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HELICOBACTER PYLORI AND PEPTIC ULCER IN ADULT
PATIENTS
1*Dr. Aded Yohanna Izhaq and
2Dr. Mohanad Anaem Hussein Al. Mayali
1M. SC, Internal Diseases.
2M. B. Ch. B, Dm.
ABSTRACT
The link between Helicobacter pylori (H. Pylori) infection and peptic
ulceration is now well established: presence of infection is a strong risk
factor for later ulcer development and ulcers rarely occur in the
absence of H. pylori or the other main risk factor, non steroidal anti-
inflammatory drugs (NSAIDs). The role of H pylori in peptic
ulceration in human is presented in this paper. A peptic ulcer is an
excoriated area of stomach or intestinal mucosa caused principally by
the digestive action of gastric juice. The two most common factors that
predispose to ulcers are chronic gastric infection with H. pylori and ingestion of non-steroidal
anti-inflammatory drugs. An effective first-line therapy for uncomplicated cases of h. pylori
infection would be Amoxicillin + Metronidazole + Pentoprazole. Treatment of H. pylori
usually leads to clearing of infection, relief of symptoms and eventual healing of ulcers.
KEYWORDS: Helicobacter pylori, peptic ulcer, stomach.
INTRODUCTION
Helicobacter pylori was rediscovered in 1982 by two Australian scientists, Robin Warren and
Barry J Marshall as a causative agent for peptic ulcer (Marshall, 1983). Prior to this, peptic
ulcer was regarded as a disease closely associated with stress or spicy food. However in their
original paper, Marshall and Warren (1984) contended that most peptic ulcers and gastritis
were caused by colonization with this bacterium, not by stress or spicy food as had been
assumed before. Earlier, John Lykoudis, a general practitioner in Greece, treated patient for
peptic ulcer disease (PUD) with antibiotics, beginning in 1958, long before it was commonly
recognized that bacteria were a dominant cause for the disease (Rigas and Papavasassiliou,
2002). Things have remarkably changed since then. The link between H. pylori infection and
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 1, 166-177 Research Article ISSN 2278 – 4357
*Corresponding Author
Dr. Aded Yohanna Izhaq
M. SC, Internal Diseases.
Article Received on
09 Nov. 2020,
Revised on 30 Nov. 2020,
Accepted on 21 Dec. 2020
DOI: https://doi.org/10.17605/OSF.IO/NW2Z7
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peptic ulceration is now well established: presence of infection is a strong risk factor for later
ulcer development and ulcers rarely occur in the absence of H. pylori or the main risk factor
NSAIDs. Peptic ulcers (duodenal type) recur in infected subjects, but the eradication of H.
pylori with antimicrobial therapy virtually eliminates further recurrence (Patchett et al., 1992;
Valle et al., 1991). Even when ulcers are not present, H. pylori infection invariably causes a
histologic gastritis (Atherton and Blaser, 1997).
METHODOLOGY
A total of 100 clinical samples diagnosed as peptic ulcer patients, were screened to find out
the prevalence of H. pylori using Stool Antigen card test and Serum antibodies card test
during the period from 20 January to 15 March 2020 at different hospitals and laboratories in
Predesigned questionnaire was used to collect information such as (age, sex, Qat chewing,
smoking, spicy foods, taking antibiotic without prescription, eat fast food and others), and
results of these criteria were recorded for each subject. Data were analyzed by the Microsoft
Excel 2010 software to compare the association between different variables and positive H.
pylori results.
RESULTS
100 clinical samples from males and females suffering from symptoms of peptic ulcer were
collected and diagnosed as positive peptic ulcer caused by H. pylori, with percentage rate of
54 and 46 %, respectively. In contrary to these findings, a study carried out in Kano, Nigeria
in 2018 found that females were more affected than male.[8]
In addition, a study carried out in
Yeme found that girls were more affected than boys.
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H. pylori is a short, spiral gram-negative microaerophilic bacterium with unusual-appearing
sheathed polar flagella (Dunn et al., 1997). It is slow growing in vitro and requires complex
media. After prolonged culture it assumes a coccoid morphology that is slowly metabolizing
and resistant to adverse conditions (Bode et al., 1993; Nilius et al., 1993). The metabolic
pathways of H. pylori, including its main energy source, are poorly characterized but three
enzymes are uniformly present and useful for laboratory identification: oxidase, catalase and
urease. Urease activity is especially intense compared with other urease – producing bacteria
and form the basis of several diagnostic tests.
HELICOBACTER PYLORI AND PEPTIC ULCER ILLNESS
The risk of an adult infected by H. pylori to develop peptic ulcer disease is four times higher
than in an H. pylori negative individual. Management and treatment of peptic ulcer disease,
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caused by different physiological alterations according to its gastric localization and etiology,
has changed dramatically since the discovery of H. pylori. Previous treatment with dietary
modifications, antacids, gastric acid suppression with H2-receptor antagonists and proton
pump inhibitors, were changed to antibiotic therapy for eradication of H. pylori infection.
Moreover, the eradication of H. pylori infection cure both gastric and duodenal ulcers, and
the cure rates are similar, suggesting that H. pylori is the key factor in peptic ulcer diseases
independent of the ulcer site.
Since peptic ulcer disease associated to H. pylori is a result of a chronic infection progress,
knowledge of specific pre-ulcers alterations caused by H. pylori can help in its prevention
and management. Therefore, the role of H. pylori in the etiology and evolution of chronic
gastritis to peptic ulcer disease has been largely investigated. The interplay of gastritis
phenotype and acid secretion are key determinants in ulcer disease outcomes. H. pylori
colonized gastric mucosa undergoes alteration in acid secretion as a result of gastric hormone
release and disruption of neural pathways. Corpus-predominant gastritis and corpus atrophy
are accompanied by hypochlorhydria and carry the highest risk for gastric ulcer and cancer,
whereas antrum-predominant gastritis with little involvement of the corpus fundic mucosa is
associated with hyperchlorhydria and predisposes to duodenal ulcer disease.
H. pylori colonization differential pattern in the gastro-duodenal tract are associated to host
and bacterium genetic factors whose interaction results in specific physiological alterations
leading to gastric and/or duodenal ulcers. As the bacterium resides in the mucosa and do not
entry gastric cells, it was adapted to produce and elicit molecules involved in survival in a
high acid environment, to adhere in gastric mucous and to escape from host immune
mechanisms.
The acid gastric environment is microbicidal and the only bacterium adapted to survive in
gastric location is H. pylori, which present several molecular mechanisms against acid milieu.
During host co-evolution a selected molecular mechanism to locally change the acid
surroundings correspond to a urea sensitive detection system associated to urease enzymes
responsible to convert urea into ammonia and bicarbonate. Also, motility and chemotaxis
systems were selected in order to avoid gastric acid juice and to enable adherence to gastric
mucosa, respectively.
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All these biological molecular strategies to survive in gastric environment and to persist in
the mucosa, involve the production of virulence factors by H. pylori, such as the urease
enzyme complex, a modified Lipopolysaccharide (LPS); Blood Group Antigen-Binding
Adhesion molecules (BabA), Outer Membrane Inflammatory Adhesion Proteins (OipA)[30]
,
Cytotoxin-Associated Gene A (CagA), Vacuolating Cytotoxin (VacA), Duodenal Ulcer
Promoting Gene (DupA) and factor induced by epithelium contact (IceA).
H. PYLORI VIRULENCE FACTORS AFFILIATION TO PEPTIC ULCER ILLNESS
H. pylori virulence factors are associated to genomic regions with high plasticity and
diversity, being present, absent, up-regulated or differentially expressed during bacteria
growth and gastric colonization persistence. The plastic H. pylori genome present strong
phylogeographic structure attained during co-evolution process in human, resulting in
different bacteria strains with specific virulence factors and disease outcome according to
geographic and population distribution.
The urease molecular complex and vacA gene are ubiquitous in H. pylori strains
corresponding to bacteria essential virulence factors. Ammonia and bicarbonate produced by
H. pylori urease enzyme complex can directly cause damage to gastric mucosa or indirectly
by toxic compounds derived from ammonia chemical processing. Also, the urease enzyme is
a strong antigen, produced in high concentration, increasing tissue injure by local
inflammatory response
The H. pylori vacA gene, correspond to an anion channel-forming cytotoxin implicated in the
formation of intracellular vacuoles in epithelial cell lines. There are three principal
polymorphic regions in vacA gene identified as Signal (s), Intermediate (i) and Middle (m),
presenting two main types (type 1 and type 2) each. Transport of the toxin to the bacteria
membrane depends on the s type allele; s1, subdivided into s1a, s1b and s1c, are responsible
for the transport of the toxin to the bacteria membrane, and the s2 allele is defective. The
toxin present cell tropism for a broader range of cells when the allele is m1 than is m2 type.
The i region is intermediate between the s and m, which i1 type associated to a stronger
vacuolating activity than the i2 type. The more severe forms of H. pylori related disease
present association of the s1, i1, and m1 types. Populations from Western countries showed
association of vacA s1 or m1 with increased risk of peptic ulcer diseases. In Asia, where there
is a high predominance of s1 alelle, the vacA m region mosaicism shows a variation within
East region population, with m1 strains being more prevalent in regions where there is a
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higher prevalence of gastric cancer, suggesting that m1 strains of H. pylori are more
pathogenic. In a Brazilian population, strains harboring the vacA m1 genotype were more
frequently associated with the development of duodenal ulcer disease when compared to
gastric ulcer.
Some strains of H. pylori harbor a type IV secretion system, derived from a transposable
element, where virulence factors, such as CagA, are encoded.[54]
The complete system is
responsible to introduce the CagA toxin into the host epithelial cell. CagA protein presents a
phosphorylation polymorphic repeated motif in its C-terminus, the EPIYA (composed of five
amino acids Glu-Pro-Ile-Tyr-Ala), where the tyrosine residue is phosphorylated by SFK
family kinases, triggering modifications in cell signaling pathways, cytoskeleton
rearrangement, and abnormal cell proliferation.
There are four distinct EPIYA motifs, named EPIYA-A to EPIYA-D, distinguished by the
number of motifs and flanking sequences, resulting in different amount of phosphorylation
sites. In Western and in Southeast Asian countries, cagA-positive patients are at a higher risk
to develop peptic ulcer disease.
Adhesion molecules as OipA and BabA are also involved in the pathophysiology of peptic
ulcer disease. The adhesin BabA adhere to ABO/Lewis B blood group antigens located in the
gastric human mucosa, inducing expression of several inflammatory cytokines. There are two
genes encoding BabA, babA1 and babA2 genes, differing by deletion of 10 bases in the signal
sequence of babA1, which is inactive. Presence of BabA encoded by babA2 gene is
associated to increased risk of peptic ulcer disease, being enhanced by the presence of cagA.
OipA adhesion molecule is expressed by occurrence of CT dinucleotide repeats slipped
strand mispairing in some H. pylori strains. Studies using mutants of oipA gene revealed its
effect on the signaling host cell pathways through tyrosine phosphorylation and actin
cytoskeleton inducing alterations. OipA protein is associated to increased mucosal
inflammation by induction of Interleukin 8 (IL-8) and to duodenal ulcer disease. ics human
Lewis blood group antigens and present a very low pyrogenic activity when compared to LPS
from others enteric bacteria. Genes associated to the biosynthetic pathways for production
Persistence of H. pylori infection is also associated to the modified LPS which mim of H.
pylori LPS present bacteria population specificity and thus, could produce different gastric
disease phenotypes.
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Expression of H. pylori DupA virulence factor occur in approximately half of the bacteria
strains worldwide, and is associated to increase the risk of duodenal ulcer disease by a
mechanism involving neutrophil infiltration and protection against physiological alterations
associated to corpus gastritis, ome produced by presence of DupA is independent from host
population regional characteristics. including inhibition of atrophy by hypochloridria related
to the development of gastric ulcer. Disease outc.
The IceA coding gene has two allelic forms iceA1 and iceA2 and expression of iceA1 is
related to induction of acute antral inflammation by increasing expression of IL-8, being a
marker for peptic ulcer disease in different populations.
HOST RISK FACTORS AFFILIATION TO H. PYLORI AND PEPTIC ULCER
ILLNESS
H. pylori diseaSE outcome are strongly related to bacterial virulence factors and human host
behavior and genetic background. Above, the virulence factors involved in bacterium
pathogenesis was discussed. In this section, host specificities associated to H. pylori infection
and peptic ulcer disease will be point out. Regional studies are very important to know
specificities which can be used to prevent and to manage gastric diseases caused by H. pylori.
A number of studies have shown the participation of non- H. pylori risk factors such as
smoking, alcohol intake and Nonsteroidal Antiinflammatory Drug (NSAID) use in the
etiology of peptic ulcer disease. Some of these factors are also associated to an increased risk
of peptic ulcer disease related to H. pylori as NSAID.
Aging is another important factor associated to peptic ulcer disease related to H. pylori, since
development of severe gastric diseases depends on chronic and persistence of the bacterium
colonization during a long time. Several cells and regulatory hormones and genes from
immunological human system are involved in H. pylori persistent chronic infection. Thus,
genetic human variants of immunological molecular features can be associated to increased
risk for peptic ulcer disease. Description of these factors is out of the scope of this chapter
and was recently reviewed.
Considering the plasticity and genetic diversity of H. pylori worldwide, bacterium and human
co-evolution specificities, and host genomic variation, regional H. pylori and human
population’s investigation have to be carried out in order to improve treatment and prevention
of severe gastric diseases as peptic ulcer.
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Diagnose
specificity and sensitivity. Invasive and/ or non-invasive tests. Various tests have been
developed for H. Pylori detection, each with advantages and disadvantages. The available
tests are generally divided into invasive tests, based on gastric specimens for histology,
culture, or other techniques and non-invasive tests, based on peripheric evidence, such as
blood samples, respiratory tests, feces, urine or saliva for antibodies or bacterial antigens
detection.
Invasive methods
1. The histological methods are the "gold standard" for diagnosing H. pylori infection,
providing information not only about the inflammation, but also the degree of atrophy
induced by the bacteria. The need for an experienced pathologist and the invasive method
represent a disadvantage. It has a higher sensitivity and specificity of about 95%.
2. Helicobacter pylori cultures are the alternative to the "gold standard"; with similar
specificity and sensitivity, they also allow testing for antimicrobial susceptibility.
3. The rapid urease test is used for the qualitative detection of Helicobacter pylori in the
urease from the biopsy sample obtained after gastroscopy. With a specificity and sensitivity
of more than 90% and with good cost-effectivness, the urease test is a quick method of
diagnosis (3 minutes), being the most common invasive method. It requires an additional test
to confirm H. pylori infection.
Non-invasive methods.
1. Testing the urea in the exhaled air is an alternative to the "gold standard" with a similar
specificity and sensitivity, the most accurate noninvasive method of diagnosis. It is also a
reliable test to evaluate the success of H. pylori eradication therapy. The major disadvantage
is the high cost of the equipment.
2. Antigen testing in stool samples, with a sensitivity greater than 90%, gas not been used
widely, but it can be reliable for assessing the success of H. pylori eradication treatment.
3. Serology (with a sensitivity of 80-90%), is mainly used for epidemiological studies; it
cannot verify the evolving infection due to immunologic memory.
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Invasive methods cause discomfort in patients during diagnosis, the reason many patients
refuse upper gastrointestinal endoscopy, especially during the check-up performed 4 weeks
after treatment. Non-invasive methods of diagnosis are recommended as an alternative for
patients under 45 years of age who do not show symptoms such as: unexplained weight loss,
digestive bleeding or repeated vomiting. Patients experiencing these symptoms require upper
gastrointestinal endoscopy.
When patients present acute gastroesophageal bleeding or are under treatment with proton
pump inhibitors, histamine antagonists or antibiotics, most diagnostic tests for H. pylori
infection may show false negative results. Because of this, it is mandatory that the treatment
with inhibitors of proton pump or histamine antagonists should be stopped two weeks before
the diagnosis test, and if the patients are receiving antibiotic treatment, it should be
discontinued at least four weeks before testing.
Blood presence in the gastric lumen can lead to false results due to the buffering effect it has
on the gastric pH. If there is upper gastrointestinal bleeding or extended mucosal atrophy,
serological tests can be useful, as they indicate a history of exposure to H. pylori, although
they do not confirm the presence of infection; so, it is necessary to repeat a non-invasive
diagnostic test (if the initial test result was negative) 4-8 weeks after the hemorrhagic event
important tools on which the therapeutic success depends.
Treatment of H. pylori
Treatment regimens for H. pylori infection have been evolving since the early 1990s.
Antimicrobial therapy for this infection is a complex issue and the following drugs are
currently used in combination regimens: Proton-pump inhibitors and/or bismuth,
metronidazole, clarithromycin, amoxicillin (Malfertheiner et al., 2002). Tetracycline is used
in rescue therapy (Gisbert and Pajares, 2001). An effective first- line therapy for
uncomplicated cases would be Amoxicillin + Metronidazole + Pentoprazole (a PPI).
Treatment of H. pylori usually leads to clearing of infection, relief of symptoms and eventual
healing of ulcers. Recurrence of infection can occur and treatment may be required, if
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necessary with other antibiotics. However, there are concerns about the emergence of
resistant strains in Nigeria (Aboderin et al., 2007). From other parts of the world strains
resistant to metronidazole (Jenks and Edward, 2002); clarithromycin (Osato et al., 2001);
amoxicillin (Wu et al., 2000) have been documented. The resistance problem with H. pylori
shows that treatment regimens will continue to evolve as the search continues for effective
treatment eradication protocols.
CONCLUSIONS
Helicobacter pylori infection is still a global concern, its diagnosis and treatment may raise
serious challenges. The diagnosis, the effective treatment and the revaluation of its
effectiveness represents the prophylaxis of some diseases such as peptic ulcer, gastric
lymphoma of mucosaassociated lymphoid tissue (MALT) and gastric cancer. These diseases
and their severe complications (bleeding, perforation) are lifethreatening for the patient.
Treatment failure is due to the patient’s non-cooperation or his/her resistance to antibiotics; it
varies depending on the patient’s country of origin, the patient him/herself, and previous
prescriptions of antibiotics for other conditions. If the second treatment (as recommended by
regional doctors) also fails, an endoscopy is required in order to have a biopsy sample from
which to perform culture and DST. Although H. pylori treatment fails in about 20% of cases,
moral support for the patient by the clinician, information about possible evolutional
complications of H. pylori infection, and periodic evaluation of the patient during therapy.
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