion.  It stimulates secretagogues, which increase H+ secretion. Inhibitory effects on HCl secretion (I think this means if there is less acid):  It inhibits the G-cells (antrum), which decreases the secretion of gastrin and so increases the pH in the stomach. • This phase accounts for about 70% of gastric secretion associated with eating a meal.

Answer 36

* This occurs as a result of the presence of food in the upper portion of the small intestine, particularly in the duodenum. * This phase has both stimulatory and inhibitory effects: Stimulatory effect:  It stimulates the G-cells (duodenum), which secrete more gastrin, resulting in an increase in the secretion of H+. Inhibitory effect: (bigger part of intestinal phase)  It inhibits chemoreceptors, which cause a decrease in nerve reflexes, thus decreasing H+ secretion.  Secretin, CCK and GIP increase the secretion of somatostatin, thus decreasing H+ secretion. • The presence of food will continue to cause stomach secretion of small amounts of gastric juice because small amounts of gastrin is released by the duodenal mucosa.

Answer 37

* Chyme initially increases gastric secretion. * However, later chyme inhibits gastric secretion. 1. Presence of food in the small intestine initiates a reverse enterogastric reflex, transmitted through the myenteric nervous system and vagus nerves, that inhibits stomach secretion.  This reflex can be initiated by distending the small bowel, by the presence of acid in the upper intestine, by the presence of protein breakdown products, or by irritation of the mucosa. 2. The hormone secretin is secreted as a result of the presence of… (listed above). It is important in the control of pancreatic secretion. Secretin opposes stomach secretion. Other hormones have a slight effects on inhibiting gastric secretion – GIP, vasoactive intestinal polypeptide and somatostatin.

Answer 38

to slow passage of chyme from the stomach when the small intestine is already filled or already overactive.

Answer 39

inhibits G-cells, ECL cells and if there is an excess of acid in the duodenum, it inhibits the parietal cells.

Answer 40

Yes • This is non-oxyntic secretion, consisting mainly of mucus, but little pepsin and almost no acid. • Emotional stimuli increase interdigestive gastric secretion.

Answer 41

- increase gastric H+ secretion - increase growth of gastric mucosa - increase gastric motility

Answer 42

I cells (duodenum, jejunum)

Answer 43

- increase pancreatic secretion - increase gall bladder contraction - decrease gastric emptying

Answer 44

- increase pancreatic HCO3- secretion - decrease gastric acid secretion - increase bile secretion

Answer 45

D cells (pancreatic islets, GI mucosa)

Answer 46

- decrease gastric acid and pepsinogen secretion - decrease pancreatic and small intestine fluid secretion - decrease gallbladder contraction - decrease insulin and glucagon release (sommm, hoommm = relax, calm, less acid, less everything)

Answer 47

ptyalin = a-amylase • This enzyme hydrolyzes starch into the disaccharide maltose and other small polymers of glucose that contain three to nine glucose molecules.

Answer 48

5% • By the time the food reaches the stomach, 30-40% of all starches have been hydrolysed mainly to form maltose. • Starch digestion sometimes continues in the body and fundus of the stomach for as long as 1hour before the food becomes mixed with the stomach secretions.

Answer 49

• Then activity of the salivary amylase is blocked by acid of the gastric secretions because the amylase is essentially non-active as an enzyme once the pH of the medium falls below about 4.0.

Answer 50

* Pepsin is most active at a pH of 2.0 to 3.0 and is inactive at a pH>5.0. * For pepsin to cause digestive action on protein, the stomach juices must be acidic.

Answer 51

• The gastric glands (parietal cells) secrete a large quantity of HCl at a pH = 0.8, but by the time it is mixed with the stomach contents and with secretions from the non-oxyntic glandular cells of the stomach, the pH then averages around 2.0 to 3.0, a highly favorable range of acidity for pepsin activity.

Answer 52

* One of the important features of pepsin digestion is its ability to digest the protein collagen, an albuminoid type of protein that is affected little by other digestive enzymes. * Collagen is a major constituent of the intercellular connective tissue of meats. * In persons who lack pepsin in the stomach juices, the ingested meats are less well penetrated by the other digestive enzymes and, therefore, may be poorly digested. * Pepsin only initiates the process of protein digestion, usually providing only 10-20% of the total protein digestion to convert the protein to proteoses, peptones, and a few polypeptides. * This splitting of proteins occurs as a result of hydrolysis at the peptide linkages between amino acids.

Answer 53

* Gastritis – inflammation of the gastric mucosa. * The inflammation of gastritis may be only superficial and therefore not very harmful, or it can penetrate deeply into the gastric mucosa, in many long-standing cases causing almost complete atrophy of the gastric mucosa. * In a few cases, gastritis can be acute and severe, with ulcerative excoriation of the stomach mucosa by the stomach’s own peptic secretions. * Gastritis is caused by chronic bacterial infection of the gastric mucosa. * This is treated by an intensive antibacterial therapy. • In addition, certain ingested irritant substances can be especially damaging to the protective gastric mucosal barrier (mucous glands and the tight epithelial junctions between the gastric lining cells), often leading to severe acute or chronic gastritis.  Two of the most common of these substances are excesses of alcohol or aspirin.

Answer 54

1. Highly resistant mucous cells that secrete a viscid and adherent mucus. 2. Tight junctions between the adjacent epithelial cells. * These two form a barrier against gastric absorption of food into the blood. * The gastric barrier is resistant to diffusion of ions across it.

Answer 55

1. The permeability of the barrier is greatly increased.  Hydrogen ions can now diffuse into the stomach epithelium, leading to stomach mucosal damage and atrophy. 2. The mucosa becomes susceptible to digestion by the peptic digestive enzymes.  This causes gastric ulcers.

Answer 56

* Gastric atrophy is the damage to the mucosal glands of the stomach, such that little or no gastric gland digestive secretion remains. * Gastric atrophy can also occur as a result of an autoimmune response against the gastric mucosa. * Loss of stomach secretions in gastric atrophy leads to ‘achlorydria’ and, occasionally, ‘pernicious anaemia’.

Answer 57

* Achlorhydria – this means that the stomach fails to secrete HCl. * Hypochlorhydria – this literally means “decreased acid secretion”. * It is diagnosed when the pH of the gastric secretions fails to decrease below 6.5 after maximal stimulation. * When acid is not secreted, pepsin also usually is not secreted; even when it is, the lack of acid prevents it from functioning because pepsin requires an acid medium for activity.

Answer 58

* Intrinsic factor must be present for absorption of vitamin B12 from the ileum. * The intrinsic factor binds with vitamin B12 in the stomach and protects it from being digested and destroyed as it passes into the small intestine. * Then, when the intrinsic factor–vitamin B12 complex reaches the terminal ileum, the intrinsic factor binds with receptors on the ileal epithelial surface. * This in turn makes it possible for the vitamin B12 to be absorbed.

Answer 59

* In the absence of intrinsic factor, only about 1/50 of the vitamin B12 is absorbed. * Vitamin B12 is not made available from the foods to cause young, newly forming red blood cells to mature in the bone marrow. * This is called pernicious anaemia.

Answer 60

* Peptic Ulcer – localised breach of the gastric or duodenal mucosa that extends through the mucosa into the submucosa or muscularis propria, caused by the digestive action of gastric juice or upper small intestinal secretions. * Epidemiology – 10% of UK population during life * Most common symptom is pain. * Most serious complication is bleeding or perforation which are life threatening. ulcer = acid/enzyme damage to stomach or intestinal wall

Answer 61

1. Excess secretion of acid and pepsin by the gastric mucosa. 2. Diminished ability of the gastrodudenal mucosal barrier to protect against the digestive properties of the stomach acid-pepsin secretion. - Occur due to increase acid and/or decrease protection

Answer 62

1. Any area exposed to gastric juices is well supplied by mucous glands to provide a viscid coating of alkaline mucus. 2. The duodenum is protected by intestinal secretions.  An important secretion is pancreatic secretion – this contains large amounts of sodium bicarbonate that neutralise the HCl of the gastric juice, thus also inactivating pepsin and preventing digestion of the mucosa. 3. Also, large amounts of bicarbonate ions are provided in:  The secretions of the large Brunner’s glands in the proximal duodenal wall. This gland also secretes mucus which helps provide an alkaline environment.  In bile coming from the liver.

Answer 63

1. When excess acid enters the duodenum, it reflexly inhibits gastric secretion and peristalsis in the stomach, both by nervous reflexes and by hormonal feedback from the duodenum, thereby decreasing the rate of gastric emptying. 2. The presence of acid in the small intestine liberates secretin from the intestinal mucosa, which then passes by way of the blood to the pancreas to promote rapid secretion of pancreatic juice. This juice causes neutralization of the acid.

Answer 64

1) Bacterial Infection by Helicobacter Pylori (H-pylori) 2) NSAIDS (e.g. Aspirin) 3) Zollinger-Ellison Syndrome 4) Other Causes - Smoking - Alcohol - Caffeine - Stress ulcers (most likely occur when you are already under medical care for a major illness, surgical procedure, trauma, or injury – the presence of a stress ulcer adds another complication to your other medical conditions that lead to the ulcer) - Steroids, Crohn’s, drugs…

Answer 65

are flagellated gram negative bacteria found on the luminal surface of the gastric epithelium that induces chronic mucosal inflammation. - 50% of people across world are colonised with H. Pylori, but only 0.5% in this country

Answer 66

the enzyme urease - these bacteria metabolise urea

Answer 67

 H-pylori is a bacteria that can live in low pH environments, such as the stomach.  It does this by metabolising urea which releases NH3 (alkali).  This causes local alkaline conditions around the bacteria, allowing it to withstand the acidic conditions of the stomach. it develops a mucous protective layer

Answer 68

by:  Its physical capability to burrow through the barrier.  Releasing bacterial digestive enzymes that liquefy the barrier, allowing the strong acidic digestive juices to penetrate the underlying epithelium and digesting the gastroduodenal wall, thus leading to peptic ulceration (in 15% of patients). - ‘burrow’ through mucus (protected from acidity to some extent) and adhere to epithelium

Answer 69

inhibits somatostatin release in the antrum, thus causing an increase in acid secretion.

Answer 70

o Urea breath test: (MAIN ONE)  This test is based on the ability of H.pylori to convert urea to NH3 and CO2.  Patients swallow a meal consisting of non-radioactive carbon-13 (13C) urea and citric acid.  Breath sample taken by direct exhalation into test tubes 15 minutes later.  Urea is split by urease into NH3 and CO2.  The detection of the labelled CO2 in the exhaled breath indicates that the urea was split; this indicated that the urease is present in the stomach, and so H.pylori is present.  Must stop PPI’s antibiotics and bismuth containing drugs for 4 weeks prior and fast 6 hours before test.  Sensitivity and specificity >95% o Heliobacter Stool Antigen Test:  Based on amplification of H.pylori RNA shed in stool  Sensitivity >90%; specificity 80-90% o Serology:  IgG indicates previous exposure, poor value  Sensitivity 90%; specificity 70-80% - Stool antigen test - PPI will interfere with result - 13urea breath test - PPI will interfere with result - Serology - cannot distinguish active from previous infection

Answer 71

o CLO (Campylobacter-like organism) or Urease Test:  2 gastric samples placed in a medium containing urea and a pH indicator.  Hydrolysis of urea by HP urease alters pH-pink colour develops in a few hours. o Gastric Biopsy for histopathology o Gastric Biopsy for culture of H.pylori

Answer 72

1. Vagal and local reflexes – increases secretion of mucus. 2. Secretin – increases secretion of bicarbonate ions 3. Prostaglandin E2 (PGE2  Normally, PGE2 inhibits HCl secretion and stimulates mucus cell secretion (mucus and bicarbonate ions).

Answer 73

 NSAIDs compromise mucosal protection.  Normally, PGE2 inhibits HCl secretion and stimulates mucus cell secretion (mucus and bicarbonate ions).  NSAIDs block the Arachadonic acid pathway by blocking COX1 and therefore increase HCl secretion and decreasing bicarbonate secretion.  Example – Misoprostol – stimulates mucus secretion (surface mucous cells and intestinal goblet cells) and inhibits H+ secretion from parietal cells.  NSAIDs inhibit PGE2 synthesis, thus increasing acid secretion and causing ulcers. - NSAIDs inhibit COX1 = decrease PGE2 in the mucosa of stomach & duodenum - Normal actions of PGE2: - stomach – parietal cells decrease H+ - stomach & duo – increase mucosal protection - So NSAIDs = increase H+ & decrease protection

Answer 74

 This is a condition where there is a gastrin-secreting tumour, thus leading to excess acid secretion.

Answer 75

- Smoking - presumably because of increased nervous stimulation of the stomach secretory glands. - Alcohol - because it tends to break down the mucosal barrier.

Answer 76

* Histamine works via the Gs intracellular protein pathway, causing an increase in acid secretion. * PGE2 works via the Gi intracellular protein pathway, causing a decrease in acid secretion.

Answer 77

• Standard Triple Therapy (first line treatment)  2 antibiotics + 1 PPI.  “CAP” = Clarityromycin (500mg bd) + Amoxicillin (1g bd) + PPI (standard dose bd)  Metronidazole (400mg bd) can be used instead of Amoxicillin • Modern Bismiuth-Based Regimens  2 antibiotics + 1 bismuth compound.  “CAR” = Clarithromycin (500 mg bd) + Amoxicillin (1 g bd) + Ranitidine bismuth citrate (400 mg bd)  Metronidazole (400 mg bd) can be used instead of Amoxicillin. • Retreatment:  Standard triple therapy  As above using a regimen different from that first employed  Quadruple Therapy  PPI (standard dose bd) + Tetracycline (4× 500 mg) + Metronidazole (3× 400 mg/ 500 mg) + Ranitidine Bismuth Citrate (400 mg bd).  Bismuth Subcitrate (4× 100 mg)/ Bismuth Subsalicylate (4× 600 mg) can be used instead of Ranitidine Bismuth Citrate

Answer 78

clarithromycin, amoxicillin, metronidazole, tetracycline

Answer 79

 Examples – Cimetidine, ranitidine  These block the H2 histamine receptors on the parietal cells.  As a result, histamine secreted by ECL cells can no longer activate parietal cells, thus preventing the secretion of HCl into the stomach lumen. - Identified by design, i.e. compounds with structural motives similar to histamine

Answer 80

 These comprise of thioamide compounds.  Examples – Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole sodium  These block the action of the H+,K+ -ATPase pump permanently in the gastric parietal cell by binding to its sulphydryl group.  Given in encapsulated formulation to avoid breakdown by stomach acid.  It is absorbed in the small intestine and travels to parietal cells in blood

Answer 81

“coating compounds” which potentiate the action of antibiotics.

Answer 82

 Examples - Sodium Carbonate, Calcium Carbonate, Magnesium or Aluminium Hydroxide  These are weak bases which react with gastric HCl to form a salt and water, relieving dyspepsia and reflux pain, by neutralising the acid secreted in response to a meal.  Antacids can interact with several drugs - Tetracyclines, Fluoroquinolones, Itriconazole and Iron.  As the metal salts are absorbed by the kidneys, long term use of antacids is unsuitable for patients with serious renal disorders.

Answer 83

* Example - Omeprazole * Lipid soluble, weak base – enters & accumulates in acid spaces (canaliculi and tubulovesicles of parietal cell). * Activated in acid - chemically altered by H+ to an active sulphenamide form. * Sulphenamide = cationic so trapped in canaliculi. * Forms irreversible S-S bond with H+,K+ ATPase, therefore blocks its action permanently. (until new pumps synthesised) *given in encapsulated formulation to avoid breakdown by stomach acid – it’s absorbed in the small intestine and travels to parietal cells via the blood = ‘slow’ onset (1-2 h)

Answer 84

• Example – Esomeprazole / Nexium • 1st generation PPIs (e.g. omeprazole) are a mixture of optical (R and S) isomers. • The S-isomer is more active in humans. • Purified S-isomer is ‘esomeprazole/nexium’ - Long-term side effects of PPIs = reduction in bone density

Answer 85

• A gastroscopy is a medical procedure where a thin, flexible tube called an endoscope is used to look inside the stomach. • An endoscope has a light and a camera at one end. The camera sends images of the inside of your body to a television monitor. • Gastroscopy is used a means of investigation and diagnosis: o Oesophagitis o Duodenal and stomach ulcers o Duodenitis and gastritis o Cancer of the stomach and oesophagus

Answer 86

for the most part no, except for sensations such as hunger and rectal distention

Answer 87

as diffuse pain • The pain fibres that originate in the viscera are transmitted via C fibres, which only transmit colicky/ cramping, poorly localized types of pain.

Answer 88

* The parietal peritoneum is innervated by extensions of the peripheral spinal nerves, which carry the same types of noxious pain sensations as those overlying the dermatomes. Therefore, parietal pain results in sharp, localized pain. * If the pathologic process progresses from the visceral to the parietal region, the referred pain will become localized, corresponding to the dermatome overlying the affected organ.

Answer 89

Peritonitis (e.g. this case) can cause irritation of the diaphragm. This will cause referred pain into the right shoulder via the C3, 4, 5 dermatome.

Answer 90

indigestion | • Dyspepsia is the chronic or recurrent pain or discomfort centred in the upper abdomen.

Answer 91

effortless regurgitation of undigested food after every meal

Answer 92

nausea and vomiting

Answer 93

type of antibiotic

Answer 94

 Epigastric pain – central upper abdominal or lower retrosternal discomfort related to eating  Postprandial fullness, unease  Accompanying symptoms may include nausea and vomiting, bloating, belching and weight loss

Answer 95

* Three times more common in men. * Most diagnosed >65 years of age * Incidence of antral and body cancer declining – probably because of falling prevalence of Helicobacter.

Answer 96

 Upper abdominal discomfort or pain  New-onset dyspepsia  Anorexia and early satiety  Weight loss  Vomiting (may be unaltered food in gastric outlet obstruction)  Iron deficiency anaemia  Distant lymphadenopathy (Virchow's node, etc.)  Metastatic spread - hepatomegaly, malignant ascites, bone pain, pulmonary metastases  Early gastric cancer is often asymptomatic

Answer 97

``` Blood tests ESTABLISHING A DIAGNOSIS:  Upper gastrointestinal endoscopy and biopsy  Barium meal?? • METHODS MAINLY FOR STAGING:  Computed tomography  Ultrasonography  Endoscopic ultrasonography  Positron emission tomography (PET) scan ```

Answer 98

 Five-year survival correlates closely with staging, with true in situ carcinoma having a survival rate of nearly 100%, through to stage 4 disease with a 5-year survival rate of 2%.

Answer 99

Tumour: T1: Tumours are confined to the mucosa and submucosa. T2: Tumours penetrate the muscularis propria but not the serosa. T3: Tumours reach the serosa but without the involvement of other organs. T4: Tumours have spread beyond the serosa. Node: N0: No nodes involved N1: Involvement of perigastric nodes within 3cm of the primary tumour N2: Spread to more distant regional lymph nodes. N3: Involvement of nodes is to more distant intra-abdominal lymph glands that are not removable with surgery ``` Metastasis: M0: No metastasis M1: Distant metastasis ```

Answer 100

 Surgery if no metastasis and patient in otherwise good health (Radical surgery has mortality of 10%)  Endoscopic Mucosal Resection for early gastric lesions confined to mucosa  Most surgery is palliative for relief of obstruction - supportive-palliative in advanced cases  Adjuvant chemotherapy  Family member, home support, liaison with GP are vital aspects of care

Answer 101

Any condition-physical or emotional-that threatens homeostasis

Answer 102

Any condition-physical or emotional-that threatens homeostasis • Stress occurs when the perceived demands of a situation are appraised as exceeding a person’s perceived resources and ability to cope • These situations are stressors and lead to the stress response • The more control we perceive we have over a situation the less stressful it is • If the stressor can be predicted, its effect is lessened • Appraisal is central to whether a person feels stressed or not • Severe or chronic stress is associated with psychological problems • Severe or chronic stress is associated with a range of illness and mortality

Answer 103

* During the alarm phase, an immediate response to the stress occurs. * This response is directed by the sympathetic nervous system. * Activation of the SNS causes increased secretion of adrenaline. * Adrenaline is the dominant hormone of the alarm phase, and its secretion accompanies a generalized sympathetic activation. • In the alarm phase: 1. Energy reserves are mobilized, mainly in the form of glucose 2. The body prepares to deal with the stress-causing factor by “fight or flight” responses • The characteristics of the alarm phase include the following: 1. Increased mental alertness. 2. Increased energy use by all cells, especially skeletal muscles. 3. Mobilization of glycogen (Hepatocytes perform glycogenolysis) and lipid reserves (adipose tissue cells perform lipolysis). 4. Changes in circulation, including increased blood flow to skeletal muscles and decreased blood flow to the skin, kidneys, and digestive organs. 5. A drastic reduction in digestion and urine production. 6. Increased sweat gland secretion. 7. Increases in blood pressure, heart rate, respiratory rate and metabolic rate. * Although the effects of adrenaline are most apparent during the alarm phase, other hormones play supporting roles. * In this phase, there is increased production of adrenaline and noradrenaline so that both the alpha and beta adrenergic receptors are activated with better efficiency. * For example, the reduction of water losses resulting from ADH production and aldosterone secretion can be very important if the stress involves a loss of blood.

Answer 104

* If a stress lasts longer than a few hours, the individual enters the resistance phase of the stress response. * Glucocorticoids (cortisol) are the dominant hormones of the resistance phase. * Growth Hormone, ADH and glucagon are also involved. * Energy demands in the resistance phase remain higher than normal. * Neural tissue has a high demand for energy, and neurons must have a reliable supply of glucose. If blood glucose concentrations fall too far, neural function deteriorates. * Glycogen reserves are adequate to maintain normal glucose concentrations during the alarm phase, but are nearly exhausted after several hours. Therefore, alternate energy sources are sought for in the resistance phase. • The endocrine secretions of the resistance phase achieve four integrated results: 1. Mobilization of remaining lipid and protein reserves:  The hypothalamus produces GHRH, stimulating the release of GH and glucocorticoids. o Adipose tissue responds to GH and glucocorticoids by releasing stored fatty acids. o Skeletal muscles respond to glucocorticoids by breaking down proteins and releasing amino acids into the bloodstream. 2. Conservation of glucose for neural tissues:  Glucocorticoids (cortisol) and GH stimulate lipid metabolism in peripheral tissues. o Peripheral tissue (except neural) breaks down lipids to obtain energy.  Neural tissues do not alter their metabolic activities, however, and they continue to use glucose as an energy source. 3. Elevation and stabilization of blood glucose concentrations:  As blood glucose levels decline, glucagon and glucocorticoids (cortisol) stimulate the liver to manufacture glucose from other carbohydrates (glycerol) and from amino acids provided by skeletal muscles. 4. Conservation of salts and water, and the loss of K+and H+:  Blood volume is conserved through the actions of ADH and aldosterone.  As Na+ is conserved, K+ and H+ are lost. • The resistance phase cannot be sustained indefinitely.  If starvation is the primary stress, the resistance phase ends when lipid reserves are exhausted and structural proteins become the primary energy source.  If another factor is the cause, the resistance phase ends due to complications brought about by hormonal side effects. • There may be side-effects experienced as a result of the hormones: 1. Glucocorticoids (cortisol): anti-inflammatory action slows wound healing and increases the body’s susceptibility to infection. 2. The continued conservation of fluids under the influence of ADH and aldosterone stresses the cardiovascular system by producing elevated blood volumes and higher-than-normal blood pressures. 3. The suprarenal cortex may become unable to continue producing glucocorticoids, eliminating acceptable blood glucose concentrations.

Answer 105

• When the resistance phase ends, homeostatic regulation breaks down and the exhaustion phase begins. • Unless corrective actions are taken almost immediately, the failure of one or more organ systems will prove fatal. • Mineral imbalances contribute to the existing problems with major systems.  The production of aldosterone throughout the resistance phase results in a conservation of Na+ at the expense of K+.  As the body’s K+ content declines, a variety of cells—notably neurons and muscle fibers—begin to malfunction.  Although a single cause (such as heart failure) may be listed as the cause of death, the underlying problem is the inability to sustain the endocrine and metabolic adjustments of the resistance phase.

Answer 106

anxiety disorders and depression

Answer 107

 Chronic stress results in excessive release of glucocorticoids (Cortisol) in the blood. It released from the adrenal cortex in response to an elevation in the blood level of adrenocorticotropic hormone (ACTH).  ACTH is released by the anterior pituitary gland in response to corticotropin-releasing hormone (CRH).  CRH is released into the blood of the portal circulation by parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus.

Answer 108

allostatic load is 'wear and tear on the body' • Stress recovery is linked with allostatic load. • The body’s physiological systems constantly fluctuate as the individual responds and recovers from stress – a state of allostasis – and that, as time progresses, recovery is less and less complete and the body is left increasingly depleted.

Answer 109

• Lazarus argued that stress involved a transaction between the individual and their external world, and that a stress response was elicited if the individual appraised a potentially stressful event as actually being stressful. • Lazarus’s “model of stress”:  Described individuals as psychological beings who appraised the outside world, not simply passively responding to it.  Lazarus defined two forms of appraisal: primary and secondary. 1. Primary appraisal:  The individual initially appraises the event itself.  There are four possible ways that the event can be appraised: 1) Irrelevant 2) Benign (gentle) and Positive 3) Harmful and a Threat 4) Harmful and a Challenge 2. Secondary appraisal:  The individual evaluating the pros and cons of their different coping strategies. • Therefore primary appraisal involves an appraisal of the outside world and secondary appraisal involves an appraisal of the individual themselves. • The form of the primary and secondary appraisals determines whether the individual shows a stress response or not. • This stress response can take different forms:  Direct action  Seeking information  Doing nothing  Developing a means of coping with the stress in terms of relaxation or defense mechanisms • Lazarus’s model of appraisal and the transaction between the individual and the environment indicated a novel way of looking at the stress response – the individual no longer passively responded to their external world, but interacted with it. • It is not an event itself that elicits stress, but the individual’s interpretation or appraisal of those events. • This appraisal can be modified by providing information or withholding information from the individual. • An event needs to be appraised as stressful before it can elicit a stress response. • It could be concluded from this that the nature of the event itself is irrelevant – it is all down to the individual’s own perception. • Multitasking seems to result in more stress than the chance to focus on fewer tasks at any one time. Therefore a single stressor which adds to a background of other stressors will be apprised as more stressful than when the same stressor occurs in isolation. • If a stressor can be predicted and controlled then it is usually appraised as less stressful than a more random uncontrollable event. • A feeling of being in control reduces the stress of an event and contributes to the process of primary appraisal. primary appraisal = is this stressful? secondary appraisal = can I cope with this?

Answer 110

``` • Acute:  Increased sympathetic activation  Increased cognitive performance  Increased muscular priming  Increased immune functioning ``` • Chronic:  Decreased immune functioning  Decreased cognitive performance  This eventually leads to exhaustion.

Answer 111

1. Alarm Phase  Shock (initial symptoms)  Flight-or-Fight response (sympathetic nervous system activated)  Hormones such as cortisol and adrenaline (epinephrine) released.  Counter-shock (homeostasis) 2. Resistance Phase  Adaption  Parasympathetic nervous system returns many physiological functions back to normal levels while body focuses resources against the stressor.  Blood glucose levels remain high (cortisol and adrenaline continue to circulate at elevated levels).  Increased heart rate, breathing and blood pressure. 3. Exhaustion Phase  Symptoms reappear  If stressor continues beyond body’s capacity, organism exhausts resources and becomes susceptible to diseases and death.

Answer 112

• This is the making of decisions/ coming to an agreement where there is a balance between physician directed decision making and strict autonomy (i.e. the patient making the decision). • Most patients and family members prefer shared decision making over either strict autonomy or physician-directed decision making. • The model for shared decision making is consistent with ethical principles and patient preferences and can be referred to as the “shared decision-making continuum” because shared decision making will necessarily take different forms in different situations.  At one end is patient- or agent-driven decision making.  At the opposite end is physician-driven decision making.  In the middle are many possible approaches. * The patient and the physician work together to reach a mutual decision. * This process often requires a longstanding relationship and both parties must understand the values and biases of the other. * Mutual respect and understanding are essential. * Because the patient and physician necessarily have different perspectives, the physician must ensure that it is the patient’s values, not his/her own, that guide decision making. * In some cases it may be appropriate for the physician to bear the major burden of decision making.

Answer 113

‘Involving patients in decisions to the extent that they desire’ • This is the making of decisions/ coming to an agreement where there is a balance between physician directed decision making and strict autonomy (i.e. the patient making the decision). • Most patients and family members prefer shared decision making over either strict autonomy or physician-directed decision making. • The model for shared decision making is consistent with ethical principles and patient preferences and can be referred to as the “shared decision-making continuum” because shared decision making will necessarily take different forms in different situations.  At one end is patient- or agent-driven decision making.  At the opposite end is physician-driven decision making.  In the middle are many possible approaches. * The patient and the physician work together to reach a mutual decision. * This process often requires a longstanding relationship and both parties must understand the values and biases of the other. * Mutual respect and understanding are essential. * Because the patient and physician necessarily have different perspectives, the physician must ensure that it is the patient’s values, not his/her own, that guide decision making. * In some cases it may be appropriate for the physician to bear the major burden of decision making.

Answer 114

* The physician explains all the option and also makes a recommendation. * The physicians must base their recommendations on the patient’s values rather than on their own. * This can require time and advanced communication skills. * When a patient asks the physician what he/she should do, the physician mist consider the patient’s perspective and ensure he/she is neither intentionally nor unintentionally coercive.

Answer 115

* With informed non-dissent decision making, the physician, guided by the patient’s values, determines the best course of action and fully informs the patient. * The patient may either remain silent, thereby allowing the physician’s decision to stand, or veto the decision. * In this approach the patient must understand all pertinent information. * Furthermore, the patient must appreciate that silence will be construed as tactic agreement.

Answer 116

mostly small intestine, very little in stomach, relatively little in colon ``` Duodenum: - Iron - Carbohydrates - Proteins, lipids, sodium, and water - Bile acids (little) Jejunum: - Carbohydrates (bit less) - Protein, lipids, sodium, and water (less) - Bile acids (little) Ileum: - Carbohydrates (lot less) - Protein, lipids, sodium, and water (less) - Cobalamin (vitamin B12) - Bile acids (lots) ```

Answer 117

- 80% ingested water - Electrolytes - Vitamins - Minerals - Carbohydrates - active/facilitated transport - monosaccharides - Proteins - di-/tripeptides - amino acids - Lipids - monoglycerides - fatty acids - micelles - chylomicrons

Answer 118

- Peptidases - amino- - di- - tri- - Sucrases - Maltase - Lactase - Saccharidases - di- - tri- - lipase - Nucleases Requires pancreatic enzymes & bile to complete digestion

Answer 119

- Huge surface area for absorption - SI epithelium is rapidly turned over (chemotherapy targets rapidly dividing cells = digestive problems) - Loss of cells at villi tips releases enzymes into lumen

Answer 120

about 2-3 litres isotonic fluid/day

Answer 121

- Coupled transport process - Sodium-potassium ATPase pumps sodium out of the basolateral membrane - This in turn drives the sodium-glucose symporter in the apical membrane - Glucose transported by a transporter protein out the basolateral membrane

Answer 122

1. Large fat globules are emulsified by bile salts in the duodenum 2. Digestion of fat by pancreatic enzyme lipase yields free fatty acids and monoglycerides, which then form micelles 3. Fatty acids and monoglycerides leave micelles and enter epithelial cells by diffusion 4. Chylomicrons containing fatty substances are transporter out of the epithelial cells and into lacteals, where they are carried away from the intestine by lymph

Answer 123

- The pancreatic lipase is a good target in the treatment of obesity - Orlistat inhibits this enzyme and significantly reduces fat absorption - Alli (a low dose orlistat preparation) is available over the counter/online in the UK - Response depends on the patient’s diet and undesired effects include an increase in the number and nature of bowel movements, abdominal discomfort, oily stools, flatulence, and oily spotting in underwear (patients started to eat less fat to minimise the side effects) - Not very common anymore

Answer 124

- Most CHO, protein, and fat are absorbed in the first 100-150cm of jejunum (normal SI length = 600cm) - Problems may occur at less than 200cm of functional SI - SBS results in a malabsorptive state - Due to insufficient absorptive surface area - Can result in fluid and electrolyte imbalances as well as poor nutritional status - May be congenital, as a result of surgical resection, or changes in blood supply to the SI - Prognosis improves with increasing length of remaining intestine - Treatment by diet supplementation, parenteral nutrition and increasingly intestinal transplant

Answer 125

- For severe obesity - BMI > 40 kg/m2 - Failure to maintain weight loss by non-surgical means over a period of months/years

Answer 126

- gastric banding - gastric bypass: small stomach pouch, and shortening of intestine – without removal of intestine - biliopancreatic diversion: removal of portion of stomach, and diversion of bile and pancreatic juices (less time for digestion and absorption)

Answer 127

painful swallowing – pain can be felt in your mouth, throat, or oesophagus

Answer 128

hen percuss abdomen you can hear and feel fluid sloshing around

Answer 129

node in left supraclavicular fossa = Troisier sign – gastric cancer (late sign)

Answer 130

measures acid reflux in the oesophagus

Answer 131

- Blood tests – FBC, UEs (urea & electrolytes), LFTs (liver function tests), iron studies - OGD (max. 8 biopsies) - CT scan (need fully functioning kidneys due to the contrast) - PET-CT scan - Laparoscopy (if someone has cancer of stomach that seen on endoscopy, but can’t see well on CT scan, will need to do laparoscopy – key hole operation done under general anaesthetic)

Answer 132

- Gastritis - Peptic ulceration - GORD (gastro-oesophageal reflux disease) – more abnormality with gastroesophageal sphincter - Achalasia – more related to LES - Functional disorders = non-malignant conditions of the stomach – bloating, delayed gastric emptying - Crohn’s disease – inflammatory condition that can affect anywhere in your GI tract – mouth to anus

Answer 133

- Pain - Heartburn - Reflux - Bleeding - Perforation - Structure/obstruction - (malignancy)

Answer 134

Ulcers that tend to bleed tend to be in the posterior part of the first part of the duodenum – due to the gastroduodenal artery running in that part Ulcers on the anterior part of the duodenal wall tend to perforate (hole that can lose a lot of bile and gut content through it) - Anterior ulcers perforate, posterior ulcers bleed

Answer 135

Hereditary diffuse gastric cancer = a rare inherited condition associated with an increased risk of gastric cancer - It tends to affect much of the stomach rather than staying in one area - The average age for someone with HDGC to be diagnosed with stomach cancer is 38 - Gene mostly commonly associated with HDGC is CDH1 – mutation in this gene gives a person an increased risk of developing gastric cancer and other cancers associated with HDGC

Answer 136

OGD & biopsy

Answer 137

OGD & biopsy | oesophago-gastro-duodenoscopy

Answer 138

- Fundus: relaxes on feeding to accommodate food without rise in pressure – vagus nerve controls this - Antrum: pumps and churns (3 waves/minute) to emulsify contents

Answer 139

- Surface epithelial cells – HCO3- and mucus secretion - Mucous neck cells – mucous secretion - Parietal cells – HCl secretion - Chief cells – pepsinogen secretion

Answer 140

- microvilli | - secretory canaliculi

Answer 141

- Resting - Secreting - Early recycling - Late recycling

Answer 142

- pH of gastric juice about 0.8 so [H+] about 0.16 M (approx. isotonic HCl) - pH of plasma about 7.4 so [H+] about 4 x 10^-8 M - so [H+]juice/[H+]plasma about 4,000,000!! = the biggest biological gradient in the human body

Answer 143

CO2 CO2 (from blood) + H2O H2CO3 HCO3- (goes through basolateral membrane to blood) + H+ (goes through apical membrane to lumen) Carbonic anhydrase catalyses CO2 + H2O H2CO3

Answer 144

- active transport of H+ by ‘proton pump’ H+, K+-ATPase - K+ recycles via K+ ion channels (channels move it out, ATPase moves it back in) - Cl- secreted via Cl- ion channels

Answer 145

- 100 kDa catalytic alpha subunit - Glycosylated beta subunit necessary for full function - 1H+:1K+:1ATP stoichiometry - similar mechanism to Na+, K+-ATPase - conformational change driven by phosphorylation and dephosphorylation structure of the alpha subunit: - Nucleotide-binding - Phosphorylation - Actuator domains

Answer 146

- HCO3- leaves the cell passively by 1:1 exchange for Cl- - Exactly balances Cl- secretion at apical membrane - Basolateral Na+, K+-ATPase maintains intracellular [Na+] and [K+]

Answer 147

Amino acids -> G-cell -> gastrin (+ ACH - vagus nerve) -> ECL -> histamine -> parietal -> H+ into lumen H+ (pH <3.5) -> D-cell -> somatostatin -> G-cell -> gastrin etc.

Answer 148

- Gut epithelium senses the chemical content of the lumen - Luminal signal = nutrients - Basolateral signal = gut hormones - Nutrients -> signal transduction -> gut hormones

Answer 149

acini cells

Answer 150

duct cells pancreatic ductal bicarbonate secretion Ducts secrete up to 140 mM HCO3-

Answer 151

NaCl & H2O go through acini cells into duct

Answer 152

NaHCO3 & H2O go through duct cells into duct

Answer 153

- pepsinogen | - gastric lipase

Answer 154

- chief cells | - mucous cells

Answer 155

ghrelin and leptin ghrelin - stimulates appetite leptin - inhibits appetite

Answer 156

reduces dietary iron (Fe3+ -> Fe2+) for absorption in duodenum

Answer 157

they delay gastric emptying and induce satiety Nutrients -> gut hormones Nutrients -> vagal afferent -> satiety

Answer 158

enteroendocrine cells - Gut epithelium is the largest endocrine and sensory organ in the body - Functionally akin to taste buds? - oral taste receptors present on EEC (enteroendocrine cells)! - sweet, bitter etc.

Answer 159

Lower part of the stomach, antrum & pylorus

Answer 160

fundus and corpus

Answer 161

bit lower down in corpus

Answer 162

substances which promote secretion

Answer 163

- G-cell & nerve -> gastrin & ACh -> ECL cell -> histamine -> parietal cell -> H+ - This is the main way, rather than gastrin and ACh directly binding to parietal cells

Answer 164

- when histamine, gastrin, ACh bind to parietal cells -> intercellular messengers, increase in intracellular calcium with gastrin & ACh, increase in cAMP with histamine - tubulovesicles insert themselves into the membrane, producing a microvillus-like appearance – packed full of proton pumps - 6 – 10 x increase in number of proton pumps at surface

Answer 165

- Predominantly in the gastric antrum - Cytotoxin-associated gene protein A (CagA) – injected cytotoxin by H. pylori - Vacuolating toxin (VacA) – secreted cytotoxin by H. pylori - Peptidoglycan, lipopolysaccharide coating (PGN, LPS)

Answer 166

- Antrum is the site of gastrin release which is inhibited by somatostatin - Inflammation in the antrum inhibits somatostatin release, therefore increase H+ secretion

Answer 167

- Somatostatin works on/inhibits G cells (in antrum), ECL cells, and parietal cells (to some extent) - Gastric inhibitory phase – acidity in the antrum stimulates delta-cells to produce somatostatin and inhibit the G cells - In intestinal phase, secretin, CCK, GIP all work on delta-cells to increase somatostatin production and reduce acid secretion

Answer 168

triple therapy has been so effecive

Answer 169

- Potassium competitive acid blockers (P-CABs) in development (& use in the Far East) =faster onset and longer lasting but more reversible - It’s all to do with pH! - H. pylori tolerates very acid pH but only grows/divides at less acid pH (>5.5) - Clarithromycin, amoxicillin & tetracycline all work best in dividing cells - PPIs reduce acidity, enhancing antibiotic action (new P-CABs may give a longer lasting high pH) - Bismuth blocks H+ influx into H. pylori so enhance antibiotic action even as the effects of PPIs are diminishing with time

Answer 170

don’t cure the ulcer, they reduce the effect of the acid and let the ulcer cure, but as soon as you go off drugs, you develop ulcers again

Answer 171

mucus glycoproteins they are extrememly large glycoprotein polymers

Answer 172

- Main molecules are enormous thread-like glycoproteins = mucins - Allows things to move through – e.g. oxygen and digested food products - Also has particular mechanisms that bind to things, e.g. viruses and bacteria, that stop them gaining access to the underlying epithelial cells - Also have membrane-associated mucins – they can report and signal to the cell that things are changing – act as a last line of defence, like a receptor

Answer 173

- Particulates - Acid/pepsin - Toxins - Pathogens - Sperm – allow or block depending on time of cycle - Pharmaceuticals/gene therapies (problem for gene therapies for cystic fibrosis)

Answer 174

- Gastric/duodenal ulcers - Ulcerative colitis - Crohn’s disease - Dry eye - Xerostomia (dry mouth) (all the above due to a loss of a barrier/loss of mucus)

Answer 175

- Antrum – more than corpus, duodenum and jejunum - Ileum – thickness increases a lot - Colon – thickness increases even more - Firmly adherent mucous layer increases bit in antrum and colon - Loosely adherent mucus layer causes the biggest changes - Nearer the epithelium you are, the firmer the mucus is and the nearer the lumen, the looser the mucus is

Answer 176

- Adherent layer (molecules tight and compact – small pore size – stops things from physically getting through) - Loose layer (nearer the lumen)

Answer 177

In the loose layer you have the beneficial bacteria and pathogens (commensal bacteria can become pathogenic if its not in the environment it should be – e.g. if it doesn’t stay in the loose layer of the mucus)

Answer 178

- Resistant barrier (physical & chemical) – as well as pathogens and commensal bacteria - Viscous highly hydrated layer - Prevents dehydration of mucosal surfaces (by binding a lot of water), provides lubrication for movement of luminal contents in the gut - Porous to large macromolecules up to very small particulate matter (not cellular microbes) - Allows absorption and secretion to continue - Self-organises around particulate matter and promotes its clearance (mechanism is unclear)

Answer 179

Mucus is a viscoelastic material: it has the viscous behaviour of a liquid and the elastic properties of a solid - Mostly water and ions – 90% - Proteins (glycoproteins) – 5-10% - Mucus glycoproteins (mucins) – 1-5% (what gives it its physical form)

Answer 180

- Protein rope with many sugars attached, repeated over and over again - Up to 80% of mass of one of molecules due to these sugars - The middle part of molecule with all the sugar has receptors that different bacteria can bind to - The long ropes take up lots of space, so when you get many of these together they intertwine with one another and they form gels - When you have a low concentration of these molecules, you have a loose gel, when you have a high concentration you form a gel that’s very tight

Answer 181

- 5 identified members - MUC 2, 5AC, 5B, 6 and 19 - Share some generic structure - Corpus and antrum = MUC5AC & MUC6 - Small intestine & colon = MUC 2 - Both genes make different types of gel

Answer 182

- Space filling – gel formation - Protease resistance (host, viral or bacterial) - Pathogen binding/evasion/killing

Answer 183

- Entanglement | - Cross links

Answer 184

- If most of the molecule is covered in sugars, protease can’t damage it - There are sites (at the beginning and end of each monomer) that can be cleaved, but it takes a lot longer to dismantle this barrier

Answer 185

- Most mucosal bacterial pathogens are flagellated – allows them to swim in mucus - Many mucosal pathogens produce enzymes to degrade the mucins and thereby disassemble the mucus barrier (enzymes that chop up the proteins and sugars) - Bacteria produce soluble toxins which can kill epithelial cells and/or arrest intestinal cell division - Many pathogens attach to the apical surface of epithelial cells and inject bacterial toxins - Many mucosal toxins disable tight junctions between adjacent epithelial cells

Answer 186

MECHANISM OF HOST DEFENCE: ‘SUGAR-COATED CELLS’ - All cells have their own sugar coat as well - So closer to the surface you have another line of defense

Answer 187

EPITHELIAL CELL SURFACE TRANSMEMBRANE (Tm) MUCINS - Important as a last line of defence - Outer part of the molecule (extracellular portion) can become detached, which sends signals to the cell that something’s happening and that it might need to replenish its mucous barrier

Answer 188

- Sugars on the outside of mucus gel – binds bacteria - The mucus gel has 100s/1000s of sugars that it can bind to - If there’s some disruption in mucus gel, the bacteria can get through and bind to sugars on the epithelial cell surface, so that it can try and get in - However, the sugars on the cell surface get shed and go through the mucus and out of it with the bacteria

Answer 189

- Majority of people are asymptomatic or have very mild symptoms - 90% of infected individuals develop chronic inflammation with persistent infection (gastritis) - Serious resulting pathologies from chronic gastritis: - gastric and duodenal ulcers - gastric carcinoma (5% of world cancer burden)

Answer 190

- Adhesin genes (colonisation) (sugar-binding proteins on Helicobacter) - SabA gene – sialic acid (sugar) binding adhesin - BabA gene – Lewis b binding adhesin

Answer 191

- CagA pathogenicity island (epithelial pathology) - CagA gene – type IV secretion system, disabling of epithelial tight junctions - VacA gene – cytotoxin

Answer 192

- MUC5AC - MUC6 - Closer to the lumen there’s more MUC5AC, whereas MUC6 seems to be much closer to the epithelial surface

Answer 193

H. pylori has adhesins for glycan structures on cell surface glycoproteins and glycolipids found on the gastric epithelial surface – BabA (Le^b) and SabA (Le^a and sialyl-Le^x) - MUC5AC – binding – has many sugars that these bacteria lectins are able to bind to - MUC6 – growth inhibition (if MUC5AC is ineffective at blocking bacteria) = mucus layer (both of them) - Glycans on MUC5AC (Le^b and Sialyl Le^x) are shared with cell surface MUC1 - Glycans on MUC6 (alpha 1-4 GlcNAc) inhibit cell wall synthesis of H. pylori and prevent infection - MUC1 is shed from the cell surface (epithelial) when H. pylori binds So, there is a system of binding, then killing, and then binding

Answer 194

- The process by which a person controls their own life

Answer 195

``` Gastric ulcers - Increase pain when eating – presence of food, HCl production - Associated with weight loss Duodenal ulcers - Decrease pain when eating - Associated with weight gain ```

Answer 196

production of dark sticky faeces containing partly digested blood, as a result of internal bleeding or the swallowing of blood

Answer 197

- Forms a gel in the highly-acidic stomach and protects the stomach mucosa - Antacids work by counteracting (neutralising) the acid in your stomach - Most alginates work by forming a gel which floats on top of the stomach contents - The get acts as a protective barrier, preventing stomach acid from irritating the oesophagus - some antacids also contain a medicine called an alginate, which produces a protective coating on the lining of your stomach - antacids should be taken when you experience symptoms or when you expect them, such as after meals or at bedtime - antacids containing alginates are best taken after meals

Case 2 Flashcards

(225 cards)