|
 |
 |
Disease |
|
|
| Helicobacter Pylori : The
Unique Organism |
| Mohammed Sultan Khuroo, MBBS,
MD, FRCP(Edin), MACP |
| Peptic ulcer disease (PUD) is a common
disorder of the community, with an overall lifetime prevalence
of around 11%.1,2 It causes significant morbidity
and mortality. In the United States alone, an estimated 15,000
deaths per year occur as a consequence of complicated PUD.3
Over the decades, the belief has been that PUD is caused by
increased acid secretion as a result of increased parietal cell
mass.4 This concept gave us H2 receptor antagonists
and proton pump inhibitors to block acid secretion and to treat
such diseases.5,6 It worked wonders, and over the
last three decades PUD became medically curable.7
The discovery of Helicobacter pylori (H. pylori) by Warren and
Marshall in 1983 was a landmark breakthrough in the understanding
of gastro-duodenal disorders.8-10 An explosion of knowledge
on H. pylori has changed our basic concept of all gastroduodenal
disorders and the famous dictum of “no acid, no ulcer”
has been replaced by “no bacterium, no ulcer.”11
Peptic ulcer, once an acid-related disease, is now classified
as a bacterial disorder.12-14 |
| |
|
| |
| Agent |
| H. pylori is a curved, spiral gram-negative
motile organism with 4 to 6 -sheathed flagellae. It is slow
growing, microaerophilic bacterium, with some striking biochemical
and biological features making it one of the unique organisms.15
H. pylori is also versed with being the most common human bacterial
infection, and infects around half of the human population.16-18
It infects the gastric antrum and causes gastritis as a result
of this infection (Figure 1). The body of the stomach can also
be infected with or without evidence of gastritis. Involvement
of gastric cardia usually leads to inflammation of this region.
However, the most striking feature of this organism is its inability
to infect normal duodenal mucosa. In sharp contrast to this,
gastric metaplasia of the duodenal mucosa is a favorite for
H. pylori colonization. In fact, it is the involvement of the
duodenal mucosa, which forms the basis for H. pylori duodenitis,
and eventually formation of duodenal ulcer.19-20 |
From the Department of Medicine,
King Faisal Specialist Hospital and Research Centre, Riyadh,
Saudi Arabia.
Address reprint requests and correspondence to Prof. Khuroo:
Department of Medicine MBC-46, King Faisal Specialist Hospital
and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
E-mail: khuroo@yahoo.com.
Accepted for publication 25 May 2002. Received 27 October 2001. |
| H. pylori organisms cannot colonize
regions of normal antrum. Intestinal metaplasia of gastric mucosa
is also hostile to bacteria and H. pylori colonization stops
sharply at the border of the metaplastic epithelium. H. pylori
are placed in the gastric mucus and underneath it, attached
to the surface epithelium. Gastric pits are a favorite site
for placement of the bacteria. However, H. pylori are not seen
inside the gastric epithelial cell or in the submucosa.15
H. pylori produce large amounts of urease and the enzyme a major
component of the bacterium.21-23 H. pylori urease
is primarily a cytoplasmic enzyme, but significant amounts are
adsorbed on the bacterial surface in vivo. When H. pylori is
incubated in vitro, urease levels increase dramatically in the
incubate. Urease production by the bacterium is controlled by
nine genes clustered together on the H. pylori chromosome and
code for assembly of the two basic subunit urease enzymes, insertion
of a nickel ion and possibly transport of the active enzyme
outside the cell. Urease is highly conserved, cross reacts with
all Helicobacter species, and is highly immunogenic, a property
being exploited for use of urease as a vaccine antigen. Urease
enzyme breaks urea into carbon dioxide and ammonia. The enzyme
plays a central role in the survival of the organism in an otherwise
unfavorable acid medium of the stomach. Understandably, production
of large amounts of ammonia does help the organism to neutralize
the acid and maintain a film of friendly pH around it for survival.
By doing so, urease helps the organism to colonize on to the
epithelium. In addition, ammonia causes tissue damage and is
involved in the pathogenesis of gastritis. Urease activity has
been exploited in two main diagnostic tests for current infection
of H. pylori, namely rapid urease test and c13 or
c14 urea breath test.24-27 |
top |
| For H. pylori to live in its host, two
phenomena, namely colonization and induction of tissue injury,
are important.15 For the organism to colonize, urease
enzyme23 and bacterial motility28 are
essential. Urease protects the organism from acid as elucidated
earlier. Motility of H. pylori is achieved by sheathed flagellae,
which allow the bacteria a burrowing movement into and through
the gastric mucus to reach the epithelium. The bacteria adhere
to the epithelium through adherence factors hemagglutinins,
an intimin-like protein, Lewis blood group and an adhesion lipoprotein.29 |
FIGURE 1. Helicobacter pylori
habitat. A) Endoscopic photograph of gastric antrum revealing
erythematous non-erosive gastritis of moderate severity, caused
by H. pylori infection. B) Microphotograph of gastric biopsy
showing numerous H. pylori organisms in the mucus layer of the
epithelium of gastric mucosa.
FIGURE 2. Natural course of Helicobacter pylori infection.
FIGURE 3. Cinical diseases caused by H. pylori. DU = Duodenal
ulcer; GU = Benign gastric ulcer; Cancer = Gastric cancer; MALT
= Gastric MALT lymphoma with chronic gastric ulcer (left panel)
and heavy lymphoplasmocytic infiltrate, centrocyte-like cells
and destruction of the gastric glands-lymphoepithelial lesions
(right panel). |
| For inducing tissue injury, the role
of urease enzyme and ammonia -related tissue injury has been
elucidated earlier. Two proteins, namely cytotoxin-associated
gene protein (cagA protein) and vacuolating-associated cytotoxin
protein (vacA protein) play a major role. These proteins are
encoded by corresponding genes, the cagA gene and the vacA gene,
both of which have been cloned and sequenced. CagA protein induces
the secretion of cytokine interleukin- 8, which recruits neutrophils
leading to inflammatory response. Many studies from developed
countries have found positive association of cag-A+
strains of H. pylori with duodenal ulcer, gastric atrophy, intestinal
metaplasia, gastric cancer and mucosa-associated lymphoid tissue
(MALT) lymphoma. However, studies from China and Japan have
found high prevalence of cagA+ strains in both diseased
states and control groups. On this basis, cagA positivity cannot
be used as a marker for pathogenic strains of H. pylori. VacA
protein has vacuolating cytopathic effects on several mammalian
cell lines in tissue culture. All H. pylori strains carry a
vacA gene. However, the gene is switched on in strains, which
produce vacuolating toxic protein and switched off in those,
which do not produce vacuolating toxic protein. The regulation
of switch on and off phenomenon of vacA gene is poorly understood.
The iceA (induced-contact epithelium) gene, which is induced
by contact with epithelium, has been recently identified. The
gene product is unknown and is likely a bacterial restriction
enzyme. Data on the disease property of this gene have shown
that it has no role in H. pylori-related disease.30-34
H pylori infection alters many aspects of gastric physiology.
It can both increase as well as decrease acid secretion, explaining
the very varied clinical manifestations of H pylori infection.
Hypergastrinemia is one of the consistent features, most likely
caused by impairment of somatostatin secretion. In addition,
H pylori is known to disrupt the gastric mucus layer. The effect
of the organism on gastric motility abnormalities has not been
conclusively established.15 |
| |
|
|
top |
| Epidemiology |
| Understanding the epidemiology of H.
pylori infection is an essential step in the development of
public health measures. |
FIGURE 4. Diagnostic algorithm
of H. pylori under different clinical situations. A) Patients
referred for endoscpy; B) test and treat policy; C) when eradication
of H. pylori is indicated.
FIGURE 5. Panel A. Helicobacter eradication rates of 197 patients
treated at King Faisal Specialist Hospital & Research Centre
Riyadh over 2 year period (1997 & 1998). Panel B. H pylori
antibiotic resistance at KFSH&RC, compared to published
data from developed (West) and developing (East) countries.
Data at KFSH&RC Riyadh were obtained from 367 isolates of
H pylori cultured from gastric biopsies obtained at upper gastrointestinal
endoscopy. |
| The studies performed on the prevalence
of H. pylori infection in developing and developed countries
have been a matter of intense debate, and consequent to this,
a model for H. pylori infection has been proposed. In this model,
H. pylori was proposed to be primarily a childhood infection
globally, with little or no disease being acquired progressively
in adulthood.39-41 The age-related prevalence of H. pylori from
the developing countries fits this model very well. In these
countries, prevalence of infection is around 70% by 15 years
of age, with little or no increase in prevalence rates above
30 years . The data from developed countries show a low prevalence
(5%-15%) of infection in childhood, with moderately high prevalence
(20%-65%) in the age group above 30 years. Such data could be
interpreted in two ways: 1) H. pylori infection is acquired
progressively throughout life; 2) infection is acquired in childhood,
with a large decrease in the risk of infection along the generations—the
so-called cohort phenomenon. Recent data generated from developed
countries on this support the fact that H. pylori is primarily
a childhood infection. Serum samples were available which had
been collected at different times over a period of 30 years
in a series of children and adults of various birth cohorts.
All these samples were analyzed for H. pylori antibodies. The
results of this study showed that people of the same age born
in different time periods do not have the same prevalence of
infection. In fact young people born in earlier cohorts had
a higher rate of infection than those of the same age born in
recent cohorts.42 |
|
top |
Epidemiological data are convincing
that H. pylori is transmitted as an enteric infection.41,43-46
Low socioeconomic factors, namely lack of education, poverty,
overcrowding, poor sanitation and unsafe water supplies are
high risk factors. Interfamilial spread of the infection has
been well documented. Medical personal are high-risk groups
and gastroenterologists have higher prevalence of infection
when compared to their other medical colleagues.47-48
Whether infection is transmitted through fecal-oral or oral-oral
route is a matter of debate. To support the fecal oral transmission
are the evidence that bacteria are excreted in feces alive,
can survive in environment including water and have been shown
to be transmitted through water and raw vegetables. Oral-oral
transmission is supported by data that bacteria colonize oral
cavity, especially the dental plaques; infection can be transmitted
by kissing and premastication of food by mothers to their babies;
and cohabitating animals can transmit the disease through habit
of extensive licking.49 However, not all studies
have shown evidence for oral-oral transmission of infection.
Of significance is the data that dentists do not have higher
prevalence of H. pylori infection, indicating that saliva is
not a risk factor.50
Non-human reservoirs for H. pylori have been suggested since
the first description of the infection, but it is only recently
that isolation of gastric helicobacter-like organisms (GHLOs)
from the inflamed gastric mucosa of domestic cats and farmyard
animals and ability to experimentally infect cats with H. pylori
has raised the possibility of zoonotic infection. GHLOs, commonly
noted in dogs and cats, are associated with approximately 0.08%-
1% of gastritis in humans. These GHLOs often infect patients
who own pets, suggesting a zoonotic link.51
The contamination of endoscopes and biopsy forceps with H. pylori
occurs readily after endoscopic examination of H. pylori-positive
patients.2 Unequivocal proof of iatrogenic transmission
of the organism has been provided. Endoscopic transmission of
H pylori should be considered a possibility, although the magnitude
of risk is largely unknown. Estimates for transmission frequency
approximate to 4 per 1000 endoscopies when the infection rate
in the endoscoped population is around 60%.3 Endoscopic
transmission of H. pylori produce what has been described by
Japanese workers as post-endoscopic acute gastric mucosal lesions.54
Traditional cleaning and alcohol rinsing is insufficient to
eliminate endoscopiic /forceps transmission. Only meticulous
adherence to disinfection recommendations guarantees H. pylori
elimination. In a survey of 74 endoscopy centers in Western
Europe, 30% of the centers inadequately disinfected endoscopes
after procedures involving patients with upper gastrointestinal
endoscopies and unknown HIV or HBV status. For routine procedures
in patients with unknown HIV or HBV status, 70% of centers did
not adequately disinfect instruments after ERCP, 87% did not
adequately disinfect instruments after colonoscopies, and 100%
did not adequately disinfect instrument after upper endoscopies.55
An Australian survey reported that only 45% of hospitals both
cleaned and disinfected endoscopes satisfactorily. In a recent
collaborative investigation of 26 health care facilities, investigators
found that 78% of them failed to sterilize biopsy forceps; they
isolated at least 100,000 colonies of H. pylori or enteric bacteria
from 25% of cultures taken from the internal channels of 71
endoscopes . Fundamental errors included respective failures
to time the period of disinfection, to clean all channels, to
flush all channels with disinfectant, to fully immerse the endoscope
in the disinfectant solution, and to use a disinfectant. Automated
endoscope washers are now widely available, but, are in use
from 17% to 69 % of endoscopic centers in various countries.56 |
| |
|
|
top |
| Natural Course |
The natural course of human H. pylori
infection has been well documented (Figure 2). H. pylori infection
causes characteristic syndrome of acute gastritis, which regresses
over a period of a few weeks. Over 80% of patients develop chronic
infection of the stomach causing chronic active gastritis. This
infection is a lifetime event in the natural setting with low
rates of loss of infection. The majority of these patients are
asymptomatic, and this is how H. pylori survives in the host.
In fact over 50% of the world population have this clinical
setting. For reasons which are ill understood at present, a
small group of individuals could fall into two alternative tracts.
About 5%-15% continue to have antral predominant gastritis with
gastric hypersecretion and formation of duodenal ulcer. A smaller
group shall develop a syndrome of multifocal atrophic gastritis,
which eventually ends up in one of the three disease states,
namely gastric ulcer, gastric cancer and MALT lymphoma. What
host or agent factors determine H. pylori pathogenicity is under
intense studies.15
Acute infection with H. pylori gives rise to self-limiting upper
abdominal symptoms, neutrophillic gastritis and reduction in
the acid secretion lasting up to four months. Persistent lifetime
infection develops in over 80% of individuals. The organism
selectively localizes in gastric antrum. All such subjects have
chronic active gastritis in gastric antrum biopsies. This form
of gastritis has three features, namely focal epithelial damage,
dense inflammatory infiltrate dominated by plasma cells with
frequent lymphocytes and little or no neutrophils, and lastly
formation of lymphoid follicles with well-developed germinal
centers—the so called mucosa-associated lymphoid tissue
lymphoma (MALToma). H. pylori organisms can be seen in the mucus
on the epithelial surface as curved spiral structures. As mentioned
earlier, such patients are asymptomatic and no clinical syndrome
has been attributed to this at present.15,57
Of great significance to the pathogenicity of H. pylori is the
understanding of the common topographical patterns of chronic
gastritis. Acute infection causes acute neutrophillic gastritis
involving the whole gastric mucosa. Chronic active gastritis
involves antrum with sparing of the corpus of the stomach (antral
predominant gastritis). Both types of gastritis do not cause
atrophic changes in the gastric mucosa. Multifocal atrophic
gastritis, as the name suggests, involves both corpus and antrum
of stomach and is accompanied over the years by atrophy and
intestinal metaplasia of gastric epithelium. Corpus predominant
gastritis without involving the antrum is associated with pernicious
anemia and has an autoimmune basis. This is not related to H.
pylori, and organisms are absent in this type of gastritis.57,58 |
| |
|
|
|
top |
|
