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.

Lage AP, Fauconnier A, Burette A, et. al. Rapid Colorimetric Hybridization Assay for Detecting Amplified Helicobacter Pylori DNA in Gastric Biopsy Specimens. Journal of Clinical Microbiology 1996; 34: 530-533.

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