ABSTRACT
Background
Recently, a great variety of studies aimed to investigate and even suggestHelicobacter pylori as an important key factor in gastrointestinal and non-gastrointestinal events development. The well-established relationship between bacterial virulence and increased risk for peptic ulcer or gastric carcinoma is not so clear when comparing inflammation markers alterations, such C-reactive protein, with the pathogen.
Objective
The objective of this study was to evaluate the presence of H. pylori, bacterial virulence and C-reactive protein serum levels in individuals diagnosed with functional dyspepsia.
Methods
Were prospectively included in this study 489 dyspeptic individuals. They fulfill Rome III clinical criteria for the diagnosis of functional dyspepsia with no organic disease at endoscopy. The bacterial infection was established by histology and urease rapid test. The levels of serum C-reactive protein were obtained by immunonefelometry and CagA status ofH. pylori positive individuals was determined through an imunoenzimatic assay.
Results
Prevalence rate of H. pylori was 66.3% and virulence factor CagA was detected in nearly 43% of positive samples. In addition, it has been noticed an association between Ilex paraguariensis(yerba maté) consumption and pathogen's prevalence. An important effect of bacterial infection on inflammation was only observed in gastric epithelium.
Conclusion
No systemic response to the pathogen, measured through C-reactive protein levels, was observed, regardless of CagA status. Otherwise, the intake of yerba maté should be considered as a cultural factor possibly related toH. pylori's transmission.
HEADINGS
Helicobacter pylori; Dyspepsia; C-reactive protein; Virulence factors; Inflammation
RESUMO
Contexto
Recentemente, uma grande variedade de estudos tem investigado e até mesmo sugerido a presença de Helicobacter pylori como um importante fator no desenvolvimento de eventos restritos ou não ao trato gastrointestinal. A relação já bem estabelecida entre virulência bacteriana e risco aumentado para úlcera péptica ou adenocarcinoma gástrico não parece estar tão elucidada quando se comparam alterações de marcadores inflamatórios, como a proteína C-reativa, com a presença do patógeno.
Objetivo
O objetivo deste estudo foi avaliar a presença da infecção por H. pylori, a virulência bacteriana e os níveis séricos de proteína C-reativa em indivíduos diagnosticados com dispepsia funcional.
Métodos
Foram incluídos neste estudo, prospectivamente, 489 indivíduos dispépticos. Os pacientes deveriam preencher os critérios clínicos de Roma III para o diagnóstico de dispepsia funcional sem apresentar doença orgânica evidenciada a partir da endoscopia. A infecção bacteriana foi estabelecida por histologia e pelo teste rápido da urease. Os níveis de proteína C-reativa foram quantificados através de imunonefelometria e o status para a presença da CagA dos indivíduos infectados por H. pylorifoi determinado por ensaio imunoenzimático.
Resultados
A taxa de prevalência de H. pylori foi de 66.3% e o fator de virulência CagA foi detectado em aproximandamente 43% das amostras positivas. Adicionalmente, denotou-se uma associação entre o consumo deIlex paraguariensis (chimarrão) e a prevalência do patógeno. Um importante efeito da infecção bacteriana na inflamação apenas foi observado localmente, no epitélio gástrico.
Conclusão
Não foi evidenciada resposta sistêmica ao patógeno aferido através dos níveis de proteína C-reativa, independentemente do status para CagA. Por outro lado, o consumo de chimarrão pode ser sugerido como um fator cultural possivelmente relacionado à transmissão de H. pylori.
DESCRITORES
Helicobacter pylori; Dispepsia; Proteína C-reativa; Fatores de virulência; Inflamação
INTRODUCTION
Since Helicobacter pylori (H. pylori) was described by Robin Warren and Barry Marshal, in 1982, this bacterium opened a new period in the gastric microbiology diagnosis and therapeutics8Dunn BE, Cohen H, Blaser MJ. Helicobacter pylori. Clin Microbiol Rev 1997;10:720-41. 24Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-5.. H. pylori causes one of the most prevalent infections in human beings with a worldwide distribution that can reach relative frequencies that vary from 20% to 90% in different populations33Queiroz DM, Carneiro JG, Braga-Neto MB, Fialho AB, Fialho AM, Goncalves MH, et al. Natural History of Helicobacter pyloriinfection in childhood: eight-year follow-up cohort study in an urban community in northeast of Brazil.. Helicobacter 2012;17:23-9. 35Ricci V, Romano M, Boquet P. Molecular cross-talk between Helicobacterpylori and human gastric mucosa. World J Gastroenterol.; 201117:1383-99.. The microorganism exhibits a high tropism to the gastric epithelium, where can causes immune and inflammatory responses that may persist for all life if not eradicated5Chmiela M, Gajewski A, Rudnicka K. Helicobacter pylori vs coronary heart disease - searching for connections. World J Cardiol. 2015;7:187-203. 10Everhart JE. Recent developments in the epidemiology of Helicobacterpylori. Gastroenterol Clin North Am. 2000;29:559-78..
This pathogen, that initially was included in the Campylobactergenus, is a Gram-negative curved bacillus, presenting 2-6 flagella and an ability to produce urease abundantly16Goodwin CS, Armstrong JA. Microbiological aspects of Helicobacterpylori (Campylobacter pylori). Eur J Clin Microbiol Infect Dis. 1990;9:1-13.
24Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-5.. Other virulence factors such CagA protein have been studied extensively7den Hoed CM, Vila AJ, Holster IL, Perez-Perez GI, Blaser, MJ, de Jongste, JC, et al. Helicobacter pylori and the birth cohort effect: evidence for stabilized colonization rates in childhood. Helicobacter.; 2011 16:405-9.
23Lima VP, Silva-Fernandes IJ, Alves MK, Rabenhorst SH. Prevalence of Helicobacter pylori genotypes (vacA, cagA, cagE and virB11) in gastric cancer in Brazilian's patients: an association with histopathological parameters. Cancer Epidemiol.; 201135:e32-7.
40Wex T, Venerito M, Kreutzer J, Gotze T, Kandulski A, Malfertheiner P. Serological prevalence of Helicobacter pylori infection in Saxony-Anhalt, Germany, in 2010. Clin Vaccine Immunol.; 201118:2109-12.. According to the recent reports, CagA positive strains can cause severe damage to the gastric epithelium, being related specially with increased levels of interleukin-8 (IL-8), gastroduodenal ulcers and gastric neoplasia occurrence26Meine GC, Rota C, Dietz J, Sekine S, Prolla JC. Relationship between cagA-positive Helicobacter pylori infection and risk of gastric cancer: a case control study in Porto Alegre, RS, Brazil. Arq Gastroenterol.; 201148:41-5.
29Parsonnet J, Replogle M, Yang S, Hiatt R. Seroprevalence of CagA-positive strains among Helicobacter pylori-infected, healthy young adults. J Infect Dis.; 1997175:1240-2.
41Yamaoka Y. Mechanisms of disease: Helicobacterpylori virulence factors. Nat Rev Gatroenterol Hepatol. 2010;11:629-41.. In addition, this virulence factor has been associated with systemic inflammation, resulting in high serum C-reactive protein (CRP) levels and the bacteria presence being related to higher cardiovascular risks21Kowalski M. Helicobacter pylori (H. pylori) infection in coronary artery disease: influence ofH. pylori eradication on coronary artery lumen after percutaneous transluminal coronary angioplasty. The detection of H. pylori specific DNA in human coronary atherosclerotic plaque. J Physiol Pharmacol. 2001;52:3-31.
37Sun J, Rangan P, Bhat SS, Liu L. A meta-analysis of the association between Helicobacter pylori infection and risk of coronary heart disease from published prospective studies.. Helicobacter2015. doi: 10.1111/hel.12234. [Epub ahead of print].
https://doi.org/10.1111/hel.12234...
.
Some behaviors have been associated to the transmission of H. pylori. Studies have reported that several aspects can be related to incidence and prevalence rates like socioeconomic status, years of study, institutionalization practice or social habits8Dunn BE, Cohen H, Blaser MJ. Helicobacter pylori. Clin Microbiol Rev 1997;10:720-41. 20Kodaira MS, Escobar AM, Grisi S. Epidemiological aspects of Helicobacterpylori infection in childhood and adolescence. Rev Saúde Publica. 2002;36:356-69.. In 2010, a Brazilian study has demonstrated an anti-H. pylori activity of plant extracts, like yerba maté tea (Ilex paraguariensis), but no association between bacteria prevalence and tea consumption has been previously described6Cogo LL, Monteiro CLB, Miguel MD, Miguel OG, Cunico MM, Ribeiro ML, et al. Anti-Helicobacter pylori activity of plant extracts traditionally used for the treatment of gastrointestinal disorders. Braz. J. Microbiol. 2010;41:304-9..
All H. pylori's infected people present histological gastritis. Moreover, the bacteria, classified as type I carcinogen32Peterson WL. Review article: Helicobacter pyloriand gastric adenocarcinoma. Aliment Pharmacol Ther 2002;16:40-46., has been associated with the pathogenesis of gastric and duodenal peptic ulcers, with gastric carcinoma and with the gastric MALT lymphoma11Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacterpylori eradication therapy: experience from a large prospective series. Gut. 2004;53:34-7.. Some studies also suggest a bacterial role in cardiovascular disorders, referring to the inflammatory process that results in the atheroma formation and evolution1Ameriso SF, Fridman EA, Leiguarda RC, Sevlever GE. Detection ofHelicobacter pylori in human carotid atherosclerotic plaques. Stroke. 2001;32:385-91. 17Huang B, Chen Y, Xie Q, Lin G, Wu Y, Feng Y, et al. CagA-positive Helicobacter pylori strains enhanced coronary atherosclerosis by increasing serum OxLDL and HsCRP in patients with coronary heart disease. Dig Dis Sci.; 2011 56:109-14.. Additionally, one of the most challenging questions related to H. pylori is the bacterium association with the functional dyspepsia12Fock KM. Functional dyspepsia, H. pylori and post infectious FD. J Gastroenterol Hepatol.; 2011 26:39-41. 25Mazzoleni LE, Sander GB, Francesconi CF, Mazzoleni F, Uchoa DM, De Bona LR, et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. Arch Intern Med.; 2011171:1929-36. 27Miwa H, Watari J, Fukui H, Oshima T, Tomita T, Sakurai J, et al. Current understanding of pathogenesis of functional dyspepsia.. J Gastroenterol Hepatol; 2011 26:53-60..
As the influence of H. pylori CagA positive strains and potential changes in systemic inflammation remains a debatable matter. Thus, our study aimed to verify a possible relationship between bacterial virulence and systemic and/or local inflammation, through the measurement of CRP levels in serum and the comparison with the histological gastric mucosa analysis from functional dyspeptic patients.
METHODS
Patients
Between November 2006 and June 2008, 489 subjects who had undergone upper gastrointestinal endoscopic evaluation to participate in HEROES trial (Helicobacter Erradication Relief of Dyspeptic Symptoms), at Hospital de Clínicas de Porto Alegre, Porto Alegre, state of Rio Grande do Sul, Brazil, were prospectively and consecutively included in this study.
As inclusion criteria, the patient should meet the Rome III criteria which includes at least one of the following symptoms: a. bothersome postprandial fullness; b. early satiation; c. epigastric pain; or d. epigastric burning. Individuals presenting organic disorders diagnosed by upper gastrointestinal endoscopy, such as esophagitis, gastric or duodenal peptic ulcers, neoplasia or other conditions that could be the cause of the referred symptoms were excluded from the study. Conditions such previous treatment to H. pylori, clinical manifestations of organic diseases or presence of significant comorbidities and non-acceptance of the intervention by the patient were equally considered exclusion criteria.
Additionaly, after informed consent form assignment, subjects answered questions about medical history, dietary habits and quality of life.
Endoscopic procedures
It was performed with a videoendoscope (GIF-100, Olympus Co). After 8 hour fast, patients were sedated intravenously according to their age, weight and tolerance to fentanyl or meperidine plus midazolam. From each patient were collected three antral fragments, one specimen from the gastric body, and one from theincisura angularis region. Biopsy samples were submitted to a H. pylori investigation by two distinct methodologies: histology and rapid urease test.
Helicobacter pylori diagnosis
A biopsy specimen from each gastric region (antrum, body and incisura angularis) was placed in a 0.5 mL Christensen solution (Uretest(r), Renylab) to verify the presence of bacterial urease. A positive result was reported if there was a color change from yellow to pink within 12h of incubation at room temperature according to the manufacturer's instructions.
Concurrently, paired biopsy specimens were collected from antrum, fixed with 10% formol and stained for Hematoxylin and Eosin (H&E) and Giemsa. Two independent, experienced and blinded pathologists performed the histological examination, and discordances were solved by a third expert's opinion. The inflammatory status was determined according to Sydney's Endoscopic Classification, as previously described14Genta RM, Dixon MF. The Sydney System revisited: the Houston International Gastritis Workshop. Am J Gastroenterol. 1995;90:1039-41.. H. pylori's infection was considered present according to the positivity in both methodologies (rapid urease test and histological evaluation).
Determination of CRP levels
Approximately 10 mL of whole blood were collected from each patient and after 3000 rpm centrifugation during 15 minutes, serum samples were stored at −80°C and analyzed for high sensivity C-reactive protein (hsCRP) and anti-CagAH. pylori antibodies, as described below.
CRP levels were measured by a immunonephelometric assay (CardioPhase(r) hsCRP Dade Behring) on a Behring Nephelometer II analyzer. The detection limit for CRP was 0.17 mg/L, and the measuring range was 0.175-1100 mg/L.
Determination of cagA status
Serological search for anti-CagA was performed with a commercial available kit (CagA IgG EIA WELL(r), Radim) according to manufacturer's instructions. After incubation, plates were read in a spectrophotometer at 450 nm and samples with IgG values higher than 15 RU/mL were considered reactive for anti-CagA IgG antibodies. Each sample was measured twice to ensure the precision of the method.
Ethical considerations
All study procedures were conducted in agreement with Declaration of Helsinki, with the Brazilian Federal Resolution 196/96 and were approved by our local institutional review board, inscribed as project number 07-547. All patients were informed about the study's objectives and subsequently provided written informed consent before any intervention.
Statistical analysis
Data are presented as mean (SD) or median (25th - 75th percentile), when otherwise stated. Quantitative variables were first analyzed concerning Gaussian distribution and assessed with t-test and one-way ANOVA (parametric) or Mann-Whitney and Kruskal-Wallis test (non-parametric). Categorical variables were described by absolute and relative frequencies and analyzed using chi-square test with adjusted residuals test. The analysis was performed using SPSS v. 18. A P value was considered significant if <0.05.
RESULTS
The characteristics of the subjects are shown in the Table 1. Regarding to the gastric H. pylori status, 66.3% of the functional dyspeptic patients were H. pylori-positive. Among these patients, 42.8% presented antibodies against CagA virulence protein.
Relevant findings include i. a higher prevalence of H. pylori in the population with less than nine years of education and ii. no association between bacterial frequency and gender, race, smoking habit or alcohol consumption was observed.
It was also asked to the patients about the habit of drinking yerba maté tea, and 45.3% of positive H. pylori individuals reported regular consumption of such beverage (P=0.006).
Table 2 shows local and systemic inflammatory status according to the presence of H. pylori and CagA virulence factor. In general, it was observed a high association between the presence of anti-CagA and a high inflammation and inflammatory activity in the gastric epithelium (P<0.001), without significantly affect the CRP values. Regarding the systemic inflammation marker (hsCRP) and local inflammatory activity or inflammation grade in dyspeptic patients, no association was observed between the systemic inflammation marker and an inflammatory activity (P=0.339) nor between systemic inflammation marker and inflammation grade (P=0.508).
Discussion
Recently, H. pylori and has been suggested as an important factor in extra-gastric manifestations such as increased serum CRP levels and high systemic inflammation leading to a higher potential risk factor to the development of cardiovascular diseases17Huang B, Chen Y, Xie Q, Lin G, Wu Y, Feng Y, et al. CagA-positive Helicobacter pylori strains enhanced coronary atherosclerosis by increasing serum OxLDL and HsCRP in patients with coronary heart disease. Dig Dis Sci.; 2011 56:109-14. 28Nazmi A, Diez-Roux AV, Jenny NS, Tsai MY, Szklo M, Aiello AE. The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of. Atherosclerosis BMC Public Health. 2010;10:706.. This study was developed in order to verify a possible relation between bacterial virulence and systemic and/or local inflammation through the measurement of CRP levels in serum and the histological evaluation of gastric mucosa of functional dyspeptic patients.
Regarding the bacterial influence on the immune system, a study conducted by Lee et al. (2010Lee JS, Paek NS, Kwon OS, Hahm KB. Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism.. J Gastroenterol Hepatol 2010;25:194-202.) indicates that H. pylori infection or their lipopolysaccharide stimulation led to significant increased expressions of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), IL-8, inducible nitric oxide synthase and cyclooxygenase- 222Lee JS, Paek NS, Kwon OS, Hahm KB. Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism.. J Gastroenterol Hepatol 2010;25:194-202.. The mechanism of this response affects the innate immunity through the recognition of some conserved m crobial constituents by receptors expressed on host-epith lial cells as well as neutrophils. In the gut, such recognition results in the activation of conserved signaling cascades mediated by nuclear factor kB (NF-kB), mitogen-act vated protein kinases and caspase-dependent signaling pathways30Peek , RM Jr Fiske C, Wilson KT . Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90:831-58..
The main findings of our study were: 1. no association between CRP serum levels inH. pylori infected patients with functional dyspepsia, independently of CagA status; 2. a remarkable inflammation and inflammatory activity in gastric epithelium of patients carrying the most virulent strain; and 3. a high prevalence of H. pylori in patients with less than nine years of education; and, 4. in those who mentioned yerba maté tea consumption.
Regarding the first finding, our results do not agree with some reports that have shown a considerable association of H. pylori and increased serum CRP levels, especially in positive-CagA strains18Jafarzadeh A, Hassanshahi GH, Nemati M. Serum levels of high-sensitivity C-reactive protein (hs-CRP) in Helicobacterpylori-infected peptic ulcer patients and its association with bacterial CagA virulence factor. Dig Dis Sci. 2009;54:2612-6.. Considering the possible association between higher systemic inflammation levels and H. pylori infection, some data show that after the pathogen eradication, serum CRP levels can decrease significantly2Ando T, Minami M, Ishiguro K, Maeda O, Watanabe O, Mizuno T, et al. Changes in biochemical parameters related to atherosclerosis afterHelicobacter pylori eradication. Aliment Pharmacol Ther. 2006;2:58-64. 19Kanbay M, Gur G, Yucel M, Yilmaz U, Boyacioglu S. Does eradication of Helicobacter pylori infection help normalize serum lipid and CRP levels?. Dig Dis Sci 2005;50:1228-31.. Otherwise, there is no consensus about this matter. For example, a strong study conducted by Brenner and cols (1999Brenner H, Berg G, Frohlich M, Boeing H, Koenig W. Chronic infection with Helicobacter pylori does not provoke major systemic inflammation in healthy adults: results from a large population-based study. Atherosclerosis. 1999;147:399-403.) involving more than 1.800 healthy subjects did not prove the relation between H. pylori, bacterial virulence and inflammation markers. Although it was observed an inverse relation betweenH. pylori infection and serum albumin, the bacteria presence was unrelated to C-reactive protein and the leukocyte count, regardless of CagA status4Brenner H, Berg G, Frohlich M, Boeing H, Koenig W. Chronic infection with Helicobacter pylori does not provoke major systemic inflammation in healthy adults: results from a large population-based study. Atherosclerosis. 1999;147:399-403.. Such result was also reported in several studies that showed no impact of H. pylori's infection in systemic markers of inflammation13Galante A, Pietroiusti A, Vellini M, Piccolo P, Possati G, de Bonis M, et al. C-Reactive protein is increased in patients with degenerative aortic valvular stenosis. J. Am. Coll. Cardiol. 2001;38:1078-82. 15Gillum RF. Infection with Helicobacterpylori, coronary heart disease, cardiovascular risk factors, and systemic inflammation: the Third National Health and Nutrition Examination Survey. J Natl Med Assoc. 2004;96:1470-6. 36Stettin D, Waldmann A, Strohle A, Hahn A. Association between Helicobacter pylori-infection, C-reactive protein and status of B vitamins. Adv Med Sci. 2008;53:205-13. 38Tamer GS, Tengiz I, Ercan E, Duman C, Alioglu E, Turk UO. Helicobacter pylori seropositivity in patients with acute coronary syndromes.. Dig Dis Sci 2009;54:1253-6..
CagA is the most extensively investigated virulence factor of H. pylori being encoded by cytotoxin-associated genes pathogenicity island (cagPAI)3Backert S, Clyne M, Tegtmeyer N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal. 2011;9:28.. A strain expressing cagA protein, which is present in more virulent isolates, is typically associated with the production of proinflammatory cytokines, especially IL-8, and such factor has been reported as an important factor related to the peptic ulcer and gastric adenocarcinoma occurrence41Yamaoka Y. Mechanisms of disease: Helicobacterpylori virulence factors. Nat Rev Gatroenterol Hepatol. 2010;11:629-41.. It was observed a remarkable inflammatory activity and inflammation in the gastric epithelium of those people with the most virulent strain, whereas, neither inflammatory activity nor inflammation were observed in more than 90% and 54% of H. pylori's negative subjects, respectively.
We also found an important association between prevalence of the pathogen and years of education and yerba maté tea consumption. As previously appointed by other Brazilian researches, 66% of our study population presented H. pylori's infection, among these patients, nearly 58% reported less than 9 years of study. This finding has been also observed in other studies and possibly indicates socioeconomic status and years of study as important conditions associated to the risk factors for H. pylori's transmission9Escobar-Pardo ML, de Godoy AP, Machado RS, Rodrigues D, Fagundes Neto U, Kawakami E. Prevalence of Helicobacter pylori infection and intestinal parasitosis in children of the Xingu Indian Reservation. J Pediatr.; 201187:393-8. 33Queiroz DM, Carneiro JG, Braga-Neto MB, Fialho AB, Fialho AM, Goncalves MH, et al. Natural History of Helicobacter pyloriinfection in childhood: eight-year follow-up cohort study in an urban community in northeast of Brazil.. Helicobacter 2012;17:23-9..
According to data previously reported (Kodaira et al.), our findings support thatH. pylori frequency is not related with smoking habit or alcohol consumption20Kodaira MS, Escobar AM, Grisi S. Epidemiological aspects of Helicobacterpylori infection in childhood and adolescence. Rev Saúde Publica. 2002;36:356-69.. On the other hand, we report here, for the first time, the association of H. pylori's infection with the cultural habit of drinking maté. Maté is an infusion of the herbIlex paraguariensis that is prepared in a gourd and is drunk very hot through a metal straw. The infusion is shared by different people using the same gourd and straw. Although it has been reported that the herb presents anti-H. pylory activity6Cogo LL, Monteiro CLB, Miguel MD, Miguel OG, Cunico MM, Ribeiro ML, et al. Anti-Helicobacter pylori activity of plant extracts traditionally used for the treatment of gastrointestinal disorders. Braz. J. Microbiol. 2010;41:304-9., this cultural habit may provide a possible route for the bacterial transmission.
Considering our study procedures, we recognize that CRP is an unspecific marker of acute inflammation and that it can be related to a several diseases and conditions. Firstly described by Tillett e Francis (1930Tillett WS, Francis T. Serological Reactions in Pneumonia with a Non-Protein Somatic Fraction of Pneumococcus. J Exp Med. 1930;52:561-71.), this inflammatory protein has an important role to predict the cardiovascular risk, among other applications31Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805-12. 39Tillett WS, Francis T. Serological Reactions in Pneumonia with a Non-Protein Somatic Fraction of Pneumococcus. J Exp Med. 1930;52:561-71.. Although we have evaluated systemic inflammation through this analyte, we agree that other parameters should be useful and more specific to determine a possible link between H. pylori's infection and systemic inflammation. In example, some studies have considered to study as inflammation markers interleukin-6 (IL-6), IL-8 and TNF-α, which seems to be specially related to bacterial infection3Backert S, Clyne M, Tegtmeyer N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal. 2011;9:28. 34Rasmi Y, Raeisi S, Seyyed Mohammadzad MH. Association of inflammation and cytotoxin-associated gene a positive strains of Helicobacterpylori in cardiac syndrome x.. Helicobacter 2012;17:116-20..
As mentioned above, regarding the remarkable association between the presence of anti-CagA antibodies and higher tissue damage, although with no systemic responses through the measurement of hsCRP levels, we encourage the development of further studies involving additional inflammatory markers that could be related to higher systemic inflammation in functional dyspeptic people carrying H. pylori and its virulence factor.
REFERENCES
- Ameriso SF, Fridman EA, Leiguarda RC, Sevlever GE. Detection ofHelicobacter pylori in human carotid atherosclerotic plaques. Stroke. 2001;32:385-91.
- Ando T, Minami M, Ishiguro K, Maeda O, Watanabe O, Mizuno T, et al. Changes in biochemical parameters related to atherosclerosis afterHelicobacter pylori eradication. Aliment Pharmacol Ther. 2006;2:58-64.
- Backert S, Clyne M, Tegtmeyer N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori Cell Commun Signal. 2011;9:28.
- Brenner H, Berg G, Frohlich M, Boeing H, Koenig W. Chronic infection with Helicobacter pylori does not provoke major systemic inflammation in healthy adults: results from a large population-based study. Atherosclerosis. 1999;147:399-403.
- Chmiela M, Gajewski A, Rudnicka K. Helicobacter pylori vs coronary heart disease - searching for connections. World J Cardiol. 2015;7:187-203.
- Cogo LL, Monteiro CLB, Miguel MD, Miguel OG, Cunico MM, Ribeiro ML, et al. Anti-Helicobacter pylori activity of plant extracts traditionally used for the treatment of gastrointestinal disorders. Braz. J. Microbiol. 2010;41:304-9.
- den Hoed CM, Vila AJ, Holster IL, Perez-Perez GI, Blaser, MJ, de Jongste, JC, et al. Helicobacter pylori and the birth cohort effect: evidence for stabilized colonization rates in childhood. Helicobacter.; 2011 16:405-9.
- Dunn BE, Cohen H, Blaser MJ. Helicobacter pylori Clin Microbiol Rev 1997;10:720-41.
- Escobar-Pardo ML, de Godoy AP, Machado RS, Rodrigues D, Fagundes Neto U, Kawakami E. Prevalence of Helicobacter pylori infection and intestinal parasitosis in children of the Xingu Indian Reservation. J Pediatr.; 201187:393-8.
- Everhart JE. Recent developments in the epidemiology of Helicobacterpylori Gastroenterol Clin North Am. 2000;29:559-78.
- Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacterpylori eradication therapy: experience from a large prospective series. Gut. 2004;53:34-7.
- Fock KM. Functional dyspepsia, H. pylori and post infectious FD. J Gastroenterol Hepatol.; 2011 26:39-41.
- Galante A, Pietroiusti A, Vellini M, Piccolo P, Possati G, de Bonis M, et al. C-Reactive protein is increased in patients with degenerative aortic valvular stenosis. J. Am. Coll. Cardiol. 2001;38:1078-82.
- Genta RM, Dixon MF. The Sydney System revisited: the Houston International Gastritis Workshop. Am J Gastroenterol. 1995;90:1039-41.
- Gillum RF. Infection with Helicobacterpylori, coronary heart disease, cardiovascular risk factors, and systemic inflammation: the Third National Health and Nutrition Examination Survey. J Natl Med Assoc. 2004;96:1470-6.
- Goodwin CS, Armstrong JA. Microbiological aspects of Helicobacterpylori (Campylobacter pylori). Eur J Clin Microbiol Infect Dis. 1990;9:1-13.
- Huang B, Chen Y, Xie Q, Lin G, Wu Y, Feng Y, et al. CagA-positive Helicobacter pylori strains enhanced coronary atherosclerosis by increasing serum OxLDL and HsCRP in patients with coronary heart disease. Dig Dis Sci.; 2011 56:109-14.
- Jafarzadeh A, Hassanshahi GH, Nemati M. Serum levels of high-sensitivity C-reactive protein (hs-CRP) in Helicobacterpylori-infected peptic ulcer patients and its association with bacterial CagA virulence factor. Dig Dis Sci. 2009;54:2612-6.
- Kanbay M, Gur G, Yucel M, Yilmaz U, Boyacioglu S. Does eradication of Helicobacter pylori infection help normalize serum lipid and CRP levels?. Dig Dis Sci 2005;50:1228-31.
- Kodaira MS, Escobar AM, Grisi S. Epidemiological aspects of Helicobacterpylori infection in childhood and adolescence. Rev Saúde Publica. 2002;36:356-69.
- Kowalski M. Helicobacter pylori (H. pylori) infection in coronary artery disease: influence ofH. pylori eradication on coronary artery lumen after percutaneous transluminal coronary angioplasty. The detection of H. pylori specific DNA in human coronary atherosclerotic plaque. J Physiol Pharmacol. 2001;52:3-31.
- Lee JS, Paek NS, Kwon OS, Hahm KB. Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism.. J Gastroenterol Hepatol 2010;25:194-202.
- Lima VP, Silva-Fernandes IJ, Alves MK, Rabenhorst SH. Prevalence of Helicobacter pylori genotypes (vacA, cagA, cagE and virB11) in gastric cancer in Brazilian's patients: an association with histopathological parameters. Cancer Epidemiol.; 201135:e32-7.
- Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-5.
- Mazzoleni LE, Sander GB, Francesconi CF, Mazzoleni F, Uchoa DM, De Bona LR, et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. Arch Intern Med.; 2011171:1929-36.
- Meine GC, Rota C, Dietz J, Sekine S, Prolla JC. Relationship between cagA-positive Helicobacter pylori infection and risk of gastric cancer: a case control study in Porto Alegre, RS, Brazil. Arq Gastroenterol.; 201148:41-5.
- Miwa H, Watari J, Fukui H, Oshima T, Tomita T, Sakurai J, et al. Current understanding of pathogenesis of functional dyspepsia.. J Gastroenterol Hepatol; 2011 26:53-60.
- Nazmi A, Diez-Roux AV, Jenny NS, Tsai MY, Szklo M, Aiello AE. The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of. Atherosclerosis BMC Public Health. 2010;10:706.
- Parsonnet J, Replogle M, Yang S, Hiatt R. Seroprevalence of CagA-positive strains among Helicobacter pylori-infected, healthy young adults. J Infect Dis.; 1997175:1240-2.
- Peek , RM Jr Fiske C, Wilson KT . Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90:831-58.
- Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805-12.
- Peterson WL. Review article: Helicobacter pyloriand gastric adenocarcinoma. Aliment Pharmacol Ther 2002;16:40-46.
- Queiroz DM, Carneiro JG, Braga-Neto MB, Fialho AB, Fialho AM, Goncalves MH, et al. Natural History of Helicobacter pyloriinfection in childhood: eight-year follow-up cohort study in an urban community in northeast of Brazil.. Helicobacter 2012;17:23-9.
- Rasmi Y, Raeisi S, Seyyed Mohammadzad MH. Association of inflammation and cytotoxin-associated gene a positive strains of Helicobacterpylori in cardiac syndrome x.. Helicobacter 2012;17:116-20.
- Ricci V, Romano M, Boquet P. Molecular cross-talk between Helicobacterpylori and human gastric mucosa. World J Gastroenterol.; 201117:1383-99.
- Stettin D, Waldmann A, Strohle A, Hahn A. Association between Helicobacter pylori-infection, C-reactive protein and status of B vitamins. Adv Med Sci. 2008;53:205-13.
- Sun J, Rangan P, Bhat SS, Liu L. A meta-analysis of the association between Helicobacter pylori infection and risk of coronary heart disease from published prospective studies.. Helicobacter2015. doi: 10.1111/hel.12234. [Epub ahead of print].
» https://doi.org/10.1111/hel.12234 - Tamer GS, Tengiz I, Ercan E, Duman C, Alioglu E, Turk UO. Helicobacter pylori seropositivity in patients with acute coronary syndromes.. Dig Dis Sci 2009;54:1253-6.
- Tillett WS, Francis T. Serological Reactions in Pneumonia with a Non-Protein Somatic Fraction of Pneumococcus. J Exp Med. 1930;52:561-71.
- Wex T, Venerito M, Kreutzer J, Gotze T, Kandulski A, Malfertheiner P. Serological prevalence of Helicobacter pylori infection in Saxony-Anhalt, Germany, in 2010. Clin Vaccine Immunol.; 201118:2109-12.
- Yamaoka Y. Mechanisms of disease: Helicobacterpylori virulence factors. Nat Rev Gatroenterol Hepatol. 2010;11:629-41.
-
3
Disclosure of funding: no funding received
Publication Dates
-
Publication in this collection
Jan-Mar 2016
History
-
Received
17 June 2015 -
Accepted
12 Sept 2015