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1. Objectives: Stomach and Ulcer Disease
Understand the normal functions of the stomach
Understand the production and regulation of gastric acid secretion
Understand the importance of the proton pump (H+-K+ ATPase)
To be able to describe how gastric acid secretion may be inhibited
To understand and describe the gastric mucosal barrier
Understand gastric and duodenal disorders associated with low, normal, or high gastric acid production
To understand the pathophysiology of peptic ulcer disease (gastric and duodenal ulcers)
To understand the importance of H pylori in peptic ulcer disease
To be able to describe the effect of NSAIDs on the stomach
2. Stomach and Ulcer Disease
Abbreviations: ECL (enterochromaffin-like cells); BAO (basal acid output); MAO (maximal acid output); Z.E. - Zollinger Ellison syndrome; DU (duodenal ulcer); GU (gastric ulcer).
2.1. Functions of stomach
Makes food isosmotic
Emptying - or solids, 4 hours for most foods; fats are delayed
Production and conversion of pepsinogen
Converted to pepsin at pH below 3.5
Pepsin is inactive at pH 4 and above
Stomach is designed to secrete: surface impermeable to water and H+; gastric fundus epithelium has very tight junction; antrum somewhat more leaky
Parietal cells :
Middle region of the gastric oxyntic gland
Secretory unit of the gastric mucosa.
Other cells are the chief, mucus neck and somatostatin cells
Parietal cells number about one billion in an adult
Parietal cell number correlate with maximum acid output, not basal output
Contain H+/K+ ATPase = “proton pump”
Resting parietal cells:
Filled with secretory vesicles that form channels communicating with the apex of the cell (i.e., the lumen) within 3 minutes of stimulation
Microvilli recede after secretion is over
2.2. Major influences that tightly regulate gastric acid secretion:
2.2.1. Paracrine (histamine; somatostatin)
Arises from histidine decarboxylase activity of the stomach mucosa
Found mainly in mucosal mast cells and ECL cells, in the oxyntic glands
Histamine release from ECL (not mast cells) is strongly gastrin-stimulated, and is the major mediator of gastric acid secretion
Interacts with both gastrin and acetylcholine in potentiating secretion; apparently, histamine must occupy its receptor for acetylcholine and gastrin to have full action
Further evidence of the importance of histamine is that H2 blockers reduce acid secretion from all of the stimuli mentioned above
2.2.2. Endocrine (gastrin)
Discovered in 1906 by Edkins
Produced by G cell in antrum
Trophic for parietal cells and for histamine-secreting enterochromaffin-like (ECL cells) that make histamine. Thus antrectomy (surgical resection of the gastric antrum) reduces gastrin levels, hence parietal cell numbers.
Release of gastrin is by 1) peptides and amino acids, not proteins and 2) distension of stomach. Minor distension inhibits acid secretion via VIP (which stimulate somatostatin release). Major distension stimulates cholinergic system, increasing gastrin and decreasing somatostatin.
Alkalinization is a minor gastrin release stimulator
Major inhibitor of gastrin release is acid, a simple negative feedback loop
CCK B/gastrin receptor of human and dog parietal cells was first expression-cloned by Kopin, Beinborn, and Lee here at Tufts-New England Medical Center. It is a typical seven transmembrane G protein binding receptor. It has about the same affinity for gastrin and CCK.
A gastrin receptor is apparently found on D cells as well—but it is a CCK-A receptor which binds CCK much more avidly than gastrin
2.2.3. Neural (acetylcholine, via the post-ganglionic vagus)
From muscarinic vagus nerve cholinergic neurons
Vital for gastric emptying and contraction
Amino acids stimulate acetylcholine release from cholinergic neurons
Major function is stimulation of gastrin release from G cells
Vagus also stimulates parietal cells directly to form acid
Acetylcholine inhibits somatostatin secretion by D cell
Acetylcholine mediates various gastric reflexes, including distension-related secretion
I.V. bolus increases acid production in normals (note: it is dangerous to infuse a calcium bolus intravenously)
2.2.4. Cessation of acid secretion
From D cells; production strongly stimulated by gastrin, and inhibited by acetylcholine
Potent inhibitor of acid secretion—major effect is blocking gastrin effect on secretion
Potent inhibitor of gastrin synthesis and gastrin release
Mice without the somatostatin receptor have 10-fold higher BAO
2.2.5. If stomach makes HCI, where does all that H+ come from?
Production of hydrogen is probably from water, and hydrogen ion in the stomach contents is 3 million-fold more than in serum
Plasma to gastric lumen pH gradient is about 6.6, unprecedented elsewhere in mammalian biology
2.3. H+/K+ ATPase exchange pump
Always in an active state, even in resting parietal cells
Resting vesicular membranes have no carrier for K+, so can't use the pump, despite its being active. This is because H+ cannot enter the vesicle without the vesicle containing sufficient K+ for the exchange. To meet this need, the active membrane has a co-transporter for K+ and Cl- (this transports chloride and potassium into the vesicle (outside cell), such that chloride is a counter-ion for hydrogen, and potassium is available for exchange.
Pump utilizes energy in ATP to exchange H+ for K+
Pump has alpha and beta subunits, the alpha having several loops through the parietal cell membrane. Parietal cell antibodies in patients who have autoimmune, type A gastritis, are against beta subunit.
When secretion stops the H/K ATPase pump is internalized, a function of its beta subunit
2.4. Stomach secretion during eating and digestion
BAO, MAO and digestive phases of acid secretion:
BAO about 2 Meq/hr, definitely less than 10 in normals
MAO stimulated by gastrin infusion: about 30 meq/hr, upper limit is 60
There are three digestive phases of acid secretion: cephalic, gastric and intestinal .
Physiologic brakes on acid secretion:
Carbohydrate foods, via intestinal mechanism
Fats, via stimulation of CCK, an inhibitor of acid production
Post-prandial acidification of the antrum, reducing gastrin secretion
Protection of Gastric Mucosa
Apical gastric mucosa is intrinsically resistant to acid as high as pH 2.2. Serosal (baso-lateral) surface is damaged severely by pH 5.5
Likely role of mucus and bicarbonate. Surface of mucosa nearly neutral pH with respect to the markedly acidic pH of the lumen. Interested students can find a good experimental paper on this at: Chu et. al. Dynamic regulation of gastric surface pH by luminal pH. J. Clin. Investigation v. 103, p 605, March 1999.
Gastric mucosal cells probably have a mechanism for defending against back-diffused H+
By pumps e.g. as Na/H on the basolateral surface
By blood flow, which promotes H+ dispersion and O2 delivery
By continual sloughing of mucosal epithelial cells
By prostaglandins: promote blood flow, and mucus and bicarbonate secretions
The gastric mucosal barrier:
A physiological concept.
Existence is manifest as electrical potential difference between mucosa and serosa
These drugs change the barrier: ASA, alcohol, high dose bile acids
These things do not change barrier at usual dose: steroids, caffeine, NSAIDs
2.5. Gastric and duodenal disease related to acid production
There are clinical illnesses that involve gastric secretion ranging in scope from no acid production whatsoever, lower and higher than average secretion, and even uncontrolled, massive secretion.
No acid: pernicious anemia
Pernicious anemia is a disorder associated with chronic atrophic gastritis. 90% of patients have anti-parietal cell antibodies which leads to reduced acid production and reduced secretion of intrinsic factor (normally produced by parietal cells). The absence of intrinsic factor leads to vitamin B12 deficiency (intrinsic factor is required for B12 absorption) and subsequently anemia
Low or normal acid: gastric ulcer
Normal or high gastric acid: duodenal ulcer
Massive acid production: Zollinger-Ellison syndrome: a non-beta cell tumor of pancreas
2.5.1. Duodenal ulcer
10% of North American persons will eventually have DU
Predisposing factors: Male, family history of DU, cigarettes, chronic obstructive pulmonary disease (ulcer independent of smoking).
Not predisposing: alcoholism, hypertension
Stress? No measureable higher risk among air traffic controllers vs. ticket agents.
Most often starts at age 40-50, and is self-limited
The stomach of duodenal ulcer :
Basal acid twice normal
High acid response to standard meal: ll6% of MAO (nls 86%)
Hypersensitivity of parietal cells to gastrin (but gastrin levels are normal after a meal)
Detection in 1983 in Australia by Marshall, a gastroenterologist, and Warren, a pathologist
Role of H. pylori in ulcer pathogenesis originally disbelieved
Evidence for H. pylori role in gastric ulcer and gastritis
Colonization by H. pylori precedes development of ulcer
Eradication of H. pylori interrupts cycle of ulcer-treatment-recurrent ulcer
Human volunteer infection
H. pylori is microaerophilic, Gram negative, spiral shaped, multiple polar flagella, and urease-positive.
Who has Helicobacter pylori in North America?
70% of patients with DU who have not used NSAIDs to excess
65-95% with GU (but in only 45% of patients with NSAID-related GU)
Almost all patients with type B antral gastritis.
About 10-20% of people with non-ulcer dyspepsia (patients with typical symptoms of ulcer disease but without ulcers of endoscopic or radiologic evaluation)
10-20% in entirely normal people
Almost never found in children under 10, and rare in teens
CagA positive H. pylori (cag=cytotoxin associated gene) co-express vacuolating VacA, a cell cytotoxin. In patients with duodenal and gastric ulcer the recovered H. pylori strains are 90% CagA positive strains. In contrast, Helicobacter found in asymptomatic people are about 60% CagA positive. Helicobacter strains recovered from patients who take NSAIDs and have an ulcer are only CagA positive in 45% of persons.
Pathology: Inflammation is mononuclear and polymorphonuclear infiltrate. H. pylori is a potent stimulus to inflammatory response by stimulating chemoattractant IL-8, in addition to IL-1, Il-6 and TNF-α
Helicobacter has a role in gastric cancer, adenocarcinoma and the much less frequent MALT (mucosa associated lymphoid tissue) lymphoma
Diagnosis of H.pylori:
Culture (rarely used)
Pathologically – special stains on gastric biopsy specimens
Rapid urease testing on gastric biopsy testing
Urea breath test
Treatment of H.pylori is with antibiotics + acid suppression
2.5.2. Gastric ulcer
Nonsteroidals anti-inflammatory drugs :
Clearly ulcerogenic in chronic users, and more troublesome in older individuals.
20% of chronic users will have true ulcer disease. If one endoscopes persons taking chronic NSAIDS irrespective of symptoms, 20-30% will have a GU, and about 1% will have a DU.
Onset may be very rapid, or may take years. Patients are often completely unaware that they have mucosal injury; i.e., these problems may be asymptomatic.
Ulcers have less surrounding inflammation than those induced by H. pylori. H. pylori is not a documented risk factor for NSAID-induced gastric injury, and its eradication prior to therapy is of unproven benefit, but thought by some to be useful.
What protects the stomach from NSAIDS under normal circumstances?
Mucus. NSAIDS are uncharged at gastric pH, so diffuse easily into mucosa
Superoxide scavengers e.g. glutathione present in the gastric mucosa
Bicarbonate, acting as acid buffer
High blood supply of stomach, promoting repair and cellular metabolic functions
So who will get NSAID-induced damage most often?
Sons with a history of ulcer disease, dyspepsia or gastritis
Older persons, assumed to have lower gastric perfusion
Persons on high NSAID dose, and for prolonged times
Persons on corticosteroids (block cyclooxygenases, as do NSAIDS)
Persons on anticoagulants
NSAIDs produce two kinds of mucosal lesions:
Superficial mucosal damage, an irritative topical effect, probably not of much importance except for occult bleeding. Most often seen in regular aspirin users. Helped by enteric coated aspirin.
Major chronic ulceration, a systemic effect, related to inhibition of prostaglandin synthesis, as all these drugs inhibit cyclooxygenase (the enzyme that converts cyclic endoperoxides from arachidonic acid for formation of prostaglandins).
Prevention of NSAID-induced gastric injury:
Misoprostil (a prostaglandin analogue) may be of clinical value in preventing NSAID-induced ulcers, but it causes diarrhea, limiting its use.
In persons with a history of ulcer, omprezole at 20 mgm daily is known to prevent both duodenal and gastric ulcers when NSAIDs are used (three month study).
H2 inhibitors have no known benefit in preventing injury.
Cox-2 cyclooxygenase inhibitors. Have much less effect on gastric mucosal cyclooxygenase, which is Cox-1. Cox-1 enzymes are found in most tissues, including those mediating gastric mucosal repair in the stomach. Cox-2 are induced by inflammation, and are the appropriate target for NSAID use. Cox-2 inhibitors have very high selectivity for inhibiting cox-2 vs. cox-1 cyclooxygenases
2.5.3. Zollinger Ellison syndrome (gastrinoma)
A condition affecting about 1% of patients with peptic ulcer
About 1/5 of affected persons have other endocrine abnormalities
90% have ulcer; 35% diarrhea (sometimes the presenting symptom)
Very high basal acid production
Tumor location is typically pancreatic, but l4% in duodenal wall. Never occur in pre-pyloric antrum.
Tumor may be too small to find surgically, or by imaging studies
About half are malignant when first found; spread is to local nodes, and less often distant metastases to liver and bone
Diagnosis is by recognition of elevated serum gastrin level in ulcer patient or someone with unexplained chronic diarrhea. Indeterminant result (200-1000 pg/Ml) requires confirmatory secretin infusion test.
Acid suppression requires very high doses of proton pump inhibitors
Postscript : The discovery of Heliobacter pylori and its presumed relationship to acid/peptic disease overturned, or at least stringently modified, a full ninety years of scientific and clinical ideas that placed hydrochloric acid as the main element in ulcer diseases. More such seismic shifts in knowledge and its application will occur in your medical lifetime. Remain vigilant, informed, and, above all, open to observations that you yourself may make in one of your patients.