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| Clinical Diseases |
What are the clinical outcomes of H.
pylori infection? H. pylori is etiologically related to four
gastroduodenal diseases, which have been examined in detail
(Figure 3). There is intense debate as to whether non-ulcer
dyspepsia is related totally or in part to underlying H. pylori
infection. There is unquestionable epidemiological evidence
that most, if not all, of the duodenal ulcers are etiologically
associated with H. pylori infection. Over 80% -95% duodenal
ulcer patients are infected with H. pylori. All case control
studies have shown significantly higher prevalence of H. pylori
in duodenal ulcer patients when compared to age and sex matched
controls. Of significance is the data that H. pylori precedes
development of duodenal ulcers. In well-done longitudinal studies,
patients chronically infected with H. pylori have three to fourfold
risk of developing ulcer than those not infected.
The final and most convincing proof that H. pylori is the key
pathogen in peptic ulcer disease is the observation that eradication
of H. pylori prevents ulcer relapses. Duodenal ulcers will relapse
in around one-half of patients after effective acid suppressant
therapy at one-year follow-up and nearly invariably over long-term
follow-up. Concomitant H. pylori eradication significantly reduces
the ulcer recurrences to less than 10% at one year. With the
exclusion of idiopathic ulceration in a small minority of patients,
ulcer recurrence is generally only associated with H. pylori
reinfection, or use of ulcerogenic drugs. Apart from defining
cause and effect relationship, these data are of major clinical
importance as ulcer disease can now be cured with a short course
of antibiotics. This data truly define ulcer as an infectious
disease rather than acid peptic disease, a doctrine that has
been preached for a long period of time.58-61
Recent data have accumulated that patients with nonvariceal
gastro-intestinal bleeding significantly benefit in the long
run by H. pylori eradication. Recurrences of gastro-duodenal
bleeds are prevented over the ensuing two to three years. Clinical
experience has shown H. pylori eradication can promote healing
of intractable non-healing or giant ulcers.62-63
|
| TABLE 1. Indications for
Helicobacter pylori eradication therapy. |
| Recommendation* |
Clinical disease |
Scientific evidence** |
| Strongly recommended |
Peptic ulcer (active or
healed) |
1 |
| |
Bleeding peptic ulcer |
1 |
| |
Low grade MALT lymphoma |
2 |
| |
Gastritis with severe
abnormalities |
2 |
| |
Post gastric cancer resection |
3 |
| Advisable |
Functional dyspepsia |
2 |
| |
Family history of gastric
cancer |
3 |
| |
Long term treatment with
PPI for GERD |
3 |
| |
Planned or existing NSAID
therapy |
2 |
| |
Following gastric surgery
for peptic ulcer |
3 |
| |
Patient’s wishes |
4 |
| Uncertain |
Prevention of gastric
cancer |
5 |
| |
Asymptomatic sub |
5 |
| |
Extra-alimentary disease |
5 |
|
| |
| The Maastricht 2-2000 concensus report
for eradication of H. pylori were recommended at 3 levels (*strongly
recommended, advisable and uncertain), these recommendations
were evidence-based at 5 levels; **1=well designed and appropriately
controlled studies; 2=well-designed cohort or case-controlled
studies with persuasive indirect evidence; 3=case reports with
suggestive indirect evidence; 4=clinical experience; 5=insufficient
experience to form an opinion. |
Several steps in the ulcerogenic pathway in H. pyloriinduced
duodenal ulcer have been documented. H. pylori induces antral
predominant chronic active gastritis. This leads to hypergastrinemia
and fall in somatostatin secretion. With normal gastric corpus,
both these hormonal changes cause gastric acid hypersecretion
through stimulation and trophic changes on the parietal cell
mass. Long- term acid hypersecretion causes gastric metaplasia
of the duodenal bulb mucosa. Gastric metaplasia is a favorite
site for H. pylori infection. This infection causes epithelial
cell damage and duodenitis and duodenal erosions are produced.
Duodenal erosions coalesce together to form duodenal ulcer.64-65
H. pylori has been defined by WHO as “class 1 carcinogen.”
The evidence that H. pylori infection is linked with the development
of non-cardiac gastric adenocarcinoma comes from different aspects
listed. There is direct strong association between seropositivity
of H. pylori and incidence and mortality from gastric adenocarcinoma
in most regions of world. The EUROGAST study, one of the largest
geographic studies of H. pylori and gastric carcinoma to date,
gathered data from 17 populations in 11 European countries,
the United States, and Japan. There was highly significant correlation
between prevalence of H. pylori infection and gastric cancer
incidence and mortality. The risk of gastric cancer was six
times greater in H. pylori infected than in uninfected persons.
However, one exception to this rule is the “Indian- African
enigma”: the prevalence of infection being high in some
regions where incidence of gastric cancer is low.66-71
Excellent data from Finland have shown similar time trends in
the incidence of gastric carcinoma and prevalence of H. pylori
gastritis at age 50 years in different birth cohorts over the
last 100 years. These figures demonstrate that incidence of
gastric cancer and the prevalence of H. pylori gastritis have
been high at the same age in the cohorts born at the beginning
of the century and low in those born recently. A gradual decrease
in the incidence of cancer and “birth cohort specific”
prevalence of gastritis had occurred over time, the so-called
cohort effect. |
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Case control studies have demonstrated
higher prevalence of H. pylori infection in patients with gastric
cancer when compared with age and sex-matched controls, with
an odds ratio of 3:4. Similar studies performed in patients
with young ages have shown a higher risk with an odds ratio
of 13. The etiological association of H. pylori with gastric
cancer has been strongly supported by prospective cohort studies.
Subjects infected with H. pylori had higher incidence of gastric
cancer than controls with an extremely high odds ratio of 12.
The magnitude of increased cancer risk associated with H. pylori
infection is substantial. Considering the above attributable
risks, prevalence of H. pylori at 35% in adults in developed
countries and 85% in adults in developing countries, a minimum
of 327,000 cases of gastric cancer per annum are being caused
by H. pylori, although the number may be as high as 609,000.
Recently gastric adenocarcinoma has been induced in ferrets
naturally infected with H. pylori by using a low dose of gastric
carcinogen N-methyl-N-nitro-N-nitrosoguanidine.
Despite such an etiological association between H. pylori and
non-cardiac gastric adenocarcioma, eradication of H. pylori
has not been shown as of today to reverse gastric atrophy, intestinal
metaplasia and reduce the risk of gastric cancer. Data in this
area are urgently needed in the near future.
MALT lymphoma is a B-cell linage tumor, which occurs at a number
of sites namely, stomach, bronchus, thyroid, etc. All these
sites lack lymphoid tissue and the disease starts by invasion
of lymphoid tissue with lymphoid follicles at these sites. This
stage is called MALToma. MALT lymphoma is diagnosed when lymphoid
follicles are accompanied by a characteristic infiltrate made
of centrocyte-like cells and plasma cells. However, the hallmark
of MALT lymphoma is occurrence of lymphoepithelial lesions,
in which gastric glands are attacked and destroyed by the characteristic
infiltrate.72-73
The etiological association of H. pylori and gastric MALT lymphoma
is stronger than gastric cancer. All such patients are infected
with the organisms. In fact one of common histological features
of H. pylori infection is induction of lymphoid follicles in
the submucosa. H. pylori has been shown to stimulate B-cells
in vitro. However, the most convincing evidence comes form the
data that low grade MALT lymphoma regress and are cured with
eradication therapy. A number of long-term studies on large
cohort of patients have been published. One of the major contested
issues in the field of helicobacteriology has been its relationship
with non-ulcer dyspepsia. Non-ulcer dyspepsia is defined as
the occurrence of persistent or recurrent epigastric pain or
discomfort referred to upper abdomen lasting for a total cumulative
duration of three months or more in the preceding 12 months. |
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An upper gastrointestinal endoscopy
is necessary to exclude an organic gastro-duodenal disease including
duodenal ulcer, gastric ulcer and gastric neoplasm. Endoscopic
and histological erythematous or erosive gastritis does not
qualify an organic disease for this definition. Such findings
are seen in patients with non-ulcer dyspepsia and asymptomatic
matched controls in equal numbers and severity excluding their
potential as an organic disorder and to explain such symptoms.
However, two patterns of symptoms must be excluded while defining
non-ulcer dyspepsia. Heartburn is a specific symptom pointing
to gastro-esophageal reflux disease (GERD), which has well known
pathogenesis, course and therapy. The majority of patients with
GERD have normal esophago -gastroduodenoscopy (endoscopy negative
GERD) and only a careful history is crucial in differentiating
the two disorders. Patients with abdominal symptom related to
bowel motions point to colonic disorder and are commonly seen
in patients with irritable bowel syndrome.74
Clinicians have a fashion to discover overlap syndromes. A sizable
percentage of patients with non-ulcer dyspepsia have two or
three groups of symptoms and patients can shift their description
of symptoms from one to another over time periods. A good clinician
uses the rule of dominance to decide on future course of action.
Patients with non-ulcer dyspepsia have been subclassified into
those with epigastric pain (ulcer type) and with distension
(dysmotility type). Such a classification may help to target
selective therapy (anti-ulcer for ulcer type and prokinetics
for dysmotility type), however, the two groups cannot be differentiated
on basis of pathogenesis and disease course.75
How common is non-ulcer dyspepsia in the community? Non-ulcer
dyspepsia is a common disorder and demonstrates a dynamic behavior.
Well-conducted community studies have estimated the prevalence
of such symptoms from 145-26%. Incidence of the disease varies
from 1%-8% per year. About a third lose their symptoms per year.
The severity of symptoms varies widely and only one-fourth would
have sought medical advice at any given time.76
Does H. pylori infection cause non-ulcer dyspepsia? The answer
is currently not known. Well-conducted interventional studies
have shown conflicting results and future work in this field
shall be watched with great interest. Until then, clinicians
should be guided by the following data. Fifty percent of non-ulcer
dyspepsia patients are infected with H. pylori (i.e., similar
to that of the general population). If untreated, around 5%-15%
of such patients have life time risk to develop duodenal ulcer
sas against no risk t o patients with eradicated or no H. pylori
infection. A small but definite risk of gastric cancer and MALT
lymphoma does exist in infected patients.
|
| TABLE 2. Recommended treatment
regimens for H. pylori eradication. |
| |
Regimen 1 |
Regimen 2 |
Regimen 3 |
| Type of therapy |
PPI-based triple therapy |
RBC-based triple therapy |
Quadruple therapy |
| Drug/dose |
PPI* (standard dose) BID |
RBC** 400 mg BID |
PPI* (standard dose) BID |
| |
Clarithromycin 500 mg
BID |
Clarithromycin 500 mg
BID |
Bismuth subcitrate 120
mg QID |
| |
Amoxicillinß 1000
mg BID |
Amoxicillinß 1000
mg BID |
Metronidazole 500 mg TID |
| Duration |
One/two weeks† |
One/two weeks† |
One week |
| Status |
First line therapy |
First line therapy |
Second line therapy |
|
| |
| *Standard dose of PPI include
omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg and
esomeprazole (Nexiumâ) 20 mg given orally twice daily;
**ranitidine bismuth citrate; b=amoxicillin can be substituted
by metronidazole in penicillin allergic patients; †Maastricht
Concensus Report 2-2000 recommends one-week therapy, while two-weeks
therapy is recommended by American Digestive Disease Foundation
and approved by FDA. |
| Eradication therapy shall give symptom
benefit at one year to 35% of patients as against 28% on placebo.
This treatment advantage of 7% is small and the number to treat
in order to cure one patient is 15. Well-done cost effective
studies have shown that eradication of H. pylori is cost effective
when compared to long-term anti-ulcer therapy. The preference
of the author is to test and treat all patients of non-ulcer
dyspepsia for H. pylori infection.77,78 |
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| Diagnosis |
H. pylori diagnosis has well-established
diagnostic tools (Figure 4). Rapid urease test and histological
examination of gastric biopsies for H. pylori organisms are
gold standards at endoscopy. H. pylori culture is recommended
only when first-line therapy fails to eradicate the infection.
Antibiotic sensitivity shall guide therapy in such patients.
PCR is at present employed only as a research tool and can help
in studying epidemiology of the organism and control of H. pylori
transmission.24-27,79-81
C13 or C14 urea breath test is a global
test for H. pylori infection with high sensitivity and specificity.
The test is best used to confirm eradication after treatment.
Rapid urease test and histology of gastric biopsies have limitation
under this setting due to reduced load of bacteria, and are
not recommended. As the test is non-invasive, sensitive and
specific, it is increasingly being used as the first-line diagnostic
test in patients not undergoing upper endoscopy. The only limitation
is limited availability of this test in the institutional setting.
Recent introduction of office type equipment to test for C13
urea breath test may obviate this difficulty.24-27
Serological tests are easy to perform but have limitation
because they cannot differentiate current from past infection,
and tests become negative after many months after eradication.
However, these tests have immensely helped in the understanding
of epidemiology and natural course of disease.82
Who should be tested and treated for H. pylori (Table 1)?83-84
All those conditions which derive potential clinical benefit
with H. pylori eradication need the test. Any uncomplicated
duodenal ulcer has a distinct advantage with therapy as ulcer
relapses are eliminated. H. pylori eradication in this setting
is cost effective when compared to long-term H2 antagonist therapy.
Gastric ulcers can be broadly classified into 2 groups depending
upon the etiology, namely, non-steroidal anti-inflammatory drugs
(NSAID) and H. pylori. Should NSAID-induced gastric ulcers be
tested and treated for concomitant H. pylori infection? The
mechanisms of peptic ulcer formation caused by H. pylori and
NSAIDs are contrasting. H. pylori causes cytotoxin-induced inflammation
and ulceration while NSAIDs cause reduced prostaglandins and
direct toxic effect on the gastric mucosa. There is no evidence
of synergy between these two etiological agents. H. pylori eradication
does not alter the relapse pattern of gastric ulcers with continued
use of NSAIDs during 6-month follow-up period. Results on the
effect and eradication of concomitant H. pylori in patients
with no underlying ulcers and on long-term NSAID therapy and
are conflicting. Thus till date, there is no strong evidence
to treat or prevent NSAID-induced gastric ulcers by concomitant
H. pylori therapy.85,86
Patients with non-variceal upper gastrointestinal bleeding should
be tested and treated for H. pylori infection. Apart from preventing
relapses it prevents longterm ulcer complications over the ensuing
2 to 3 years. MALT lymphomas are invariably H. pylori positive
and low-grade gastric MALT lymphoma regresses with H. pylori
eradication therapy. Long-term emissions and cures have been
well documented. The majority of the clinicians do test and
treat H. pylori infection in patients presenting with non-ulcer
dyspepsia. The evidence for and against has been presented.
How should the diagnostic tests be used judiciously in various
clinical settings? Patients with suspected ulcer disease and
no prior treatment need an upper endoscopy and rapid urease
test, and histological examination of gastric biopsies is ideal
for this group of patients. Unless the ulcer disease is complicated
or life-threatening, there is no need to check for eradication
of H. pylori.27
If H. pylori eradication is to be confirmed after treatment,
C13 or C14 urea breath test has the distinct
advantage of being a global test and has good sensitivity under
these circumstances. Negative urea breath test indicates cure.
Patients with positive test need an upper endoscopy and gastric
biopsies. Gastric biopsies must be cultured and antibiotic sensitivity
defined to choose the proper drug combination therapy. Unfortunately
this can only be done in a tertiary care setting due to inherent
problems in culturing H. pylori. As dyspepsia is a common primary
care problem and access to endoscopy is limited to gastroenterology
practice, many primary health care services have adopted a test
and treat policy for dyspepsia.
In this, only a small high-risk group (gastric neoplasm) of
newly diagnosed cases of dyspepsia are referred for upper endoscopy.
This group is identified by age and seven alarm symptoms, namely,
weight loss (>3 kg in last 3 months), anemia, dysphagia,
abdominal mass, GI bleed, family history of gastric cancer and
anorexia/vomiting. All other patients are offered a noninvasive
test for H. pylori, either urea breath test or serological test
for H. pylori antibodies. Patients with evidence of infection
are treated for H. pylori and those with negative test receive
empirical treatment. Patients with continued or recurrent symptoms
at 12 weeks are offered an upper endoscopy. Test and treat policy
has been found to be safe and cost effective in many health
care delivery systems with low prevalence of upper GI cancers.74 |
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