Asian Journal of Pharmaceutical Education and Research

Vol -10, Issue-4, October- December 2021

ISSN:2278 7496
REVIEW ARTICLE Impact Factor: 7.014

PEPTIC ULCER: A REVIEW ON ETIOLOGY, PATHOGENESIS AND

TREATMENT
Falguni Jaiswal*, Dr. A. K. Rai, Dr. Parnay Wal , Ankita Wal and Shashi Pratap Singh
Pranveer Singh Insitute of Technology, Kanpur, Kanpur- Agra-Delhi, NH2, Bhauti, Kanpur,
Uttar Pradesh 209309.
*Corresponding Author’s E mail: [email protected]
Received 20 July 2021; Revised 11 Sept. 2021; Accepted 21 Sept. 2021, Available online 10 Oct 2021

Cite this article as: Jaiswal F, Rai AK, Wal P, Wal A and Singh SP. Peptic Ulcer: A Review
on Etiology, Pathogenesis and Treatment. Asian Journal of Pharmaceutical Education and
Research. 2021; 10(4): 01-17.
https://dx.doi.org/10.38164/AJPER/9.4.2021.01-17

ABSTRACT
Peptic ulcer disease, which includes both stomach and duodenal ulcers, accounts for a significant portion
of people seeking surgical advice around the world. A peptic ulcer is a lesion that develops on the
stomach or duodenal lining. “Gastric ulcers” and “duodenal ulcers” are the two most prevalent peptic
ulcer kinds. Peptic ulcers are caused by an imbalance between aggressive factors like hydrochloric acid
(HCL), pepsin, refluxed bile, leukotrienes (LTs), reactive oxygen species (ROS), and defensive factors
like the mucus-bicarbonate barrier, prostaglandins (PGs), mucosal blood flow, cell renewal and
migration, nonenzymatic and enzymatic antioxidants. The most common causes of peptic ulcer disease
are H. pylori infection and the use of nonsteroidal anti-inflammatory medications (NSAIDs). In addition,
a variety of variables are implicated in the pathogenesis of gastric ulcer, including bacterial infection
(Helicobacter pylori), certain drugs (NSAID), chemicals (Hcl/ethanol), and stomach cancer, with minor
factors including stress, smoking, spicy food, and nutritional deficiencies. The goal of treating ulcers is
to reduce the quantity of acid produced by your stomach, neutralize the acid produced, and protect the
wounded area so it can recover. The major purpose of this review study was to summarize the ulcerogenic
mechanisms of numerous mediators implicated in Peptic ulcer disease.
Keywords: Peptic Ulcer, Types, Helicobacter pylori, Diagnosis & Treatment.
INTRODUCTION

Peptic ulcer is a chronic disease that results from an imbalance between endogenous protective factors
of gastric mucosa (mucus and bicarbonate secretion, adequate blood flow, prostaglandin E2, nitric oxide,
sulfhydryl compounds and antioxidants enzymes, and others) and aggressive factors (acid and pepsin
secretions). Behavioral and environmental factors such as smoking, poor diet, alcohol and non-steroidal
anti-inflammatory drugs ingestion, and Helicobacter pylori infection, among others have also been
implicated in the etiology of gastric ulcer 1. Peptic ulcer disease is often defined as a mucosal break

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greater than 3-5 mm in the stomach or duodenum with a visible depth. It is therefore an endoscopic
diagnosis in contrast to dyspepsia, which is a clinical diagnosis based on symptoms alone. Peptic ulcer
disease results from an imbalance between factors that protect the mucosa of the stomach and duodenum,
and factors that cause damage to it Patients with gastric and duodenal ulcers present similarly. They may
report epigastric or retrosternal pain, early satiety, nausea, bloating, belching, or postprandial distress.
These symptoms are non-specific and may be difficult to distinguish clinically from functional
dyspepsia2. Ulcers are an open sore of the skin or mucus membrane characterized by sloughing of
inflamed dead tissue. Ulcers are lesions on the surface of the skin or a mucous membrane characterized
by a superficial loss of tissue. Ulcers are most common on the skin of the lower extremities and in the
gastrointestinal tract, although they may be encountered at almost any site. There are many types of ulcer
such as mouth ulcer, esophagus ulcer, peptic ulcer, and genital ulcer 3. Ulcer is one of the most common
diseases affecting throughout the world population. The allopathic treatment of ulcer adversely affects
the health by causing harmful side effects. It impedes the organ of which that membrane is a part from
continuing its normal functions. It is of many forms which occur on both, inside and outside of the human
body. Currently, different types of ulcer forms are recognized in medicine such as peptic ulcer, corneal
ulcer, stomach ulcer, foot or leg ulcer etc4. The Gram-negative bacterium Helicobacter pylori remain
present between the mucous layer and the gastric epithelium and are strategically designed to live within
the aggressive environment of the stomach. Initially, Helicobacter pylorus reside in the antrum but over
time migrates toward the more proximal segments of the stomach. Peptic ulcer is one of the world’s
major gastrointestinal disorders and affecting 10% of the world population. About 19 out of 20 peptic
ulcers are duodenal. An estimated 15000 deaths occur each year as a consequence of peptic ulcer. Annual
incidence estimates of peptic ulcer hemorrhage and perforation were 19.4–57 and 3.8–14 per 100,000
individuals, respectively. The average 7-day recurrence of hemorrhage was 13.9% and the average long-
term recurrence of perforation was 12.2% 5. Ulcer index Scoring of ulcer was done as follows: No
ulcer=0; Superficial ulcers= 1; Deep ulcers=2; Perforation=3. Mean ulcer score for each animal will be
expressed as ulcer index. The percentage of ulcer protection was determined by formula: % Protection=
[(Control mean ulcer index - Test mean ulcer index)/ Control mean ulcer index 100 6.

TYPES OF ULCER
Peptic Ulcer
Peptic ulcer is a broad term which includes ulcers of digestive tract in the stomach or the duodenum.
Earlier it was believed that one developed this type of ulcers due to stress and spicy food. However,
recent research has shpwn that these are just the aggravating factors. The causative agent is infection
caysed by the bacteria H. pylori or reaction to certain medicines like non-steroidal anti –inflammatory

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drugs. Symptoms of peptic ulcers include weight loss, poor appetite, bloating, nausea, and vomit and
black stools that indicate gastrointestinal bleeding.7
Aphthous Ulcers
Sores that develop in the inner lining of the mouth are referred to as mouth ulcers. Mouth ulcers are
common and are usually due to trauma such as from ill fitting dentures, fractured teeth, or fillings,
Anemia, measles, viral infection, oral candidiasis, chronic infections, throat cancer, mouth cancer and
vitamin B deficiency are some of the common causes of ulcers or sores in the mouth. Aphthous minor is
amongst the most common from of oral ulcerative diseases and affects an estimated 15-20% of the
population worldwide. In some populations, the prevalence has been documented as being as high as 50-
66% and it is especially common in North America. The incidence of aphthous ulcers has been found to
be lower in smokers than in non -smokers.7
ETIOLOGY AND PATHOGENESIS OF ULCER H. PYLORI
H. Pylori is the main cause of stomach ulcers, was first identified by the two Australian scientists in
1982. H. Pylori possess a pathogenic activity, that encodes the effector protein cytotoxin-associated gene
A. After translocation into the host cell, cagA effects cell shape, increases cell motility, disturbs cell
junctional activity and thus responsible for gastric carcinomas and gastric ulcers. H.Pylori causes
increases expression of cytokines such as THF-α in gastritis. Further, IL-1β is too overexpressed in the
H. Pylori- induced gastritis. H. pylori-infected gastric mucosa showed infiltration of polymorphonuclear
leukocytes, lymphocytes, monocytes and plasma cells in the lamina propria, and intraepithelial severe
neutrophil infiltration. The appropriate with complete resolution of mucosal inflammation and a minimal
chance for recurrence of ulcers.6-7
Gastric acid secretions
Gastric acid is established as one of the major ulcerogenic factor for the induction of gastric ulcer disease.
It has been reported that about 50% of gastric ulcer patients arepepsin and acid hypersecretors . But on
the other hand , gastric acid plays a stringent role in gastric defense. It is the first line of mucosal defense
to prevent bacterial colonization and reduced their ability to entrance in the mucosal layer. Acid secretion
is suggested to be stimulated by three principle secretion is suggested to be stimulated by three principle
secretagogues histamine, acetylcholine and gastrin. The receptors on the surface of parietal cell include
H2 receptors responding to histamine relased from specialized mast cells, receptors that are sensitive to
the muscarinic gastrin.Gastrin stimulates acid secretion either by direct stimulation of parietal cells or by
the release of histamine from ECL cells 8. It has been argued consistently that pressure ulcer risk
assessment scales need to be developed on the basis of multivariable analyses to identify factors which
are independently associated with pressure ulcer development. An improved understanding of the relative

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contribution risk factors makes to the development of pressure ulcers and an improved ability to identify
patients at high risk of pressure ulcer development would enable us to better target resources in practice.
Early epidemiological evidence identified that reduced activity and mobility is the key risk factor for
pressure ulcer development, but the relative contribution other risk factors make cannot be reliably
determined from individual studies. To inform an emerging National Institute for Health Research
(NIHR) Programme Grant on pressure ulcer prevention we sought to systematically review existing
research to identify factors independently associated with pressure ulcer development, that is, ‘‘a risk
factor that retains its statistical association with the outcome when other established risk factors for the
outcome are included in the statistical model’’. The aim of this study was to identify risk factors
independently predictive of pressure ulcer development in adult patient populations 9. Peptic ulcer
disease (PUD) develops when the protective mechanisms of the gastrointestinal mucosa, such as mucus
and bicarbonate secretion, are overwhelmed by the damaging effects of gastric acid and pepsin. Peptic
ulcers occur mainly in the stomach [gastric ulcer (GU)] or proximal duodenum [duodenal ulcer (DU)].
Helicobacter pylori infection was originally identified as the main cause of PUD; however, GU has
become more commonly associated with the use of nonsteroidal anti-inflammatory drugs and
acetylsalicylic acid (ASA)10. Duodenal ulcers were, as expected, strongly associated with age and
smoking.1920 Surprisingly, men had lower odds than women, Blacks and Hispanics had lower odds than
non-Hispanic Whites, and there was little relationship between either low education or income and
duodenal ulcer. Throughout this century, men have had a greater burden from duodenal ulcer than
women11.

USE OF FOOD FIBERS IN PEPTIC ULCER TREATMENT

The physicochemical properties of fiber fractions produce different physiological effects in the organism.
Soluble fibers, found in apple, oatmeal, and pear are responsible, for instance, for an increased viscosity
in the intestinal content. Insoluble fibers (whole grains, granola, flaxseed) increase stool bulk, reduce
transit time in the large intestine, and make fecal elimination easier and quicker. Fibers regulate the bowel
function, which make them vital for the well being of healthy people and in the dietary treatment of many
pathologies 12. Recommended daily diat preferred of pathologies as in Table 1.

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TABLE 1- Recommended daily diet for peptic ulcer37

Characteristics Recommendations
Daily energy needs Sufficient to maintain or recover the
(DEN) nutritional status
20-25 Kcal/Kg: weight loss
25-30 Kcal/Kg: maintenance
30-35 Kcal/Kg: weight gain31
Acute phase Recovery phase
Carbohydrate (%)29 50-60 50-60
Protein (g/Kg/weight)29 1.2 1.5
Lipid (%)18,29 25-30 25-30
Zinc (mg)¹³ 11 40
Selenium (μg)20 55 400
Vitamin A (μg)113 900 3000
Vitamin C (mg)13 75 500
Vitamin B¹² (μg)13 2.4 2.4
Folic acid (μg)13 400 400
Iron (mg)13 45 45
Fibers (g)13 20 to 30 20 to 30
Probiotics (UFC/day)18 10⁹ to 10¹¹ lactic acid 10⁹ to 10¹¹ lactic acid
bacteria bacteria

PEPTIC ULCER DIAGNOSIS

All participants were asked if they had been diagnosed with a peptic ulcer within the 11 year observation
period. Participants with a first time diagnosed ulcer reported how and when the diagnosis was made. To
ensure that all first time diagnosed ulcers were recorded, information was also obtained from the National
Danish Hospital Discharge Registry (NDHDR) in which all cases of hospital admissions in Denmark are
registered with a discharge diagnosis. The search included the following PUD diagnoses (WHO ICD-8
codes: 531.X (gastric ulcer), 532.X (duodenal ulcer), and 533.X (gastro-duodenal ulcer)). Medical
records from those who reported an ulcer or who were registered with a PUD diagnosis in the NDHDR
were retrieved and reviewed. Only ulcers verified by upper endoscopy, barium meal examination, or
surgery were regarded as true incident ulcers. 13. Diagnosis is usually made by endoscopic examination
of the upper gastrointestinal tract (oesophago-gastro-duodenoscopy e OGD) and the majority of peptic
ulcers are treated medically. Therapeutic endoscopy, interventional radiology and surgery are usually
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reserved for the management of complications of peptic ulcer disease: such as bleeding, perforation and
outflow obstruction. Ulcers may be single or multiple and most commonly affect the lesser curve of the
stomach and the first part of the duodenum. The rapid urease test (CLO test) is widely available and the
most commonly used method of detecting H. pylori during endoscopy. It has the advantage of being
quick, cost effective, with a high sensitivity (97%) and specificity (100%) when multiple biopsies are
taken. If H. pylori infection is present the organism will produce the enzyme urease, which catalyses the
conversion of urea (within the gel in which it is placed), resulting in the production of alkaline ammonium
ions that will increase the pH and result in change in the colour of the gel from yellow to red. Histological
identification and microbiological culture are costly and labour intensive and are therefore used less
commonly. Less invasive diagnostic tests for H. pylori are also available for those patients who do not
proceed to endoscopy. These include a urea breath test (sensitivity 95% and specificity 100%) that relies
on the ability of H. pylori to metabolize orally administered carbon radio-labelled urea to carbon dioxide,
which is exhaled by the patient and subsequently detected on the breath. Recent studies evaluating the
increasingly common H. pylori stool antigen test as an alternative non-invasive test have demonstrated
sensitivity and specificity of approximately 95%. Serology for H. pylori antigen is generally not
recommended as it has potential to give false positive results in those with past but no current infection14.

Fig. 1 - Some common symptoms of ulcer38

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Radiology
An erect chest X-ray is commonly performed in patients with acute upper abdominal pain suspected of
perforat ion. CT scans can rule out other acute abdominal conditions such as acute cholecystitis, acute
pancreatitis, acute appendicitis and acute mesenteric ischemia to name but a few. Some of these acute
abdominal conditions may not require surgical intervention at least in the initial phase. In resource-poor
healthcare facilities, an erect chest X-ray is extremely useful in detecting free air under the diaphragm
confirming visceral perforation. Peptic ulcer perforation can also generate detectable sonographic signs,
such as pneumoperitoneum; free intraperitoneal air tends to accumulate around the liver, duodenum, and
stomach, local thickening of the gastroduodenal wall containing an echogenic focus or line, the presence
of localized extraluminal gas and fluid 15.

PUD mortality risk factor analysis: correlation

The scatterplots in display the correlation between mortality rates and the selected covariates. As shown
in, duodenal ulcers were negatively associated with mortality rates (r=−0.19, p=0.07); however, gastric
ulcers were positively associated with mortality (r=0.23, p=0.036;). Although both bleeding and
perforated ulcers were both positively associated with mortality, the latter had a stronger association
(r=0.41, p<0.0001). To test the hypothesis that survival rates are increasing in recent years, we
investigated the correlation between publication year and mortality. There was a positive association
between publication year and perioperative death rates (r=0.22, p=0. 032; Likewise, as shown in,
mortality rate increased with increasing age at surgery (r=0.23, p=0.036).15
PUD mortality risk factor analysis: meta-regression
To further investigate the sources of heterogeneity, we applied meta-regression analysis using the
following covariates: study-level mean or median age at surgery, year of publication, sub-region and
study quality score. Substantial heterogeneity of effect estimates on perioperative mortality rate was
evident (p value for heterogeneity of <0.0001). Multivariable meta-regression model including the
above-mentioned covariates indicated that per every 10-year increase in publication year, the mortality
rates increased by 1%. Regions and sub-regions were not significantly associated with mortality rates.
However, the association between age and mortality risk was marginally significant. With every 10-year
increase in age, the mortality rate increased by2% (p=0.07) 16. The treatment of acid – related diseases–
peptic ulcer disease and gastrooesophageal reflux disease (GERD) – has undergone several major
changes in the past two decades. Although pharmacological inhibition of gastric acid secretion reliably
heals duodenal and gastric ulcers, both usually recur when treatment is stopped. The discovery of the
relationship between Helicobacter pylori and peptic disease. For the first time, it was demonstrated that

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eradication of H. pylori infection cold prevents the relapse of –i.e. cure – peptic ulcers 17. Less than 3
decades ago, Robin Warren and Barry Marshall definitively identified Helicobacter pylori by culturing
an organism from gastric biopsy specimens that had been visualized for almost a century by pathologists.
In 1994, H. pylori was recognized as a type I carcinogen, and now it is considered the most common
etiologic agent of infection-related cancers, which represent 5.5% of the global cancer burden. In 2005,
Marshall and Warren were awarded the Nobel Prize of Medicine for their seminal discovery of this
bacterium and its role in peptic ulcer disease. H. pylori is a Gram-negative bacterial pathogen that
selectively colonizes the gastric epithelium. The bacterium is urease, catalase, and oxidase positive, is
spiral shaped, and possesses 3 to 5 polar flagella that are used for motility. In addition, the majority of
H. pylori strains express virulence factors that have evolved to affect host cell signaling pathways. H.
pylori has evolved the ability to colonize the highly acidic environment found within the stomach by
metabolizing urea to ammonia via urease, which generates a neutral environment enveloping the
bacterium 18.

FIG. 5- Acid secretion and the associated pattern of gastritis play an important role in disease
outcome in H. pylori infection. The figure displays the correlations between the pattern of H. pylori
colonization, inflammation, acid secretion, gastric and duodenal histology, and clinical outcome38.

The present study also demonstrated that subjects with low education level have a higher risk of
asymptomatic PUD. It has been well documented that PUD is associated with low socioeconomic status.
That association may be explained by a higher risk of Helicobacter pylori (H. pylori) infection among
less educated groups, probably due to poor standards of hygiene. Psychological stress, risk lifestyle
behaviors, and hard physical work may be other important risk factors for PUD in low education

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populations 19. Several factors have been associated with the aggressiveness of H. pylori and hence
implicated in epithelial damage, including the virulent East Asian CagA genotype, and environmental
and dietary factors. Recently, some researchers have also proposed that certain dietary elements such as
chili peppers and garlic play a protective role against H. pylori infection. Fox and colleagues have shown
the protective role of infection of helminths and parasites against H. pylori infection 20. Helicobacter
pylori (H. pylori) is a spiral shaped, gram negative, microaerophilic bacterium that persistently colonizes
the gastric mucosa of humans. The estimated lifetime risk of peptic ulcer disease is 20 percent and gastric
cancer is 1–2 percent with H pylori infection. Epidemiological knowledge of H. pylori infection in early
studies emphasized on H. pylori infection in symptomatic patients presenting for endoscopy and hence
little information is known about the frequency of H pylori in the general population. This study enhances
the knowledge of the important role of H pylori in upper gastrointestinal disease worldwide.
The specific objectives of this study were to:
1. Estimate the prevalence of Helicobacter pylori in asymptomatic individuals
2. Determine the association of the Helicobacter pylori with potential
Risk factors such as age, gender and the sociodemographic status (level of education, number of rooms
and family member living in/ with, source of drinking water, sharing of a bed and animal ownership)21.
In the present study, we defined H. pylori-associated PUD as the use of any recorded H. pylori eradication
therapy medications, such as a combination medication prescription of 7–14 days of any of the following
antibiotics in the same medication order such as clarithromycin or metronidazole and amoxicillin or
tetracycline, in addition to a PPIs or H2 blockers (H2RAs) 22.
The H+, K+-ATPase enzyme utilises ATP hydrolysis to drive electroneutral exchange of cytoplasmic
protons for luminal K+, thus acidifying the gastric juice. Proton pump inhibitors (PPIs), such as
omeprazole, are currently administered to suppress acid secretion in the treatment of acid-related diseases
such as gastric ulcer or gastroesophageal reflux. This mechanism results in a relatively slow onset of acid
inhibition. The short dwell-times of PPIs in the blood and their instability under acidic conditions also
negatively affect their efficacy as acid-suppressing drugs. Another class of H+, K+-ATPase drugs, K+-
competitive acid blockers (P-CABs), are under development and some are now available for clinical use.
The rapid and long-lasting acid suppression by P-CABs is expected to provide more immediate and
efficient therapy for acid-related disease23. Gastric H+, K+-ATPase is responsible for gastric acid
secretion. ATPdriven H+ uptake into the stomach is efficiently accomplished by the exchange of an equal
amount of K+, resulting in a luminal pH close to 1. Because of the limited free energy available for ATP
hydrolysis, the stoichiometry of transported cations is thought to vary from 2H+/2K+ to 1H+/1K+ per

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hydrolysis of one ATP molecule as the luminal pH decreases, although direct evidence for this hypothesis
has remained elusive 24.
CAUSES OF NON-H. PYLORI, NON-NSAID PEPTIC ULCERS25
 Gastric adenocarcinoma
 Gastric lymphoma
 Local drug irritation
 Irritation at the neck of a hiatus hernia (Cameron’s ulcer)
 Idiopathic
 Anastomotic ulceration after previous gastric surgery
 After radiotherapy
 ZollingereEllison syndrome (gastrinoma) e particularly for duodenal ulcers
 Multiple endocrine neoplasia type-I
 Hyperparathyroidism without multiple endocrine neoplasia type-I
 Systemic mastocytosis
 Severe systemic illness stress ulcers (Cushing’s ulcer)
 Idiopathic eosinophilic and lymphocytic gastritis
 Duodenal Crohn’s disease
 Coeliac axis stenosis
 Hepatic artery chemotherapy25.
ROLE OF H+-ATPASE IN MAINTAINING THE MEMBRANE POTENTIAL AND ACIDIC PH
AT THE PLASMA MEMBRANE SURFACE
Plant cell growth is highly influenced by the environ-ment, as well as by predetermined developmental
pro-grams. Plasma membrane H+-ATPases (H+-pumps) are the primary active transporters that
translocate protons to the outside of each cell, providing the electrical and chemical energy that drives
solute transport. In plants, this enzyme also provides an acidic environment in the cell wall that is
favorable for cell expansion. In animals, a Na+/K+ ATPase provides similar function as the primary
active transport system, in creating a mem-brane potential and a chemical gradient of sodium that drives
sodium-coupled transporters and ion channels. In addition to this fundamental difference in the choice
of cation used to drive transport, there is also a much higher membrane potential found in plants and this
may reflect a need to drive potassium inward to very high concentrations even in soil with low potassium
levels, in order to maintain turgor pressure required for plant form and function26.

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Assay of H+-K+ ATPase activity

Proton potassium ATPase was prepared from mucosal scrapings of goat by the method reported by
Cheon, with necessary modifications. Stomach from freshly slaughtered goats was washed gently with
tap water. The mucosal layer of fundus was scrapped and homogenized in ice-cold phosphate buffer, pH
7.4. The homogenate was centrifuged for 20 min at 18,000 rpm. The supernatant so obtained was
recentrifuged for 60 min at 100,000 rpm. The pellet was resuspended in homogenisation buffer.
Ficollsucrose discontinuous density gradient centrifugation was utilized to prepare H+K+ATPase.
Protein was determined by the method of Lowry. Different concentrations of the extract 10-50 μg/ml
were incubated in the reaction mixture (40 mM Tris-HCl buffer, pH 7.4, containing 2 mM MgC12 and
10 μg membrane protein) to make a volume of 1 ml. Then, 2 mM ATP Tris salt was utilized to start the
reaction, this preparation was incubated for 20 min for 37°C. The reaction was terminated by adding 1
ml of ice-cold trichloroacetic acid (10% v/v). The H+-K+ ATPase activity was assayed in the presence
and the absence of different doses of the extract and omeprazole. The amount of inorganic phosphate
released from ATP was determined spectrophotometrically at 400 nm27. Gastric cancer is one of the most
prevalent causes of cancer deaths worldwide. Therefore, efforts are underway to eradicate this cancer
type based on the elimination of H. pylori. Eradication of H. pylori before the development of significant
gastric damage, can prevent cancer and the gastric cancer in such cases is known to be an inflammation-
associated malignancy. It has been reported that, eradication therapy of H. pylori usually consists of a
proton pump inhibitor or bismuth compounds in combination with different antibiotics. The conventional
antibiotics most widely used for H. pylori therapy include amoxicillin, tetracycline, metronidazole,
levofloxacin, clarithromycin and bismuth. However, the resistance of H. pylori to the commonly used
antibiotics is still increasing worldwide, and this resistance has been considered a major reason for
therapy failure in the eradication of H. pylori infections, with failure rates of more than 40% 28.
Functional Domains of Gastric HK ATPase
A binding is removed by glycopeptidase F(N-glycopeptidase). If indeed the consensus starting at asn
493 is N-glycosylated from the extracellular face, perhaps there are regions of the putative cytosolic
domain of the pump protein that are membrane inserted. The membrane insertion would be between the
peptide chains, rather than in the phospholipid of the bilayer, which would not allow prediction based on
hydrophobicity. On the other hand, although it is unlikely that N-glycosylation occurs from the cytosolic
face, it is not certain, following glycosylation, that this orientation is maintained in the mature protein,
nor that all the protein is indeed glycosylated29.

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Peptic ulcer treatment and helicobacter pylori eradication

Recent studies found that liver cirrhosis increased the risk of peptic ulcers. The prevalence of peptic
ulcers is higher in decompensated cirrhosis than in compensated cirrhosis. Currently, PPIs are the
mainstay treatment option of peptic ulcers in the general population. Cirrhotic patients also have a high
proportion of helicobacter pylori infection. Helicobacter pylori promotes the conversion of urea into
ammonia, which enters into the systemic circulation. Helicobacter pylori infection contributes to the
development of hyperammonemia and subsequent episodes of HE in cirrhosis. Helicobacter pylori
eradication has been improved by PPIs-based triple therapy. Notably, blood ammonia concentration is
significantly reduced after PPIs-based triple treatment in cirrhotic patients. As well known, the
application of PPIs triple therapy can effectively treat helicobacter pylori infection which can increase
the risk of HE. Therefore, it might be true that PPIs reduce the risk of HE in patients with helicobacter
pylori infection 30.
Risk factors for the presence of symptoms in patients with PUD
Subjects with symptomatic PUD had higher alcohol consumption than those with asymptomatic PUD
(p=0.025). Furthermore, the presence of active-stage ulcers was more common in subjects with
symptomatic PUD than in subjects with asymptomatic PUD (p=0.003). Between the symptomatic and
asymptomatic PUD groups, there were no significant differences in age, sex, BMI, smoking, H. pylori
infection, use of NSAIDs, ulcer location, or ulcer number. Multivariate analysis revealed that heavy
drinking (OR, 2.515; 95% CI, 1.315–4.812; p=0.005) and active-stage ulcer (OR, 2.143; 95% CI, 1.323–
3.472; p=0.002) were independent risk factors for the presence of symptoms in PUD 31.
PATHOGENESIS
The intestinal mucosa is composed of 3 layers: epithelium, lamina propria, and muscularis mucosa.
Gastritis is described as the presence of inflammatory cells. Gastropathy occurs when there is gastric
mucosal damage with no inflammatory cells. Peptic ulcers occur when gastric or duodenal inflammation
leads to defects of the muscularis mucosa. The acidic gastric contents, which normally aid in digestion,
become corrosive when there is an increase in acid production or a disruption of protective factors.
Parietal cells of the stomach produce gastric acid via proton pumps (Hþ/Kþ ATPase) in response to
acetylcholine from vagal efferents, histamine from enterochromaffin cells, and gastrin from G cells.
There are several mechanisms to protect the gastric mucosa, including a mucus layer, a pH-neutral buffer
zone, an epithelial layer, and a rich gastric blood supply. The mucus layer is composed of mucin secreted
by surface foveolar cells. This mucus layer acts as a diffusion barrier and overlies a pH-neutral buffer
zone composed of bicarbonate secreted by epithelial cells. Prostaglandin release mediates mucin
secretion from surface foveolar cells and bicarbonate release from epithelial cells. Epithelial cells have

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tight junctions that act as an additional barrier of protection. A rich gastric blood supply redistributes
excess protons that reach the lamina propria. Ultimately, peptic ulcers are formed when the damaging
factors overcome the protective mechanisms32. Hypothermic stress ulcer was involved with significant
reduction of GSH (p < 0.01), but not SOD and catalase in combination with decrease in mucin and
protein (p < 0.01-0.001 respectively). Hesperidin treated animals showed significantly increased level of
GSH, protein (0.05) and mucin (0.001) only at highest dose 450 mg/kg, other doses were ineffective.
Gastric wall mucosa plays a main role in the protection of the gastric walls from aggressive factors that
are responsible for gastric damage. The mucous layer forms a barrier between gastric wall and acid.
Normal animal gastric mucosa showed clear and proper arrangement of cells in photographic
representations. Indomethacin induced redness, spot and hemorrhagic ulcers .33
Diabetes mellitus is 1 of the most well-known chronic diseases in almost all countries. With the
development of society and technology, people have changed their lifestyle, as characterized by
decreased physical exercise and increased obesity, which are responsible for the increase in the number
of people with diabetes mellitus. It was estimated that 415 million people all over the world had diabetes
in 2013, and the number is expected to rise to 592 million by 2035. In addition, the complication of
diabetes mellitus is also an issue urgent to be solved. Diabetic foot ulcer (DFU) is 1 of the most common
complications of diabetes and leads to high hospital costs. It was reported that the total additional medical
cost associated with diabetes for treating diabetic
foot diseases in America ranges from $9 to $13 billion. These chronic, nonhealing foot ulcers occur in
approximately 15% of all people with diabetes and are responsible for patients’ decreased quality of life.
Unfortunately, if a DFU has developed, there is a high risk of wound
progression, which may result in amputation. It was reported that >85% of foot amputations in patients
are caused by DFU. Therefore, the International Diabetes Foundation is paying more attention toDFUs,
taking into consideration the substantial social, medical, and economic
burdens 34.
ULCER PREVENTION
The realization in recent years that selective cyclooxygenase (COX)-2 inhibitors were not as ‘GI safe’ as
their promotional materials suggested led to several evaluations of alternative methods for preventing
gastric ulceration induced by non-steroidal anti-inflammatory drugs (NSAIDs). Proton pump inhibitors
(PPIs) have long been suggested to reduce the incidence of serious gastrointestinal complications during
NSAID use. further support to this notion by reporting that the use of PPIs was associated with a
significant reduction in the risk of ulcer in both acute and chronic users of NSAIDs. Moreover, the
‘number needed to treat’ to avoid one peptic ulcer in the elderly was low: three for both acute and chronic

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NSAID users. Chan et al. examined the utility of PPIs for prevention of recurrent ulcer bleeding in
patients taking aspirin to prevent vascular diseases. Patients who presented with ulcer bleeding were
randomized, after their ulcers had healed, to receive aspirin plus a PPI (esomeprazole), or another
antiplatelet drug (clopidogrel). Clopidogrel is an ADP receptor antagonist that inhibits platelet
aggregation and is recommended for patients who have major gastrointestinal intolerance of aspirin35.
USE OF ANTIOXIDANTS TO ERADICATE HELICOBACTER PYLORI
Some authors show that the best treatment is the eradication of the bacteria18. Accordingly, some studies
in humans 40 used antioxidants to eradicate H. Pylori and observed that vitamin C has important effects
in the bacteria eradication in patients with peptic ulcer. But these studies
showed that smaller doses of vitamin C for a longer period of time had a better response when compared
with higher doses. Thus, it is observed that patients with peptic ulcer by H. pylori can take up to 500
mg/day of vitamin C for a period of three months, which does not exceed the recommended UL of 2000
mg, according to DRIs13. Another antioxidant used to eradicate H. pylori is the capsaicin present in
pepper and chilies. Studies on animals showed that capsaicin has effect in healing gastrointestinal lesions.
Likewise, some researchers39 studied the effect
of capsaicinoids in individuals with peptic ulcer by H.pylori or aspirin and showed that these substances
are gastroprotective only in individuals with aspirin-induced lesions. It is worth noting that peppers may
be associated with irritations in the gastric mucosa, and may not have a gastroprotective effect in some
individuals with peptic ulcer36.
Depression, a type of mood disorder, is characterized by emotional dysregulation and depressive
cognition, which induces distress in patients. In patients with depression, stress not only plays a major
role in pathogenesis but also is associated with the disturbance of the hypothalamus-pituitary-adrenal
(HPA) axis. Additionally, patients with depression have been reported to experience somatic
consequences associated with HPA axis dysregulation. Regarding the gastrointestinal (GI) system,
evidences have shown that depression is associated with irritable bowel syndrome, ulcerative colitis,
dyspepsia, and gastroesophageal reflux disease. However, few studies have reported evidence regarding
the relationship between peptic ulcer disease (PUD) and depression. PUD, including gastric and peptic
ulcers, is a prevalent GI disease with a high mortality. Evidence has shown that both physical stress and
psychological stress are closely related to PUD. Notably, PUD risk among schizophrenia or anxiety
disorder patients has been documented, but not for depression patients. To make the diagnosis of unipolar
depression, patient should not have mania or hypomania, or their diagnosis should be bipolar disorders
(BD) instead. However, evidence had shown that some patients with BD have unipolar depression as
their initial presentation, before mania or hypomania. Eventhough the differential diagnosis between BD

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and unipolar depression was challenging, they shared the common manifestation of having depressive
episode. Particularly, we have previously demonstrated a positive association between BD and PUD.
However, we could not identify whether the depression, mania, or hypomania predisposed the patients
having subsequent PUD. Therefore, we investigated the association between depression and PUD. We
hypothesized that if depression was associated with subsequent PUD, more concern would be raised
among patients with unipolar depression or depressive episode of BD 39.
CONCLUSION
Peptic ulcer illness is still a common clinical concern in our society, affecting people of all ages. Peptic
ulcer disease is predicted to continue to have a large global influence on health-care delivery, health
economics, and patient quality of life as the prevalence of the illness rises with age.
Peptic ulcer illness continues to be a problem in medical visits. The majority of people who present with
dyspepsia should be examined for peptic ulcer disease. Gastric acid secretion must be understood in order
to determine which portion of the stomach is most impacted by the etiologic agent of peptic ulcer disease.
H. pylori has remained a risk factor for the development of peptic ulcer disease until now. This bacteria's
predilection location determines its clinical prognosis. Understanding the pathophysiology of peptic
ulcers can help doctors be more aware of potential complications, such as stomach cancer.
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