Peptic ulcer pathophysiology
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Peptic ulcer pathophysiology On the Web |
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Risk calculators and risk factors for Peptic ulcer pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]
Overview
A major causative factor (60% of gastric and 90% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori that colonize the antral mucosa. The immune system is unable to clear the infection, despite the appearance of antibodies. Thus, the bacterium can cause a chronic active gastritis known as type B gastritis. This results in a defect in gastrin production leading to increasedgastrin secretion. Gastrin stimulates the production of gastric acid by the parietal cells. The acid erodes the mucosa and causes the ulcer. Another major cause of peptic ulcer disease is the chronic use of NSAIDs The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins. NSAIDs block the function of cyclooxygenase 1 (cox-1), which is essential for the production of these prostaglandins.
Pathophysiology
Peptic ulcer occurs due to distruption of muscularis mucosa which is required in the maintenance of the integrity of the gastric mucosa
Defensive mechanism of gastric mucosa
Mucosal barrier consists of three protective components which include:[1][2][3][4]
- Layer of epithelial cell lining which is bound by tight junctions that repel fluids
- Layer of mucus, secreted by surface epithelial cells and foveolar cells which forms a protective gel-like coating over the entire gastric mucosal surface
- Layer of bicarbonate ions, secreted by the surface epithelial cells which neutralize acids
Source:Wikimedia Commons [5]
The two most important etiological factors in the development of PUD are:[6][7][8]
Role of Helicobacter pylori
Penetration
Factors that help in penetration and growth of Helicobacter pylori are:[9][10]
- Bicarbonate-mediated chemotactic motility of Helicobacter pylori which facilitates its penetration
- Neutral pH favors the growth of helicobacter pylori
Colonzation:
- The colonization of virulent CagA-positive Helicobacter pylori strains leads to the degeneration of surface epithelial cells
- This degeneration results in increased exfoliation of surface epithelial cells
- The exfoliation mediated compensatory cell proliferation leads to the movement of immature cells to the foveolae and surface
- Immature cells leads to impaired mucin and bicarbonate production and the integrity of the mucous barrier may be compromised
- All of above factors lead to activation of complement via the alternative pathway and the release of chemical mediators by mast cells and activated polymorphs may lead to microvascular disturbances and focal ischemic damage to the surface epithelium
- Helicobacter pylori infection down-regulates E-cadherin expression in gastric epithelial cells which affect the resistance of the mucosa to acid attack
- Decreased mucus production, release of chemical mediators and down-regulation of E- cadherin leads to mucosal damage leads to ulcer formation[11][12][13]
Immunological response
Factors responsible for immunological response of Helicobacter pylori are :
- Helicobacter pylori infection triggers local production various proinflammatory mediators (cytokines, neutrophil infiltration, specific T- and B- cells)
- Of all the cytotoxins and virulence factors Cag A, VacA, and OipA play a key role in the pathogenesis of Helicobacter pylori infection
- Cag A, VacA, and OipA not only helps in the colonization of Helicobacter pylori but and also modulates host's immune system
- Bacterial factors and complement activation leads to neutrophilic activation including reactive oxygen,release of leukocytes enzymes and leukotriens lead to mucosal injury [14] [15][16][17][7]
- Helicobacter pylori secretes various enzyme :Urease,Phospholipases,Alcohol dehydrogenase and Catalases- causes damage the host gastric muscosa by generating toxic metabolities[18][19][20]
| Helicobacter pylori infection | |||||||||||||||||||||||||||||||||||||
| Inflammatory response secretes IL-8 ,IL-1b | Production of alkaline ammonia | Production of urease bacterial phospholipase A | |||||||||||||||||||||||||||||||||||
| Infux ofneutophilsandmacrophages release of lysosomal enzymes leukotrienes (LT)and reactive oxygen | Inhibition of D-cells leads to inappropriate release of somatostatin and hypergastrinemia | Production of urease ,phospholipase A and C release toxic metabolities | |||||||||||||||||||||||||||||||||||
| Mucosal injury | |||||||||||||||||||||||||||||||||||||
Role of Helicobacter pylori in causing gastric ulcer
- Factors responsible for ulcer formation:[21]
- There is decrease in acid and decrease in parietal cell volume which further predisposes to development to ulcer formation.[13]
Role of Helicobacter pylori in causing duodenal ulcer
- Factors responsible for ulcer formation:
- Hypergastrenemia which leads to low pH
- Decreased in bicarbonate secretion
- Both of these factors leads to gastric metaplasia induced duodenitis [22][23][24][25][26]
Role of NSAIDS
- NSAID's are more commonly responsible for gastric ulcers than duodenal ulcers
- NSAID's cause ulcers by following mechanism:[27][28][29]
- Inhibit systemic prostaglandins production
- Decreases blood flow
- Decreases mucus production
- Inhibits leucocyte adhesion
- Inhibit systemic prostaglandins production
| NSAIDs | |||||||||||||||||||||||||||||||||||||
| COX-1 inhibitor | Topical irritation | COX-2 inhibitor | |||||||||||||||||||||||||||||||||||
| Decreased blood flow | Epithelial damage | Inhibit leucocyte adhesion | |||||||||||||||||||||||||||||||||||
| Mucosal injury | |||||||||||||||||||||||||||||||||||||
Other factors
Other factors responsible for peptic ulcer disease:
Smoking
- Decreases the production of prostaglandins
- Triggers reflux of bile acids into the duodenum which results in alteration of blood flow leading to ischaemia
Severe stress
- Severe stress eg: brain injury, burns causes increase in production of gastric acid and increases the risk of ulcer formation
Genetics
- Genes involved in the pathogenesis of peptic ulcer disease include:[31][32]
- cagA
- vacA
Associated Conditions
- The conditions associated with infection caused by helicobacter pylori include:[33][34][35][36][37]
- Gastric cancer
- Gastric mucosa-associated lymphoid tissue lymphoma (MALT)
- Idiopathic thrombocytopenic purpura
Gross Pathology
- Gastric ulcers are most often localized on the lesser curvature of the stomach
- Duodenal ulcers are more located at bulb of duodenum
- Characteristic findings of a peptic ulcer on gross pathology include:
- Round to oval
- Two to four cm diameter
- Smooth base with perpendicular borders.
- Parietal scarring with radial folds may be evident in the surrounding mucosa
-
A benign gastric ulcer (from the antrum) of a gastrectomy Source:https://commons.wikimedia.org/wiki/File:Benign_gastric_ulcer_1.jpg#/media/File:Benign_gastric_ulcer_1.jpg
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Duodenal ulcer specimen. Source: https://commons.wikimedia.org/wiki/File:Duodenal_ulcer01.jpg#/media/File:Duodenal_ulcer01.jpg
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Gastric ulcer specimen Source:https://commons.wikimedia.org/wiki/File:Gastric_ulcer_3.jpg#/media/File:Gastric_ulcer_3.jpg
.jpg)
Microscopic Pathology
- A peptic ulcer is a mucosal defect produced by acid-pepsin aggression which penetrates the muscularis mucosae and muscularis propria
- There is increased plasma cells, neutrophilic infiltrate, villous blunting
- The surface epithelium usually shows mucous cell (pseudopyloric) metaplasia
- During the active phase, the base of the ulcer shows 4 zones:
- Inflammatory exudate: polymorphonuclear infiltration which along with bacterial products stimulate the production of IL-8 and tumor necrosis factor alpha (TNF-α) and IL-1 released by macrophages in response to bacterial lipopolysaccharide
- Fibrinoid necrosis
- Granulation tissue
- Fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis[38]
.jpg)
References
- ↑ Butler BD, Lichtenberger LM |title=Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach |journal=Am. J. Physiol. |volume=244 |issue=5 |pages=G561–8 |year=1983 |pmid=6846549 |doi= |url=}}
- ↑ Clamp JR, Ene D (1989). "The gastric mucosal barrier". Methods Find Exp Clin Pharmacol. 11 Suppl 1: 19–25. PMID 2657286.
- ↑ Werther JL (2000). "The gastric mucosal barrier". Mt. Sinai J. Med. 67 (1): 41–53. PMID 10677782.
- ↑ Forssell H (1988). "Gastric mucosal defence mechanisms: a brief review". Scand. J. Gastroenterol. Suppl. 155: 23–8. PMID 3072665.
- ↑ By M•Komorniczak(http://creativecommons.org/licenses/by/3.0)
- ↑ url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307 |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}
- ↑ 7.0 7.1 "Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM".
- ↑ Hawkey CJ (1999). "Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance". Aliment. Pharmacol. Ther. 13 (6): 695–702. PMID 10383497.
- ↑ Kusters JG, van Vliet AH, Kuipers EJ (2006). "Pathogenesis of Helicobacter pylori infection". Clin. Microbiol. Rev. 19 (3): 449–90. doi:10.1128/CMR.00054-05. PMC 1539101. PMID 16847081.
- ↑ Huang JQ, Sridhar S, Hunt RH (2002). "Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis". Lancet. 359 (9300): 14–22. doi:10.1016/S0140-6736(02)07273-2. PMID 11809181.
- ↑ Kim JS, Jung HC, Kim JM, Song IS, Kim CY (1998). "Interleukin-8 expression by human neutrophils activated by Helicobacter pylori soluble proteins". Scand. J. Gastroenterol. 33 (12): 1249–55. PMID 9930387.
- ↑ Kimura K (1972). "Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach". Gastroenterology. 63 (4): 584–92. PMID 5077145.
- ↑ 13.0 13.1 Malaty HM, Graham DY, Isaksson I, Engstrand L, Pedersen NL (2000). "Are genetic influences on peptic ulcer dependent or independent of genetic influences for Helicobacter pylori infection?". Arch. Intern. Med. 160 (1): 105–9. PMID 10632311.
- ↑ url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307 |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}
- ↑ Logan RP (1996). "Adherence of Helicobacter pylori". Aliment. Pharmacol. Ther. 10 Suppl 1: 3–15. PMID 8730255.
- ↑ Crabtree JE (1996). "Gastric mucosal inflammatory responses to Helicobacter pylori". Aliment. Pharmacol. Ther. 10 Suppl 1: 29–37. PMID 8730257.
- ↑ Ernst PB, Jin Y, Reyes VE, Crowe SE (1994). "The role of the local immune response in the pathogenesis of peptic ulcer formation". Scand. J. Gastroenterol. Suppl. 205: 22–8. PMID 7863238.
- ↑ Mobley HL (1996). "The role of Helicobacter pylori urease in the pathogenesis of gastritis and peptic ulceration". Aliment. Pharmacol. Ther. 10 Suppl 1: 57–64. PMID 8730260.
- ↑ Nilius M, Malfertheiner P (1996). "Helicobacter pylori enzymes". Aliment. Pharmacol. Ther. 10 Suppl 1: 65–71. PMID 8730261.
- ↑ Slomiany BL, Kasinathan C, Slomiany A (1989). "Lipolytic activity of Campylobacter pylori: effect of colloidal bismuth subcitrate (De-Nol)". Am. J. Gastroenterol. 84 (10): 1273–7. PMID 2801678.
- ↑ Sipponen P, Varis K, Fräki O, Korri UM, Seppälä K, Siurala M (1990). "Cumulative 10-year risk of symptomatic duodenal and gastric ulcer in patients with or without chronic gastritis. A clinical follow-up study of 454 outpatients". Scand. J. Gastroenterol. 25 (10): 966–73. PMID 2263883.
- ↑ Wyatt JI, Rathbone BJ, Dixon MF, Heatley RV (1987). "Campylobacter pyloridis and acid induced gastric metaplasia in the pathogenesis of duodenitis". J. Clin. Pathol. 40 (8): 841–8. PMC 1141122. PMID 3654985.
- ↑ el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE (1995). "Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease". Gastroenterology. 109 (3): 681–91. PMID 7657096.
- ↑ el-Omar E, Penman I, Dorrian CA, Ardill JE, McColl KE (1993). "Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer". Gut. 34 (8): 1060–5. PMC 1374354. PMID 8174954.
- ↑ el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE (1995). "Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease". Gastroenterology. 109 (3): 681–91. PMID 7657096.
- ↑ el-Omar E, Penman I, Dorrian CA, Ardill JE, McColl KE (1993). "Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer". Gut. 34 (8): 1060–5. PMC 1374354. PMID 8174954.
- ↑ Borody TJ, George LL, Brandl S, Andrews P, Ostapowicz N, Hyland L, Devine M (1991). "Helicobacter pylori-negative duodenal ulcer". Am. J. Gastroenterol. 86 (9): 1154–7. PMID 1882793.
- ↑ Huang JQ, Sridhar S, Hunt RH (2002). "Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis". Lancet. 359 (9300): 14–22. doi:10.1016/S0140-6736(02)07273-2. PMID 11809181.
- ↑ Holvoet J, Terriere L, Van Hee W, Verbist L, Fierens E, Hautekeete ML (1991). "Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study". Gut. 32 (7): 730–4. PMC 1378985. PMID 1855677.
- ↑ Müller-Lissner SA (1986). "Bile reflux is increased in cigarette smokers". Gastroenterology. 90 (5 Pt 1): 1205–9. PMID 3956939.
- ↑ Räihä I, Kemppainen H, Kaprio J, Koskenvuo M, Sourander L (1998). "Lifestyle, stress, and genes in peptic ulcer disease: a nationwide twin cohort study". Arch. Intern. Med. 158 (7): 698–704. PMID 9554675.
- ↑ FakhreYaseri H, Shakaraby M, Bradaran HR, Soltani Arabshahi SK, Fakhre Yaseri AM (2014). "CagA and VacA genotypes in peptic ulcer disease and non-ulcer dyspepsia: a case-control study". Med J Islam Repub Iran. 28: 104. PMC 4301206. PMID 25664305.
- ↑ Jung DH, Kim JH, Chung HS, Park JC, Shin SK, Lee SK, Lee YC (2015). "Helicobacter pylori Eradication on the Prevention of Metachronous Lesions after Endoscopic Resection of Gastric Neoplasm: A Meta-Analysis". PLoS ONE. 10 (4): e0124725. doi:10.1371/journal.pone.0124725. PMC 4411104. PMID 25915048.
- ↑ Nakamura S, Sugiyama T, Matsumoto T, Iijima K, Ono S, Tajika M, Tari A, Kitadai Y, Matsumoto H, Nagaya T, Kamoshida T, Watanabe N, Chiba T, Origasa H, Asaka M (2012). "Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan". Gut. 61 (4): 507–13. doi:10.1136/gutjnl-2011-300495. PMID 21890816.
- ↑ {{cite journal |vauthors=Suzuki T, Matsushima M, Masui A, Watanabe K, Takagi A, Ogawa Y, Shirai T, Mine T |title=Effect of Helicobacter pylori eradication in patients with chronic idiopathic thrombocytopenic purpura-a randomized controlled trial |journal=Am. J. Gastroenterol. |volume=100 |issue=6 |pages=1265–70 |year=2005 <ref name="pmid18945961">Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, Provan D, Newland A, Amadori S, Bussel JB (2009). "Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review". Blood. 113 (6): 1231–40. doi:10.1182/blood-2008-07-167155. PMID 18945961.
- ↑ {{cite journal |vauthors=Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA |title=The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia |journal=Blood |volume=117 |issue=16 |pages=4190–207 |year=2011 |
- ↑ name="urlAmerican Journal of Gastroenterology - ACG Clinical Guideline: Treatment of Helicobacter pylori Infection">"American Journal of Gastroenterology - ACG Clinical Guideline: Treatment of Helicobacter pylori Infection".
- ↑ "ATLAS OF PATHOLOGY". Retrieved 2007-08-26.