Peptic ulcer pathophysiology: Difference between revisions

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{{Peptic ulcer}}
{{Peptic ulcer}}
{{CMG}}
{{CMG}} ;{{AE}} {{MKK}}
 
==Overview==
==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 [[Gastritis|chronic active gastritis]] known as type B gastritis. This results in a defect in [[gastrin]] production leading to increased[[gastrin]] secretion. [[Gastrin]] stimulates the production of [[gastric acid]] by the [[Parietal cell|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 [[Prostaglandin|prostaglandins]]. [[NSAIDs]] block the function of cyclooxygenase 1 (cox-1), which is essential for the production of these [[Prostaglandin|prostaglandins]].
==Pathophysiology==
==Pathophysiology==
A major causative factor (60% of gastric and 90% of duodenal ulcers) is chronic [[inflammation]] due to ''[[Helicobacter pylori]]'' that colonizes (''i.e.'' settles there after entering the body) the [[Pyloric antrum|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]] (type B gastritis), resulting in a defect in the regulation of [[gastrin]] production by that part of the stomach, and gastrin secretion is increased. [[Gastrin]], in turn, stimulates the production of [[gastric acid]] by parietal cells. The acid erodes the [[mucosa]] and causes the ulcer.
[[Peptic ulcer]] occurs due to distruption of [[Muscularis mucosae|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:<ref><nowiki>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=}}</nowiki></ref><ref name="pmid2657286">{{cite journal |vauthors=Clamp JR, Ene D |title=The gastric mucosal barrier |journal=Methods Find Exp Clin Pharmacol |volume=11 Suppl 1 |issue= |pages=19–25 |year=1989 |pmid=2657286 |doi= |url=}}</ref><ref name="pmid10677782">{{cite journal |vauthors=Werther JL |title=The gastric mucosal barrier |journal=Mt. Sinai J. Med. |volume=67 |issue=1 |pages=41–53 |year=2000 |pmid=10677782 |doi= |url=}}</ref><ref name="pmid3072665">{{cite journal |vauthors=Forssell H |title=Gastric mucosal defence mechanisms: a brief review |journal=Scand. J. Gastroenterol. Suppl. |volume=155 |issue= |pages=23–8 |year=1988 |pmid=3072665 |doi= |url=}}</ref>
*Layer of [[Epithelial cells|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 barrier|gastric mucosal surface]]
*Layer of [[Bicarbonate buffering system|bicarbonate ions]], secreted by the surface [[epithelial cells]] which [[Neutralization|neutralize acids]]
[[Image: Stomach mucosal layer labeled.svg.png|center|frame|Diagram of alkaline Mucous layer in stomach with mucosal defense mechanisms<br> '''Source''':Wikimedia Commons <ref>By M•Komorniczak(http://creativecommons.org/licenses/by/3.0) </ref>]]
 
'''The two most important etiological factors in the development of PUD are''':<ref>url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307<nowiki> |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}</nowiki></ref><ref name="urlPathogenesis of Peptic Ulcer and Implications for Therapy — NEJM">{{cite web |url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307 |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}</ref><ref name="pmid10383497">{{cite journal |vauthors=Hawkey CJ |title=Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance |journal=Aliment. Pharmacol. Ther. |volume=13 |issue=6 |pages=695–702 |year=1999 |pmid=10383497 |doi= |url=}}</ref>
*[[Helicobacter pylori infection]]
*[[Non-steroidal anti-inflammatory drug|Nonsteroidal anti-inflammatory drugs]] (NSAIDs)
===Role of Helicobacter pylori===
'''Penetration'''
 
Factors that help in penetration and growth of [[Helicobacter pylori]] are:<ref name="pmid16847081">{{cite journal |vauthors=Kusters JG, van Vliet AH, Kuipers EJ |title=Pathogenesis of Helicobacter pylori infection |journal=Clin. Microbiol. Rev. |volume=19 |issue=3 |pages=449–90 |year=2006 |pmid=16847081 |pmc=1539101 |doi=10.1128/CMR.00054-05 |url=}}</ref><ref name="pmid118091812">{{cite journal |vauthors=Huang JQ, Sridhar S, Hunt RH |title=Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis |journal=Lancet |volume=359 |issue=9300 |pages=14–22 |year=2002 |pmid=11809181 |doi=10.1016/S0140-6736(02)07273-2 |url=}}</ref>
* [[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<ref name="pmid9930387">{{cite journal |vauthors=Kim JS, Jung HC, Kim JM, Song IS, Kim CY |title=Interleukin-8 expression by human neutrophils activated by Helicobacter pylori soluble proteins |journal=Scand. J. Gastroenterol. |volume=33 |issue=12 |pages=1249–55 |year=1998 |pmid=9930387 |doi= |url=}}</ref><ref name="pmid5077145">{{cite journal |vauthors=Kimura K |title=Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach |journal=Gastroenterology |volume=63 |issue=4 |pages=584–92 |year=1972 |pmid=5077145 |doi= |url=}}</ref><ref name="pmid10632311">{{cite journal |vauthors=Malaty HM, Graham DY, Isaksson I, Engstrand L, Pedersen NL |title=Are genetic influences on peptic ulcer dependent or independent of genetic influences for Helicobacter pylori infection? |journal=Arch. Intern. Med. |volume=160 |issue=1 |pages=105–9 |year=2000 |pmid=10632311 |doi= |url=}}</ref>
====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 <ref>url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307<nowiki> |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}</nowiki></ref> <ref name="pmid8730255">{{cite journal |vauthors=Logan RP |title=Adherence of Helicobacter pylori |journal=Aliment. Pharmacol. Ther. |volume=10 Suppl 1 |issue= |pages=3–15 |year=1996 |pmid=8730255 |doi= |url=}}</ref><ref name="pmid8730257">{{cite journal |vauthors=Crabtree JE |title=Gastric mucosal inflammatory responses to Helicobacter pylori |journal=Aliment. Pharmacol. Ther. |volume=10 Suppl 1 |issue= |pages=29–37 |year=1996 |pmid=8730257 |doi= |url=}}</ref><ref name="pmid7863238">{{cite journal |vauthors=Ernst PB, Jin Y, Reyes VE, Crowe SE |title=The role of the local immune response in the pathogenesis of peptic ulcer formation |journal=Scand. J. Gastroenterol. Suppl. |volume=205 |issue= |pages=22–8 |year=1994 |pmid=7863238 |doi= |url=}}</ref><ref name="urlPathogenesis of Peptic Ulcer and Implications for Therapy — NEJM"><nowiki>{{cite web </nowiki><nowiki><ref name="pmid16847081"></nowiki>{{cite journal |vauthors=Kusters JG, van Vliet AH, Kuipers EJ |title=Pathogenesis of Helicobacter pylori infection |journal=Clin. Microbiol. Rev. |volume=19 |issue=3 |pages=449–90 |year=2006 |pmid=16847081 |pmc=1539101 |doi=10.1128/CMR.00054-05 |url=}}</ref>
*[[Helicobacter pylori]]  secretes various enzyme :[[Urease]],[[Phospholipase|Phospholipases]],[[Alcohol dehydrogenase]] and Catalases- causes damage the host [[gastric]] muscosa by generating [[toxic]] metabolities<ref name="pmid8730260">{{cite journal |vauthors=Mobley HL |title=The role of Helicobacter pylori urease in the pathogenesis of gastritis and peptic ulceration |journal=Aliment. Pharmacol. Ther. |volume=10 Suppl 1 |issue= |pages=57–64 |year=1996 |pmid=8730260 |doi= |url=}}</ref><ref name="pmid8730261">{{cite journal |vauthors=Nilius M, Malfertheiner P |title=Helicobacter pylori enzymes |journal=Aliment. Pharmacol. Ther. |volume=10 Suppl 1 |issue= |pages=65–71 |year=1996 |pmid=8730261 |doi= |url=}}</ref><ref name="pmid2801678">{{cite journal |vauthors=Slomiany BL, Kasinathan C, Slomiany A |title=Lipolytic activity of Campylobacter pylori: effect of colloidal bismuth subcitrate (De-Nol) |journal=Am. J. Gastroenterol. |volume=84 |issue=10 |pages=1273–7 |year=1989 |pmid=2801678 |doi= |url=}}</ref>
 
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'''Role of Helicobacter pylori in causing gastric ulcer'''
*Factors responsible for [[ulcer]] formation:<ref name="pmid2263883">{{cite journal |vauthors=Sipponen P, Varis K, Fräki O, Korri UM, Seppälä K, Siurala M |title=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 |journal=Scand. J. Gastroenterol. |volume=25 |issue=10 |pages=966–73 |year=1990 |pmid=2263883 |doi= |url=}}</ref>
*There is decrease in acid and decrease in parietal cell volume which further predisposes to development to ulcer formation.<ref name="pmid10632311">{{cite journal |vauthors=Malaty HM, Graham DY, Isaksson I, Engstrand L, Pedersen NL |title=Are genetic influences on peptic ulcer dependent or independent of genetic influences for Helicobacter pylori infection? |journal=Arch. Intern. Med. |volume=160 |issue=1 |pages=105–9 |year=2000 |pmid=10632311 |doi= |url=}}</ref>
 
'''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]] <ref name="pmid36549852">{{cite journal |vauthors=Wyatt JI, Rathbone BJ, Dixon MF, Heatley RV |title=Campylobacter pyloridis and acid induced gastric metaplasia in the pathogenesis of duodenitis |journal=J. Clin. Pathol. |volume=40 |issue=8 |pages=841–8 |year=1987 |pmid=3654985 |pmc=1141122 |doi= |url=}}</ref><ref name="pmid765709622">{{cite journal |vauthors=el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE |title=Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease |journal=Gastroenterology |volume=109 |issue=3 |pages=681–91 |year=1995 |pmid=7657096 |doi= |url=}}</ref><ref name="pmid817495422">{{cite journal |vauthors=el-Omar E, Penman I, Dorrian CA, Ardill JE, McColl KE |title=Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer |journal=Gut |volume=34 |issue=8 |pages=1060–5 |year=1993 |pmid=8174954 |pmc=1374354 |doi= |url=}}</ref><ref name="pmid76570962">{{cite journal |vauthors=el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE |title=Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease |journal=Gastroenterology |volume=109 |issue=3 |pages=681–91 |year=1995 |pmid=7657096 |doi= |url=}}</ref><ref name="pmid81749542">{{cite journal |vauthors=el-Omar E, Penman I, Dorrian CA, Ardill JE, McColl KE |title=Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer |journal=Gut |volume=34 |issue=8 |pages=1060–5 |year=1993 |pmid=8174954 |pmc=1374354 |doi= |url=}}</ref>


Another major cause is the use of [[NSAID]]s (see above). 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. Newer NSAIDs ([[celecoxib]], [[rofecoxib]]) only inhibit''cox-2'', which is less essential in the gastric mucosa, and roughly halve the risk of NSAID-related gastric ulceration.
===Role of NSAIDS===
*[[NSAID's]] are more commonly responsible for [[gastric]] [[Ulcer|ulcers]] than [[duodenal]] [[Ulcer|ulcers]]
*[[NSAID's]] cause [[ulcers]] by following mechanism:<ref name="pmid1882793">{{cite journal |vauthors=Borody TJ, George LL, Brandl S, Andrews P, Ostapowicz N, Hyland L, Devine M |title=Helicobacter pylori-negative duodenal ulcer |journal=Am. J. Gastroenterol. |volume=86 |issue=9 |pages=1154–7 |year=1991 |pmid=1882793 |doi= |url=}}</ref><ref name="pmid11809181">{{cite journal |vauthors=Huang JQ, Sridhar S, Hunt RH |title=Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis |journal=Lancet |volume=359 |issue=9300 |pages=14–22 |year=2002 |pmid=11809181 |doi=10.1016/S0140-6736(02)07273-2 |url=}}</ref><ref name="pmid1855677">{{cite journal |vauthors=Holvoet J, Terriere L, Van Hee W, Verbist L, Fierens E, Hautekeete ML |title=Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study |journal=Gut |volume=32 |issue=7 |pages=730–4 |year=1991 |pmid=1855677 |pmc=1378985 |doi= |url=}}</ref>
**Inhibit systemic [[prostaglandins]] production 
***Decreases [[blood flow]]
***Decreases [[mucus]] production
***Inhibits [[leucocyte]] [[adhesion]]  
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[[Tobacco smoking]], [[Blood type|blood group]], spices and other factors that were suspected to cause ulcers until late in the 20th century, are actually of relatively minor importance in the development of peptic ulcers.<ref>For nearly 100 years, scientists and doctors thought that ulcers were caused by stress, spicy food, and alcohol. Treatment involved bed rest and a bland diet. Later, researchers added stomach acid to the list of causes and began treating ulcers with antacids.[http://digestive.niddk.nih.gov/ddiseases/pubs/hpylori/ National Digestive Diseases Information Clearinghouse]</ref>
===Other factors===
Other factors responsible for [[peptic ulcer disease]]:
===='''Smoking'''====
* Chronic smoking leads to  [[mucosal]] damage or deals healing of ulcer by following mechanism:<ref name="pmid3956939">{{cite journal |vauthors=Müller-Lissner SA |title=Bile reflux is increased in cigarette smokers |journal=Gastroenterology |volume=90 |issue=5 Pt 1 |pages=1205–9 |year=1986 |pmid=3956939 |doi= |url=}}</ref>


[[Glucocorticoid]]s lead to atrophy of all [[epithelium|epithelial]] tissues. Their role in ulcerogenesis is relatively small.
*Decreases the production of [[prostaglandins]]
*Triggers reflux of bile acids into the [[duodenum]] which results in alteration of [[blood flow]] leading to [[Ischemia|ischaemia]]  
===Severe stress===
*Severe stress eg: [[brain injury]], [[burns]] causes increase in production of [[gastric acid]] and increases the risk of [[ulcer]] formation


There is debate as to whether ''Stress'' in the psychological sense can influence the development of peptic ulcers (see Stress and ulcers above). [[Burn (injury)|Burns]] and [[head trauma]], however, can lead to "stress ulcers", and it is reported in many patients who are on [[mechanical ventilation]].
==Genetics==
*[[Genes]] involved in the pathogenesis of [[peptic ulcer]] disease include:<ref name="pmid9554675">{{cite journal |vauthors=Räihä I, Kemppainen H, Kaprio J, Koskenvuo M, Sourander L |title=Lifestyle, stress, and genes in peptic ulcer disease: a nationwide twin cohort study |journal=Arch. Intern. Med. |volume=158 |issue=7 |pages=698–704 |year=1998 |pmid=9554675 |doi= |url=}}</ref><ref name="pmid25664305">{{cite journal |vauthors=FakhreYaseri H, Shakaraby M, Bradaran HR, Soltani Arabshahi SK, Fakhre Yaseri AM |title=CagA and VacA genotypes in peptic ulcer disease and non-ulcer dyspepsia: a case-control study |journal=Med J Islam Repub Iran |volume=28 |issue= |pages=104 |year=2014 |pmid=25664305 |pmc=4301206 |doi= |url=}}</ref>
**cagA
**vacA
==Associated Conditions==
*The  conditions associated with infection caused by helicobacter pylori include:<ref name="pmid25915048">{{cite journal |vauthors=Jung DH, Kim JH, Chung HS, Park JC, Shin SK, Lee SK, Lee YC |title=Helicobacter pylori Eradication on the Prevention of Metachronous Lesions after Endoscopic Resection of Gastric Neoplasm: A Meta-Analysis |journal=PLoS ONE |volume=10 |issue=4 |pages=e0124725 |year=2015 |pmid=25915048 |pmc=4411104 |doi=10.1371/journal.pone.0124725 |url=}}</ref><ref name="pmid21890816">{{cite journal |vauthors=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 |title=Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan |journal=Gut |volume=61 |issue=4 |pages=507–13 |year=2012 |pmid=21890816 |doi=10.1136/gutjnl-2011-300495 |url=}}</ref><ref name="pmid15929755">{{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 <nowiki><ref name="pmid18945961"></nowiki>{{cite journal |vauthors=Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, Provan D, Newland A, Amadori S, Bussel JB |title=Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review |journal=Blood |volume=113 |issue=6 |pages=1231–40 |year=2009 |pmid=18945961 |doi=10.1182/blood-2008-07-167155 |url=}}</ref><ref name="pmid21325604"><nowiki>{{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 |</nowiki></ref><ref>name="urlAmerican Journal of Gastroenterology - ACG Clinical Guideline: Treatment of Helicobacter pylori Infection">{{cite web |url=https://www.nature.com/ajg/journal/v112/n2/full/ajg2016563a.html#bib31 |title=American Journal of Gastroenterology - ACG Clinical Guideline: Treatment of Helicobacter pylori Infection |format= |work= |accessdate=}}</ref>
**[[Gastric cancer]]
**Gastric mucosa-associated lymphoid tissue lymphoma ([[MALT]])
**[[Idiopathic thrombocytopenic purpura]]


[[Tobacco smoking|Smoking]] leads to [[atherosclerosis]] and vascular spasms, causing vascular insufficiency and promoting the development of ulcers through [[ischemia]].
==Gross Pathology==
*[[Gastric|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
<gallery widths="250px">


Overuse of laxatives is also known to cause peptic ulcers.
Benign gastric ulcer 1.jpg|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''


A [[Family history (medicine)|family history]] is often present in duodenal ulcers, especially when [[ABO blood group system|blood group O]] is also present. Inheritance appears to be unimportant in gastric ulcers.
Duodenal ulcer01 (1).jpg|Duodenal ulcer specimen. ''Source: https://commons.wikimedia.org/wiki/File:Duodenal_ulcer01.jpg#/media/File:Duodenal_ulcer01.jpg''


[[Gastrinoma]]s ([[Zollinger-Ellison syndrome]]), rare gastrin-secreting tumors, cause multiple and difficult to heal ulcers.
Gastric ulcer 3.jpg|Gastric ulcer specimen ''Source:https://commons.wikimedia.org/wiki/File:Gastric_ulcer_3.jpg#/media/File:Gastric_ulcer_3.jpg''


==Pathology==
</gallery>
[[Image:Benign gastric ulcer 1.jpg|thumb|center|200px|A benign gastric ulcer (from the antrum) of a [[gastrectomy]] specimen.]]


==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<ref name="pathologyatlas">{{cite web | url=http://www.pathologyatlas.ro/Peptic%20ulcer.html| title=ATLAS OF PATHOLOGY|accessdate=2007-08-26}}</ref>


==References==
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{{reflist|2}}
 
Erosive gastric ulcer (1).jpg| [[Erosive gastric ulcer ]]''source: https://commons.wikimedia.org/wiki/File:Erosive_gastric_ulcer.jpg#/media/File:Erosive_gastric_ulcer.jpg''


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</gallery>


==References==
{{reflist|2}}
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Latest revision as of 23:37, 29 July 2020

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2017 ACG Guidelines for Peptic Ulcer Disease

Guidelines for the Indications to Test for, and to Treat, H. pylori Infection

Guidelines for First line Treatment Strategies of Peptic Ulcer Disease for Providers in North America

Guidlines for factors that predict the successful eradication when treating H. pylori infection

Guidelines to document H. pylori antimicrobial resistance in the North America

Guidelines for evaluation and testing of H. pylori antibiotic resistance

Guidelines for when to test for treatment success after H. pylori eradication therapy

Guidelines for penicillin allergy in patients with H. pylori infection

Guidelines for the salvage therapy

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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]

Diagram of alkaline Mucous layer in stomach with mucosal defense mechanisms
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]

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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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

Role of NSAIDS

 
 
 
 
 
 
 
 
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

  • Chronic smoking leads to mucosal damage or deals healing of ulcer by following mechanism:[30]

Severe stress

Genetics

Associated Conditions

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

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]

References

  1. ↑ 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=}}
  2. ↑ Clamp JR, Ene D (1989). "The gastric mucosal barrier". Methods Find Exp Clin Pharmacol. 11 Suppl 1: 19–25. PMID 2657286.
  3. ↑ Werther JL (2000). "The gastric mucosal barrier". Mt. Sinai J. Med. 67 (1): 41–53. PMID 10677782.
  4. ↑ Forssell H (1988). "Gastric mucosal defence mechanisms: a brief review". Scand. J. Gastroenterol. Suppl. 155: 23–8. PMID 3072665.
  5. ↑ By M•Komorniczak(http://creativecommons.org/licenses/by/3.0)
  6. ↑ url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307 |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}
  7. ↑ 7.0 7.1 "Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM".
  8. ↑ Hawkey CJ (1999). "Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance". Aliment. Pharmacol. Ther. 13 (6): 695–702. PMID 10383497.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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. ↑ 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.
  14. ↑ url=http://www.nejm.org/doi/full/10.1056/NEJM199003293221307 |title=Pathogenesis of Peptic Ulcer and Implications for Therapy — NEJM |format= |work= |accessdate=}}
  15. ↑ Logan RP (1996). "Adherence of Helicobacter pylori". Aliment. Pharmacol. Ther. 10 Suppl 1: 3–15. PMID 8730255.
  16. ↑ Crabtree JE (1996). "Gastric mucosal inflammatory responses to Helicobacter pylori". Aliment. Pharmacol. Ther. 10 Suppl 1: 29–37. PMID 8730257.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Nilius M, Malfertheiner P (1996). "Helicobacter pylori enzymes". Aliment. Pharmacol. Ther. 10 Suppl 1: 65–71. PMID 8730261.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Müller-Lissner SA (1986). "Bile reflux is increased in cigarette smokers". Gastroenterology. 90 (5 Pt 1): 1205–9. PMID 3956939.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ {{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.
  36. ↑ {{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 |
  37. ↑ 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".
  38. ↑ "ATLAS OF PATHOLOGY". Retrieved 2007-08-26.

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