Helicobacter pylori Beijing, China 2007 Noel Lee MD.
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Transcript of Helicobacter pylori Beijing, China 2007 Noel Lee MD.
Helicobacter pyloriHelicobacter pyloriBeijing, China 2007Beijing, China 2007
Noel Lee MDNoel Lee MD
Case PresentationCase Presentation
51 year old Mainland Chinese male comes 51 year old Mainland Chinese male comes in with epigastric pain, nausea, heartburn for in with epigastric pain, nausea, heartburn for 2 months duration2 months duration
Patient was scheduled for elective EGD: Patient was scheduled for elective EGD: EGD found gastric ulcer. EGD found gastric ulcer.
Rapid H pylori test: positiveRapid H pylori test: positive
H Pylori OverviewH Pylori Overview
HistoryHistory StructureStructure BacteriologyBacteriology Pathology of PUDPathology of PUD TransmissionTransmission DiagnosisDiagnosis TreatmentTreatment
*Courtesy of the Helicobacter *Courtesy of the Helicobacter
FoundationFoundation
HistoryHistory
1875: German scientists found helical-shaped bacteria 1875: German scientists found helical-shaped bacteria living in the lining of the stomach but could not culture itliving in the lining of the stomach but could not culture it
1893: Italian scientist Giulio Bizzozero found helical 1893: Italian scientist Giulio Bizzozero found helical shaped bacteria in acidic environment of dog’s stomachshaped bacteria in acidic environment of dog’s stomach
1899: Walery Jaworski of Jagiellonian University found 1899: Walery Jaworski of Jagiellonian University found helical shaped bacteria in human gastric washings: helical shaped bacteria in human gastric washings: named it Vibrio Rugulanamed it Vibrio Rugula He was the first to suggest connection between He was the first to suggest connection between
bacteria and gastric diseasesbacteria and gastric diseases Written up in “Handbook of Gastric Diseases” in Written up in “Handbook of Gastric Diseases” in
PolishPolish
Warren/MarshallWarren/Marshall
Rediscovered in 1979 by Australian pathologist Rediscovered in 1979 by Australian pathologist Robin Warren and gastroenterologist Barry Robin Warren and gastroenterologist Barry Marshall who started research in 1981Marshall who started research in 1981
Isolated the bacteria from stomach and first to Isolated the bacteria from stomach and first to successfully culture itsuccessfully culture it
In their original paper (1983), concluded that In their original paper (1983), concluded that ulcers and gastritis were from H Pylori and not ulcers and gastritis were from H Pylori and not stress and spicy food stress and spicy food
**Sichuan food**Sichuan food
ProofProof
Medical community couldn’t believe a Medical community couldn’t believe a bacteria could survive the aciditybacteria could survive the acidity
Marshall drank a petri dish of Hpylori, Marshall drank a petri dish of Hpylori, developed gastritis symptoms, recovered developed gastritis symptoms, recovered the bacteria from his stomach lining, and 10 the bacteria from his stomach lining, and 10 days later had endoscopy where found days later had endoscopy where found signs of gastritis and H pylori.signs of gastritis and H pylori.
He then treated himself with Bismuth and He then treated himself with Bismuth and Metronidazole Metronidazole
RecognitionRecognition
1994: NIH published their opinion that most 1994: NIH published their opinion that most gastric ulcers were from H pylori and that gastric ulcers were from H pylori and that antibiotics should be used for treatmentantibiotics should be used for treatment
2005: Marshall and Warren awarded Nobel 2005: Marshall and Warren awarded Nobel Prize in MedicinePrize in Medicine
Of note, Marshall alsoOf note, Marshall also
worked at UVA for 10 yrs!worked at UVA for 10 yrs!
BacteriologyBacteriology
Gram neg. helical-shaped bacterium 3 microns Gram neg. helical-shaped bacterium 3 microns long with 4-6 flagellalong with 4-6 flagella
Microaerophilic (requires oxygen)Microaerophilic (requires oxygen) Also coccoid forms found in cultureAlso coccoid forms found in culture
Thought to represent an adaptation to hostile Thought to represent an adaptation to hostile surroudningssurroudnings
More resistant and enable to survive outsideMore resistant and enable to survive outsideHuman host (feces, drinking water)Human host (feces, drinking water)
http://info.fujita-hu.ac.jp/~tsutsumi/photohttp://info.fujita-hu.ac.jp/~tsutsumi/photo
Bacteriology: UreaseBacteriology: Urease
hydrolyzes gastric luminal urea to form hydrolyzes gastric luminal urea to form ammonia that neutralizes gastric acid and ammonia that neutralizes gastric acid and forms protective cloudforms protective cloud
ammonium chloride and monochloramine ammonium chloride and monochloramine also directly damages epithelial cellsalso directly damages epithelial cells
Also antigenic and activates human immune Also antigenic and activates human immune system which indirectly causes injurysystem which indirectly causes injury
Urease: also basis for many diagnostic testsUrease: also basis for many diagnostic tests
BacteriologyBacteriology
Catalase: antioxidant and protects from toxic Catalase: antioxidant and protects from toxic oxygen metabolites from activated oxygen metabolites from activated neutrophilsneutrophils
Protease: further degrade mucusProtease: further degrade mucus Phospholipase: alter phospholipid content of Phospholipase: alter phospholipid content of
gastric barrier to change surface tension, gastric barrier to change surface tension, hydrophobicity, and permeabilityhydrophobicity, and permeability
Receptor-mediated adhesion: Cag genes Receptor-mediated adhesion: Cag genes encode bacterial membrane proteinsencode bacterial membrane proteins
Cytotoxin-associated gene ACytotoxin-associated gene A
Only 10-15% patients with H pylori infection Only 10-15% patients with H pylori infection will actually develop ulcer disease, will actually develop ulcer disease, indicating that bacterial strain is importantindicating that bacterial strain is important
Only strains with CagA can coexpress a Only strains with CagA can coexpress a vacuolating cytotoxin (VacA) toxin that can vacuolating cytotoxin (VacA) toxin that can cause cell injury in vitrocause cell injury in vitro
85-100% patients with DU have CagA+ 85-100% patients with DU have CagA+ strains, compared to 30-60% of infected strains, compared to 30-60% of infected patients who don’t develop ulcerspatients who don’t develop ulcers
DupADupA
Another H pylori gene associated with Another H pylori gene associated with developing DUdeveloping DU
Positive DupA have more intense antral Positive DupA have more intense antral inflammation, higher IL-8inflammation, higher IL-8
Also less gastric atrophy, intestinal Also less gastric atrophy, intestinal metaplasia, and gastric ca (all associatedi metaplasia, and gastric ca (all associatedi with duodenal ulcer disease)with duodenal ulcer disease)
Pathology of PUDPathology of PUD
Increased gastric secretionIncreased gastric secretion Gastric metaplasiaGastric metaplasia Immune ResponseImmune Response Mucosal defense mechanismsMucosal defense mechanisms
Increased gastric secretionIncreased gastric secretion
Initially, hypochlorhydria but chronic infection Initially, hypochlorhydria but chronic infection leads to increased basal and stimulated acid leads to increased basal and stimulated acid outputoutput
Increased gastrin (trophic action on parietal cells Increased gastrin (trophic action on parietal cells and histamine-secreting enterochromaffin-like and histamine-secreting enterochromaffin-like cellscells
Decreased somatostatinDecreased somatostatin However, hypergastrinemia alone not explain However, hypergastrinemia alone not explain
increased acid output: gastrin levels often return to increased acid output: gastrin levels often return to normal within one month after eradication, while normal within one month after eradication, while peak acid output still highpeak acid output still high
Gastric metaplasiaGastric metaplasia
From increased acid secretion and impaired From increased acid secretion and impaired duodenal bicarb secretion (also induced by H duodenal bicarb secretion (also induced by H pylori)pylori)
Metaplasia occurs when luminal pH is less than Metaplasia occurs when luminal pH is less than 2.52.5
Allows for H pylori colonizationAllows for H pylori colonization Also allows development of duodenitisAlso allows development of duodenitis
88% patients with active duodenitis had more than 5% 88% patients with active duodenitis had more than 5% gastric metaplasia and hpylori gastritisgastric metaplasia and hpylori gastritis
But in no duodenitits, only 0.43% had metaplasia AND H pylori But in no duodenitits, only 0.43% had metaplasia AND H pylori gastritisgastritis
Immune ResponseImmune Response Recall H Pylori is non-invasive but stimulates hearty Recall H Pylori is non-invasive but stimulates hearty
inflammatory/immune responseinflammatory/immune response Marked increase in platlet activation and aggregation: Marked increase in platlet activation and aggregation:
contribute to microvascular dysfunction and contribute to microvascular dysfunction and inflammatory cell recruitmentinflammatory cell recruitment
Antigenic substances: heat shock protein, urease, Antigenic substances: heat shock protein, urease, lipopolysaccharide (all activate T cells)lipopolysaccharide (all activate T cells) Cellular disruption at epithelial tight junctions enhances Cellular disruption at epithelial tight junctions enhances
antigenic presentationantigenic presentation Increased IL-1, IL-6, TNF-alpha, and most notably IL-8 Increased IL-1, IL-6, TNF-alpha, and most notably IL-8
IL-8: chemotactic, activates, recruits neutrophilsIL-8: chemotactic, activates, recruits neutrophils
Immune ResponseImmune Response
Also stimulates B cell response (IgG and IgA) Also stimulates B cell response (IgG and IgA) locally and systemically (role of local antibodies locally and systemically (role of local antibodies unclear)unclear)
IgM antibodies: insensitive indicator of acute IgM antibodies: insensitive indicator of acute infection (and not clinically useful)infection (and not clinically useful)
IgA and IgG remain present while infection active IgA and IgG remain present while infection active and decrease after infection curedand decrease after infection cured
Antibodies to CagA protein detectable in gastric Antibodies to CagA protein detectable in gastric tissue and serum (more virulent organism)tissue and serum (more virulent organism)
Mucosal defense mechanismsMucosal defense mechanisms
H pylori downregulates epidermal growth factor (EGF) H pylori downregulates epidermal growth factor (EGF) and transforming growth factor(TGF)-alpha: potent and transforming growth factor(TGF)-alpha: potent gastric acid inhibitors and stimuli of mucosal growth and gastric acid inhibitors and stimuli of mucosal growth and protectionprotection After H pylori eradication, EGF sign. Increased: role in ulcer After H pylori eradication, EGF sign. Increased: role in ulcer
healinghealing Patients with DU have decreased mucosal bicarbonate Patients with DU have decreased mucosal bicarbonate
production (not sure if from H pylori but once production (not sure if from H pylori but once eradicated, bicarb output is normalized)eradicated, bicarb output is normalized)
H pylori releases proteases that degrade protective H pylori releases proteases that degrade protective mucous glycoproteinsmucous glycoproteins
ReservoirReservoir
Humans: major reservoir but seen in Humans: major reservoir but seen in primates and domestic cats (may transfer to primates and domestic cats (may transfer to humans!)humans!)
Sheep: natural host? Sheep: natural host? H pylori seen in milk and gastric tissueH pylori seen in milk and gastric tissue Higher infection rate in shepherds!Higher infection rate in shepherds!
TransmissionTransmission
Person to person: isolations of genetically identical Person to person: isolations of genetically identical strains from multiple family membersstrains from multiple family members
Fecal/oral: contaminated water in developing Fecal/oral: contaminated water in developing countries (h pylori can remain viable in water for countries (h pylori can remain viable in water for several days)several days)
Oral/oral: seen in dental plaque but prevalence is low Oral/oral: seen in dental plaque but prevalence is low dentists don’t have higher prevalencedentists don’t have higher prevalence
Iatrogenic infection: from endoscopesIatrogenic infection: from endoscopes GI docs/nurses increased risk for H pylori infection!GI docs/nurses increased risk for H pylori infection!
Prevalence Prevalence Conservative estimates: 50% of the world is affectedConservative estimates: 50% of the world is affected Developing nations: majority of children infected before Developing nations: majority of children infected before
age 10 and prevalence of adults peaks at more than age 10 and prevalence of adults peaks at more than 80% after age 5080% after age 50
In developed nations (US), infection in children In developed nations (US), infection in children unusual: increases to 10% between 18 and 30 years unusual: increases to 10% between 18 and 30 years and 50% older than age 60and 50% older than age 60 More common in blacks, hispanicsMore common in blacks, hispanics
Increased prevalence with older age thought to Increased prevalence with older age thought to represent continuing rate of bacterial acquisitionrepresent continuing rate of bacterial acquisition But most evidence now states most infections are acquired in But most evidence now states most infections are acquired in
childhood even in developed nationschildhood even in developed nations
Predisposing Factors for InfectionPredisposing Factors for Infection Socioeconomic factors and living conditions early in lifeSocioeconomic factors and living conditions early in life
Density of housing, overcrowding, number of siblings, Density of housing, overcrowding, number of siblings, sharing a bed, lack of running watersharing a bed, lack of running water
Genetic factorsGenetic factors H pylori patients who develop DU have higher parietal cell H pylori patients who develop DU have higher parietal cell
mass or sensitivity to gastrin than H pylori positive healthy mass or sensitivity to gastrin than H pylori positive healthy adultsadults
May also determine duodenal cytokine response to infectionMay also determine duodenal cytokine response to infection Monozygotic twins in different households greater Monozygotic twins in different households greater
concordance of infection than dizygotic twins concordance of infection than dizygotic twins Hereditary susceptibility: not provenHereditary susceptibility: not proven Environmental factors: smoking, NSAIDSEnvironmental factors: smoking, NSAIDS
Link to DiseasesLink to Diseases
Duodenal ulcers: h pylori detectable in at Duodenal ulcers: h pylori detectable in at least 80-95% of patients with DUleast 80-95% of patients with DU Prevalence lower with complicated DU (ex. Prevalence lower with complicated DU (ex.
bleeding or perforation)bleeding or perforation) Gastric ulcers: 60-95%Gastric ulcers: 60-95% Dyspepsia: 20-60%Dyspepsia: 20-60% Gastric Cancer: 70-90%Gastric Cancer: 70-90% Asymptomatic patients: 20-45%Asymptomatic patients: 20-45%
H pylori and GERDH pylori and GERD Some suggest that H pylori positive patients have less Some suggest that H pylori positive patients have less
GERD and esophagitis severity decreasedGERD and esophagitis severity decreased Also lower prevalence of Barretts metaplasia and esophageal Also lower prevalence of Barretts metaplasia and esophageal
adenocaadenoca Further studies suggest that CagA strains are especially Further studies suggest that CagA strains are especially
protectiveprotective One mechanism purposed is that H pylori may modify One mechanism purposed is that H pylori may modify
gastric refluxate. Gastrin levels are higher and do not gastric refluxate. Gastrin levels are higher and do not exhibit normal feedback inhibitionexhibit normal feedback inhibition BUT Corpus-predominant gastritis reduces acid secretion (as BUT Corpus-predominant gastritis reduces acid secretion (as
opposed to antral-predominant): this is thought to be because opposed to antral-predominant): this is thought to be because of local inflammationof local inflammation
This eventually leads to hypochlorhydria and gastric atrophyThis eventually leads to hypochlorhydria and gastric atrophy
H pylori and Gastric cancerH pylori and Gastric cancer
Potentially important observation is source of Potentially important observation is source of gastric cancer may not be from gastric epithelial gastric cancer may not be from gastric epithelial cells themselves but from bone-marrow derived cells themselves but from bone-marrow derived cells that differentiate into gastric epithelial cells in cells that differentiate into gastric epithelial cells in presence of H pyloripresence of H pylori
Treating H pylori has been associated with Treating H pylori has been associated with reduction in cell proliferation, resolution of reduction in cell proliferation, resolution of inflammation, disappearance of hyperplastic inflammation, disappearance of hyperplastic polyps, normalization of apoptotic rates, and polyps, normalization of apoptotic rates, and regression of glandular atrophy intestinal regression of glandular atrophy intestinal metaplasiametaplasia
H pylori and Gastric CancerH pylori and Gastric Cancer
However, several studies show H pylori eradication However, several studies show H pylori eradication may improve gastritis and superficial epithelial may improve gastritis and superficial epithelial damage but degree of intestinal metaplasia and damage but degree of intestinal metaplasia and atrophy did not change (controlled trial in China)atrophy did not change (controlled trial in China)
Another trial in China found that H pylori eradication Another trial in China found that H pylori eradication did not decrease the overall incidence of gastric did not decrease the overall incidence of gastric cancer during mean followup of 7.5 yearscancer during mean followup of 7.5 years
Wong, BC, Lam, SK, Wong, WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291:187.
H pylori and other CancersH pylori and other Cancers
Lymphoma: normal stomach does not have Lymphoma: normal stomach does not have significant amount of lymphoid tissue but H pylori significant amount of lymphoid tissue but H pylori leads to aggregation of CD4+ lymphocytes and B leads to aggregation of CD4+ lymphocytes and B cells cells
MALToma: especially seen in CagA+MALToma: especially seen in CagA+ Remission of tumor with eradication of H pylori (but not Remission of tumor with eradication of H pylori (but not
all have complete remission possibly due to coexisting all have complete remission possibly due to coexisting lymphoma)lymphoma)
Colon Ca: uncertain but maybe from high gastrinColon Ca: uncertain but maybe from high gastrin Pancreatic Ca: especially with CagA+Pancreatic Ca: especially with CagA+
DiagnosisDiagnosis
Recommendations for diagnostic testing for H Recommendations for diagnostic testing for H Pylori first purposed by National Institutes of Pylori first purposed by National Institutes of Health (NIH) in 1994 with more recent guidelines Health (NIH) in 1994 with more recent guidelines in 1998 by ACG.in 1998 by ACG. H pylori is common in general populationH pylori is common in general population Diagnostic testing should only be performed if treatment Diagnostic testing should only be performed if treatment
is intendedis intended
Testing only indicated with active PUD, past hx of Testing only indicated with active PUD, past hx of documented PUD, or gastric MALT lymphomadocumented PUD, or gastric MALT lymphoma
Uncomplicated duodenal ulcersUncomplicated duodenal ulcers
H Pylori present in majority of patients, especially H Pylori present in majority of patients, especially if NSAIDS excludedif NSAIDS excluded
Thus, it is argued that no diagnostic method is Thus, it is argued that no diagnostic method is cost-effective, and treatment should be empiric.cost-effective, and treatment should be empiric.
However, h pylori absent in up to 27% of patients However, h pylori absent in up to 27% of patients with endoscopically proven duodenal ulcerswith endoscopically proven duodenal ulcers Worse outcome especially when treated empiricallyWorse outcome especially when treated empirically
Thus confirmation of infection should be obtained Thus confirmation of infection should be obtained Biopsy urease test Biopsy urease test
Uncomplicated Gastric UlcerUncomplicated Gastric Ulcer
H pylori neg. gastric ulcers increasingly H pylori neg. gastric ulcers increasingly recognized recognized Likely from unrecognized use of NSAIDSLikely from unrecognized use of NSAIDS
Test before antibiotic treatmentTest before antibiotic treatment Obtain biopsies from ulcer edge to exclude Obtain biopsies from ulcer edge to exclude
gastric cancer gastric cancer Also at least 2 separate sites in gastric mucosa Also at least 2 separate sites in gastric mucosa
distant from ulcer to id H pyloridistant from ulcer to id H pylori
Bleeding GU or DUBleeding GU or DU
Should be tested for H pyloriShould be tested for H pylori Although accuracy to detect may be affected with Although accuracy to detect may be affected with
recent bleedrecent bleed Sensitivity low but specificity high for biopsy-based methods Sensitivity low but specificity high for biopsy-based methods
like rapid urease test (67%, 93%), histology (70%, 90%), like rapid urease test (67%, 93%), histology (70%, 90%), and culture (45%, 95%)and culture (45%, 95%)
Noninvasive tests like urea breath test (93%, 92%), stool Noninvasive tests like urea breath test (93%, 92%), stool antigen test (87%, 70%), and serology (88%, 69%)antigen test (87%, 70%), and serology (88%, 69%)
Gastric mucosal biopsy suggested at initial Gastric mucosal biopsy suggested at initial endoscopy. If not obtained, start with urea breath testendoscopy. If not obtained, start with urea breath test Gisbert, JP, Abraira, V. Accuracy of Helicobacter pylori Diagnostic Tests in Patients with
Bleeding Peptic Ulcer: A Systematic Review and Meta-analysis. Am J Gastroenterol 2006; 101:848.
Past hx of PUDPast hx of PUD
If past hx documented by endoscopy or If past hx documented by endoscopy or radiology but not treated for H pylori, test radiology but not treated for H pylori, test and then treat if positiveand then treat if positive
Reasonable to start with noninvasive test Reasonable to start with noninvasive test like breath test, serology, or stoollike breath test, serology, or stool
Asymptomatic patients and familyAsymptomatic patients and family
Usually not tested for H pyloriUsually not tested for H pylori Exception: family hx of gastric ca especially Exception: family hx of gastric ca especially
in Japanese, Chinese, Korean, and Russian in Japanese, Chinese, Korean, and Russian descent (gastric ca incidence increased)descent (gastric ca incidence increased)
Treating asymptomatic family members of Treating asymptomatic family members of patients with H pylori to reduce risk of patients with H pylori to reduce risk of reinfection: unclearreinfection: unclear
Other Indications to TestOther Indications to Test
Prior to treatment with NSAIDS (esp. if Prior to treatment with NSAIDS (esp. if expect long use)expect long use)
Patients with ITPPatients with ITP Patients with unexplained Fe deficiency Patients with unexplained Fe deficiency
anemiaanemia
Endoscopy TestingEndoscopy Testing
ACG guidelines state that if endoscopy used, first ACG guidelines state that if endoscopy used, first test of choice is urease test on antral biopsytest of choice is urease test on antral biopsy
Routine gastric histology: not necessary and Routine gastric histology: not necessary and expensiveexpensive
If urease test neg, then use histology, culture, If urease test neg, then use histology, culture, noninvasive tests (breath, stool)noninvasive tests (breath, stool) Serology not reliably distinguish between active and Serology not reliably distinguish between active and
past infectionpast infection One cost-saving measure: obtain but delay sending One cost-saving measure: obtain but delay sending
histology pending biopsy urease testhistology pending biopsy urease test
Biopsy Urease TestBiopsy Urease Test
Sensitivity: 90-95% but specificity is 95-Sensitivity: 90-95% but specificity is 95-100%.100%.
False neg: recent GIB or with use of PPI, H2 False neg: recent GIB or with use of PPI, H2 blockers, antibiotics, or bismuth-containing blockers, antibiotics, or bismuth-containing compoundscompounds
So neg. urease test in patients taking these So neg. urease test in patients taking these above drugs does not rule out H pyloriabove drugs does not rule out H pylori Antisecretory Rx also interfere with histology so Antisecretory Rx also interfere with histology so
best to send serologybest to send serology
Rapid Urease TestRapid Urease Test
Know patient’s H pylori status before leave Know patient’s H pylori status before leave endoscopy suite endoscopy suite Within one hourWithin one hour Biopsy specimens sandwiched between reagent Biopsy specimens sandwiched between reagent
strip with pH indicator and pad containing urea. strip with pH indicator and pad containing urea. One hour sensitivity and specificity: 89-98% and One hour sensitivity and specificity: 89-98% and
89-93%89-93% Used commonly in Beijing HospitalUsed commonly in Beijing Hospital
CultureCulture
Historically hard to culture but techniques Historically hard to culture but techniques improvingimproving
Metronidazole resistance observed in 22-Metronidazole resistance observed in 22-39% of isolates 39% of isolates
Clarithromycin resistance in 11-12% isolatesClarithromycin resistance in 11-12% isolates Resistance to amoxicillin and tetracycline Resistance to amoxicillin and tetracycline
rarerare Note, routine culture not recommendedNote, routine culture not recommended
But if refractory disease, may benefitBut if refractory disease, may benefit
Urea Breath TestUrea Breath Test
ACG: best nonendoscopic test for documenting H ACG: best nonendoscopic test for documenting H pylori infectionpylori infection
Reasonable to confirm eradication of infection in Reasonable to confirm eradication of infection in all patients 4-6 weeks following treatment (esp. all patients 4-6 weeks following treatment (esp. since cheap test)since cheap test)
Sensitivity and specificity 88-95% and 95-100%Sensitivity and specificity 88-95% and 95-100% Again, false neg. with antisecretory therapy, Again, false neg. with antisecretory therapy,
bismuth, or antibioticsbismuth, or antibiotics Patients should be off these meds at least 4 weeks and Patients should be off these meds at least 4 weeks and
off PPI for at least 2 weeksoff PPI for at least 2 weeks
SerologySerology
Lab-based serology using ELISA to detect IgG or Lab-based serology using ELISA to detect IgG or IgA inexpensive and well-suited to primary careIgA inexpensive and well-suited to primary care
But less sensitive and specific (90-100% and 76-But less sensitive and specific (90-100% and 76-96%)96%)
In young, symptomatic patients may be good In young, symptomatic patients may be good alternativealternative Obviously depends on pretest probability of H pylori in Obviously depends on pretest probability of H pylori in
population being studiedpopulation being studied Inaccurate tests common in elderly, cirrhoticsInaccurate tests common in elderly, cirrhotics Not useful for follow-up testing since many Not useful for follow-up testing since many
patients have antibodies for months-years post Rxpatients have antibodies for months-years post Rx
Stool antigenStool antigen
Sensitivity and specificity: 94% and 86% in Sensitivity and specificity: 94% and 86% in one studyone study
Same limitations of other tests using ureaseSame limitations of other tests using urease
Other Developing Tests?Other Developing Tests?
13C bicarbonate serologic assay using 2 13C bicarbonate serologic assay using 2 serum specimens: one before meal and next serum specimens: one before meal and next 60 minutes after ingestion of 13C-urea rich 60 minutes after ingestion of 13C-urea rich mealmeal
PCR: only useful in detecting organism PCR: only useful in detecting organism when ordinary culture difficult when ordinary culture difficult
Salivary assay: oral cavity can be reservoirSalivary assay: oral cavity can be reservoir Urinary assayUrinary assay
First-Line TreatmentFirst-Line Treatment The Regimen most commonly recommended for first The Regimen most commonly recommended for first
line treatment: PPI (lansoprazole 30mg bid, line treatment: PPI (lansoprazole 30mg bid, omeprazole 20mg bid, pantoprazole 40 mg bid, omeprazole 20mg bid, pantoprazole 40 mg bid, rabeprazole 20mg bid, or esmeprazole 40 mg daily), rabeprazole 20mg bid, or esmeprazole 40 mg daily), amoxicillin (1 gm bid), and clarithromycin (500 mg bid) amoxicillin (1 gm bid), and clarithromycin (500 mg bid)
7-14 days7-14 days Longer duration maybe more effective in curing but this is Longer duration maybe more effective in curing but this is
controversialcontroversial Lansoprazole+amox+clarithromycin= PrevpacLansoprazole+amox+clarithromycin= Prevpac Metronidazole (500mg bid) substituted for amox if Metronidazole (500mg bid) substituted for amox if
Pen-allergic (high rates of Metronidazole resistance)Pen-allergic (high rates of Metronidazole resistance)
Sequential triple with Three Abx?Sequential triple with Three Abx?
May improve eradication rates, esp. with May improve eradication rates, esp. with clarithromycin-resistant strainsclarithromycin-resistant strains
Eradication found to be greater in one study with 5 Eradication found to be greater in one study with 5 day regimen (pantoprazole, amox, placebo) folllowed day regimen (pantoprazole, amox, placebo) folllowed by 5 day of another therapy (pantoprazole, by 5 day of another therapy (pantoprazole, clarithromycin, and tinidazole) vs. standard 10 day of clarithromycin, and tinidazole) vs. standard 10 day of pantoprazole, clarithromyin, amoxicillinpantoprazole, clarithromyin, amoxicillin Differences pronounced in subset with clarithromycin-Differences pronounced in subset with clarithromycin-
resistant h pyloriresistant h pylori
Vaira, D, Zullo, A, Vakil, N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med 2007; 146:556.
Dual Therapy (PPI plus One abx)Dual Therapy (PPI plus One abx)
Cannot be recommended because Cannot be recommended because eradication rates much lower than standard eradication rates much lower than standard regimensregimens
However, 2 week dual therapies with PPI However, 2 week dual therapies with PPI and clarithromycin or amoxicillin are FDA and clarithromycin or amoxicillin are FDA approvedapproved
Failed Treatment?Failed Treatment?
Alternate regimen using different Alternate regimen using different combination of meds combination of meds
Or quadruple therapy (PPI BID and bismuth-Or quadruple therapy (PPI BID and bismuth-based therapy-ex. Pepto plus tetracycline based therapy-ex. Pepto plus tetracycline 500 mg qid and metronidazole 500mg qid) 500 mg qid and metronidazole 500mg qid) for 14 daysfor 14 days
Antibiotic ResistanceAntibiotic Resistance
One study conducted from 1993 to 1999 across One study conducted from 1993 to 1999 across US showed Metronidazole resistance 22-39% and US showed Metronidazole resistance 22-39% and Clarithromycin resistance 11-12%Clarithromycin resistance 11-12% More common in women More common in women Resistance increased gradually up to age 70, then Resistance increased gradually up to age 70, then
declineddeclined Regional differences not notedRegional differences not noted
Osato, MS, Reddy, R, Reddy, SG, et al. Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States. Arch Intern Med 2001; 161:1217.
Antibiotic ResistanceAntibiotic Resistance
Metronidazole resistance is “relative”: can Metronidazole resistance is “relative”: can be overcome by using higher dose (500mg) be overcome by using higher dose (500mg) or using it in combination with Bismuthor using it in combination with Bismuth
Clarithromycin resistance is absolute: Clarithromycin resistance is absolute: cannot be overcome by highercannot be overcome by higher Also more likely to predict treatment failureAlso more likely to predict treatment failure
Medication Side EffectsMedication Side Effects
Reported in up to 50% of patients taking Reported in up to 50% of patients taking triple therapy (but often mild)triple therapy (but often mild) Fewer than 10% must top because of effectsFewer than 10% must top because of effects
Most common: metallic taste due to Most common: metallic taste due to Metronidazole or ClarithromycinMetronidazole or Clarithromycin
Continued Acid SuppressionContinued Acid Suppression
Can discontinue PPI after 4 weeks in Can discontinue PPI after 4 weeks in uncomplicated ulcersuncomplicated ulcers
But maintenance acid suppression may be But maintenance acid suppression may be warranted (even after H pylori eradication) in warranted (even after H pylori eradication) in complicated ulcers since cure does not complicated ulcers since cure does not mean elimination of complicationsmean elimination of complications
Once daily dose of PPI effective Once daily dose of PPI effective Maintains pH >3 Maintains pH >3
Vaccination?Vaccination?
Mucosal immune response is key to vaccination Mucosal immune response is key to vaccination strategiesstrategies
Prelim studies show preventive vaccination may Prelim studies show preventive vaccination may be possiblebe possible
Immunization with crude sonicates of bacteria and Immunization with crude sonicates of bacteria and recombinant urease subunits and catalase have recombinant urease subunits and catalase have protected against H pylori in animal modelsprotected against H pylori in animal models
Problem: effective adjuvant to deliver antigens to Problem: effective adjuvant to deliver antigens to hosthost
Therapeutic vaccine? Too boost natural immune Therapeutic vaccine? Too boost natural immune response or enhance effectiveness of antibioticsresponse or enhance effectiveness of antibiotics
ReferencesReferences Beswick E, Suarez G, Reyes V. H Pylori and Host Interactions that Influence Pathogenesis.
World J Gastroetnerol 2006; 12(35): 5599-5605. Gisbert, JP, Abraira, V. Accuracy of Helicobacter pylori Diagnostic Tests in Patients with
Bleeding Peptic Ulcer: A Systematic Review and Meta-analysis. Am J Gastroenterol 2006; 101:848.
Hobsely, M, Tovey F, Holton J. Precise Role of H Pylori in Duodenal Ulceration. World J Gastroenterol 2006; 12 (40): 6413-6419.
Konturek PC, Konturek SJ, Brzozowski T. Gastric Cancer and Helicobacter Pylori Infection. Journal of Physiology and Pharmacology 2006; 57: 51-65.
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