Kumar Sunil et al.

IRJP 2012, 3 (6)

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com ISSN 2230 – 8407
Review Article

PEPTIC ULCER: A REVIEW ON ETIOLOGY AND PATHOGENESIS

Kaur Amandeep, Singh Robin, Sharma Ramica, Kumar Sunil*
Rayat Institute of Pharmacy, Railmajra, S. B. S. Nagar, Gujarat, India
Article Received on: 06/04/12 Revised on: 11/05/12 Approved for publication: 21/05/12

*Email- [email protected]
ABSTRACT
A peptic ulcer is a sore on the lining of the stomach or duodenum. The two most common types of peptic ulcer are called “gastric ulcers” and “duodenal
ulcers”. Peptic ulcers are found to be due to an imbalance between aggressive factors such as hydrochloric acid (HCL), pepsin, refluxed bile, leukotrienes
(LTs), reactive oxygen species (ROS) and defensive factors, which include the function of the mucus-bicarbonate barrier, prostaglandins (PGs), mucosal blood
flow, cell renewal and migration, nonenzymatic and enzymatic antioxidants and some growth factors. H. pylori infection and the use of nonsteroidal anti-
inflammatory drugs (NSAIDs) are the predominant causes of peptic ulcer disease. Also, a numbers of factors are implicated in the pathogenesis of gastric
ulcer, among which major factors involved are bacterial infection (Helicobacter pylori), certain medications (NSAID), chemicals (Hcl/ethanol) ,gastric cancer
and minor factors are stress, smoking, spicy food and nutritional deficiencies. The idea behind treating ulcers is to lower the amount of acid that your stomach
makes, to neutralize the acid that is made and to protect the injured area so it can have time to heal. The main aim of this review article has to summarize the
ulcerogenic mechanisms of various mediators involved in Peptic ulcer disease.
KEYWORDS: Peptic Ulcer, Types, Pathogenesis and Mediators.

INTRODUCTION causative agent is infection caused by the bacteria H. pylori

Ulcers are deep lesions penetrating through the entire or reaction to certain medicines like non-steroidal anti-
thickness of the gastrointestinal tract (g.i.t) mucosa and inflammatory drugs (NSAIDs)1. Symptoms of peptic ulcers
muscularis mucosa. Peptic ulcer has unquestionably been a include abdominal discomfort and pain. Other symptoms
disease of the twentieth century. Epidemiological data for this include weight loss, poor appetite, bloating, nausea, and
disease and its complications have shown striking vomiting. Some may also experience blood in stool and
geographical variations in incidence and prevalence. There vomit, and black stools that indicate gastrointestinal
are different types of ulcers most common are peptic ulcer: bleeding2.
gastric ulcer, which appeared to be due to damage to the Aphthous Ulcers: Sores that develop in the inner lining of
lining of the stomach, and duodenal ulcer, which was the mouth are referred to as mouth ulcers. Mouth ulcers are
associated with excessive acid secretion by the stomach. The common and are usually due to trauma such as from ill fitting
aetiology of peptic ulcer was fiercely debated. It is believed dentures, fractured teeth, or fillings. Anemia, measles, viral
that peptic ulcers develop due to an imbalance between infection, oral candidiasis, chronic infections, throat cancer,
aggressive factors (Helicobacter pylori, NSAIDs, gastric mouth cancer and vitamin B deficiency are some of the
acid) and protective factors (mucin, bicarbonate, common causes of ulcers or sores in the mouth 3. Aphthous
prostaglandins), leading to an interruption in the mucosal minor is amongst the most common form of oral ulcerative
integrity. Various factors are implicated that play a pivotal diseases and affects an estimated 15-20% of the population
role in the pathogenesis of ulcertions like, sedentary life worldwide. In some populations, the prevalence has been
style, alcohol intake, spicy food, drugs and various bacterial documented as being as high as 50-66% and it is especially
infections. Moreover, several endogenous substances have common in North America 4-5. The incidence of aphthous
been identified and are reported to be involved in the ulcers has been found to be lower in smokers than in non-
production of gastrointestinal lesions in animals. The more smokers 6.
important ones include some of the bacterial infection, Esophageal Ulcers: Esophageal ulcers are lesions that occur
various drugs and chemicals, gastric secretion, lipid in the esophagus (the food pipe). These are most commonly
metabolites, neuropeptides, inflammatory mediators and formed at the end of the food pipe and can be felt as a pain
reactive free radicals. Oxidative stress has emerged as one of right below the breastbone, in the same area where symptoms
the major pathogenic factors in progression of ulcer that of heartburn are felt. Esophageal ulcers are associated with
directly impaired the cellular functions and promotes cellular acid reflux or GERD, prolonged use of drugs like NSAIDs,
organelles damage in the cells, including mitochondria, and smoking 7.
lysosomes, and nucleus. Also, NO is accepted as vital ETIOLOGY AND PATHOGENESIS OF ULCER
mediator of GIT mucosal defense as decreased NO H. Pylori
generation or synthesis contribute to the pathogenesis of H. Pylori is the main cause of stomach ulcers, was first
ulceration. The present study summarizes the ulcerogenic identified by the two Australian scientists in 1982. H. Pylori
mechanisms of these substances and the enable us to is a gram negative bacillus, motile, microaerophilic,
understand better the etiology of peptic ulcer. flagellated and spiral shaped bacteria 8. Type I strains of H.
TYPES OF ULCER Pylori possess a pathogenic activity, that encodes the effector
Peptic Ulcer: Peptic ulcer is a broad term which includes protein cytotoxin-associated gene A (cagA). After
ulcers of digestive tract in the stomach or the duodenum. translocation into the host cell, cagA effects cell shape,
Earlier it was believed that one developed this type of ulcers increases cell motility, disturbs cell junctional activity and
due to stress and spicy food. However, recent research has thus responsible for gastric carcinomas and gastric ulcers 9.
shown that these are just the aggravating factors. The H.Pylori causes increases expression of cytokines such as
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TNF-α in gastritis. Further, IL-1β is too overexpressed in the worsen the NSAID effects by deepening superficial lesions,
H. Pylori-induced gastritis 10. H. pylori-infected gastric interfering with platelet aggregation, and impairing the ulcer
mucosa showed infiltration of polymorphonuclear healing process 27-28.
leukocytes, lymphocytes, monocytes and plasma cells in the Reserpine
lamina propria, and intraepithelial severe neutrophil The pathogenesis of gastric ulceration induced by drugs is not
infiltration 11. The appropriate antibiotic regimens can yet clear. It has found that histamine, catecholamines and
successfully eradicate the infection with complete resolution acetylcholine have been implicated in the ulcerogenic activity
of mucosal inflammation and a minimal chance for of a number of drugs viz. phenylbutazone, acetyl salicyclic
recurrence of ulcers 12. Triple therapy regimens comprising of acid, oxyphenbutazone, indomethacin and reserpine 29-31.
a proton pump inhibitor or ranitidine bismuth citrate and two Reserpine is one of the drugs, derived from the roots of the
antibiotics (amoxicillin and clithromycin) are the standard rawolfia serpentine reported to have pivotal role in the
therapy to treat H. pylori infection 13. progression of ulcer. Various reports indicate that reserpine
Gastric acid secretions causes the degranulation of mast cells with increase in the
Gastric acid is established as one of the major ulcerogenic gastric acid secretion by sympathetic activation 32. Reserpine
factor for the induction of gastric ulcer disease. It has been is documented to generate free redicals and inhibit the
reported that about 50% of gastric ulcer patients are pepsin prostaglandin synthesis. The exact mechanism how reserpine
and acid hypersecretors 14. But, on the other hand, gastric caused gastric ulceration is not clear. It has appeared that
acid plays a stringent role in gastric defense. It is the first line peripheral cholinergic and adrenergic mechanisms are
of mucosal defense to prevent bacterial colonization and involved in the ulceration induced by reserpine 33. It has
reduced their ability to entrance in the mucosal layer 15. Acid demonstrated that reserpine produced gastric ulceration due
secretion is suggested to be stimulated by three principle to a release of catecholamines from the sympathetic nerve
secretagogues histamine, acetylcholine and gastrin. The endings 34-35. Both at peripheral level and central nervous
receptors on the surface of parietal cell include H2 receptors system, reserpine depletes catecholamine, serotonin (5-HT)
responding to histamine released from specialized mast cells, and histamine (H2) stores. Also, it is releasing gastrin and
receptors that are sensitive to the muscarinic effects of corticosteroids 36. From these released endogenous
acetylcholine released from the vagus nerve and probably molecules, serotonin can act directly on the gastric mucosa.
receptors responsive to endogenous circulating gastrin 16. Also, number of authors explains the formation of ulcers by
Gastrin stimulates acid secretion either by direct stimulation intervention of reserpine in the metabolism of serotonin. As
of parietal cells or by the release of histamine from ECL cells in is well known, serotonin and its precursors, when applied
17-18
. In the 1972, Black et al, postulated that histamine in larger doses, are capable of causing destructive changes in
stimulated acid secretion through a novel histamine receptor, the stomach wall 37. As for the catecholamines, the
the H2 receptor 19. Moreover, various studies indicate involvement in the ulcerative process is more complicated. In
numerous epithelial cells at the base of pyloric glands contain a first stage, released catecholamines act on gastric blood
histamine and histidine decarboxylase (HDC), the enzyme vessels and later, after the stores are depleted, they generate a
responsible for the synthesis of histamine 20. functional adrenergic deficit. This phasic action on
The only source of the acetylcholine (Ach) that can act adrenergic mechanisms is prevalent at the central nervous
directly on the parietal cell is from the postganglionic fibres system level. The result is an imbalance between the
of the enteric nervous system. The muscarinic- 1 agonist adrenergic and the cholinergic tonus with important
McN-A-343 stimulates acid secretion without affecting consequences on gastric function 38. Alteration of the
histamine release, thus suggesting that the muscarinic adrenergiccholinergic balance is transmitted to the gastric
receptor on the parietal cell 21. level via the vagus nerve. It is known the fact that vagotomy
NSAIDs (Non-steroidal anti-inflammatory drugs) and muscarinic and nicotinic-cholinolitic drugs decrease the
NSAIDs are valuable therapeutics that acts not only as anti- gastric ulcerative action of the reserpine 39. Restoration of the
inflammatory, but also as analgesics and antipyretics. They adrenergic activity by catecholamine precursors and drugs
are used in a wide variety of clinical conditions, including that stimulate the biosynthesis and release of the precursors
arthritis and other musculoskeletal disorders. Unfortunately, also have protective action at gastric level.
their use has been limited by their gastric ulcer-inducing Ethanol
effects. Nearly 25% of chronic users of these drugs develop The mechanism of ethanol-induced gastric lesions is varied,
gastric ulcer disease 22. Various studies indicates that including the depletion of gastric mucus content, damaged
NSAIDS helps in the progression of ulceration by mucosal blood flow and mucosal cell injury. It has been
overcoming the expression of enzyme cyclo-oxygenase documented that ethanol causes severe damage to the
(COX) which has been documented to inhibit the conversion gastrointestinal mucosa starts with microvascular injury
of AA to PG’s, that impairs the mucosal barrier and results in results in increase vascular permeability, edema formation
corrosive action with pepsin and results in the progression of and epithelial lifting. Szabo et al suggested that after
peptic ulcers 23-24. Further, COX-1 inhibition by the NSAIDS intragastric administration of ethanol a rapid and time
leads to the significant release of the endothelin-1(ET-1) dependent release of endothelin-1 into the systemic
which is a potent vasoconstriction which has been shown to circulation preceded the development of the hemorrhagic
induce mucosal injury. NSAIDs by inhibiting the mucosal erosions by vasoconstriction 14. Moreover, by
prostaglandin synthesis prostaglandins causes the activation decreasing the secretion of biocarbonate (HCO3-) and mucus
of neutrophils and the local release of reactive oxygen species production, ethanol produces the necrotic lesions in gastric
(ROS) and thus initiates the gastric injury 25. Further NSAID mucosa. Further ethanol also has been reported to activate
also causes marked reduction in mucosal blood flow, mucus- TNF-α and mitogen activated protein kinases (MAPK) 40.
bicarbonate secretions, impaired platelet aggregation, reduced Also, ethanol has also initate apoptosis which lead to cell
epithelial cell renewal and increased leukocyte adherence that death 40. Further, ethanol after metabolism has been reported
are responsible for pathogenesis of ulceration 26. Gastric acid to releases superoxide anion and hydroperoxy free radicals
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 Kumar Sunil et al. IRJP 2012, 3 (6)
which lead to an increased lipid peroxidation 41. Increase in species in the biologic system 62. Also, Nitric oxide inhibits
lipid peroxide content and oxygen-derived free radicals gastric secretion by suppression of histamine release from
results in marked changes in cellular levels and causes enterochromaffin-like cells 63-64.
membrane damage, cell death, exfoliation and epithelial Prostaglandins
erosion 41-42. Prostaglandins are 20-carbon fatty acids produced from
Cytokines arachidonic acid via the enzyme cycylooxygenase. Hawkey
Cytokines play a central role in the regulation of the mucosal and Rampton found that prostaglandins exert their
immune system, and therefore are extremely important in cytoprotective actions by stimulating the mucus and
mucosal defense. Several proinflammatory cytokines are bicarbonate secretion, maintaining mucosal blood flow, and
involved in the pathogenesis of peptic ulcer, like interleukin by enhancing the resistance of epithelial cells to injury
(IL)-1β, IL-2, IL-6, IL-8 and tumor necrosis factor (TNF)-α. induced by cytotoxins 65. Prostaglandins found to be inhibits
When inflammation of the gastric mucosa occurs, it leads to the leukocyte recruitment which could contribute to the
infiltration of neutrophils and mononuclear cells that beneficial effects of these substances in situations in which
stimulates the transcription and leads to the synthesis of the GI mucosa is inflamed 66. Prostaglandin E2 (PGE2) has
several proinflammatory cytokines 43. IL-1 has been shown to been shown to be a potent suppressor of release of PAF,
reduce the severity of gastroduodenal damage and increase histamine and of TNF-α from peritoneal and intestinal
the resistance to injury 44-45. The mechanism underlying the mucosal mast cells 67-68. Another, it has also found that
protective actions of IL-1 is not fully understood, but it has prostaglandins suppress the generation of reactive oxygen
been found that IL-1 reduces injury through a paradoxical metabolites by neutrophils 69.
inhibitory action on leukocyte adherence. Further, IL-1 has LTs (Leukotrienes)
also play a role in the inhibition of gastric acid secretion Leukotrienes are derived from arachidonic acid through the
44,46,47
. Also, IL-1 stimulates the release of prostaglandin and action of lipoxygenase and are considered to be important
NO possibly by inducing iNOS expression and COX-2 mediators of inflammatory and allergic reactions 70. Two
expression, thus provide a protection to gastroduodenal main subclasses of LTs has been suggested, leukotriene B4
mucosa 48. Furthermore, IL-1 has been shown to inhibit the and the peptido-leukotrienes (LTC4, LTD4, and LTE4).
release of other ulcer-promoting mediators like PAF and LTB4 is a very potent chemotaxin for neutrophils, it
histamine from mast cells. Also, Lychkova et al, 2007 stimulate the release of reactive oxygen metabolites from
demonstrate the role of immune system in the pathogenesis of neutrophils and contributes significantly to the tissue injury
ulcers, mainly T-lymphocytes and cytokines produced by associated with mucosal inflammation. Goldberg and Subers
them. Takeuchi et al, 2002 found that NF- B activation described the role of LTs) on the stomach 71. It has been
followed by TNF- release contribute to tissue damage in shown that LTs induce vasoconstriction in the vascular bed of
gastric ulcer 49-50. the stomach followed by leakage of macromolecules from the
VEGF (Vascular endothelial growth factor) postcapillary venules. Further, various other studies reported
VEGF, a 46-kDa homodimeric glycoprotein, is the most that LTC4 can also induce vasoconstriction in both the
potent stimulator of angiogenesis which is produced by a venous and arteriolar vessels in rat submucosa, which results
variety of cell types including macrophages, smooth muscle in tissue necrosis 70,72. Therefore, LTs could serve as a
cells, fibroblasts, megakaryocytes, and neoplastic cells 51-53. potential proulcerogenic agent. It has been reported that on
Angiogenesis and VEGF play a major role in many repair ethanol administration there is a concentration-dependent
processes such as healing of gastric ulceration resulting from increase in gastric mucosal LTC4 73 and B4 synthesis which
a disturbed balance between factors which damage the gastric provide the evidence of LTs as mediators in ethanol-induced
mucosa barrier and those which have a protective role. gastric damage 74. The mechanism by which ethanol
Several studies have provided evidence for a role of VEGF in stimulates LT formation by the rat gastric mucosa is not
gastric ulcer healing. Jones et al observed enhanced ulcer known. It may be caused by the perturbation of cell
healing in rats following a single injection of naked DNA membranes, resulting in the activation of phospholipase
encoding VEGF 54. activity and increase in arachidonic acid level, with a
NO (Nitric oxide) subsequent enhancement of LT synthesis. Moreover, LTB4
NO is synthesized from L-arginine via the catalytic action of has been suggested to contribute to the pathogenesis of
a group of enzymes, the NO synthases (NOS). NO has been NSAID-induced gastric damage through its ability to
studied to play an important role in GI mucosal defense and promote leukocyte adherence to the vascular endothelium 66.
the pathogenesis of mucosal injury 55. Also, NO may Also, LTB4 may play a similar role in the pathogenesis of
influence muscle tone as well as endocrine and exocrine ulceration associated with Helicobacter pylori infection.
secretion. cNOS, nNOS, eNOS are very important in the Interestingly, gastric juice LTB4 levels are significantly
normal function of the GI tract in that inhibition of these higher in patients with gastric H. pylori colonization than in
enzymes can result in disturbances of GI motility, blood those who are H. pylori negative 75.
flow, secretion, etc 56. On the other hand, the inducible NOS Endothelin
(iNOS), which produces relatively large amounts of NO Endothelin is a 21-amino acid peptide derived from vascular
under certain pathological conditions, contributes to mucosal endothelial cells and it has been suggested that it has a patho-
injury and dysfunction 57-58. Suppression of NO synthesis physiological role in conditions characterized by vascular
renders the gastric mucosa more susceptible to injury. NO spasm. Furthermore, endothelin may act as an endogenous
inhibits recruitment of neutrophils to sites of inflammation. regulator of vascular tone, with opposite actions to
NO reduces neutrophil infiltration into the GI tract mucosa 59. endothelium-derived relaxing factors (EDRF) and
The events related to the gastroprotective effects of nitric prostacyclin (PGI2). Vascular congestion is a feature
oxide include a reduction in acid secretion and promotion of characterizing gastric ulceration induced by substances such
angiogenesis 60-61. Gastroprotective effects of nitric oxide as ethanol and aspirin 76. Several lipid mediators have
may be due to itis rapid reactivity with various oxygen ulcerogenic actions in the gastric mucosa, and these actions
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 Kumar Sunil et al. IRJP 2012, 3 (6)
may affect the vascular endothelium and/or vascular smooth 11. Fan XG, Kelleher D, Fan XJ, Xia HX, Keeling PW. Helicobacter
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ACKNOWLEDGEMENT gastrointestinal bleeding associated with low-dose aspirin. Best Pract
We are highly thankful to Management and Chairman of our Res Clin Gastroenterol. 2012;26:125-40.
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their co-operation and providing us scientific facilities.
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