HELICOBACTER PYLORI AND PEPTIC ULCER IN ADULT PATIENTS

www.wjpps.com │ Vol 10, Issue 1, 2021. │ ISO 9001:2015 Certified Journal │

166

Izhaq et al. World Journal of Pharmacy and Pharmaceutical Sciences

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


167


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.


168



169


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,


170


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.


171


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


172


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.


173


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.


174


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.


175


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


176


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.

REFERENCES

1. Warren JR, BJ Marshall. Unidentified curved bacilli on gastric epithelium in active

chronic gastritis. Lancet, 1983; 1: 1273-1275.

2. Dunn BE, Cohen H, Blaser MJ. Helicobacter pylori. Clin Microbiol Rev, 1997; 10:

720-741.

3. Jones DM, Lessells AM, Eldridge J. Campylobacter like organisms on the gastric

mucosa: culture, histological, and serological studies. J Clin Pathol, 1984; 37: 1002-1006.

4. Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, et al. Mosaicism in

vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types

5. Momtaz H, Souod N, Dabiri H, Sarshar M. Study of Helicobacter pylori genotype status

in saliva, dental plaques, stool and gastric biopsy samples. World J Gastroenterol, 2012;

18: 2105-2111.


177


6. Assumpção MB, Martins LC, Melo Barbosa HP, Barile KA, de Almeida SS. Helicobacter

pylori in dental plaque and stomach of patients from Northern Brazil. World J

Gastroenterol, 2010; 16: 3033-3039.

7. Mendall MA, Northfield TC. Transmission of Helicobacter pylori infection. Gut, 1995;

37: 1-3.

8. Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol

Rev, 2000; 22: 283-297.

9. Graham DY, Malaty HM, Evans DG, Evans DJ Jr, Klein PD, et al. Epidemiology of

Helicobacter pylori in an asymptomatic population in the United States. Effect of age,

race, and socioeconomic status. Gastroenterology, 1991; 100: 1495-1501.

10. Duque X, Vilchis J, Mera R, Trejo-Valdivia B, Goodman KJ, et al. Natural History of

Helicobacter pylori Infection in Mexican Schoolchildren: Incidence and Spontaneous

Clearance. J Pediatr Gastroenterol Nutr, 2012; 55: 209-216.

11. Mégraud F. [Helicobacter pylori infection: Review and practice]. Presse Med, 2010; 39:

815-822.

12. Ernst PB, Gold BD. Helicobacter pylori in childhood: new insights into the

immunopathogenesis of gastric disease and implications for managing infection in

children. J Pediatr Gastroenterol Nutr, 1999; 28: 462-473.

13. Pattison CP, Combs MJ, Marshall BJ. Helicobacter pylori and peptic ulcer disease:

evolution to revolution to resolution. AJR Am J Roentgenol, 1997; 168: 1415-1420.

14. Sugiyama T, Sakaki N, Kozawa H, Sato R, Fujioka T. Sensitivity of biopsy site in

evaluating regression of gastric atrophy after Helicobacter pylori eradication treatment.

Aliment Pharmacol Ther, 2002; 16 Suppl 2: 187-190.

15. Wilhelmsen I, Berstad A. Quality of life and relapse of duodenal ulcer before and after

eradication of Helicobacter pylori. Scand J Gastroenterol, 1994; 29: 874-879.

16. Helicobacter Pylori Infection in Peptic Ulcer Diseases, Márcia Aparecida Sperança1* and

Rodrigo Buzinaro Suzuki1,2,1Universidade Federal do ABC, Centro de Ciências

Naturaise Humanas, Brazil,2Department of Genotyping, Hemocenter, Marilia Medical

School, Brazil.

17. Helicobacter pylori: types of diseases, diagnosis, treatment and causes of therapeutic

failure. Cosmin Vasile Obleaga, Craiova University of Medicine and Pharmacy,

Department of Surgery, [email protected].

Documents

HELICOBACTER PYLORI AND PEPTIC ULCER IN ADULT PATIENTS