The 2005 Nobel Prize in Physiology or Medicine



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The 2005 Nobel Prize in Physiology or Medicine

  • The 2005 Nobel Prize in Physiology or Medicine

  • 3 October 2005

  • The Nobel Assembly at Karolinska Institutet

  • has today decided to award

  • The Nobel Prize in Physiology or Medicine for 2005

  • jointly to Barry J. Marshall and J. Robin Warren for their discovery of

  • "the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"



What is it?

  • What is it?

    • A spiral-shaped gram-negative bacterium
  • Found in colonized gastric mucosa or adherent to the epithelial lining of the stomach

  • Causes continuous gastric inflammation in virtually all infected persons

  • Urease hydrolyzes urea into CO2 and ammonia and allows H. pylori to survive in acidic environment



Infection is acquired via ingestion orally

  • Infection is acquired via ingestion orally

  • Transmitted during childhood in most cases

  • Prevalence varies geographically

  • Risk factors—increased age, AA or LA, lower level of education, developing country

  • May be asymptomatic (90% of infected)

  • May have sx of dyspepsia –burning, distention/bloating, nausea, belching/ flatulence, halitosis



What percent of U.S. population is infected with H. pylori?

  • What percent of U.S. population is infected with H. pylori?

  • Estimated 30-40%



A. duodenal ulcers

  • A. duodenal ulcers

  • B. gastric ulcers

  • C. gastroesophageal reflux

  • D. gastric MALT lymphoma

  • E. gastric cancer



A. duodenal ulcers

  • A. duodenal ulcers

  • B. gastric ulcers

  • C. gastroesophageal reflux

  • D. gastric MALT lymphoma

  • E. gastric cancer



H. pylori is the cause of most cases of Peptic Ulcer Disease (PUD)

  • H. pylori is the cause of most cases of Peptic Ulcer Disease (PUD)

    • Increases risk of both duodenal and gastric ulcers
    • 95% of pt with duodenal ulcers and 80% of pt with gastric ulcers are infected
    • Lifetime risk of peptic ulcer in pt with H. pylori is ~3%.
  • H. pylori causes chronic gastritis

  • H. pylori is a primary risk factor for gastric cancer (4th most common CA worldwide)

    • Categorized as a group I carcinogen
    • Increased risk if H. pylori infxn for >10 yrs.
  • H. pylori increases risk of MALT lymphoma



A. 63 yo female with anemia and early satiety.

  • A. 63 yo female with anemia and early satiety.

  • B. 46 yo male with progressive dysphagia and history of weight loss

  • C. 56 yo with new onset dyspepsia and recurrent vomiting for the past 2-3 months

  • D. 40 yo female with abdominal pain and dyspepsia



American College of Gastroenterology Guidelines

  • American College of Gastroenterology Guidelines

    • Previously in 1998
    • Revised in August 2007 and published in American Journal of Gastroenterology
  • Diagnostic testing for H. pylori should only be performed if tx is intended



Established indications for eradication of H pylori include

  • Established indications for eradication of H pylori include

    • peptic ulcer disease: active PUD, a h/o documented peptic ulcer
    • gastric MALT lymphoma, gastric cancer
    • uninvestigated dyspepsia: “test and treat strategy”


Uninvestigated dyspepsia (ie, unknown if pt has PUD)

  • Uninvestigated dyspepsia (ie, unknown if pt has PUD)

  • <55 years age

  • No “alarm features”

    • Bleeding
    • Anemia
    • Early satiety
    • Unexplained weight loss
    • Progressive dysphagia
    • Odynophagia
    • Recurrent vomiting
    • FMH GI CA
    • Previous esophagogastric CA


Still controversy regarding whether to test for H pylori in

  • Still controversy regarding whether to test for H pylori in

    • functional dyspepsia—a subset of patients with functional dyspepsia benefit from H pylori eradication
    • nonsteroidal anti-inflammatory drug (NSAID) use
    • iron-deficiency anemia—recent evidence suggests a link between H pylori infection and unexplained iron-deficiency anemia.
    • risk factors for developing gastric cancer
    • family members of patients with ulcer disease or gastric cancer


Prevalence of H. pylori is lower among patients with GERD and those with esophageal adenocarcinoma

  • Prevalence of H. pylori is lower among patients with GERD and those with esophageal adenocarcinoma

  • H. pylori-associated atrophic gastritis reduces acid secretion and may provide protection against these diseases.



Randomized trials of H. pylori eradication in nonulcer dyspesia (aka functional dyspepsia) have shown no benefit

  • Randomized trials of H. pylori eradication in nonulcer dyspesia (aka functional dyspepsia) have shown no benefit

  • There is little evidence that chronic H. pylori infection in the absence of gastric or duodenal ulceration causes UGI symptoms.



Non-invasive Diagnostic Tests

  • Non-invasive Diagnostic Tests

    • Serologic tests
    • Urea breath tests
    • Stool antigen
  • Endoscopic Tests

    • Urease
    • Histology
    • Culture
    • PCR


According to 2007 ACG Guidelines “there is no single test that can be considered the gold standard for the diagnosis of H. pylori

  • According to 2007 ACG Guidelines “there is no single test that can be considered the gold standard for the diagnosis of H. pylori

  • Most appropriate test depends on clinical situation



ELISA to detect IgG or IgA antibodies

  • ELISA to detect IgG or IgA antibodies

  • IgG Ab appear 2-3 weeks following infxn and slowly decrease after eradication

  • Inexpensive and widely available

  • Sensitivity and specificity

    • Sensitivity 85% and specificity ~80% (from meta-analysis)
    • Lower than in previous reports
  • If pretest probability is low, a negative test excludes dz. If test is positive it may be a false + so recheck with a confirmatory test



False + are more common in elderly and pt w/ cirrhosis

  • False + are more common in elderly and pt w/ cirrhosis

  • Also, may underestimate infxn in elderly b/c lack of Ab response (false -)

  • Not reliable in young children

  • Poor PPV in low prevalence populations

  • Limited use for F/U of therapy

    • Takes a long time for serology to become negative
    • In pt cured of infection, titers are at ~50% at 3 mths


For populations with a low pretest probability of H pylori infection, the nonendoscopic urea breath and fecal antigen tests have a better positive predictive value than do antibody tests.

  • For populations with a low pretest probability of H pylori infection, the nonendoscopic urea breath and fecal antigen tests have a better positive predictive value than do antibody tests.

  • Antibody testing identifies an immunologic reaction to the infection, whereas the urease tests and fecal antigen test identify the presence of active H pylori infection.



A. H. pylori IgG serology

  • A. H. pylori IgG serology

  • B. Fecal antigen test

  • C. Urea breath test

  • D. EGD



Serology would be appropriate in this scenario for patients on PPI therapy who cannot stop therapy for two weeks prior to the tests of active infection, i.e. stool antigen or breath test.

  • Serology would be appropriate in this scenario for patients on PPI therapy who cannot stop therapy for two weeks prior to the tests of active infection, i.e. stool antigen or breath test.



Hydrolysis of urea  CO2 and NH3. Measures labeled carbon.

  • Hydrolysis of urea  CO2 and NH3. Measures labeled carbon.

  • Sensitivity and specificity typically >95% in most studies

  • False negatives with PPI, Abx, bismuth

    • Off Abx and bismuth for >4 weeks
    • Off PPI for > 2 weeks
  • Used for both initial dx and F/U



Sensitivity and specificity ~90%

  • Sensitivity and specificity ~90%

  • False positive (decreased specificity) in pt with acute UGI bleed

  • False negative tests (decreased sensitivity) if patient is on PPI in prior 2 weeks or has taken antibiotics in prior 4 weeks. (24 hours for H2 blocker)

  • Useful for documenting if eradication has been successful

  • Wait 4-8 weeks before repeat



Reliable in kids >6 yrs

  • Reliable in kids >6 yrs

  • Best test in elderly population

  • Most reliable non-endoscopic test to document eradication after treatment



When to choose endoscopy

  • When to choose endoscopy

    • Alarm sx such as anemia, GI bleeding, weight loss
    • >50 yrs age
  • 4 methods of testing: biopsy urease test, histology, bacterial culture, PCR

  • According to AAFP article (2002) Steiner’s stain for microscopic exam is gold standard

  • According to ACG (1998), first choice is urease test on an antral biopsy



Sensitivity >90% and Specificity >95%

  • Sensitivity >90% and Specificity >95%

  • Biopsy urease testing is less expensive than histology

  • If biopsy urease test is negative, consider histology or serology

  • Biopsy urease tests have decreased sensitivity in pt on PPI and in pt with recent or active bleeding

  • False negatives: recent bleed, PPI, H2 blocker, Abx, bismuth

  • Stop PPI and other meds that may interfere 4 wks prior to endoscopy



In pt who have not been on PPI within 1-2 wk OR Abx or bismuth within 4 wk of EGD, the rapid urease test provides an accurate, inexpensive means of identifying H. pylori

  • In pt who have not been on PPI within 1-2 wk OR Abx or bismuth within 4 wk of EGD, the rapid urease test provides an accurate, inexpensive means of identifying H. pylori

  • For pt who have been taking a PPI, Abx, or bismuth, EGD testing for H. pylori should include bx from the gastric body and antrum for histology +/- rapid urease testing



Primary means by which Abx sensitivities can be determined

  • Primary means by which Abx sensitivities can be determined

  • Neither is widely available for clinical use

  • Not routinely recommended



Eradication

  • Eradication

    • Results in ulcer healing
    • Decreases risk of ulcer recurrence—more than a 30% reduction in the risk for recurrent ulcer at 1 year
    • Reduces risk for serious ulcer complications (perforation or bleeding)
    • Leads to regression of MALT lymphoma
    • Eradication of H pylori is less robust in reducing rates of dyspepsia and gastric cancer.


H. pylori regimens should have cure rates of at least 80% (desirable)

  • H. pylori regimens should have cure rates of at least 80% (desirable)

  • Dual therapy (PPI + one abx) regimens have eradication rates of 60-85% and are not recommended

  • Triple therapy: combination of antibiotics and PPI or H2 blocker or bismuth



Previously 3 regimens consistently eradicated H. pylori with rates >90% now may be dropping to ~75-80% b/c of clarithromycin resistance

  • Previously 3 regimens consistently eradicated H. pylori with rates >90% now may be dropping to ~75-80% b/c of clarithromycin resistance

  • First Line (ACG and Maastricht Consensus—European)

  • PPI (lansoprazole 30 mg po BID), amoxicillin 1 gram po BID, clarithromycin 500 mg po BID x 14 days (Prevpac)

  • Above but change amoxicillin to metronidazole 500 mg po BID for PCN allergic

  • Alternative: PPI or H2, bismuth 525 mg po QID, 2 antibiotics (metronidazole 500 mg po QID, tetracycline 500 mg po QID) x10-14 days



Course of 7-14 days

  • Course of 7-14 days

  • 7-day course more common in Europe

  • 10-14-day course recommended in US

    • Triple therapy: 14 days
    • Quadruple therapy: 10-14 days


Trial of quadruple therapy for non-responsive cases (ie, salvage)

  • Trial of quadruple therapy for non-responsive cases (ie, salvage)

  • Regimens with levofloxacin instead of clarithromycin

  • Sequential therapy

    • 5 days of one regimen (PPI + amoxicillin) followed by 5 days of a second regimen (PPI, clarithromycin, tinidazole)
  • Lactoferrin and Probiotics



New studies adding these agents to triple therapy

  • New studies adding these agents to triple therapy

  • De Bortoli et al in Italy

  • 206 patients

  • Esomeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg, all twice daily for 7 days

  • +/- bovine lactoferrin 200 mg and probiotic Probinul (Cadigroup) tablets twice daily



Main study outcome was negative 13C-urea breath testing at 8 wks after completion

  • Main study outcome was negative 13C-urea breath testing at 8 wks after completion

  • Eradication of H pylori in 88.6% of intervention group vs. 72.5% of control group.

  • Rates of adverse events were 9.5% in the intervention group vs 40.6% in the control group.

    • Side effects of nausea, diarrhea, glossitis, and abdominal pain were more common in the control group.


Eradication

  • Eradication

  • Pt is treated but H. pylori remains positive (Failure of initial treatment)

  • Pt is treated and follow-up tests are initially negative at 4 weeks (Eradication) but then become positive later (Recurrence)

    • Recurrence can be caused by either Recrudescence or Re-infection


To confirm eradication of H pylori infection, testing should be performed in

  • To confirm eradication of H pylori infection, testing should be performed in

    • patients with PUD
    • persistent dyspeptic symptoms following the test-and-treat strategy
    • H pylori-associated MALT lymphoma
    • status post resection of early gastric cancer


H. pylori infection increases risk of PUD, chronic gastritis, gastric CA, and MALT lymphoma

  • H. pylori infection increases risk of PUD, chronic gastritis, gastric CA, and MALT lymphoma

  • Check for H. pylori in pt with PUD, MALT lymphoma, undifferentiated dyspepsia

  • Serology less reliable test; urea breath test and fecal antigen testing preferred

  • Consider EGD for alarm sx or age >50 yrs

  • Triple therapy for treatment has decreasing efficacy—now ~75-80%

  • Test for eradication if PUD, persistent sx, MALT lymphoma, s/p gastric CA resection



Chey WD, Wong BC et al. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol 2007 Aug; 102(8):1808-25.

  • Chey WD, Wong BC et al. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol 2007 Aug; 102(8):1808-25.

  • De Bortoli N, Leonardi G, Ciancia E, et al. Helicobacter pylori Eradication: A Randomized Prospective Study of Triple Therapy Versus Triple Therapy Plus Lactoferrin and Probiotics. Am J Gastroenterol. 2007; 102: 951-956.

  • Fisschbach L and Evans E. Meta-analysis: The Effect of Antibiotic Resistance Status on the Efficacy of Triple and Quadruple First-line Therapies for Helicobacter pylori. Aliment Pharmacol Ther 2007; 26(3): 343-357.



Gisbert J. The Recurrence of Helicobacter pylori Infection: Incidence and Variables Influencing It. A Critical Review. Am J Gastroenterol 2005; 100: 2083-2099.

  • Gisbert J. The Recurrence of Helicobacter pylori Infection: Incidence and Variables Influencing It. A Critical Review. Am J Gastroenterol 2005; 100: 2083-2099.

  • Meurer L et al. Management of Helicobacter pylori Infection. American Family Physician 2002; 65 (7): 1327-1336.

  • Salles N and Megraud F. Current Management of Helicobacter pylori Infections in the Elderly. Expert Rev Anti Infect Ther. 2007; 5(5): 845-856.

  • Suerbaum S and Michetti P. Helicobacter Pylori Infection. NEJM 2002; 347 (15): 1175-1186.

  • Up to Date



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