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| Helicobacter Pylori Infection: Current
Status |
YK Joshi
Additional professor
Deptt. Of Gastroenterology & HNU
All India Institute of Medical Sciences
New Delhi |
| Peptic ulcer disease (PUD) is a common
problem encountered by physicians in day-to-day practice. Its
prevalence varies from country to country and from place to
place within the country. Till recently a number of factors
were incriminated as the cause of the disease. These included
food habits, smoking, heredity, physical stress, psychological
stress, alcohol, coffee, drugs, infectious agents like virus,
etc. All these factors were thought to be responsible for increased
acid output, which is the responsible for increased acid output,
which is the requirement for the occurrence of the ulcer. It
was believed that "no acid, no ulcer". During the
last two decades there has been a tremendous progress in understanding
the etiology, pathogenesis and management of the disease. Now,
it is certain that the bacterial infection by H. Pylori is the
main etiological agent of peptic ulcer. Of course, acid remains
in the limelight and it does play an important role of H. pylori
in peptic ulcer and its managements. |
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| Epidemiology and Prevalence1-3 |
| Humans are the only host for H. pylori,
which is found in stomach, and in duodenum oesophagus and rectum
on areas of metaplastic gastric epithelium. Other Helicobacter
species have been isolated from the animals. Animal models of
Helicobacter infection have been developed due to the shared
characteristics of other Helicobacter like H. mustelae and H.
felis with H. pylori.
H. pylori exists the world over and its prevalence in the
population increases with age. In developed countries, prevalence
increase about 1 percent per year of age where it is rare
in children, and reaches 70 percent in the seventh decade.
In developing countries, more than 50 percent children acquire
the infection by the age of 10 years, and more than 80 percent
of the population gents infected by the age of 20 years. In
asymptomatic individuals prevalence of H. Pylori infection
varies from 31 percent-84 percent.
H. pylori infection is chronic and once acquired remains
life long, unless eradicated by antibiotics given for some
other conditions. Humoral and tissue immune response by the
host is usually not sufficient to clear the infection. Though
the mode of transmission in not yet well established, most
probably it takes place by oral-oral or faeco-oral route and
important risk factors are socioeconomic status and age. Overcrowding,
poor socio-economic status and poor hygiene are associated
with high infection rate. Re-infection rate after eradication
is quite high in developing countries due to the above mentioned
risk factors.
Colonization of H. pylori occurs by producing urease and
gastric acid inhibitory protein. It can colonize only in gastric
type epithelium and cannot stay anywhere else in the GI tract
in absence of gastric mucosa. Metaplasia, which is present
in more than 90 percent of patients of duodenal ulcer, occurs
by replacing the columnar cells, normally covering the duodenal
villi, by gastric type epithelium. Adhesion of H. pylori to
the gastric epithelium occurs by tissue specific proteins.
Colonization of the duodenal bulb by H. pylori leads to mucosal
inflammation which makes it vulnerable to attack by acid or
pepsin or bile resulting into ulceration, however, factors
leading to gastric metaplasia in the duodenal bulb are not
known. Stimulation of the immune system of H. pylori contributes
to host damage and it evades the immunological clearance. |
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| Bacterial Factors4-7 |
| Direct damage to the host occurs by
urease and other enzymes and toxins produced by the bacteria.
Depending on the enzymes and toxins production, H. pylori strains
phenotypically can be divided into two groups, i.e., type 1
and type 2. Type 1 contains vacuolating toxin, encoded by the
gene vacA (94-kda vacA) and cytotoxin-associated protein encoded
by the gene cagA (120-128-kcagA). The second group ie, type
2 contains non-cytoxic vacA and cagA negative strains. It has
been observed that type 1 strains cause more intensive inflammation
than type 2. Such strain diversity may explain why some infected
individuals do not develop diseases while some may develop peptic
ulcer and gastric cancer which may be due to different type
of strains. The studies from other countries have reported that
about 70 percent of strains isolated from patients with DU produce
this toxin compared to about 30 percent isolated from non-ulcer
dyspepsia. There is also some evidence to suggest that the degree
of inflammation and subsequently clinical consequences of H.
pylori infection are related to density of bacterial colonization.
The enzyme produced by both types of strains plays an important
role in the pathogenesis. Urease hydrolyses urea into ammonia
and creates alkaline surroundings, thus creating a neutral microenvironment
for the bacteria. It may also have role in H. pylori metabolism
as a part of nitrogen cycle. It has been presumed that the ammonia
produced by the urease activity works with cytotoxin inducing
vacuoles.
Though H. pylori is strongly antigenic and leads to humoral
and cellular immune response, the human host is unable to
clear the infection that pay persist life long. The local
inflammatory response leads to accumulation of a number of
different cytokines that includes IL-8 and tumour necrosis
factor alpha. These two cytokines play an important role in
the formation of inflammatory infiltrate. Type 1 H. pylori
strains have been shown to induce significantly higher IL-8
than type 2 strains. |
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| Effects on Gastric Secretions 8-10 |
| Gastrin produced by the G cells stimulates
the acid secretion and has a trophic action on mucosal cells
in the stomach. It has been found that H. pylori increases the
fasting serum gastrin levels in health subjects and also in
patients with duodenal ulcer. The D cells produce the main inhibitor
of gastrin secretion and excretion somatostatin. Somatostatin
levels are decreased in H. pylori positive individuals. H. pylori
also decreased the gastric body mucosal histamine. There are
two main opposite effects of H. pylori on acid secretion function
of the stomach. viz, its effect on fundal histamine decreases
acid output while the effect on somatostatin leading to hypergastrinaemia
increases the gastric acid output. The basal and peak acid output
changes after eradication of H. pylori supports the hypothesis
that H. pylori causes impairment in the inhibitory control of
gastric acid. In the early stage of infection acid output increases,
leading to gastric metaplasia in duodenum, which in turn gets
infected with H. pylori and development of duodenal ulcer. With
diffuse disease the acid output falls. |
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| Diseases associated with H. pylori12-14 |
| H. pylori infection is found to be associated
with gastritis, non-ulcer dyspepsia (NUD), duodenal ulcer, gastric
ulcer, gastric cancer, gastric lymphoma of mucosa associated
lymphoid tissue (MALT), non-Hodgkin's lymphoma and even coronary
heart disease. It has now been well established that H. pylori
is the cause of almost all duodenal ulcers (DU) and chronic
benign gastric ulcers (GU) which are not associated with NSAIDs.
More than 95 percent of DU and 90 percent of GU are associated
with H. pylori infection and there is a dramatic decrease in
their relapse rate after the H. pylori eradication. Right now
there is no convincing evidence that NUD symptoms are due to
H. pylori infection. Prevalence of H. pylori infection is comparable
between health individuals and patients with the symptoms of
NUD. Recurrent abdominal pain in children suggestive of NUD
subsides after the eradication of H. pylori that indirectly
associates H. pylori infection with NUD. However, further studies
are necessary in this regard and at present there is no indication
to eradicate H. pylori in NUD.
Association between H. pylori and gastric cancer has been
reported in several retrospective epidemiological studies.
It is postulated that starting with acute gastritis, H. pylori
infection leads to chronic atrophic gastritis, intestinal
metaplasia, dysplasia and ultimately progression to gastric
adenocarcinoma. High H. pylori infection rate has been reported
in patients with gastric cancers compared to healthy subjects.
The WHO has put H. pylori in group I, a definite carcinogen.
H. pylori has also been found to be associated with development
of MALT and subsequent transformation to malignant lymphoma.
Eradication of H. pylori has shown regression of low-grade
b cell gastric lymphoma of MALT type. There is some epidemiological
evidence that H. pylori infection is associated with non-Hodgkin's
lymphoma that is comparatively rare in stomach. |
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| Diagnosis15-17 |
| A number of invasive and non-invasive
tests with almost comparable sensitivity and specificity are
available. Invasive tests require upper GI endoscopy and biopsy
from stomach for histology, bacterial culture, rapid urease
test (RUT) and PCR. Biopsy if fixed in 10 percent formalin and
stained with hematoxylin and eosin or by modified Giemsa information
on gastritis, metaplasia and dysplasia. In experienced hands
histology has <90% sensitivity and >95% specificity. Biopsy
specimen can also be used for bacterial culture in selective
or non-selective media. Though the sensitivity and specificity
of this test is >95% and <80% respectively, it is time
consuming and expensive and also it is not easy to culture this
bacteria.
RUT is 90% sensitive and 100% specific, inexpensive and provides
results within 20 minutes. Urease produced by the bacteria
hydrolyses urea into ammonia. A change in pH changes colour
of the indicator from yellow to pink. In case of low urease
activity it may take as long as 24 hours to change the colour.
False negative result may be there if the number of bacteria
in the specimen less of if the antral biopsy is ten after
one week of proton pump inhibitors, antibiotics or bismuth
treatment, when H. pylori colonize in body or fundus.
PCR is highly sensitive and specific but it may detect DNA
of non-viable bacteria also giving false positive results
and also has a limited role in confirming eradication of H.
pylori after treatment. It is usually used for molecular typing
of H. pylori and for research.
Non-invasive tests include serology and urea breath test
(UBT). Commercially available ELISA kits detect IgG antibodies
in sera. This test is useful to screen the patients for H.
pylori infection, usually to find out prevalence of H. pylori
infection in the community. It is a relatively sensitive and
specific test and also inexpensive. But it has a limited role
in diagnosing acute infection and in confirming eradication.
UBT is a good non-invasive test. Although it is expensive,
it is highly sensitive (95%) and specific (100%) and also
ideal to check the post-treatment eradication. Detection of
labeled CO2 (13C or 14C) in expired air indicates hydrolysis
of urea and presence of urease producing organism in stomach.
Difference between 13C UBT and 14 C UBT are shown in table
1.
Follow-up tests to check the eradication should be done atleast
four weeks after the completion of treatment to minimize the
likelihood of false negative results. At present, no single
test is the gold standard for diagnosis of H. pylori. The
combination of two or more of above mentioned tests are use
for this purpose |
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13C-UBT |
14C-UBT |
| Sensitivity |
90-100% |
90-100% |
| Specificity |
90-100% |
90-100% |
| Radioactive |
No |
Yes |
| Analysis |
Isotope ratio mass Spectrometry |
Liquid scintillation counter |
| Advantages |
Simple to do Commercially
Available |
Cheap immediate results
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| Disadvantages |
High Cost |
Nuclear Medicine Department
regulation |
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| Treatment18-23 |
| The main aim of treating H. pylori is
to eradicate the organism from the foregut. Eradication is defined
as negative test results for H. pylori four weeks or longer
after the antibacterial therapy. The National Institute of Health
of USA recommends eradication of all H. pylori in all patients
with active peptic ulcer disease or a history of it and proved
infection.
Antimicrobial treatment of H. pylori is difficult, as the
bacteria are located below the mucus layer, adherent to gastric
mucosa where the access of antimicrobial drugs, given either
by enteral or parenteral route is limited and H. pylori may
acquire resistance to commonly or frequently used antibacterial
drugs. These vary from country to country depending on the
use of different antibacterial drugs. For example, resistance
of H. pylori to clarithromycin in UK is less than 5 percent
while in Spain and France it is as high as 15-17 percent.
It is because of this problem, the treatment regimen using
two or three antimicrobial agents have been developed.
This ideal therapy for any infection should be simple, safe,
free from side effects, with 100 percent efficiency and low
cost and it applies to H. pylori infection also. The ideal
treatment regimen has not yet been established, so there is
no definite recommendation for the optimal treatment schedule.
The treatment for H. pylori should be given only after the
clinical diagnosis and proper indication for eradication.
Eradication therapy should not be taken lightly. All the treatment
schedules have side effects but they are mild and usually
do not interfere with patient's compliance if given with proper
instruction. Effect of the antimicrobial agent depends on
the acid environment of stomach that may decrease the effectiveness
of some antibiotics. Usually the concentration of antibiotics
is low in stomach.
Colloidal bismuth subcitrate (CBS) penetrates trans mucosally,
and has been shown to block adhesion of H. pylori to epithelial
cells and to form protective complexes with glycoproteins
and to stimulate mucosal bicarbonate secretion. In vitro studies
have shown bacteriostatic effect of proton pump inhibitors
(PPI) on H. pylori. PPI also may interfere with energy production
of bacteria. All the PPI have also been found to cause decreased
in antral H. pylori density during the therapy, although the
fundal court may increase leading to fundal gastritis. This
is an important effect one has to keep in mind while keeping
the patient on maintenance therapy for gastroesophageal reflux
disease. Clarithromycin is one of the most effective antimicrobial
agents against H. pylori in vitro. It is quickly absorbed
and at pH 5.5, obtained with the help PPIs, it is the most
effective antimicrobial agent. |
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