Helicobacter pylori

Preface
Contents
Part I: Epidemiology
	1: Prevalence and Transmission Routes of H. pylori
		1.1	 Introduction
		1.2	 Prevalence of H. pylori
			1.2.1	 Prevalence of H. pylori in the Adults
				1.2.1.1	 Asia Pacific Area
				1.2.1.2	 Europe
				1.2.1.3	 North America
				1.2.1.4	 Latin America
				1.2.1.5	 Africa
				1.2.1.6	 Summary
			1.2.2	 Prevalence of H. pylori in Children
				1.2.2.1	 Asia
				1.2.2.2	 Europe
				1.2.2.3	 North America
				1.2.2.4	 Latin America
				1.2.2.5	 Summary
		1.3	 Risk Factors of H. pylori Infection
		1.4	 Transmission of H. pylori
			1.4.1	 Transmission of H. pylori in the Developing Countries
			1.4.2	 Transmission of H. pylori in the Developed Countries
		1.5	 Conclusion
		References
Part II: Pathophysiology
	2: Gastric Colonization by H. pylori
		2.1	 Introduction
		2.2	 Gastric Environment at the Site of Infection
		2.3	 Motility
		2.4	 Adhesion
		2.5	 Acid Acclimation
		2.6	 pH Alteration and Treatment Efficacy
		2.7	 Conclusions
		References
	3: Immunological Reactions on H. pylori Infection
		3.1	 Introduction
		3.2	 Microbiota and General Immune Mechanism in the Stomach
			3.2.1	 Microbiota in the Stomach and Their Possible Role
			3.2.2	 General Immune Mechanism of Stomach
				3.2.2.1	 IgA and IgG Response of Stomach
				3.2.2.2	 CD4+ T-Cell Responses
		3.3	 Immune Response to H. pylori
			3.3.1	 Immune Evasion
				3.3.1.1	 Inhibition of Innate Immune Recognition by H. pylori
					Evasion of Recognition by Pattern Recognition Receptors
					Inhibition of Phagocytic Killing
					Inhibition of Killing by Reactive Oxygen Species and Nitric Oxide
				3.3.1.2	 Modulation of Adaptive Immunity by H. pylori
				3.3.1.3	 Inhibition of Effective T-Cell Response
				3.3.1.4	 Evasion of Humoral Response
				3.3.1.5	 Genetic Diversity in Immune Evasion
			3.3.2	 Innate Immunity Activation Due to H. pylori
			3.3.3	 Adaptive Immunity Activation Due to H. pylori
			3.3.4	 Interaction of H. pylori with Tight Junction Proteins
		3.4	 Conclusion
		References
	4: Change of Acid Secretions, Ghrelin, and Leptin, by H. pylori
		4.1	 Introduction
		4.2	 Gastric Acid Secretion and H+, K+-ATPase with Regard to H. pylori Infection
			4.2.1	 Gastric Acid Secretion and H+, K+-ATPase
			4.2.2	 Effect of H. pylori Infection on the Gastric Acid Secretion
				4.2.2.1	 Acute Phase of H. pylori Infection Causes Hypochlorhydria
				4.2.2.2	 Effect of H. pylori Infection on H+, K+-ATPase
				4.2.2.3	 Interaction Between H. pylori Infection and Gastric Acid Secretion Determining the Pattern of Gastritis
				4.2.2.4	 Chronic Phase of H. pylori Infection and Gastric Acid Secretion
				4.2.2.5	 Gastrin and Somatostatin in Regard to H. pylori Infection
			4.2.3	 Effect of H. pylori Eradication on Gastric Acid Secretion
		4.3	 Ghrelin
			4.3.1	 Role of Ghrelin
			4.3.2	 Regulation of Ghrelin in Regard to H. pylori Infection
			4.3.3	 Effect of Eradication of H. pylori on Ghrelin
		4.4	 Leptin
			4.4.1	 Regulation and Role of Gastric Leptin
			4.4.2	 Regulation of Leptin in Regard to H. pylori Infection
		4.5	 Conclusions
		References
	5: H. pylori Virulence Factors: Toxins (CagA, VacA, DupA, OipA, IceA)
		5.1	 Introduction
		5.2	 Cytotoxin-Associated Gene A (CagA)
			5.2.1	 cag Pathogenicity Island (cag PAI)
			5.2.2	 Diversity of the cagA Gene
			5.2.3	 The Relevance Between the EPIYA Segment and Pathogenicity of CagA
			5.2.4	 Tyrosine Phosphorylation of CagA
			5.2.5	 Phosphorylation-Independent Signaling of CagA
		5.3	 Vacuolating Cytotoxin (VacA)
			5.3.1	 VacA Structure
			5.3.2	 vacA Gene Diversity
			5.3.3	 vacA Genotype in Relation to Gastroduodenal Diseases
			5.3.4	 Biological Functions of VacA
		5.4	 Outer Membrane Inflammatory Protein (OipA)
		5.5	 Induced by Contact with Epithelium (IceA)
		5.6	 Duodenal Ulcer Promoting Gene (dupA)
		5.7	 Other Virulence Factors
			5.7.1	 Shape Switch
			5.7.2	 High-Temperature Requirement A (HtrA) and Heat-Shock Proteins (Hsps)
			5.7.3	 Arginase
			5.7.4	 Catalase and Superoxidase Dismutase (SOD)
			5.7.5	 Cholesteryl α-Glucosyltransferase
		5.8	 Conclusion
		References
	6: H. pylori Virulence Factors: Genetic Polymorphism and Disease
		6.1	 Introduction
		6.2	 Cytotoxin-Associated Gene A (cagA)
			6.2.1	 cagA Type: Western Versus East Asian
		6.3	 Vacuolating Cytotoxin (vacA)
			6.3.1	 Geographic Differences in vacA Genotypes
		6.4	 Induced by Contact with Epithelium (iceA)
		6.5	 Outer Membrane Protein
			6.5.1	 Outer Inflammation Protein (oipA)
			6.5.2	 Duodenal Ulcer Promoting Gene A (dupA)
			6.5.3	 Blood Group A Antigen-Binding Adhesion (babA)
			6.5.4	 HomA and HomB
		6.6	 Conclusion
		References
	7: Host Factor: Genetic Polymorphism
		7.1	 Introduction
		7.2	 Interleukin-1β
		7.3	 Tumor Necrosis Factor-α
		7.4	 Interleukin-10
		7.5	 Interleukin-8
		7.6	 Toll-Like Receptor 4
		7.7	 Nucleotide-Binding Oligomerization Domain-Like Receptors (NLRs)
		7.8	 Conclusions
		References
Part III: Diagnosis
	8: Serology
		8.1	 Introduction
		8.2	 Advantages and Disadvantages of Serological Diagnosis
		8.3	 Serological Diagnosis
			8.3.1	 Bacterial Agglutination, Complement Fixation, and Indirect Immunofluorescence Test (IIF)
			8.3.2	 EIA and ELISA
			8.3.3	 Commercial Serological ELISA Kits Depending on H. pylori Antigen
			8.3.4	 Genedia® H. pylori ELISA and Its Use on Nationwide H. pylori Epidemiological Survey in Korea
			8.3.5	 Genedia® H. pylori ELISA and Its Use on Nationwide H. pylori Epidemiological Survey in Korea
		8.4	 Conclusions
		References
	9: Histopathologic Diagnosis of H. pylori Infection and Associated Gastric Diseases
		9.1	 Introduction
		9.2	 Histological Diagnosis of H. Pylori
			9.2.1	 Hematoxylin and Eosin (H&E) Stain
			9.2.2	 Special Stain and Immunohistochemistry (IHC)
		9.3	 Molecular Tests
		9.4	 Pathologic Features of H. Pylori-Associated Gastritis
			9.4.1	 Acute Gastritis
			9.4.2	 Chronic Gastritis
		9.5	 Sequelae of Chronic Gastritis
			9.5.1	 Atrophic Gastritis
			9.5.2	 Intestinal Metaplasia
			9.5.3	 Mucosa-Associated Lymphoid Tissue (MALT)
			9.5.4	 Gastric Cancer
		9.6	 Pathologic Findings of Peptic Ulcer
		9.7	 Conclusion
		References
	10: Culture
		10.1	 Introduction
		10.2	 Culture Method
			10.2.1	 Specimen Collection
			10.2.2	 Transport of Biopsy Specimens
			10.2.3	 Incubation
			10.2.4	 Identification
		10.3	 Antimicrobial Susceptibility Testing
			10.3.1	 Agar Dilution Method
			10.3.2	 Disk Diffusion Method
			10.3.3	 Broth Dilution Method
			10.3.4	 E-Test
		10.4	 Conclusions
		References
	11: Urea Breath Test
		11.1	 Introduction
		11.2	 Principle of the Urea Breath Test
		11.3	 Urea Substrate and Measuring Equipment of the Urea Breath Test
		11.4	 Test Meal
		11.5	 Time of Breath Collection
		11.6	 Diagnostic Accuracy and Appropriate Cutoff Point of the Urea Breath Test
		11.7	 Conclusion
		References
	12: H. pylori Stool Antigen Test
		12.1	 Introduction
		12.2	 Diagnostic Accuracy of H. Pylori Stool Antigen Test
			12.2.1	 Diagnostic Accuracy of H. Pylori Stool Antigen Test in Untreated Patients
			12.2.2	 Diagnostic Accuracy of H. Pylori Stool Antigen Test After Eradication
		12.3	 Types of H. Pylori Stool Antigen Test
			12.3.1	 H. Pylori Stool Antigen Test Based on Enzyme Immunoassay
			12.3.2	 H. Pylori Stool Antigen Test Based on Immunochromatography
			12.3.3	 Novel H. Pylori Stool Antigen Tests
		12.4	 H. Pylori Stool Antigen Test in Specific Conditions
		12.5	 Conclusion
		References
	13: Specific Conditions: Children
		13.1	 Introduction
		13.2	 Endoscopic Diagnosis of H. pylori Infection in Children
			13.2.1	 Application of Endoscopy with Biopsy in Children
			13.2.2	 Endoscopic Findings in H. pylori-Infected Children
			13.2.3	 Histopathologic Findings in H. pylori-Infected Children
		13.3	 Noninvasive Diagnosis of H. pylori Infection in Children
			13.3.1	 Urea Breath Test in Children
			13.3.2	 H. pylori Stool Antigen Test in Children
			13.3.3	 H. pylori Antibody Tests
		13.4	 Treatment of H. pylori Infection in Children
		13.5	 Conclusion
		References
	14: Specific Conditions: Diagnosis of H. pylori Infection in Case of Upper Gastrointestinal Bleeding
		14.1	 Introduction
		14.2	 Accuracy of Diagnostic Methods for H. Pylori in Upper Gastrointestinal Bleeding
			14.2.1	 Invasive Tests
				14.2.1.1	 Rapid Urease Test (RUT)
				14.2.1.2	 Histology
				14.2.1.3	 Culture
				14.2.1.4	 Polymerase Chain Reaction (PCR)
			14.2.2	 Noninvasive Tests
				14.2.2.1	 Urea Breath Test
				14.2.2.2	 H. pylori Stool Antigen Test
				14.2.2.3	 Serology
		14.3	 Appropriate Methods for Detection of H. pylori in Upper Gastrointestinal Bleeding
		14.4	 Conclusion
		References
	15: Diagnosis of H. pylori Infection After Gastric Surgery
		15.1	 Introduction
		15.2	 Dynamic Changes of H. pylori Status in Patients Who Underwent Gastric Cancer Surgery
			15.2.1	 Possible Mechanisms for the Dynamic Changes of H. pylori Status
			15.2.2	 Affecting Factors for H. pylori Status in Patients Who Underwent Gastric Cancer Surgery
				15.2.2.1	 Operation Methods
				15.2.2.2	 Bile Reflux
				15.2.2.3	 Postgastrectomy-Induced Hypochlorhydria
		15.3	 Diagnostic Methods
			15.3.1	 Histology
			15.3.2	 Rapid Urease Test
			15.3.3	 Serology
			15.3.4	 13C-Urea Breath Test
				15.3.4.1	 Efficacy of 13C-Urea Breath Test in the Remnant Stomach After Partial Gastrectomy
				15.3.4.2	 Clinical Factors that Caused False Positive 13C-UBT Results After H. pylori Eradication in the Remnant Stomach
		15.4	 Conclusion
		References
Part IV: Symptom
	16: Symptoms of Acute and Chronic H. pylori Infection
		16.1	 Introduction
		16.2	 The Induction Mechanisms of Symptoms After H. pylori Infection
		16.3	 Brain-Gut Axis, a Possible Mechanism of Symptoms of H. pylori Infection
		16.4	 Symptoms and Endoscopic and Histological Findings of Acute H. pylori Infection
		16.5	 Symptoms of Chronic H. pylori Infection
			16.5.1	 Brain-Gut Axis Relationship with Chronic H. pylori Infection
			16.5.2	 Extragastric Diseases of Chronic H. pylori Infection
		16.6	 Conclusions
		References
Part V: Disease
	17: Synopsis of H. pylori-Associated Diseases
		17.1	 Introduction
		17.2	 H. pylori-Associated Gastric Diseases
			17.2.1	 Acute and Chronic Gastritis
				17.2.1.1	 Acute Gastritis
				17.2.1.2	 Chronic Gastritis
			17.2.2	 Nonulcer Dyspepsia
			17.2.3	 Gastric or Duodenal Ulcers
			17.2.4	 Gastric MALT Lymphoma
			17.2.5	 Gastric Cancer
		17.3	 Gastroesophageal Reflux Disease, Barrett’s Esophagus, and Esophageal Adenocarcinorma
		17.4	 Extraintestinal Manifestations of H. pylori Infection
		17.5	 Conclusions
		References
	18: Atrophic Gastritis and Intestinal Metaplasia
		18.1	 Introduction
		18.2	 Atrophic Gastritis and Intestinal Metaplasia as Precursor Lesions of Gastric Cancer
		18.3	 Prevalence of Atrophic Gastritis and Intestinal Metaplasia
		18.4	 Risk Factors of Atrophic Gastritis and Intestinal Metaplasia
		18.5	 Classification of Atrophic Gastritis and Intestinal Metaplasia
		18.6	 Diagnosis of Atrophic Gastritis and Intestinal Metaplasia
			18.6.1	 Endoscopic Diagnosis
			18.6.2	 Histological Diagnosis
			18.6.3	 Diagnosis by Serum Pepsinogen I/II Ratio
		18.7	 Management for Atrophic Gastritis and Intestinal Metaplasia
		18.8	 Conclusions
		References
	19: Functional Dyspepsia
		19.1	 Introduction
		19.2	 Definition of Functional Dyspepsia
		19.3	 Pathophysiology of Functional Dyspepsia
		19.4	 Diagnostic Approach to Functional Dyspepsia
		19.5	 Treatment of Functional Dyspepsia
		19.6	 Conclusions
		References
	20: Peptic Ulcer
		20.1	 Introduction
		20.2	 Epidemiology
		20.3	 Causative Factors
			20.3.1	 H. pylori Infection
			20.3.2	 NSAIDs
			20.3.3	 Non-H. pylori, Non-NSAID Ulcer
		20.4	 Clinical Features
		20.5	 Diagnosis
		20.6	 Treatment
		20.7	 Complications
			20.7.1	 Gastroduodenal Hemorrhage
			20.7.2	 Intestinal Perforation
			20.7.3	 Gastric Outlet Obstruction
			20.7.4	 Penetration and Fistula
			20.7.5	 Prevention of Peptic Ulcer
		20.8	 Conclusions
		References
	21: Gastric Extranodal Marginal Zone B-Cell Lymphoma of MALT
		21.1	 Introduction
		21.2	 Pathogenesis of Gastric MALT Lymphoma
			21.2.1	 H. pylori
			21.2.2	 Genetic Variation
		21.3	 Clinical Feature and Diagnosis
			21.3.1	 Clinical Characteristics and Endoscopic Features
			21.3.2	 Diagnosis and Pathology
			21.3.3	 Staging
		21.4	 Therapeutic Options
			21.4.1	 Anti-H. pylori Therapy
				21.4.1.1	 Indication and the Effect
				21.4.1.2	 The Predictive Factors for Regression After Anti-H. pylori Therapy
				21.4.1.3	 Assessment of the Response to Treatment
				21.4.1.4	 Long-Term Outcome after Successful Eradication
				21.4.1.5	 Histological Residual Disease
			21.4.2	 Nonresponder to Anti-H. pylori Therapy
				21.4.2.1	 Radiotherapy
				21.4.2.2	 Chemotherapy
			21.4.3	 H. pylori-Negative Gastric MALT Lymphoma
		21.5	 Surveillance After Remission
		21.6	 Recurrent Disease
		21.7	 Conclusions
		References
	22: Gastric Cancer: Synopsis and Epidemiology of Gastric Cancer
		22.1	 Introduction
		22.2	 Incidence and Mortality
			22.2.1	 Incidence
			22.2.2	 Mortality
			22.2.3	 Incidence and Mortality in Lynch Syndrome Carriers
		22.3	 Risk Factors
			22.3.1	 Helicobacter pylori
			22.3.2	 Other Risk Factors
		22.4	 Future Trends
		22.5	 Conclusions
		References
	23: Gastric Cancer: Genetic Alternations Induced by H. pylori Infection: The Role of Activation-Induced Cytidine Deaminase
		23.1	 Introduction
		23.2	 Genetic Alternations in Gastric Carcinogenesis
		23.3	 Chronic Inflammation and Genetic Alternations
			23.3.1	 Free Radicals
			23.3.2	 Activation-Induced Cytidine Deaminase
		23.4	 Genetic Alternations in H. pylori-Associated Gastric Carcinogenesis
		23.5	 Conclusions
		References
	24: Gastric Cancer: Epigenetic Mechanisms: Aberrant DNA Methylation and Dysregulation of MicroRNA
		24.1	 Introduction
		24.2	 H. pylori-Induced Gastric Carcinogenesis and Aberrant DNA Methylation
			24.2.1	 Underlying Mechanisms of Induction of Aberrant DNA Methylation by H. pylori Infection
			24.2.2	 Reversibility of Aberrant DNA Methylation Following H. pylori Eradication
			24.2.3	 Epigenetic Fingerprint of H. pylori Infection and Epigenetic Field for Cancerization
		24.3	 H. pylori-Induced Gastric Carcinogenesis and miRNA
			24.3.1	 H. pylori and miRNA: Underlying Mechanisms
				24.3.1.1	 Modulation of Host Inflammatory Immune Response
				24.3.1.2	 Promotion of Cell-Cycle Progression
				24.3.1.3	 Inhibition of Apoptosis and Promotion of Proliferation
				24.3.1.4	 Promotion of Tumor Invasion and Metastasis
		24.4	 Conclusions
		References
	25: Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor
		25.1	 Introduction
		25.2	 Introduction of Macrophage Migration Inhibitory Factor
		25.3	 Role of Macrophage Migration Inhibitory Factor in Tumorigenesis and Tumor Progression
		25.4	 H. pylori and Macrophage Migration Inhibitory Factor
		25.5	 Potential for Future Studies
		25.6	 Conclusions
		References
	26: Gastric Cancer: Epithelial-Mesenchymal Transition
		26.1	 Introduction
		26.2	 Three Types of EMT
			26.2.1	 Type 1: Embryogenesis
			26.2.2	 Type 2: Tissue Regeneration and Organ Fibrosis
			26.2.3	 Type 3: Invasiveness and Metastasis of Cancer
		26.3	 Major Signal Pathways of EMT
			26.3.1	 TGF-β/Smad Signaling
				26.3.1.1	 Smad Signaling
				26.3.1.2	 Non-Smad Signaling
			26.3.2	 Wnt/β-Catenin Signaling
			26.3.3	 Notch Signaling
		26.4	 EMT and Gastric Cancer
			26.4.1	 Association Between Gastric Cancer and EMT
				26.4.1.1	 CagA, Cytotoxin-Associated Gene Toxin
				26.4.1.2	 VacA, Vacuolating Cytotoxin
			26.4.2	 EMT Factors Related to Gastric Cancer
				26.4.2.1	 Regulation of E-Cadherin
					Functional Loss Through CDH1 Mutation
					Repression for the Transcription of CDH1
				26.4.2.2	 Epigenetic Regulation of EMT via miRNA
				26.4.2.3	 Other EMT Regulatory Factors
					Vimentin
					Bone Morphogenetic Protein (BMP)
					Claudin
					Gastrokine
			26.4.3	 EMT, Cancer Stem Cells, and H. pylori
				26.4.3.1	 Promotion of Production of TGF-β- or TNF-α-Inducing Protein
				26.4.3.2	 Activation of Snail, Twist, or β-Catenin
				26.4.3.3	 Hypermethylation of CDH1 Promoter
				26.4.3.4	 Association Between Emergence of Cancer Stem Cells and Chronic H. pylori Infection
			26.4.4	 Clinical Implications of EMT and Cancer Stem Cells
				26.4.4.1	 Markers for EMT
				26.4.4.2	 Prognostic Factors
				26.4.4.3	 Cancer Stem Cells
				26.4.4.4	 Targets for the Cancer Treatments
		26.5	 Conclusions
		References
	27: Gastric Cancer: ABO Blood Type
		27.1	 Introduction
		27.2	 The Association of ABO Blood Group with Different Diseases
		27.3	 Association Between ABO Blood Groups and H. pylori Infection
		27.4	 Research Studies Explaining the Interaction Between H. pylori and ABO Antigen, the Results, and Hypotheses
			27.4.1	 Immune Evasion by Molecular Mimicry
			27.4.2	 Adhesion Molecules onto Which H. pylori can Attach
			27.4.3	 Decoy Mechanism by Secretors
		27.5	 The Association of ABO Blood Group with Gastric Cancer
		27.6	 The Association of ABO Blood Group with Gastric Cancer by Way of H. pylori Infection
		27.7	 Conclusions
		References
	28: Gastric Cancer: First Relatives of Gastric Cancer
		28.1	 Introduction
		28.2	 Difference of H. pylori Infection Rate Depending on Family History on Gastric Cancer
		28.3	 Risk Increment of Gastric Cancer in the Presence of H. pylori Infection and Family History of Gastric Cancer and the Preventive Effect of H. pylori Eradication
			28.3.1	 Risk Increment of Gastric Cancer in the Presence of H. pylori Infection and Family History of Gastric Cancer
			28.3.2	 The Preventive Effect of H. pylori Eradication in Subjects with a Family History of Gastric Cancer
		28.4	 Risk Factors for Gastric Cancer According to the Number of Affected Relatives and According to the Affected Family Member
		28.5	 Family-Based Exome Sequencing Combined with Linkage Analyses Identifies Rare Susceptibility Variants of MUC4 for Gastric Cancer
		28.6	 Family History of Gastric Cancer as a Risk Factor for Intestinal Metaplasia
		28.7	 Prognosis of Gastric Cancer in the Relatives of Gastric Cancer
		28.8	 Guideline of Gastric Cancer Screening in Case of Family History of Gastric Cancer
		28.9	 Conclusions
		References
	29: H. pylori Infection-Negative Gastric Cancer
		29.1	 Introduction
		29.2	 Definition of H. pylori Infection-Negative Gastric Cancer
		29.3	 Incidence
		29.4	 Clinicopathologic Characteristics
		29.5	 Molecular Characteristics
		29.6	 Prognosis
		29.7	 Conclusions
		References
	30: Gastroesophageal Reflux Disease
		30.1	 Introduction
		30.2	 Epidemiology of GERD in H. pylori-Infected Population
		30.3	 The Impact of H. pylori Infections on GERD
		30.4	 Influence of H. pylori Eradication on GERD
			30.4.1	 Antral-Predominant Gastritis
			30.4.2	 Corpus-Predominant Gastritis
		30.5	 Conclusions
		References
	31: NSAID-Induced Gastropathy and H. pylori Infection
		31.1	 Introduction
		31.2	 NSAID-Induced Gastropathy
			31.2.1	 Mechanisms
			31.2.2	 Nonselective and Selective NSAIDs
		31.3	 Association Between NSAID-Induced Gastropathy and H. pylori Infection
			31.3.1	 Pathophysiology
			31.3.2	 Diagnosis of H. pylori Infection in NSAID Users
			31.3.3	 Therapeutic Approach (Table 31.1)
				31.3.3.1	 H. pylori Infection in Initial NSAID Users
					NSAIDs (Excluding Aspirin)
					Aspirin
				31.3.3.2	 H. pylori Infection in Long-Term NSAID Users Without Peptic Ulcer Complications
					NSAIDs (Excluding Aspirin)
					Aspirin
				31.3.3.3	 H. pylori Infection in Long-Term NSAID Users with Peptic Ulcer Complications
					NSAIDs (Excluding Aspirin)
					Aspirin
				31.3.3.4	 H. pylori Infection in COX-2 Inhibitor Users
				31.3.3.5	 Meta-analysis Results
			31.3.4	 Guidelines for Management of H. pylori Infection in NSAID Users
				31.3.4.1	 Korea
					Clinical Guidelines for Drug-Related Peptic Ulcer, 2020 Revised Edition [31]
				31.3.4.2	 Overseas Countries
					Management of H. pylori Infection: The Maastricht VI/Florence Consensus Report [32]
					Treatment of H. pylori Infection: ACG Clinical Guideline [33]
					Management of H. pylori Infection: Italian Guideline [34]
					Evidence-Based Clinical Practice Guidelines for Peptic Ulcer Disease 2020 in Japan [35]
		31.4	 Conclusions
		References
	32: Extraintestinal Manifestations of H. pylori Infection: H. pylori-Associated Iron Deficiency Anemia
		32.1	 Introduction
		32.2	 Clinical Studies
		32.3	 Epidemiology
		32.4	 Mechanisms
			32.4.1	 Chronic Gastrointestinal Blood Loss Induced by H. pylori Infection
			32.4.2	 The Effect of Chronic H. pylori Gastritis on Gastric Acid Secretion and Iron Absorption
			32.4.3	 Increased Iron Consumption by H. pylori
			32.4.4	 Iron Sequestration in Gastric Mucosa
			32.4.5	 Higher Hepcidin Levels in H. pylori-Infected Patients with Iron Deficiency Anemia
		32.5	 Conclusions
		References
	33: Extraintestinal Manifestations of H. pylori Infection: Idiopathic Thrombocytopenic Purpura
		33.1	 Introduction
		33.2	 Idiopathic Thrombocytopenic Purpura (Immune Thrombocytopenic Purpura)
		33.3	 Association Between Immune Thrombocytopenic Purpura and H. pylori
		33.4	 Mechanisms
		33.5	 Conclusions
		References
	34: Extraintestinal Manifestations of H. pylori Infection: Heart Disease
		34.1	 Introduction
		34.2	 H. pylori and Lipid Profile
		34.3	 H. pylori and Coronary Artery Disease
		34.4	 H. pylori and Arrhythmia
		34.5	 Conclusions
		References
	35: Extraintestinal Manifestations of H. pylori Infection: Asthma and Allergic Disorders
		35.1	 Introduction
		35.2	 H. pylori and Allergic Asthma: Epidemiological Evidence
		35.3	 H. pylori and Allergic Asthma: Proposed Mechanisms Underlying Protective Effects of H. pylori
			35.3.1	 Basic Concept on the Pathophysiology of Allergic Asthma
			35.3.2	 Hygiene Hypothesis and Disappearing Microbiota Hypothesis
			35.3.3	 Theoretical Hypothesis to Explain Protective Effect by H. pylori
		35.4	 Conclusions
		References
	36: Extragastric Manifestations of H. pylori Infection: Lower GI Disorders
		36.1	 Introduction
		36.2	 Colorectal Cancer or Adenoma
			36.2.1	 Clinical Studies
			36.2.2	 Possible Mechanisms for Causal Effects
		36.3	 Inflammatory Bowel Disease
			36.3.1	 Clinical Studies
			36.3.2	 Possible Mechanisms for Causal Effects
		36.4	 Irritable Bowel Syndrome
			36.4.1	 Clinical Studies
			36.4.2	 Possible Mechanisms for Causal Effects
		36.5	 Conclusions
		References
	37: Extraintestinal Manifestations of H. pylori Infection: Neurologic Disease
		37.1	 Introduction
		37.2	 Pathophysiology
			37.2.1	 The Microbiota-Gut-Brain Axis
			37.2.2	 Pathophysiology of H. pylori Infection on the MGBA
				37.2.2.1	 Route of H. pylori Entering the CNS
				37.2.2.2	 Neuroinflammation by H. pylori Infection
				37.2.2.3	 Dysbiosis by H. pylori Infection
				37.2.2.4	 Effects of H. pylori on Neurotransmitters
				37.2.2.5	 Microelement Deficiency
		37.3	 Related Neurologic Diseases
			37.3.1	 Parkinson’s Disease
			37.3.2	 Alzheimer’s Disease
			37.3.3	 Demyelinating Diseases of the CNS; Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders
			37.3.4	 Guillain–Barré Syndrome
			37.3.5	 Ischemic Stroke
			37.3.6	 Migraine
		37.4	 H. pylori Eradication Effects on Neurologic Diseases
			37.4.1	 Parkinson’s Disease
			37.4.2	 Alzheimer’s Disease
			37.4.3	 Other Diseases
		37.5	 Conclusions
		References
Part VI: Antibiotic Resistance
	38: Synopsis of Antimicrobial Resistance
		38.1	 Introduction
		38.2	 Mechanisms of Resistance to Antibiotics
			38.2.1	 Acquisition of Mobile Genetic Elements
			38.2.2	 Resistance Acquired by Point Mutation
			38.2.3	 Efflux Pumps and H. pylori Resistance
		38.3	 Resistance Observed in H. pylori and Its Consequences
			38.3.1	 Macrolides
			38.3.2	 Fluoroquinolones
			38.3.3	 Amoxicillin
			38.3.4	 Tetracyclines
			38.3.5	 Rifampin
			38.3.6	 5-Nitroimidazoles
		38.4	 Methods to Detect H. pylori Resistance
			38.4.1	 Phenotypic Methods
			38.4.2	 Genotypic Methods
		38.5	 Prevalence of H. pylori Resistance
		38.6	 Conclusions
		References
	39: Clarithromycin
		39.1	 Introduction
		39.2	 The Antimicrobial Mechanism of Clarithromycin
		39.3	 The Prevalence and Trends of Clarithromycin Resistance
		39.4	 Diagnosing Clarithromycin Resistance
			39.4.1	 Diagnosing Clarithromycin Resistance: Conventional Culture and Susceptibility
			39.4.2	 Diagnosing Clarithromycin Resistance: Molecular Tests
		39.5	 Mechanisms of Clarithromycin Resistance
		39.6	 Current Clarithromycin Resistance Studies and Its Prospection
			39.6.1	 Current Clarithromycin Resistance Studies
			39.6.2	 The Prospect About Future Clarithromycin Resistance Studies
		39.7	 Conclusions
		References
	40: Amoxicillin
		40.1	 Introduction
		40.2	 Prevalence of H. pylori Resistance to Amoxicillin
		40.3	 The Role and Resistance Mechanism of Amoxicillin in Eradication of H. pylori
			40.3.1	 Target of ß-Lactam Antibiotics in H. pylori
			40.3.2	 The Resistance Mechanism of Amoxicillin
		40.4	 Conclusions
		References
	41: Fluoroquinolone
		41.1	 Introduction
		41.2	 Mechanism of Action of Fluoroquinolone
		41.3	 Epidemiology of Fluoroquinolone Resistance
		41.4	 Diagnosis of Fluoroquinolone Resistance
		41.5	 Mechanism of Fluoroquinolone Resistance
			41.5.1	 Mechanism of Fluoroquinolone Resistance of H. pylori
			41.5.2	 Distinct Feature of Genes Responsible for Fluoroquinolone Resistance
		41.6	 Present Status of the Studies About Fluoroquinolone Resistance
		41.7	 Perspective and Limitation of Studies About Fluoroquinolone Resistance Mechanism
		41.8	 Conclusions
		References
	42: Metronidazole
		42.1	 Introduction
		42.2	 Epidemiological Aspects of Metronidazole Resistance
			42.2.1	 The Resistance Rate
			42.2.2	 Correlations Between the Resistance and the Eradication Failures
		42.3	 Principles of Metronidazole Resistance
			42.3.1	 Mode of Action
			42.3.2	 Mechanism of Resistance
				42.3.2.1	 Mutations in rdxA and frxA
				42.3.2.2	 Structural Alterations in RdxA
				42.3.2.3	 Other Mechanisms of Resistance
		42.4	 Conclusions
		References
Part VII: Treatment
	43: Synopsis of Antibiotic Treatment
		43.1	 Introduction
		43.2	 Why Are H. pylori Infections So Difficult to Cure?
		43.3	 Causes of Treatment Failure
		43.4	 Evidence-Based Therapy Is Susceptibility-Based Therapy
		43.5	 General “Rules” for Choosing a Regimen
		43.6	 H. pylori Therapies
			43.6.1	 Triple Therapies (Generally Only Used for Susceptibility-Based Therapy)
			43.6.2	 Four-Drug Therapies
				43.6.2.1	 Bismuth Quadruple Therapy
				43.6.2.2	 Bismuth Furazolidone Quadruple Therapy
			43.6.3	 Non-Bismuth Quadruple Therapies
				43.6.3.1	 Sequential Therapy (Generally Considered Obsolete Because of Antimicrobial Misuse)
				43.6.3.2	 Concomitant Therapy (Generally Considered Obsolete Because of Antimicrobial Misuse)
				43.6.3.3	 Hybrid and Reverse Hybrid Therapy (Generally Considered Obsolete Because of Antimicrobial Misuse)
			43.6.4	 PPI-Amoxicillin High-Dose Dual Therapy
		43.7	 Patient Education to Enhance Adherence
		43.8	 Recommendations
		References
	44: Triple Therapy
		44.1	 Introduction
		44.2	 Current Status of the Eradication Rates of Standard Triple Therapy
		44.3	 Factors Influencing the Eradication Rate of Standard Triple Therapy
			44.3.1	 H. pylori Factors
				44.3.1.1	 Antibiotic Resistance
				44.3.1.2	 Other H. pylori Factors
			44.3.2	 Host Factors
				44.3.2.1	 Medication Adherence
				44.3.2.2	 Excess Gastric Acid Secretion
				44.3.2.3	 Treatment Duration
				44.3.2.4	 Drug Side Effects
				44.3.2.5	 Underlying Gastroduodenal Disease
				44.3.2.6	 Gastritis Patterns
				44.3.2.7	 Smoking
				44.3.2.8	 Other Factors
		44.4	 Conclusions
		References
	45: Quadruple Therapy
		45.1	 Introduction
		45.2	 Efficacy of Bismuth Quadruple Therapy as Second-Line Treatment
		45.3	 Efficacy of Bismuth Quadruple Therapy as First-Line Treatment
		45.4	 Factors Affecting the Bismuth Quadruple Therapy Eradication Rate: Antimicrobial Resistance
		45.5	 Conclusions
		References
	46: Sequential Therapy
		46.1	 Introduction
		46.2	 Theoretical Background of Sequential Therapy
		46.3	 Types of Sequential Therapy
		46.4	 Outcome of Sequential Therapy
			46.4.1	 Eradication Rate
			46.4.2	 Adverse Events
		46.5	 Limitations of Sequential Therapy
			46.5.1	 The Complexity of Regimen
			46.5.2	 Rescue Treatment After Failure
			46.5.3	 Antimicrobial Resistance
			46.5.4	 Insufficient Quality of Clinical Trials
		46.6	 Conclusions
		References
	47: Concomitant Therapy and Hybrid Therapy
		47.1	 Introduction
		47.2	 Theoretical Background of Concomitant and Hybrid Therapies
		47.3	 Outcome of Concomitant and Hybrid Therapies
			47.3.1	 Eradication Rate
			47.3.2	 Adverse Events
		47.4	 Limitations of Concomitant Therapy
			47.4.1	 Rescue Therapy After Eradication Failure
			47.4.2	 Antibiotic Resistance
		47.5	 Conclusions
		References
	48: Tailored Therapy Based on Antibiotic Resistance
		48.1	 Introduction
		48.2	 The Patient-Specific Therapy: Why Tailored Therapy Is Needed
		48.3	 Detection of Antibiotic Resistance in H. pylori
			48.3.1	 Culture-Guided Method for Antibiotic Susceptibility Test in H. pylori
			48.3.2	 Molecular Methods for Antibiotic Susceptibility Test in H. pylori
		48.4	 The Efficacy of Tailored Therapy and Guideline for Tailored Therapy Based on Antibiotic Susceptibility Test
		48.5	 Conclusions
		References
	49: Fluoroquinolone and Rifabutin-Containing Therapy
		49.1	 Introduction
		49.2	 Fluoroquinolone-Containing Triple Therapy
			49.2.1	 Theoretical Background
			49.2.2	 Eradication Rate
			49.2.3	 Adverse Events
			49.2.4	 Antibiotic Resistance and Limitations
		49.3	 Rifabutin-Containing Therapy
			49.3.1	 Theoretical Background
			49.3.2	 Eradication Rate
			49.3.3	 Adverse Events
			49.3.4	 Antibiotic Resistance and Limitations
		49.4	 Conclusions
		References
	50: Probiotics
		50.1	 Introduction
		50.2	 Mechanism of Action of Probiotics on H. pylori Infection
			50.2.1	 Immunological Mechanisms
			50.2.2	 Nonimmunological Mechanisms
		50.3	 Probiotic Treatment of H. pylori Infection
			50.3.1	 Studies Using Animals and Cell Line
			50.3.2	 Human Studies
		50.4	 Safety
		50.5	 Conclusions
		References
	51: Treatment Guidelines
		51.1	 Introduction
		51.2	 South Korean Guidelines
		51.3	 Japanese Guidelines
		51.4	 European Guidelines (The Maastricht VI/Florence Consensus Report, 2022)
		51.5	 Conclusions
		References
	52: Gastric Cancer Screening
		52.1	 Introduction
		52.2	 Accuracy of Gastric Cancer Screening Methods
			52.2.1	 Endoscopic Screening
			52.2.2	 Radiographic Screening
			52.2.3	 Comparison of Sensitivity Between Endoscopic and Radiographic Screening
		52.3	 Effect of Gastric Cancer Screening on Gastric Cancer Mortality
			52.3.1	 Endoscopic Screening
			52.3.2	 Radiographic Screening
		52.4	 Guidelines
			52.4.1	 Updated Korean Guideline 2015
			52.4.2	 Further Supporting Evidence After 2015 Guideline
			52.4.3	 Japanese Guideline
		52.5	 Serologic Test for Gastric Cancer Screening
			52.5.1	 Serum Pepsinogen
			52.5.2	 Serum Trefoil Factor 3
			52.5.3	 MicroRNAs
			52.5.4	 Multianalyte Blood Tests
		52.6	 Conclusion
		References
	53: Recrudescence and Reinfection After H. pylori Eradication Treatment
		53.1	 Introduction
		53.2	 Systematic Review with Meta-Analysis: The Global Recurrence Rate of H. pylori
		53.3	 Recrudescence After H. pylori Eradication Therapy
		53.4	 Reinfection After H. pylori Eradication Therapy
		53.5	 Risk Factors of Reinfection After H. pylori Eradication Therapy
		53.6	 Conclusions
		References
Part VIII: Consequences of H. pylori Eradication
	54: Peptic Ulcer Disease
		54.1	 Introduction
		54.2	 The Role of H. pylori infection in Peptic Ulcer Disease Pathogenesis
		54.3	 Impact on Peptic Ulcer Disease Healing
		54.4	 Impact on Peptic Ulcer Disease Recurrence
		54.5	 Impact on Peptic Ulcer Disease Complications
			54.5.1	 Bleeding
			54.5.2	 Perforation
			54.5.3	 Obstruction
		54.6	 Conclusions
		References
	55: Atrophic Gastritis and Intestinal Metaplasia
		55.1	 Introduction
		55.2	 The Effect of H. pylori Eradication on the Atrophic Gastritis and Intestinal Metaplasia
			55.2.1	 Key Individual Studies
			55.2.2	 Meta-Analyses
			55.2.3	 Guidelines
			55.2.4	 Limitations
		55.3	 Affecting Factors on the Decrease of Atrophic Gastritis and Intestinal Metaplasia by H. pylori Eradication
		55.4	 Underlying of Reversibility of Atrophic Gastritis and Intestinal Metaplasia
			55.4.1	 CDX1 and CDX2
			55.4.2	 Gastric Stem Cells
		55.5	 Conclusions
		References
	56: Primary Prevention of Gastric Cancer
		56.1	 Introduction
		56.2	 Key Individual Studies
		56.3	 Meta-Analyses
		56.4	 Guidelines
		56.5	 The Underlying Mechanisms of Chemopreventive Effect of H. pylori Eradication on Gastric Cancer
		56.6	 Conclusions
		References
	57: Secondary Prevention of Gastric Cancer After Endoscopic or Surgical Treatment
		57.1	 Introduction
		57.2	 Chemoprevention Effect of H. pylori Eradication After Endoscopic Treatments
		57.3	 Chemoprevention Effect of H. pylori Eradication After Surgery
		57.4	 Survival Benefits of H. pylori Eradication After Surgery
		57.5	 Conclusions
		References
	58: Extraintestinal Manifestations Depending on Sex/Gender and Age: Metabolic Parameters and Glycosylated Hemoglobin A1c
		58.1	 Introduction
		58.2	 Metabolic Syndromes and H. pylori Infection
			58.2.1	 The Effect of H. pylori on the Metabolic Parameters Depending on Age and Sex/Gender
			58.2.2	 The Underlying Mechanisms of H. pylori on the Metabolic Parameters
			58.2.3	 The Effect of H. pylori Eradication on the Metabolic Parameters
				58.2.3.1	 Different Effects of H. pylori Eradication on the Metabolic Parameters
				58.2.3.2	 The Underlying Mechanisms of Different Effects of Sex on the H. pylori Eradication-Induced Metabolic Parameters
		58.3	 The Effects of H. pylori and its Eradication on the Insulin Resistance or Hemoglobin A1c Depending on Sex/Gender and Age
			58.3.1	 The Effects of H. pylori on the Insulin Resistance or Glycosylated Hemoglobin A1c
			58.3.2	 The Effects of H. pylori Eradication on the Insulin Resistance or Hemoglobin A1c and the Possible Underlying Mechanism
			58.3.3	 The Effects of H. pylori Eradication on the Hemoglobin A1c Depending on Age and Sex
		58.4	 Conclusions
		References
Part IX: The Effect of H. pylori on the Gastric Microbiota
	59: The Effect of H. pylori Infection on the Gastric Microbiota
		59.1	 Introduction
		59.2	 The Development of Analysis Methods of Gastric Microbiota
		59.3	 Various Conditions Affecting the Gastric Microbiota
			59.3.1	 The Effect of Sampling Site on the Gastric Microbiota Analysis: Mucosa vs. Gastric Fluid
			59.3.2	 Corpus Biopsy Was More Favorable for the Analysis Regarding a Possible Role of Bacteria Other than H. pylori in the Gastric Carcinogenesis
			59.3.3	 Influence of Change of pH on the Gastric Microbiota
		59.4	 The Effect of H. pylori Infection on the Gastric Microbiota
			59.4.1	 Under the Normal Acidic Condition of a Healthy Stomach Without H. pylori
			59.4.2	 What Happens When H. pylori Infection Occurs
			59.4.3	 An Appropriate Cutoff Value for Determining the Colonization of Helicobacter pylori by the Pyrosequencing Method
		59.5	 Altered Microbiota Composition Related with Disease State
			59.5.1	 Altered Microbiota Composition in the Gastric Cancer in the Presence of H. pylori
			59.5.2	 Altered Microbiota Composition in the Gastric Cancer in the Absence of H. pylori
		59.6	 Link Between Gastric Microbiota and Gastric Cancer
			59.6.1	 Nitrosating and/or Urease Producing Bacteria
			59.6.2	 Bacterial Metabolites
			59.6.3	 Bacterial Genotoxins
		59.7	 Conclusions
		References
	60: The Effect of H. pylori Eradication on the Gastric Microbiota
		60.1	 Introduction
		60.2	 Gastric Microbiota Changes in the Absence or in the Presence of H. pylori Infection
			60.2.1	 Gastric Microbiota Changes in the Absence of H. pylori Infection
			60.2.2	 Gastric Microbiota Changes in the Presence of H. pylori Infection
		60.3	 The Effect of H. pylori Eradication on the Gastric Microbiota
			60.3.1	 The Effect of H. pylori Eradication on the Gastric Microbiota Composition and Diversity
			60.3.2	 The Reversibility of Gastric Microbiota Composition and Diversity to that of H. pylori-Negative Individuals After H. pylori Eradication
			60.3.3	 The Effect of H. pylori Eradication on the Gastric Microbiota Function
		60.4	 The Effect of H. pylori Eradication on the Gut Microbiota
			60.4.1	 The Effect of H. pylori Eradication on the Gut Microbiota Depending on H. pylori Eradication Regimens
			60.4.2	 The Effect of Probiotics on the H. pylori Eradication-Induced Gut Microbiota Changes
			60.4.3	 The Effect of Probiotics on the H. pylori Eradication-Induced Gut Microbiota Function
			60.4.4	 Gastric Microbial Composition Changes in the Persistent H. pylori Infection
		60.5	 Conclusions
		References
Part X: Animal Model
	61: Animal Models of H. pylori Infection
		61.1	 Introduction
		61.2	 Selection of Animal Models
		61.3	 Selection of Strains
			61.3.1	 Characteristic and Morphologic Differences Between H. felis and H. pylori SS1
			61.3.2	 Pathological Difference Between H. felis and H. pylori SS1
		61.4	 Differences in Individual Responses
		61.5	 Transgenic or Knockout Mouse Models
			61.5.1	 INS-GAS Mice
			61.5.2	 IFN-γ and TNF-α Knockout Mice
			61.5.3	 IL-1β Transgenic Mice
			61.5.4	 IL-10 Knockout Mice
			61.5.5	 Fas Antigen Transgenic Mice
			61.5.6	 p27-Deficient Mice
			61.5.7	 cagA-Transgenic Mice
		61.6	 Limitations of Mouse Models of Infection
		61.7	 Conclusions
		References
Index