Helicobacter pylori

Dr.B.Boyle
 Contents/Aims of
Lecture
 History  Clinical Outcomes of
 Introduction Infection
 Microbiology  Diagnosis

 Epidemiology and  Treatment Options

Transmission  Future
 Pathogenesis

Objectives: to have a clear understanding of disease caused by

Helicobacter pylori in terms of the above headings
 Helicobacter pylori
History
 In 1982 following the
Easter holidays in the
Microbiology Dept of the
Royal Perth Hospital a
culture of a spiral-
shaped bacterium from
gastric biopsies of
patients with gastritis
was isolated
 The discovery was by
Dr.Robin Warren and
Dr.Barry Marshall
 Introduction
 This discovery have revolutionised the
diagnosis, treatment and prognosis of
upper gastrointestinal disease
 H.pylori causes gastritis in over half of the
world`s population and is the aetiological
agent of 95% of duodental ulcers, 70-80%
of gastric ulcers and has casual rate in
probably up to 60-70% of Gastric Cancer
 H.pylori -Microbiology
 Small curved microaerophilic gram-
negative rods 2-4ųm long
 Selective medium required for isolation-
10% sheep blood agar + selective
antibiotic supplement
 Incubated at 80-85% N2, 5-10% CO2, 5-
10% H2 O @ 37ºC
 Identified by urease, oxidase, catalase
 Basis of Urease Test

NH2

Urease

H 2O 2NH3+ + CO2
C O +

NH2
Ammonia formed results in ⇈pH
 Epidemiology
 Infection occurs worldwide
 Prevalence will depend on the country and
population groups
 Overall prevalence strongly correlates with
socio-economic conditions
 In Middleaged adults in developing countries
prevalence is 80%, in industralised countries
20-50% ( rate of acquistion decreasing)
 Acquisition:Oral Ingestion of the bacterium
 Transmission:Within families in early
childhood, not isolated from water etc, e
Epidemiology
 H.pylori infection in
adults is usually chronic
without specific therapy:
on the other hand ,
spontaneous elimination
of the bacterium in
childhood is probably
relatively common
 NEJM , Vol. 347, No. 15
Oct 10, 2002

mm.HH
The anatomical regions of the stomach, showing the common
location of ulcers (X)
 Pathogenesis
 H. pylori is found only on gastric epithelium
where the organisms tend to cluster around the
junctions between cells and virtually never
penetrate the cells themselves.
 H. pylori is able to survive in the gastric
environment which is hostile to growth of most
bacteria.
Figure 2. Pathogen–Host Interactions in the Pathogenesis of
Helicobacter pylori Infection.
 Pathogenesis
 Factors permitting colonisation:
 (i) Spiral shape and flagellate – for motility
within this mucous layer.
 (ii) Urease activity – which generate
ammonium ions that buffer gastric activity
 (iii) Micro-aerophilism – for survival within the
mucous gel
 (iv) Attachment to epithelial cells
 (v) Evasion of Immune response
 Vac A
Pathogenesis Vac A Gene
Variants ,
H.pylori Genome
More severe
Changes
disease
continuously

Cag Pathogenicitiy
Hop Proteins,
Island, translocates
Adhesins
CagA into host cell
,phosphorylated ,
Bab A adhesin, Binds SHP-2 TP→
Ure 1, p H Binds fucosylated Lewis B Growthfactor-like
Gated urea Blood group antigen Cellular response and
channel Cytokine production
by Host cell
 Pathogenesis
 Hop proteins-enzymes which modify the
antigenic structure of surface molecules,
control entry of foreign DNA into bacteria
and influence motility
 VacA-95 kd protein, vaculoating cytotoxin
inserts itself into the epithelial cell
membrane and forms a hexameric anion-
selective, voltage dependent channel, in
through which nutrients like HCO3- and
organic anions can be released and targets
mitochondrial membrane inducing
apoptosis
Figure 1. The cag Pathogenicity Island.

Virtually all patients with Duodenal ulcer have cag-PAI + strains

Figure 2. Pathogen–Host Interactions in the Pathogenesis of
Helicobacter pylori Infection.
 Host Response to H.pylori
 H.pylori causes continuous gastric
inflammination in virtually all infected persons
 Host response triggered by attachment to
gastric epithelium (Class II MHC-apotosis)
 Initially neutrophils then T and B cells,plasma
cells and macrophages
 Role of cag-PAI(Stronger response IL8) and
transolation of Cag A into gastric cells, Urease
contributes
 Infected gasric epithelium have increased levels
of interleukin-1ß, interleukin-2,interleukin 6,
interleukin-8 and TNFà.Interleukin 8 key role
 Host Response to H.pylori
 H.pylori induces a strong systemic and mucosal
humoral response
 This does not eradicate the pathogen but leads
to further damage (useful in diagnosis)
 For example : HP infected individuals may
have an autoantibody response resulting in
atrophy of the corpus due to antibodies against
H+/K+ -ATPase of gastric pariental cells
 Host Response to H.pylori
 Although the pathogen is extracellular
the T cell response of the gastric mucosa
is Th1 , the resulting cytokines from Th1
response (Interleukin 2 and Interferon –
ŷ) promote gastritis( whereas Th2
cytokines are protective)
 The Th1 response may be due in part to
antral production of Interleukin 18
 The Th1 response and Fas mediated
apoptosis may favour survival of the
organism
 Gastrin/Somatostatin
(Duodenal Ulcer ,H.pylori infected)

Bacterial products e.g Urea

Inflammatory mediators e.g
Interleukin 1B, TNF)
Histamine relase from Mast cells

Low gastric somatostain level

6x↑Gastrin Releasing Peptide( mediates release of Gastrin, group of

Peptide hormones produced by antral G cells), more if Cag A +
strain ↑HyperGastrinaemia ↑Pariental cells mass( body)
↠Hypersecretion Acid
May be genetic determinant of more response to Gastrin
(if D.U ↑ basal secretion of acid secretion)
 The hormonal control of acid secretion

H+

Parietal cell

(+)
(+) (–)

Mast cell
(+) (–)
Histamine

Antral G cell D cell

Gastrin somatostatin
(–)
Other Methods of Epithelial
Damage
 Activated netrophils  Proinflamminatory
polymorphisms of the
release oxygens and Interleukin -1ß gene favour
nitrogens radicals the development of gastritis in
the body of the stomach
 Chronic associated with
inflammination leads hypochlorhydria, gastric
atrophy and gastric
to epithelial cell carcinoma ( Fas, NF-KB AND
turnover and map kinases)
apoptosis ( Fas  In the absence of POLY, HP
mediated gastritis develops
mediated contact ILY predominately in the antrum
and Th1) with normal to high level acid
secretion, leading to Duodenal
ulcer or Asyptomatic infection
Figure 3. Natural History of Helicobacter pylori Infection.
 Clinical Outcome
 This is determine by Host and Pathogen factors
 H.pylori is responsible for the majority of
duodenal and gastric ulcers(50-80% of benign)
 The lifetime risk of peptic ulcer is 3% in U.S.
and 25% Japan-Treatment for HP lowers
recurrence rate
 1994 H.pylori was classified as a type 1- definite
carcinogen
 Uemura et al 2001 1526, 2.9% of 1246 patients
infected with H.pylori developed Gastric
Cancer over 7.8 years as compared to none of
280 controls non-infected or 253 treated group
 Clinical Outcome
 H.pylori Infection
increase risk of MALT
lymphoma and 72-98% of
pts with MALT
lymphoma are infected
 Therapy causes
regression of MALT
lymphoma in 70-80%
cases
 The role of H.pylori
Infection in dyspepsia not
associated with ulcers
 Diagnosis

Non-invasive
[13C] Urea Breath Test
[14C] Urea Breath Test
ELISA( Serology)
Stool Antigen Test- may be ideal in children , follow up
after 8 week interval ( not on table),
Invasive
Culture
Histology
Urease

Consider Test of Cure

 Diagnosis
MODALITY ADVANTAGES DISADVANTAGES

Endoscopy with Permits inspection of Invasive, expensive, time

Biopsy ( must be pathology, allows detention of consuming.
performed ulcers, neoplasms.
symtoms of
Gastriccarcinoma
or > 50Years)
Culture Permits determination of Not optimally sensitive in
Performed in those antimicrobial susceptibilities most laboratories.
Who have failed 2nd and pathogenic features of Requires several days for
Line therapy isolates. results.

Histology Generally more sensitive than Gastritis may be patchy

culture. Allows direct
visualisation of organism and
extent and nature of tissue
involvement.
and biopsy may be
performed on wrong
area. Insensitivity to
detect small numbers of
organisms. Requires
several days for results.
 Diagnosis
Urease Detection Rapid, most positives seen
within 2 hours
Serology Noninvasive, rapid,
Not reliable in young quantitative, inexpensive.
children
Urea Breath Tests Relatively non-invasive,
90% sensitivity and relatively rapid, quantitative,
specificity rapidly responsive to therapy.
Most valuable for assessing
response to eradication therapy
after 4-8 weeks.
Increased sensitivity
requires longer incubation.
May be false positives with
bacterial overgrowth.
No determination of
lesions or pathology, no
antimicrobial
susceptibility. Not rapidly
responsive to therapy.
Involves expensive
instrumentation or
administration of
radioisotopes. More
invasive and less
convenient than serology.
No determination of
lesions or pathology, no
antimicrobial
 Stool Antigen Test
 Advantages : non-invasive , EIA format,
easy to automate , results in hours,
improving with Monoclonal design
 Disadvantages: Not as good Negative
predictive value as UBT, Kits vary
 Therapy
 The Goal of therapy is eradication of the
organism as if this is achieved reinfection rate
are low and the benefit of treatment is longterm
 2 antimicrobials reduces the selection of
resistance
 Testing for Infection only required if treatment
is intended
 If test for H.pylori positive , use eradication
therapy
Standard triple therapy-Eradication therapy, which
is probably the most widely used treatment for eradication
of H. pylori.-7days mimimal

Proton pump inhibitor B.D. (e/g Lansoprazole 30 mg BD)

+
Clarithromycin 500mg B.D. 1/52 90% plus effective
+
Amoxycillin 1g B.D.
Or If penicillin allergic
Proton pump inhibitor B.D. (e/g Lansoprazole 30 mg)
Clarithromycin 500mg B.D.
Metronidazole 400 mg B.D
If treatment failure refer to Gasterenterologist
 Resistance to therapy
 Geographical variation, depends on
surveillance
 Approx, 10% to clarithromycin
 Approx. 30-50% to metronidazole in some
studies
 Treatment success correlates with
compliance and active therapy
 FUTURE
 ?Vaccination- possibly therapeutic or
preventative
 Eluciadation of the Immunology of the
human stomach
SUGGESTED READING

NEJM , Vol. 347, No. 15 Oct 10, 2002