Helicobacter pylori 幽門螺旋桿菌 馬偕紀念醫院新竹分院一般內科, 肝膽腸胃科陳重助醫師

Helicobacter pylori 幽門螺旋桿菌 馬偕紀念醫院新竹分院一般內科, 肝膽腸胃科陳重助醫師

Hp : Helicobacter pylori Part 1. Pathophysiology and immune response Pathogenesis of Hp infection Part 2. Clinical manifestation Part 3. Dx tests for Hp infection Part 4. Tx of Hp infection

Part 1. Pathophysiology and immune response. Part A. Bacterial factors 1. Bacterial attachment 2. Release of enzymes 3. Bacterial strain differences -- CagA & VacA Part B. Inflammatory Response Part C. Antibody Response

.

Part 1. Pathophysiology and immune response Part A. Bacterial factors Tissue injury induced by H. pylori depends upon bacterial attachment and the subsequent release of enzymes that can cause cellular damage. 1. Bacterial attachment Bacterial adhesins recognize and specifically bind to host receptors expressed on the cell surface. The attachment process may morphologically or functionally alter the epithelial cell or activate certain bacterial functions making them more toxic 2. Release of enzymes

(2) Bacterial phospholipases (3) Catalase enzyme ( an antioxidant, may protect the organism from toxic oxygen metabolites) (4) Bacterial proteolytic enzyme activity can further degrade mucus. Part 1. Pathophysiology and immune response Part A. Bacterial factors 2. Release of enzymes H. pylori elaborates several enzymes that can cause cellular damage by direct or indirect mechanisms. (1) Urease Urea H p : Urease hydrolysis of urea CO 2 + NH 3 HCl NH 4 Cl

Part 1. Pathophysiology and immune response Part A. Bacterial factors 3. Bacterial strain differences CagA and VacA Functional differences exist between strains of H. pylori that may relate to virulence and tissue damage. CagA and VacA (vacuolating cytotoxin) causes cell injury in vitro and gastric tissue damage in vivo. All H. pylori contain the gene coding for VacA; however, only those strains with the cytotoxin-associated gene A (caga), coding for a 128 to 140 kd protein (CagA), coexpress VacA. VacA behaves as a passive urea transporter thereby creating a favorable environment for H. pylori infectivity. Strains producing VacA and CagA cause more intense tissue inflammation and induce cytokine production.

Part 1. Pathophysiology and immune response Part B. Inflammatory Response Although H. pylori is a noninvasive organism, it stimulates a robust inflammatory and immune response. A variety of factors may contribute to these changes: The organism produces a number of antigenic substances, including heat shock protein, urease, and lipopolysaccharide, all of which can be taken up and processed by lamina propria macrophages and activate T-cells. Cellular disruption, especially adjacent to epithelial tight junctions. The net result is increased production of inflammatory cytokines such as IL-1, IL-6, IL-8 tumor necrosis factor alpha (TNFa)

Part 1. Pathophysiology and immune response Part C. Antibody Response IgA and IgG antibodies are produced in response to infection, remain present as long as infection is active, and quantitatively decrease after infection is cured. Antibodies to CagA protein are detectable in gastric tissue and serum and permit the identification of infection with presumably more virulent organisms. IgA antibodies may modulate mucosal injury by inhibiting antigen uptake, disrupting bacterial adherence and motility, and neutralizing various toxins. IgG antibodies presumably augments inflammatory injury by activating complement and facilitating neutrophil activation.

Part 2. Clinical manifestation GI tract Extra-gastric disorders.

..

Hp and extra-gastric disorders 1 I.T.P. (idiopatic/immune thrombocytopenic purpura) 2 I.D.A ( Iron-deficiency anemia ) Am J Hematol 2005;78:142-150 Br J Hematol 2004;124:91-96 Arch Intern Med 2004;164:1904-7 Am Jgastroenterol 2005;100:453-9 Dig Liver Dis 2004;36:455-60 3 Coronary artery disease & Atherosclerosis Attenuate reduction of coronaryartery lumen after angioplasty Hp eradication reduced blood pressure value increased HDL and APO AIc AII reduced plasma prothrombin fragment Dig Liver Dis 2001, Am J Cardiol 2004

Part 3. Dx tests for Hp infection Part A. Endoscopic Testing 1.Biopsy urease test (CLO test), 2.Histology, 3.Bacterial culture ( less commonly ) Part B. Noninvasive Testing 1. Breath testing (UBT), 2. Stool antigen testing, 3. Serology 4. PCR ( polymerase chain reaction) Part C. Who shoud be tested for H. pylori? Initial diagnosis before Hp eradication Follow-up after Hp eradication

Part 3. Dx tests for Hp infection Guidelines have been approved by the ACG, AGA UBT CLO

Part 3. Dx tests for Hp infection Part A. Endoscopic Testing The diagnosis of H. pylori can usually be established during endoscopy by one of 3 methods: 1.Biopsy urease test (CLO test), 2.Histology, 3.Bacterial culture ( less commonly ) Choosing among these tests depends upon the clinical circumstance, the accuracy of the tests, and the relative costs.

Part 3. Dx tests for Hp infection General recommendations have been proposed by the American College of Gastroenterology 1. When endoscopy is indicated, the test of first choice is a urease test (CLO test) on an antrum. 2. If a biopsy urease test is negative, H. pylori infection may be diagnosed by histology or serology. Biopsy urease tests have reduced sensitivity in patients taking PPIs, Antibiotics in recent or active bleeding. 3. Histology is generally not necessary and is expensive, except for different diagnosis.

Part 3. Dx tests for Hp infection. Biopsy urease testing (CLO test ) The sensitivity is 90 to 95 %, and specificity is 95 to 100 % False negative results can occur in patients with recent GI bleeding with inadequate samples with the use of PPIs, H2 antagonists, antibiotics, or bismuth-compounds. Rapid urease testing One hour sensitivity and specificity are comparable ( 89~98 % and 89~93 %, respectively) to those seen with agar gel tests at 24 hours.

Part 3. Dx tests for Hp infection 2. Histology (expensive) Gastric biopsy It also provides additional information regarding the presence of gastritis, adenocarcinoma the detection of intestinal metaplasia mucosa-associated lymphoid tissue (MALT) Potential problems with histologic examination : (1). The density of H. pylori can vary at different sites, possibly leading to sampling error. (2) Interobserver variability. can be improved by Giemsa or immune stains. (3). The sensitivity of histology may be decreased in patients taking antisecretory therapy (PPI), but is still higher in this setting than biopsy urease testing.

Part 3. Dx tests for Hp infection 3. Bacterial culture and sensitivity testing H. pylori has historically been difficult to culture, but techniques are improving. Biopsies for culture should be obtained before the forceps are contaminated with formalin. Routine culture for H. pylori is not currently recommended. However, patients with refractory disease may benefit from culture and sensitivity testing. for the sensitivity test in vitro, especially for the resistance in metronidazole and macrolide for the analysis caga, VacA

Part 3. Dx tests for Hp infection Part B. Noninvasive Testing 1. Breath testing (UBT), 2. Stool antigen testing, 3. Serology 4. PCR ( polymerase chain reaction) The ACG guidelines recommend the UBT as "the best nonendoscopic test for documenting H. pylori infection," although stool antigen testing appears to be equally accurate and is more widely available. In the past, post treatment testing was recommended only for patients with complicated ulcer disease or with persistent or recurrent symptoms. Because the cost of noninvasive stool and breath tests have fallen, it is now reasonable to confirm eradication of infection in all patients

Part 3. Dx tests for Hp infection 1. UBT ( Urea breath testing) 13 C, 14 C H p : Urease Urea CO 2 + NH 3 hydrolysis of urea The dose of radiation in the 14 C test is minimal (approximately 1 microci) and equivalent to one day of background radiation exposure. Even though this dose of radiation is small, it may still be better to use an alternative to 14 C in young children and pregnancy. The sensitivity : 88 ~ 95 % specificity : 95 ~100 % False positive results are uncommon. False negative results may be observed in

Part 3. Dx tests for Hp infection To prevent false negative results, the patient should be off PPIs,Bismuth for at least 2 weeks, and off antibiotics for at least 4 weeks. UBT is now reasonable to confirm eradication of infection in all patients 4~6 weeks following treatment.

Part 3. Dx tests for Hp infection 2. Serology test ELISA technology to detect IgG or IgA antibodies is inexpensive, noninvasive, and well-suited to primary care practice. However, concerns over its accuracy have limited its use. high sensitivity ( 90 ~ 100% ) but variable specificity ( 76 ~ 96 % ) accuracy has ranged from 83 ~ 98 %. False positive results in following antibiotic Tx for H. pylori eradication. Suggest : confirmation of H. pylori eradication is desired one year or more following therapy.

Part 3. Dx tests for Hp infection 2. Serology test Correlation of serology results with H. pylori eradication revealed the following observations: (a). In patients cured of infection : H. pylori titers declined by approximately 50 % at 3 months. (b). At 18 months, only 60 % patient had undetectable antibody titers. Seroconversion from detectable to undetectable levels at 18 months after Hp eradication had a sensitivity ( 60 % ) and specificity (100 %).

Part 3. Dx tests for Hp infection 3. Stool antigen assay The sensitivity is 94 % and specificity is 86%. use polyclonal Ab, monoclonal Ab, ELISA (a). False positive & negative results : in patients with acute UGI bleeding (b). False negative results : in post-eradication 4~6 weeks ( rate : 20 %) use of Bismuth( rate : 15%) or PPIs, Lansoprazole (up to 25 %) In contrast, false negative results were not observed with ranitidine.

Part 3. Dx tests for Hp infection 4. PCR (Polymerase chain reaction) not practical for the routine diagnosis of H. pylori. 5. Salivary assays The oral cavity can serve as a reservoir for H. pylori. Both saliva and dental plaque contain H. pylori as demonstrated by serology and PCR. Although there is some appeal to being able to avoid vein puncture (particularly in children), current studies indicate that IgG assays of saliva are not as sensitive when compared to histology or serum testing. 6. Urinary assays based on ELISA sensitivity is 96% and specificity is 79 %

~100% 80~90 % ~99%

Part 3. Dx tests for Hp infection Guidelines have been approved by the ACG, AGA UBT CLO

Part 3. Dx tests for Hp infection art C. Who shoud be tested for H. pylori? most commonly recommended for p t with : 1. Peptic ulcer disease active gastric or duodenal ulcers or a past history of documented ulcers. not all ulcer patients have H. pylori 2. Atrophic gastritis 3. Long- term medications (eg, Aspirin and NSAIDs) 4. Low-grade gastric MALToma ( mucosa-associated lymphoid tissue lymphoma ) 5. Gastric cancer resection. 6. First-degree relatives of gastric cancer

Part 3. Dx tests for Hp infection Recommendation in initial Dx and follow-up Initial diagnosis (1). Whole blood or serum serology is a cost-effective initial approach to testing for H. pylori in symptomatic or at-risk asymptomatic patients (such as those with known peptic ulcer disease ) (2). The stool antigen assay may be an alternative in patients who are not taking PPIs or Bismuth and who do not have acute GI bleeding.

Part 3. Dx tests for Hp infection Recommendation in initial Dx and follow-up Initial diagnosis (3). Endoscopic biopsy should be reserved for patients who are undergoing : (a) a diagnostic endoscopy (b) an ulcer and for those who require endoscopy to follow-up a gastric ulcer or MALT lymphoma. (4).Biopsy urease testing is performed in patients not taking antibiotics or a PPI when histopathology is not required.

Part 3. Dx tests for Hp infection Recommendation in initial Dx and follow-up 2. Follow-up Confirmation of eradication is reasonable because of the availability of accurate, relatively inexpensive noninvasive tests (stool and breath tests), and has been recommended by a European consensus panel (1) UBT ( Urea breath testing) performed at least 4 weeks after treatment has been promoted as the test of choice to confirm eradication of infection. (2) Stool antigen testing is a more widely available alternative, but it may be less accurate. the stool antigen test should not be performed sooner than 4~6 weeks after Hp eradication.

Part 3. Dx tests for Hp infection Recommendation in initial Dx and follow-up 2. Follow-up (3). Antibiotics and bismuth should be discontinued for at least 4 weeks, and PPIs at least 1~2 weeks to reduce the chance of false-negative results, by urea breath test, stool antigen testing, or endoscopic urease testing. (4). Endoscopy with biopsy for culture can be performed when antibiotic resistance is suspected. for histopathology only is during follow-up of complicated ulcer disease. (5) Serologic testing is not useful for follow-up since many patients continue to have antibodies for months or even years after eradication therapy.

Part 4. Tx of Hp infection Part A. Who should be treated for H.p? Guidelines of the Hp eradication strongly recommended & Advised Part B. Treatment regimens for H.p? Triple therapy ( PPI + A or C or M ) Quadruple therapy (P.B.M.T.) New Quadruple therapy ( P.B.A.T ) New combination : Rifabutin, Levofloxacin If second-line quadruple therapy fails Part C. Side effect of drugs

Part 4. Tx of Hp infection Part A. Who should be treated for H.p? 2000 Maastricht-2 Guidelines is strongly recommended in all patients with 1. Peptic ulcer disease 2. low-grade gastric MALToma ( mucosa-associated lymphoid tissue lymphoma ) 3. Atrophic gastritis 4. Gastric cancer resection. 5. First-degree relatives of gastric cancer 6. According to patients' wishes after full consultation.

Part 4. Tx of Hp infection 2000 Maastricht-2 Guidelines is Advised that H. pylori eradication is considered to be an appropriate option in infected patients with 1. Functional dyspepsia: it may leadsto long-term symptom improvement in a subset of patients. 2. NSAIDs It was agreed that the eradication of H. pylori prior to the use of NSAIDs reduces the incidence of peptic ulcer, but does not enhance the healing of gastric or duodenal ulcer in patients receiving antisecretory therapy who continue to take NSAIDs. 3. GERD : the eradication of H. pylori is not associated with the development of GERD in most cases, and does not exacerbate existing GERD.

.2005 Maastricht-3 Guidelines is 1. Dyspepsia Test and treat is appropriate in uninvestigated dyspepsia 2. GERD (a) Hp eradication does not cause GERD (b) A negative association between the prevalence of Hp and GERD 3. NSAIDs (a) Hp eradication is insufficient to prevent NSAID related ulcer disease (b) Naïve NSAID users should be tested for Hp and received eradication therapy (c) Long-term aspirin ulcers who bleed should be tested for Hp 4. Pediatrics 5. Other disease IDA

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p. 1. First-line eradication therapies : should be treated with triple therapy PPIs (proton pump inhibitor) or Ranitidine bismuth citrate, combined with Clarithromycin Amoxicillin Metronidazole. 2. Second-line therapy : should use quadruple therapy with P.B.M.T. PPIs ( proton pump inhibitor ) +Bismuth, +Metronidazole + Tetracycline. Where bismuth is not available, second-line therapy

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p Successful rate : 85~90 % when treatment duration is 10 ~14 days The regimen of choice is triple therapy with a PPI ( proton pump inhibitor ): Lansoprazole ( Takepron) 30 mg twice daily, Omeprazole ( Losec) 20 mg twice daily, Pantoprazole (Pantoloc) 40 mg twice daily, Rabeprazole ( Pariet ) 20 mg twice daily, or Esomeprazole ( Nexium ) 40 mg once daily + Amoxicillin (1 g twice daily), + Clarithromycin ( K-mycin,500 mg twice daily) for 10~14 days

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p. For patients failing one course of H. pylori treatment, we recommend : 1.an alternate regimen using a different combination 2. Quadruple therapy P.B.M.T. x 14 days PPI Bid + Bismuth-based therapy (Pepto Bismol 2# Qid ) + Tetracycine 500 mg, Qid + High dose Metronidazole 500 mg, Qid preferably given with meals for 14 days One large prospective study suggested that one-week treatment with a quadruple regimen may be sufficient as primary therapy. However, two weeks should be the duration of subsequent courses of treatment.

. #

Antibiotic resistance 1. Metronidazole resistance : 22~39 % significantly associated with female sex, Asian 2. Clarithromycin resistance : 11~12 % significantly associated with geographic region, older age, female sex, and the presence of inactive ulcer disease. 3. H. pylori are naturally resistant to several commonly used antibiotics, including vancomycin, trimethoprim, and sulfonamides. 4. Amoxicillin and Tetracycline was rare resistance.

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p. For patients failing one course of H. pylori treatment, we recommend : 3. New Quadruple therapy consisting of For 7 days course Omeprazole (20 mg, Bid ) + Bismuth salts + Amoxicillin + Tetracycline 78 % eradication rate + Metronidazole 58 % eradication rate Eradication rates were significantly higher in the group receiving tetracycline (78 versus 58 percent).

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p. For patients failing one course of H. pylori treatment, we recommend : 4. New combination of antibiotics as "rescue" therapy : ( eradication rate 87 % ) with "PPI-based triple therapy" consisted of Pantoprazole (40 mg, Bid ) + Rifabutin (150 mg or 300 mg, Qd ), + Amoxicillin (1 g, Bid) for 10 days. The higher dose rifabutin (87%) combination was significantly more effective than the lower dose combination or quadruple therapy ( 67%) with P.B.M.T group. ( pantoprazole, bismuth, metronidazole, and tetracycline)

Part 4. Tx of Hp infection Part B. Treatment regimens for H.p. For patients failing one course of H. pylori treatment, we recommend : 5. New combination of antibiotics as "rescue" therapy : ( eradication rate 70 % ) with "PPI-based triple therapy" consisted of Pantoprazole (40 mg, Bid ) + Levofloxacin ( 250 mg, Bid ), + Amoxicillin (1 g, Bid) for 10 days. Triple therapy containing levofloxacin (70 %) was better than quadruple therapy (P.B.M.T=37%).

Second-line quadruple therapy P.B.M.T. First-line triple therapies

Pure antibiotics. PPI + 1 antibiotics Bismuth +2 antibiotics

.

Part 4. Tx of Hp infection If second-line quadruple therapy fails patients should be referred to a specialist. Subsequent failures should be handled on a case-by-case basis by the specialist. Endoscopy with culture Routine culture for H. pylori is not currently recommended. However, patients with refractory disease may require culture and sensitivity testing since the incidence of resistance is dramatically high in this subgroup.

..

Part 4. Tx of Hp infection Part C. Side effects up to 50 % of patients taking the triple regimens. But the adverse effects associated with H. pylori therapy are usually mild. Less than 10 percent of patients stop treatment due to side effects 1. The most common side effect is a metallic taste due to Metronidazole or Clarithromycin. 2. Amoxicillin can cause diarrhea or an allergic reaction. 3. Metronidazole can cause a peripheral neuropathy, seizures, and a disulfuram-like reaction when taken with alcohol. 4. Tetracycline can induce a photosensitivity reaction, and avoid in pregnant women.

...