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Author: Andrew Plaut, M.D.
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1. Objectives: Stomach and Ulcer Disease

  1. Understand the normal functions of the stomach

  2. Understand the production and regulation of gastric acid secretion

  3. Understand the importance of the proton pump (H+-K+ ATPase)

  4. To be able to describe how gastric acid secretion may be inhibited

  5. To understand and describe the gastric mucosal barrier

  6. Understand gastric and duodenal disorders associated with low, normal, or high gastric acid production

  7. To understand the pathophysiology of peptic ulcer disease (gastric and duodenal ulcers)

  8. To understand the importance of H pylori in peptic ulcer disease

  9. 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

  1. Vomiting

  2. Makes food isosmotic

  3. Emptying - or solids, 4 hours for most foods; fats are delayed

  4. Production and conversion of pepsinogen

    1. Converted to pepsin at pH below 3.5

    2. Pepsin is inactive at pH 4 and above

  5. Anti-microbial

  6. Stomach is designed to secrete: surface impermeable to water and H+; gastric fundus epithelium has very tight junction; antrum somewhat more leaky

  7. Parietal cells :

    1. Middle region of the gastric oxyntic gland

    2. Secretory unit of the gastric mucosa.

    3. Other cells are the chief, mucus neck and somatostatin cells

    4. Parietal cells number about one billion in an adult

    5. Parietal cell number correlate with maximum acid output, not basal output

    6. Contain H+/K+ ATPase = “proton pump”

    7. Resting parietal cells:

      1. Filled with secretory vesicles that form channels communicating with the apex of the cell (i.e., the lumen) within 3 minutes of stimulation

      2. Microvilli recede after secretion is over

2.2. Major influences that tightly regulate gastric acid secretion:

2.2.1. Paracrine (histamine; somatostatin)

  1. Histamine :

    1. Arises from histidine decarboxylase activity of the stomach mucosa

    2. Found mainly in mucosal mast cells and ECL cells, in the oxyntic glands

    3. Histamine release from ECL (not mast cells) is strongly gastrin-stimulated, and is the major mediator of gastric acid secretion

    4. Interacts with both gastrin and acetylcholine in potentiating secretion; apparently, histamine must occupy its receptor for acetylcholine and gastrin to have full action

    5. 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)

  1. Gastrin :

    1. Discovered in 1906 by Edkins

    2. Produced by G cell in antrum

    3. 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.

    4. 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.

    5. Alkalinization is a minor gastrin release stimulator

    6. Major inhibitor of gastrin release is acid, a simple negative feedback loop

    7. 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.

    8. 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)

  1. Acetylcholine :

    1. From muscarinic vagus nerve cholinergic neurons

    2. Vital for gastric emptying and contraction

    3. Amino acids stimulate acetylcholine release from cholinergic neurons

    4. Major function is stimulation of gastrin release from G cells

    5. Vagus also stimulates parietal cells directly to form acid

    6. Acetylcholine inhibits somatostatin secretion by D cell

    7. Acetylcholine mediates various gastric reflexes, including distension-related secretion

  2. Calcium :

    1. 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

  1. Somatostatin :

    1. From D cells; production strongly stimulated by gastrin, and inhibited by acetylcholine

    2. Potent inhibitor of acid secretion—major effect is blocking gastrin effect on secretion

    3. Potent inhibitor of gastrin synthesis and gastrin release

    4. Mice without the somatostatin receptor have 10-fold higher BAO

2.2.5. If stomach makes HCI, where does all that H+ come from?

  1. Production of hydrogen is probably from water, and hydrogen ion in the stomach contents is 3 million-fold more than in serum

  2. Plasma to gastric lumen pH gradient is about 6.6, unprecedented elsewhere in mammalian biology

2.3. H+/K+ ATPase exchange pump

  1. Always in an active state, even in resting parietal cells

    1. 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.

      1. Pump utilizes energy in ATP to exchange H+ for K+

      2. 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.

      3. When secretion stops the H/K ATPase pump is internalized, a function of its beta subunit

2.4. Stomach secretion during eating and digestion

  1. BAO, MAO and digestive phases of acid secretion:

    1. BAO about 2 Meq/hr, definitely less than 10 in normals

    2. MAO stimulated by gastrin infusion: about 30 meq/hr, upper limit is 60

  2. There are three digestive phases of acid secretion: cephalic, gastric and intestinal .

  3. Physiologic brakes on acid secretion:

    1. Carbohydrate foods, via intestinal mechanism

    2. Fats, via stimulation of CCK, an inhibitor of acid production

    3. Post-prandial acidification of the antrum, reducing gastrin secretion

  4. Protection of Gastric Mucosa

    1. 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

    2. 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.

    3. Gastric mucosal cells probably have a mechanism for defending against back-diffused H+

      1. By pumps e.g. as Na/H on the basolateral surface

      2. By blood flow, which promotes H+ dispersion and O2 delivery

      3. By continual sloughing of mucosal epithelial cells

      4. By prostaglandins: promote blood flow, and mucus and bicarbonate secretions

    4. The gastric mucosal barrier:

      1. A physiological concept.

      2. Existence is manifest as electrical potential difference between mucosa and serosa

      3. These drugs change the barrier: ASA, alcohol, high dose bile acids

      4. 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.

  1. No acid: pernicious anemia

    1. 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

  2. Low or normal acid: gastric ulcer

  3. Normal or high gastric acid: duodenal ulcer

  4. Massive acid production: Zollinger-Ellison syndrome: a non-beta cell tumor of pancreas

2.5.1. Duodenal ulcer

  1. DU incidence
    1.81000--men
    0.81000--women

  2. 10% of North American persons will eventually have DU

  3. Predisposing factors: Male, family history of DU, cigarettes, chronic obstructive pulmonary disease (ulcer independent of smoking).

  4. Not predisposing: alcoholism, hypertension

  5. Stress? No measureable higher risk among air traffic controllers vs. ticket agents.

  6. Most often starts at age 40-50, and is self-limited

  7. The stomach of duodenal ulcer :

    1. Basal acid twice normal

    2. High acid response to standard meal: ll6% of MAO (nls 86%)

    3. Empty faster

    4. Hypersensitivity of parietal cells to gastrin (but gastrin levels are normal after a meal)

  8. Helicobacter pylori:

    1. Detection in 1983 in Australia by Marshall, a gastroenterologist, and Warren, a pathologist

    2. Role of H. pylori in ulcer pathogenesis originally disbelieved

      1. Evidence for H. pylori role in gastric ulcer and gastritis

        1. Colonization by H. pylori precedes development of ulcer

        2. Eradication of H. pylori interrupts cycle of ulcer-treatment-recurrent ulcer

        3. Human volunteer infection

        4. Animal models

    3. H. pylori is microaerophilic, Gram negative, spiral shaped, multiple polar flagella, and urease-positive.

    4. Who has Helicobacter pylori in North America?

      1. 70% of patients with DU who have not used NSAIDs to excess

      2. 65-95% with GU (but in only 45% of patients with NSAID-related GU)

      3. Almost all patients with type B antral gastritis.

      4. About 10-20% of people with non-ulcer dyspepsia (patients with typical symptoms of ulcer disease but without ulcers of endoscopic or radiologic evaluation)

      5. 10-20% in entirely normal people

      6. Almost never found in children under 10, and rare in teens

    5. 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.

    6. 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

    7. Helicobacter has a role in gastric cancer, adenocarcinoma and the much less frequent MALT (mucosa associated lymphoid tissue) lymphoma

    8. Diagnosis of H.pylori:

      1. Culture (rarely used)

      2. Pathologically – special stains on gastric biopsy specimens

      3. Rapid urease testing on gastric biopsy testing

      4. Urea breath test

    9. Treatment of H.pylori is with antibiotics + acid suppression

2.5.2. Gastric ulcer

  1. Nonsteroidals anti-inflammatory drugs :

    1. Clearly ulcerogenic in chronic users, and more troublesome in older individuals.

    2. 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.

    3. 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.

    4. 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.

    5. What protects the stomach from NSAIDS under normal circumstances?

      1. Mucus. NSAIDS are uncharged at gastric pH, so diffuse easily into mucosa

      2. Superoxide scavengers e.g. glutathione present in the gastric mucosa

      3. Bicarbonate, acting as acid buffer

      4. High blood supply of stomach, promoting repair and cellular metabolic functions

    6. So who will get NSAID-induced damage most often?

      1. Sons with a history of ulcer disease, dyspepsia or gastritis

      2. Older persons, assumed to have lower gastric perfusion

      3. Persons on high NSAID dose, and for prolonged times

      4. Persons on corticosteroids (block cyclooxygenases, as do NSAIDS)

      5. Persons on anticoagulants

    7. NSAIDs produce two kinds of mucosal lesions:

      1. 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.

      2. 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).

    8. Prevention of NSAID-induced gastric injury:

      1. Misoprostil (a prostaglandin analogue) may be of clinical value in preventing NSAID-induced ulcers, but it causes diarrhea, limiting its use.

      2. 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).

      3. H2 inhibitors have no known benefit in preventing injury.

      4. 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)

  1. A condition affecting about 1% of patients with peptic ulcer

  2. About 1/5 of affected persons have other endocrine abnormalities

  3. 90% have ulcer; 35% diarrhea (sometimes the presenting symptom)

  4. Very high basal acid production

  5. Tumor location is typically pancreatic, but l4% in duodenal wall. Never occur in pre-pyloric antrum.

  6. Tumor may be too small to find surgically, or by imaging studies

  7. About half are malignant when first found; spread is to local nodes, and less often distant metastases to liver and bone

  8. 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.

  9. Therapy

    1. Surgical resection

    2. 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.