Journal of M ind and M edical Scie nces [622393]

Journal of M ind and M edical Scie nces
Volume 3 |Issue 2 Article 7
2016
Helicob acter pylori: types of di seases, di agnosis,
treatme nt and c auses of the rapeutic failure
Cosmin V asile Oble aga
Craiova University of M edicine and Ph armacy, Department of Su rgery, cosmin .obleaga@gm ail.com
Cristin C ons tantin V ere
Craiova University of M edicine and Ph armacy, Department of G astroenterology
Ionic a Daniel V alce a
Craiova University of M edicine and Ph armacy, Department of Su rgery
Mihai C alin C iorb agiu
Craiova University of M edicine and Ph armacy, Department of Su rgery
Emil Moraru
Craiova University of M edicine and Ph armacy, Department of Su rgery
See ne xt page for add itional authors
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Common s
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Helicob acter pylori: types of di seases, di agnosis, treatme nt and c auses of
therapeutic failure
Cover Page Footn ote
This study w as fin ancially suppor ted by the pr oject: "The r ole of H elicobacter pylori infe ction in u pper
gastrointestinalnon-v ariceal bleedings. A cl inical , endos copic, serological a nd hi stopathological s tudy "
spon sored by "The M edical C enter Amaradia"(Contract N o. 723/ 25.06.2014, p artner of UMF of C raiova)
Auth ors
Cosmin V asile Ob leaga, Cristin C onstantin V ere, Ionica D aniel Valcea, Mihai C alin C iorbagiu, Emil Moraru,
and C ecil Sorin M irea
This review article i s available in J ournal of M ind a nd M edical S ciences:http://s cholar.valpo .edu/jmm s/vol3/iss2/7

J Mind Med Sci. 2016; 3(2 ): 150-161. Review Article

Corresponding author: Dr. Cosmin Vasile Obleaga , SCJU Craiov a, Clinic II of Surgery, Tabaci Street No.1, Craiova ,
(200642 ); e-mail: [anonimizat]

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

1Cosmin Vasile Obleaga, 2Cristin Constantin Vere, 1Ionica Daniel Valcea, 1Mihai
Calin Ciorbagiu, 1Emil Moraru, 1Cecil Sorin Mirea
1Craiova University of Medici ne and Pharmacy, Department of surgery; 2 Craiova University of Medicine and Pharmacy,
Department of Gastroenterology

Abstract

Acute upper gastrointestinal lesions have a multifactorial etiology but, regardless of the cause,
they are related to mucosal barrier destruction. Since Helicobacter pylori induces a superficial
chronic gastritis with the infiltration of neutrophils in the mucosa, it was speculated that Helicobacter
pylori infection could also cause bleeding lesions. The diagnosis, the p roper treatment and the
revaluation of its effectiveness actually represent the prophylaxis of some diseases such as peptic
ulcer, gastric lymphoma or mucosa -associated lymphoid tissue (MALT) and gastric cancer. These
diseases and their severe complication s are life -threatening for the patient. Periodic renewal of the
treatment a nd knowing the real causes of Helicobacter pylori resistance to various antibiotics must
always be understood by the clinician. Although Helicobacter pylori treatment fails in about 20% o f
cases, moral support of the patient by the clinician, information about possible evolutional
complications of Helicobacter pylori infection , and periodic evaluation of the patient during therapy,
are important tools on which the therapeutic success depends.

Keywords : helicobacter pylori, diagnosis, bleeding, treatment resistance

Cosmin V. Obleaga et al.
151
Introduction
Helicobacter pylori bacterium (H. pylory) is
the first officially recognized carcinogen . Over half
the world's population is colonized with this
bacterium , being the best known gram negative
bacteria. Because histopathological changes
induced gastric mucosam , the Helicobacter pylori
infection represents a determining factor in the
occurrence of the gastrointestinal disease that can
range from chr onic gastritis without clinical
symptoms to serious neoplastic diseases. In man y
cases, the clinical signs of upper gastrointestinal
bleeding is the first symptom of gastrointestinal
infection with Helicobacter pylori.The disease is the
result of complex i nteractions between host and
bacteria (1).
History
Barry Marshall and Robin Warren were first
to describe the isolation and culture of a bacterium
in the human stomach, later known as H. pylori (2).
Their experiments on themselves using self –
ingestion (3, 4) and those on volunteers showed
that bacteria can col onize the human stomach and
can induce inflammation of the stomach mucosa
(5).
Later research has shown that colonization of
H. pylori can cause chronic gastritis, peptic ulcers,
as well as gastri c lymphoma mucosa associated
lymphoid tissue (MALT) or gastric cancer. Morphology
H. pylori is a gram negative bacterium,
measuring 2 to 4 pm in length and 0.5 to 1 pm in
width. The body has 2 to 6 flagella and the motility
of the flagella confers and allo ws rapid movement
in viscous solutions, such as the mucus layer of the
gastric epithelial cell (6). Unlike many other
gastrointestinal tract pathogens, Helicobacter pylori
does not have fimbriae adhesins. The growth occurs
at a temperature of 34 – 40° C, w ith an optimum of
37ș C. Although its natural habitat is the acid gastric
mucosa, H. pylori is considered to be a neutrophil.
The bacterium survives to pH < 4 exposure, but the
growth occurs only in relatively narrow pH range of
5.5 to 8.0, with optimal gr owth at neutral pH (7, 8).
Geographical distribution
A high diversity in prevalence of H. pylori
infection among adults in Europe was registered in
2000, with a global prevalence in adulthood of
18.3-82.5%, with variations from country to
country. The high est prevalence, 82.5% for adults
older than 18 years old , was measured in Turkey,
on a natio nally representative population; and the
lowest prevalence, 18,3%, was found in Denmark
(9). H. pylori prevalence shows large geographical
variations. In various de veloping countries, more
than 80% of the population is H. pylori positive,
even at young ages. H. pylori prevalence in
industrialized countries remains generally below
40% and is significantly lower in children than in

Helicobacter pylori: diagnosis and therapy
152
adults and the elderly. In geographic al areas, the
prevalence of H. pylori correlates inversely with
socioeconomic status, particularly regarding living
conditions during childhood (10).
H. pylori colonization is not a disease itself,
but it influences the relative risk of developing
differen t clinical conditions of the gastrointestinal
tract and possibly the hepatobiliary tract. Therefore,
routine or random testing for H. pylori has no
benefit, but testing should be performed in order to
find the cause of diseases such as peptic ulcer, or,
for the prevention of diseases, such as in subjects
with family history of gastric cancer. In these cases,
a positive test result justifies a treatment and a
negative result may indicate the need to search for
other etiological factors and preventive measur es.
For these reasons, a correct understanding of
disorders associated with H. piloryis needed.
Types of diseases
Gastritis lesions occur in all H. pylori
infected subjects, but only a minority develop
clinical signs of this colonization. It is estimated
that H. pylori posit ive patients have a risk of 10 –
20% of developing pep tic ulcer and 1 -2% of them
have a risk of developing gastric cancer (11, 12,
13). The emergence of these disorders depends on
the type and severity of gastritis.
In acute and chronic gastritis, due to H. pylori
infection, the infiltration of gastric mucosa most frequently appears in the antrum and gastric body
with mononuclear and neutrophil cells. Active
chronic gastritis is the main condition linked to the
colonization with H. pylor i, and other disorders
associated with H. pylori results in particular
because of the chronic inflammatory process (1).
Causes of gastritis, other than H. pylori
infection are: excessive consumption of alcohol and
nonsteroidal antiinflammatory drugs (NSAI Ds),
cytomegalovirus infections, and chronic idiopathic
diseases (Crohn's disease and pernicious anemia).
Gastric and duodenal ulcers (commonly
referred to as peptic ulcers) are defined as mucosal
defects with a diameter of at least 0.5 cm
penetrating the mucous and/or muscular tunica.
Gastric ulcers occur mainly along the lesser
curvature of the stomach, particularly in the mucosa
in the lining of the boundary between the body and
antrum (1), the duodenum being the most exposed
area to gastric acid.
The i nitial worldwide reports, in the first
decade after discovering H. pylori, associated this
infection with about 95% of duodenal ulcers and
85% of gastric ulcers (14). H.pylori eradication has
changed the natural history of ulcer disease and
ulcer recurrenc e was prevented almost completely
(15). These data show that gastric and duodenal
ulcers seem to be strongly linked by H. pylori
infection. However, recurrent ulcer s can be
registered after H. pylori eradication therapy

Cosmin V. Obleaga et al.
153
because of the persistence or reinf ection with H.
pylori, NSAID use, or in case of idiopathic ulcer.
The most common com plication of ulcer is
bleeding and perforation, followed by stomach
obstruction. It is estimated that 15 -20% of peptic
ulcers are complicated by hemorrhage and that
approx imately 40% of patients who develop upper
gastrointestinal bleeding are also suffering of ulcer
(1).
The primary treatment for ble eding in
ulcerous disease is endoscopic therapy, which is
mandatory in order to establish the bleeding cause,
to estimate it s gravity , and to reduce the risk of
recurrent bleeding. H. pylori eradication markedly
reduc es the risk of ulcer as wekk as the risk of re –
bleeding for those patients whose bleeding was
caused by H. pylori infection (16). In general, a
small percentage of bleeding ulcers requires very
careful management, and the indications for
emergency surgery in such cases are: hemodynamic
instability, failure in performing endoscopic
hemostasis , and bleeding recurrences despite
endoscopic attempts to stop it. Regardin g the third
indication, many doctors indicate surgery after two
failed endoscopic attempts to stop the bleeding (17).
Several studies have shown that some perforated
peptic ulcers can be treated conservatively, but in
any patient with a perforated peptic u lcer, showing
peritoneal signs, surgery is required, and then it is necessary to decrease the acid secretion and
antibacterial therapy in H. pylori -positive patients.
Chronic ulcer, especially in the pyloric and bulbar
regions, can lead to hypertrophic sca rs and stenosis,
impairing the gastric eviction process. In these
patients, malignancy as a cause of obstruction must
first be ruled out. Most benign obstructions
associated with H. pylori respond well to the
eradication therapy, due to the reduction or
disappearance of inflammation and edema. In
refractory patients, local reconstruction surgery, or
a distal gastric resection is mandatory (1).
Atrophic gastritis, intestinal metaplasia and
gastric inflammation, cancer.
In histopat hogic terms, in chronic gast ritis
induced by H. Pylori , studies have shown a loss of
the normal architecture through the destruction of
the gastric mucosa and gastric glands , with normal
mucosa replaced by areas of fibrosis and intestinal
epithelium. These changes occur in areas of the
gastric or duoudenal mucosa , with that
inflammation being more severe in 50% of subjects
aproxim ativ H. pylori positive (18). The risk of
atrophic gastritis depends on the distribution and
the chronic a ctive inflammation model; therefore,
subjects wi th decreasing acid production show a
faster progression to atrophic gastritis (19).
Various studies have shown that H. pylori
positive subjects have increased risk of developing

Helicobacter pylori: diagnosis and therapy
154
gastric cancer compared to uni nfected persons by
sequence of atrophy and metap lasia (20). This idea
is supported by studies showing links between
geographic prevalenceof H. pylori and incidence of
stomach cancer (21). Factors that influence the
occurrence of gastric atrophy and later, of stomach
cancer in H. pylori positive subjec ts are both linked
to host and bacteria, by the severity of chronic
inflammatory response caused by them. Therefore,
the risk of developing gastric atrophy is increased in
subjects with strains CagA positive (22), but also in
those with a genetic predispos ition to high yields of
IL-1, as a result of the response to the colonization
of the bacteria (23).
Although lymphoid tissue is not normally
present in the gastric mucosa, MALT almost always
occurs in response to infection with H. pylori. This
tissue may give birth to a population of B
monoclonal cells from w hich can proliferate and
form a MALT lymphoma. Almost all patients with
a MALT lymphoma are H. pylori -positive (24) and
H. pylori positive subjects have a significantly
increased risk of developing gas tric MALT
lymphoma (25). Different series of "case -report s"
have shown that H. pylori eradication may lead to
complete remission in patients with MAL T
lymphoma stage IE confined to the stomach (26,
27). Generally, about 60 to 80% of these patients
achieve complete remission after H. pylori
eradication, about 10% continue to have signs of residual disease, while the rest show no response
(1).
There have been cases where the disease
evolution depends on the correct guided therapy for
H.pilory. For example, t wo subjects from the same
family colonized with H. pyloriwho manifest ed
clinical signs of disease and had positive laboratory
tests (the mucosal lesions are highlighted by up per
gastrointestinal endoscopy). O ne of them receiv ed
the correct t reatment to erad icate H. Pylori and had
symptoms remission, while th e other, who did not
receive treatment, developed a hemorrhagic MALT
lymphoma 10 years after the diagnosis.
Diagnose : specificity and sensitivity. Invasive
and/ or non -invasive tests.
Various tests have b een 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
peripheri c evidence, such as blood samples,
respiratory tests, feces, urine or saliva for antibodies
or bacterial antigens detection.
Invasive methods:
1. The hist ological methods are the "gold
standard" for diagnosing H. pylori infection,
providing information not only about the
inflammation, but also the degree of atrophy

Cosmin V. Obleaga et al.
155
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 ar e 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 fr om the biopsy sample obtained after
gastroscopy. With a specificity and sens itivity 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 addition al 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 non –
invasive method of diagnosis. It is also a relia ble
test to evaluate the success of H. pylori eradication
therapy. The major disadvantage is the high cost of
the equipment.
2. A ntigen testing in stool samples, with a
sensitivity greater than 90%, gas not been used
widely , but it can be reliable for asse ssing the
success of H. pylori eradication treatment. 3. Serology (with a sensitivity of 80 -90%), is
mainly used for epidemiol ogical studies; it cannot
verify the evolving infection due to immunologic
memory.
Invasive methods cause discomfort in patien ts
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 sh ow symptoms such
as: unexplained weight loss, digestive bleeding or
repeated vomiting. Patients experiencing these
symptoms require upper gastrointestinal endoscopy.
When patients present acute ga stroesophageal
bleeding or are under treatment wit h 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 shoul d 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 (28).
Blood presence in the gastric lumen can lead
to false results due to the buffering effect it has o n
the gastric pH. If there is upper gastrointestinal
bleeding or extended mucosal atrophy, serological
tests can be useful, as they indicate a history of

Helicobacter pylori: diagnosis and therapy
156
exposure t o H. pylori, although they do not confirm
the presence of infection; so, it i s necessary to
repeat a non -invasive diagnostic test (if the in itial
test result was negative) 4 -8 weeks after the
hemorrhagic event (28).
Treatment
Helicobacter pylori eradication methods have
continued to evolve over the last 20 years.
Originally, the tr eatment used H -2 histamine
receptor antagonists and an antibiotic with a success
rate of 73 -84% (29). In time, t his therapy has been
used less frequently , thanks to new treatment
regimens having much better results. Currently,
triple therapy based on proto n pump inhibitors is
the most commonly used method. This system
includes the use of PPIs in combination with
amoxicillin and clarithromycin.
Eradication therapy
1.The PPI-based triple therapy consists of
Esomeprazole 20 mg twice a day, or 20 mg of
omeprazo le twice a day, Amoxicillin 1 g twice a
day and Clarithromycin 500 mg twice a day. The
treatment must be taken for 7 days ; this therapy is
highly recommended in Australian guidelines (30).
2.The quadruple therapy includes Omeprazole
20mg per day subsalicyl ate 120 mg four times a
day, metronid azole 400 mg three times a day,
tetracycline 500 mg four times. The treatment is
prescribed between 7 and 14 days (30). Therapy control
Because treatment of H. pylori fails f or
approximately 20% of cases for any number of
different reasons , verifying eradication of infection
after treatment is required in patients at risk. The
same control is mandatory in patients with peptic
ulcer s, with MALT , and if patients whose dyspeptic
symptoms are persistent. For efficacy evalua tion of
the t reatment, 13 C marked urea or f eces antigen
tests are reccomended. Testing of urea in the
patient's exhaled air has a precision higher than the
antigen in feces and is preferred in these cases (28).
Causes of treatment failure
1. Antibiotic re sistance of Helicobacter pylori
strains.
Diabetes can be a risk factor for resistance to
antibiotics used for Helicobacter pylori eradication.
Although in a study in Taiwan, a better rate of H.
pylori eradication in patients with diabetes was
observed (31), several studies have shown opposite
results. Impaired microvascular gastric absorption
lowering drugs, gastroparesis and the use of
antibiotics for recurrent urogenital infections,
respiratory infections, and skin resistance represent
the main causes of H. pylori resistance to standard
treatment in patients with diabetes. Diabetic
gastroparesis affects approximately 40% of patients
with diabetes type 1 and 30% of patients with
diabetes type 2 , especially those with long -term

Cosmin V. Obleaga et al.
157
illness. In a study published by Ojetti et al. (32), H.
pylori eradication rate is lower in diabetic adults
than in children, probably due to more frequent
infections and antibiotic therapies. Bismuth -based
therapy has better results for H. pylori eradication
in these patients, compar ed with the triple therapy
(33).
The treatment of recurrent respiratory
infections or urogenital tract, often treated with
antibiotics, is another cause of bacteria resistance to
the drugs used in different regimens for H. pylori
eradication. Amoxicillin, clarithromycin, metro –
nidazole and tetracycline are antibi otics used in
first-line treatment of various respiratory or
urogenital tract infections; in many cases, patients
undergoing trea tment for H. pylori eradication have
used these antibiotics regimen f or treating other
infections.
Increased resistance to levofloxacin in several
European countries is also worrying because it
opposes its use of empirical anti -H pylori treatment
regimens without prior sensitivity tests (34). In the
same study publ ished by Megraud F, a significant
positive association was shown between the use of
antibiotics in the ambulatory and the primary
degree of resistance observed in antimicrobial key
agents used for the eradication of H pylori.
Knowledge about the antibiot ics used i n a particular
region or by every patient can provide information
regarding the sensitivity or the resistance of H pylori not only to quinolones and macrolides, but
also to other antibiotics, and thus the rehabilitation
of the treatment strategies where th e tests of
sensitivity of H .pylori strains, isolated from the
patient, are not available.
H. pylori strains that grow in the presence of
cholesterol are more resistant to multiple antibiotics
(35). The antibiotics with this kind of resistance
from the pat ients, in relation with cholesterol, are
included in some treatment schemes used for to
treat H. pylori infections, with recent work showing
that H. pylori has a resistance dependent on bile
salts cholesterol (36). This suggests that H. pylori
can use the cholesterol modifying its envelope so as
to resist to multiple antibiotics (37).
Clarithromycin and tetracycline are antibiotics
which inhibit protein synthesis and are used to treat
H. pylori infection. A study based on the effect of
antibiotics on the v iability of H. pylori cultivated in
the presence or absence of cholesterol showed how
cholesterol substantially increased H. pylori
resistance to tetracyclin and clarithromycin.
Ciprofloxacin and Metronidazole inhibit the
DNA replication, and they are als o used for the
treatment of H. pylori infections. However, H.
pylori grown with cholesterol was more resistant to
ciprofloxacin than H. pylori grown without
cholesterol. H. pylori grown with cholesterol
showed a modest increase resistance to

Helicobacter pylori: diagnosis and therapy
158
metronidazole (about 10 to 30 times). For
antibiotics that inhibit the biosynthesis of the cell
wall, i.e., ampicillin and amoxicillin, there were
similar results: H. pylori strains grown on the
medium with cholesterol levels were up to 1,000
times more resistant to ant ibiotics than those grown
without cholesterol. B ismuth compounds are part of
the regimen of H. pylori infection in some
countries. H. pylori cultivated with cholesterol was
significantly more resistant to bismuth (up to 107),
than H. pylori bacteria grown without cholesterol.
H. pylor i grown without cholesterol was also more
susceptible to rifampicin than H. pylori grown with
cholesterol (35).
2.Patient non -cooperation. Quitting the initial
treatment.
Many patients abandon treatment and the
therapeutic sche me after being diagnosed with H.
pylori infection , typically for two reasons:
improvement and disappearance of symptoms of
peptic ulcer ; or the side e ffects of the treatment . The
recurrence of symptoms at some time after giving
up the initial treatment req uires H. pylori culture,
allowing thus antimicrobial susceptibility testing.
The patie nt's support by the clinician about the
awareness of the disease, information about the
possible complications of this disease, and periodic
evaluation dur ing therapy is important for patient
compliance to treatment and therapeutic success. Conclusions
Helicobacter pylori infectio n is still a global
concern, it s diagnosis and trea tment may raise
serious challenges . The diagnosis, the effective
treatment and the revaluatio n of its effectiveness
represents the prophylaxis of some diseases such as
peptic ulcer, gastric lymphoma of mucosa –
associated lymphoid tissue (MALT) and gastric
cancer. These diseases and their severe
complications (bleeding, perforation) are life –
threate ning 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
condi tions. If the second treatment (as
recommended by regional do ctors) also fails, an
endoscopy is required in order to have a biopsy
sample from which to perform culture and DST.
Although H. pylori treatment f ails 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, are
important tools on which the therapeutic success
depends.
Acknowledgment:
This study was fin ancially supported by the
project: "The role of Helicobacter pylori infection
in upper gastrointestinalnon -variceal bleedings. A

Cosmin V. Obleaga et al.
159
clinical, endoscopic, serological and
histopathological study" sponsored by "The
Medical Center Amaradia" (Contract No. 723/
25.06.2014, partner of UMF of Craiova)

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