The aim of this investigation was to determine whether Helicobacter pylori infection (HBPI) is an independent risk factor for acute noncardioembolic stroke, and also if there is a link between HBPI and other established and well-known risk factors for stroke, as well, to find if there is link between HBPI and severity of disease. In this prospective single centre study where enrolled 82 patients with acute stroke and control group was consistented 93 healthy individuals. The results of this study showed no difference between H.pylori seropositivity distribution in the investigate and control group (25.8 vs. 34.8%), additionally, there was no significant difference on the severity of the disease. Furthermore there was no evident association between acute stroke and HBPI in the patientes with three and more risk factors, but we found significant link between HBPI and carotid stenosis. Further studies are needed to clarify the possible causal relation between infection by this organism and stroke. It is necessary not only the elucidate of pathophysiology related to the association, but also to evaluate whether antibiotic treatment may result in clinical benefit of the patient

Balen, Sanja

Duka Glavor, Klaudia

Ivanac, Krešimir

Mrđen, Anamarija

Nakić, Dario

Včev, Aleksandar

Repository of the University of Rijeka, Faculty of Medicine

1Received for publication November 7, 2013Helicobacter Pylori Infection and Acute StrokeAnamarija Mrđen1, Aleksandar Včev2, Dario Nakić3, Sanja Balen4, Krešimir Ivanac1, Klaudia Duka Glavor11Department of Neurology, General Hospital Zadar, Zadar, Croatia2Department of Internal Medicine, School of Medicine, University „J.J.Strossmayer“ Osijek, Osijek, Croatia3Department of Internal Medicine, General Hospital Zadar, Zadar, Croatia4Department of Transfusiology, School of Medicine, University of Rijeka, Rijeka, CroatiaColl. Antropol. 41 (2017) 4: ???–???Original scientific paperstroke are controversial due to degree of studies pro2,8-10 and many contra11,12 that association. In this study we investigated a possible association between HPBI and acute stroke and the purpose was to determine whether HBPI is an indipendent risk factor for stroke, if there is a link between HBPI and severity of disease, find out is there relations between HBPI and established risk factors for stroke.Material and MethodsIn this prospective study were enrolled 82 patients con-secutively admitted with acute stroke, but without known peptic ulcer disease or reciving therapy for H. pylori erad-ication in the last year. All subjects had given informed consent to inclusion in the study and research was carried out according with principles of Declaration of Helsinki. Control group consists of healthy subjects and they were excluded if they had history of peptic ulcer disease, re-ceived therapy for eradication H. pylori or received acid-suppresive drugs in last 12 months.A B S T R A C TThe aim of this investigation was to determine whether Helicobacter pylori infection (HBPI) is an independent risk factor for acute noncardioembolic stroke, and also if there is a link between HBPI and other established and well-known risk factors for stroke, as well, to find if there is link between HBPI and severity of disease. In this prospective single cen-tre study where enrolled 82 patients with acute stroke and control group was consistented 93 healthy individuals. The results of this study showed no difference between H.pylori seropositivity distribution in the investigate and control group (25.8 vs. 34.8%), additionally, there was no significant difference on the severity of the disease. Furthermore there was no evident association between acute stroke and HBPI in the patientes with three and more risk factors, but we found sig-nificant link between HBPI and carotid stenosis. Further studies are needed to clarify the possible causal relation between infection by this organism and stroke. It is necessary not only the elucidate of pathophysiology related to the association, but also to evaluate whether antibiotic treatment may result in clinical benefit of the patient.Key words: Helicobacter pylori infection, acute strokeIntroductionStroke is amnog the most frequent causes of death and persisting disability in the world1. Classical risk factors cannot fully explain the clinical and epidemiological fea-tures of the disease2. There are several studies which showes that HBPI cause low grade infection which can lead to production vasoactive supstancies and can contrib-ute to development of atherosclerosis and stroke3. Some mechanisms may play role in atherogenesis of HPBI: free radical formation and immune mediated mechanisms, direct influence on coagulation system. HPBI may cause prothrombotic status, could induce changes in coagulation with elevated serum levels of fibrinogen, prothrombin fragments, plasminogen-activating inhibitor-1 (PAI 1) and factor VII. Another possible mechanism linking HBPI and atherogenesis is lipid peroxidation due to an antioxidans loss or could be mediated by increasing cytokine levels4-6. There is potential that chronic bacterial infection may ag-gravate pre-existing plaque by enhancing T-cell activation as well as other inflammatory responses that may par-ticipate in the destabilization of the intimal cap resulting in plaque rupture, progression to acute ischemic syn-dromes, and ultimate enlargment of the atherosclerotic plaque7. Results on the association betweeen HBPI and 2A. Mrđen et al.: Helicobacter Pylori Infection and Acute Stroke, Coll. Antropol. 41 (2017) 4: ???–???All patients underwent cranial MSCT scaning, Duplex ultrasonography of the extracranial carotid arteries and transthoracic echocardiography to exclude patientis with cardioembolic stroke. Analyzed risk factors for stroke in-cluded hypertension, diabetes, hyperlipidemia, obesity, gender and cigarette smoking. Carotid stenosis is the pos-sible cause of 1/3 patients with ischemic stroke. Abnormal findings of Duplex ultrasonography of the extracranial carotid arteries were further subdivided into groups ac-cording to the percent of stenosis. First degree of carotid stenosis (<50%), with middle stenosis (50-75%) and severe stenosis (>75%). Hypertension was considered in the pa-tients with arterial pressure >140/90 mmHg, or were be-ing treated with antihypertensive drugs or dietary modi-fications. Diabetic patients were considered to have diabetes if they have had fasting glucose >6.4 mmol/L, HbA1c>6.0% or were taking insulin, hypoglicemic agents or dietary modification to control the disease. Hyperlipid-emia was considered in patients with serum cholesterol levels >5.2 mmol/L or receiving lipid lowering agents. Obe-sity status was defined followed by body mass index (BMI): subjects with BMI <24 were considered normal, BMI 25–29 were considered overweight and BMI >30 were con-sidered obese. Smoking as risk factor was not considered in patients who had stopped smoking >20 years ago or who were <30 years of age when they stopped smoking. All subjects (patients with AMI and control group) underwent an enzyme-linked Immulite (chemiluminescent) analyzer IgG serologic test for H. pylori diagnosis (Diagnostic Prod-ucts Corp., Los Angeles, CA, USA). The test had a sensi-tivity of 97% and a specificity of 98%.The severity of dis-ease was present according to the National Institute of Health Stroke Scale (NIHSS). Statistical analysis was carried out by using SPSS software (Statistical Package for the Social Sciences, version 11,0, SPSS Inc., Chicago, IL, USA). For comparing differences between sets of re-sults we used t–tests and for associations between vari-ables correlation methods. Regression analysis was used for prediction of H. pylori seropositivity, χ² test was used to find out differences between frequency of risk factors. Results were shown by average values with standard de-viations. A value of p < 0.05 was considered statistically significant.ResultsInvestigate group was consisted of 83 patients with acute stroke consecutively admitted in stroke care unit. There was 32 men and 34 women, average age of 72.8 years. 20 (30.3%) had haemorrhagic stroke and 46 (69.7%) ischemic stroke. 16 patients were excluded because of car-dioembolic stroke. The control group consists of 93 healthy individuals. (Table 1)There was 80.3% hypertonic patients in the investigate group, there was 39.4% diabetic patients. Dyslipidemia was present in the 56% patients. In the investigate group 33.3% patients were overweight, there were 21.2% smok-ing patients. On the carotid ultrasonography there were 20.2% with normal findings, 31.8% with first degree of TABLE 1DEMOGRAPHIC CHARACTERISTICS OF PATIENTS (N=66)Characteristics No (%)SexMale 32 (48.5)Female 34 (51.5)AgeMean±SD — yr 72.8±9.6ICVHaemorrhagic 20 (30.3)Ischemic 46 (69.7)NIHSS*Minor 8 (12.1)Moderate 50 (75.8)Severe 8 (12.1)Carotide stenosisNo stenosis 14 (21.2)First degree stenosis <50% 21 (31.8)Mild stenosis 50-75% 24 (36.4)Severe stenosis >75% 7 (10.6)HypertensionNo 13 (19.7)Yes 53 (80.3)SmokingNo 52 (78.8)Yes 14 (21.2)CholesterolNormal 29 (43.9)High 37 (56.1)DiabetesNo 40 (60.6)Yes 26 (39.4)ObesityNo 44 (66.7)Yes 22 (33.3)LeukocytesNormal 43 (65.2)High 23 (34.8)CRPNormal 28 (42.4)High 38 (57.6)FibrinogenNormal 45 (68.2)High 21 (31.8)HBP testNegative 43 (65.2)Positive 23 (34.8)*National Institutes of Health Stroke Scalecarotid stenosis (<50%), 36.4% with middle stenosis (50-75%) and severe stenosis (>75%) 10.6% patientes. There was no significant differences between HBP seropositiv-ity distribution in the investigate and control group (34.8% vs 25.8% Table 2), also there was no significant differ-ences between men and women. (Table 2)3A. Mrđen et al.: Helicobacter Pylori Infection and Acute Stroke, Coll. Antropol. 41 (2017) 4: ???–???χ2=0.759, df=1, p=0.3836 There was no significant dif-ferences on the association of H. pylori infection with cigarette smoking.Measurement of CRP, fibrinogn and leukocyte was performed in all stroke patients. There was no significant diference between group with HBP seropositivity versus group with no seropositivity.There was no significant as-sociation between HBP seropositivity and acute stroke in the patients with 3 and more risk factors, but we found significant link between HBPI and carotid stenosis (Ta-ble 8). In summary our study shows no association be-tween HBPI and stroke.There were no significant diferrences between men and women in distribution of hypertension, obesity, dia-betes, hyperlipidaemia, cigarette smoking. There was no significant differences on the severity of the disease ac-cording to the H. pylori seropositivity. Procalcitonin as a marker for infection was in normal levels in both patients and control group, independent of H. pylori seropositivity. There was no significant differences on the association of H. pylori infection with well known risk factors (hyperten-sion, obesity, diabetes, hyperlipidaemia, cigarette smoking including gender) and we did not established HBPI as an independent risk factor for stroke (Tables 3-7). TABLE 2DISTRIBUTION OF HBP IN THE INVESTIGATE AND CONTROL GROUPControl Investigate  Negative 69 43 112 (70.4%)Positive 24 23 47 (29.6%) 93 (58.5%)66 (41.5%) 159χ2=1.113, df=1, p=0.2914 There was no significant differences between HBP seropositivity distribution in the investigate and control group.TABLE 3DISTRIBUTION OF HYPERTENSIVE PATIENTS ACCORDING INCIDENCE OF HBPHBP negative HBP positive  No 7 6 13 (19.7%)Yes 36 17 53 (80.3%) 43 (65.2%)23 (34.8%) 66 (100%)χ2=0.397, df=1, p=0.5286 There was no significant differences on the association of H. pylori infection with hypertension.TABLE 8DISTRIBUTION OF PATIENTS WITH CAROTIDE STENOSIS ACCORDING INCIDENCE OF HBPHBP positive HBP negative  No stenosis 2 12 14 (21.2%)First degree stenosis <50% 9 12 21 (31.8%)Mild stenosis 50-75% 12 12 24 (36.4%)Severe stenosis >75% 0 7 7 (10.6%) 23 (34.9%)34 (65.1%) 66 (100%)χ2=9.371, df=3, p=0.0247 There were significant differences be-tween HBP positive and HBP negative according the carotide steno-sis. TABLE 4DISTRIBUTION OF OBESITIVE PATIENTS ACCORDING INCIDENCE OF HBPHBP negative HBP positive  No 27 17 44 (66.7%)Yes 16 6 22 (33.3%) 43 (65.2%)23 (34.8%) 66 (100%)χ2=0.409, df=1, p=0.5225 There was no significant differences on the association of H. pylori infection with obesity.TABLE 5DISTRIBUTION OF DIABETIC PATIENTS ACCORDING INCIDENCE OF HBPHBP negative HBP positive  No 26 14 40 (60.6%)Yes 17 9 26 (39.4%) 43 (65.2%)23 (34.8%) 66 (100%)χ2=0,054, df=1, p=0,8612 There was no significant differences on the association of H. pylori infection with diabetes.TABLE 6DISTRIBUTION OF PATIENTS WITH HYPERLIPIDEMIC PATIENTS ACCORDING INCIDENCE OF HBPHBP negative HBP positive  Normal 19 10 29 (43.9%)High 24 13 37 (56.1%) 43 (65.2%)23 (34.8%) 66 (100%)χ2=0.042, df=1, p=0.8376 There was no significant differences on the association of H. pylori infection with cholesterol.TABLE 7DISTRIBUTION OF CIGARETTE-SMOKING PATIENTS ACCORDING INCIDENCE OF HBPHBP negative HBP positive  Non-smoker 32 20 52 (78.8%)Smoker 11 3 14 (21.2%) 43 (65.2%)23 (34.8%) 66 (100%)4A. Mrđen et al.: Helicobacter Pylori Infection and Acute Stroke, Coll. Antropol. 41 (2017) 4: ???–???R E F E R E N C E S1. KADOJIĆ D, Acta Clin Croat, 41 (2002). — 2. GRAU AJ, BUGGLE F, LICHY C, BRANDT T, BECHER H, RUDI J, J Neurol Sci, 186 (2001) 1. PII: S0022-510X(01)00507-X. — 3. TRKANJEC Z, Acta Clin Croat, 41 (2002). — 4. STONE AF, MENDALL MA, KASKI JC, EDGER TM, RISLEY P, POLINIECKI J et al, Circulation, 106 (2002) 1219. DOI: 10.1161/ 01.CIR.0000027820.66786.CF. — 5. MARKUS HS, MENDALL MA, J Neurol Neurosurg Psychiatry, 64 (1998) 104. DOI:10.1136/jnnp.64.1.104. — 6. HAMED SA, AMINE NF, GALAL GM, HELAL SR, TAG EL-DIN LM, SHAWKY OA, AHMED EA, ABDEL RAH-MAN MS, J Stroke Cerebrovasc Dis, 17 (2008) 86. DOI: 10.1016/j.jstrokecerebro-vasdis.2007.10.006. — 7. AMERISO SF, FRIDMAN EA, LEIGUARDA RC, SEVLEVER GE, Stroke, 32 (2001) 385. DOI: 10.1161/ 01.STR.32.2.385. — 8. BIAGI P, FABBRINI D, BOCCHINI S, Panminerva Med, 42 (2000) 183. — 9. SAWAYAMA Y, ARIYAMA I, HAMADA M, OTAGURO S, MACHI T, TAIRA Y, HAYASHI J, Atherosclerosis, 178 (2005) 303. DOI:10.1016/j.atherosclero-DiscussionCardiovascular diseases are important cause of mortal-ity. Classical risk factors cannot fully explain epidemio-logical variations of these disease. Helicobacter pylori are gram-negative bacteria which produce a chronic infection in humans associated with peptic ulcer disease, gastritis. H. pylori infection may increase risk for acute stroke through the changes in the lipid status with lower HDL cholesterol values and elevated serum trigliceride values, changes in the coagulation paremeters with elevated fi-brinogen, prothrombin fragments, plasminogen-activating inhibitor 1 (PAI-1) and factor VII , increased concentrations of markers of inflammation as a tumor necrosis factor – α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8) and oth-ers. J. Majka reported HPBI as an risk factor for stroke via an interaction of HP cytoxins or cytokines with atheroscle-rotic plaques in carotic arteries. It has been noticed possible direct effect on the stability of the atherosclerotic plaque. Most studies suggested that HBPI might be associated with stroke due to an increased prevalence of this organism in patientes with stroke. The pathophysiological mechanism underlying this association seems likely to be chronic in-flamatory response to bacterial infection13. Since 1994 sev-eral studies have been performed on the correlation be-tween HBPI and atherosclerosis. Despite all these studies there are still many controversies about the role of HBPI in stroke. Although most respective studies analyzed IgG an-tibodies against H. pylori in patientes with acute stroke and find association between HBP serpositivity and stroke, find HBPI as an independent risk factor for stroke of athero-thrombotic origin2,14. The results of Sawayama suggest that chronic HBPI may be a triggering factor that increases the risk of acute ischemic stroke. Some prospective studies founded the strongly relation between HBPI and major cerebrovascular risk factors particulary cigarette smoking, diabetes, hypertension. With respect to stroke a nested case-control study with 137 patientes and 137 control sub-ject found a trend to an increased risk by positive HBPI in adult with lower socioeconomic status and vascular risk factors15. H. pylori infection and cerebrovascular disease are associatted with lower socioeconomic status and their frequency is higher with older age16. In our study we faund 34.8% patients HBP seropositive patients with acute stroke vs. 25.8 seropositive healthy controls. There was not sig-nificant statistical difference (p=0.29 ) between these groups which sugest that HBPI is not independent risk fac-tor for acute stroke. In our study there was significantly lower incidence of HBPI in both patients and controls, par-ticulary due to exclusion criteria of all participants with known gastric disease, or reciving therapy for gastric dis-ease or eradication for H. pylori, particulary for better so-cioeconomic conditions compare to postwar period in Croa-tia in recent studies17. Age of patientes in investigate group is not the limitation of the present study according to the results of Biagi P. who found the same prevalence of HBPI in group of hospitalized geriatric patients as in yonger group.Our study investigated the relation between HBPI and carotid stenosis and found significant association. One study in Argentina guided by F. Ameriso demonstrated the presence of the microorganism in carotid lesions but they where unable to speculate on the role of HBPI18. Pas-ceri et al have demonstrated a higher prevalence of either H. pylori infection or Cag-A positive strains in 52% of the vascular disease patientes compared to 43% of controls. On the other site Sulewska A. found no DNA of HBP in atherosclerotis plaques, just like Stephen D. H. who re-ported no evidence for physical localization of HBP in ca-rotid atherosclerotic plaques19. Just like F. Ameriso et al Michael R. Preuch supported the hypothesis of an asso-ciation between infection CaG A-positive HBP strains and acute stroke. According to same recent studies and com-paring the results of our patientes we noticed possible direct effect HBPI on the stability of the atherosclerotic plaque. Our prospective study does not provide evidence of any strong association between the HBPI and stroke. Further studies are are required to reveal the role HBPI as an risk factor cerebrovascular disease and to confirm our findings.sis.2004.08.025. — 10. SULEWSKA A, MODRZEJEWSKI W, KOVALCHUK O, KASACKA I, JACKOWSKI R, HIRNLE T, MUSIAŁ W, CHYCZEWSKI L, Rocz Akad Med Bialymst, 49 (2004) 239. — 11. STÖLLBERGER C, FINSTER-ER J, Clin Diagn Lab Immunol, 9 (2002) 207. DOI: 10.1128/CDLI.9.2.207-215.2002. — 12. PARK MH, MIN JY, KOH SB, KIM BJ, PARK MK, PARK KW, LEE DH, Thromb Res, 118 (2006) 671. DOI:10.1016/j.thromres.2005.11.007. — 13. WHINCUP PH, MENDALL MA, PERRY IJ, STRACHAN DP, WALKER M, Heart, 75 (1996) 568. — 14. MANOLAKIS A, KAPSORITAKIS AN, POTA-MIANOS SP, Helicobacter, 12 (2007) 287. DOI: 10.1111/j.1523-5378.2007.00511.x. — 15. BABUS V, PRESECKI V, KATICIĆ M, BALIJA M, ZORIĆ I, KRONJA L, SABO A, VRLICAK J, CUKOVIĆ-CAVKA S, Lijec Vjesn, 119 (1997) 139. — 16. MALNICK SD, GOLAND S, KAFTOURY A, SCHWARZ H, PASIK S, MASHIACH A, STHOEGER Z, Am J Cardiol, 83 (1999) 1586. PII: S0002-9149(99)00158-7.5A. Mrđen et al.: Helicobacter Pylori Infection and Acute Stroke, Coll. Antropol. 41 (2017) 4: ???–???INFEKCIJA HELIBACTER PYLORI I AKUTNI MOŽDANI UDARS A Ž E T A KCilj ovog istraživanja je bio odrediti da li infekcija Helicobacter pylori predstavlja neovisan faktor rizika za moždani udar, odrediti da li postoji povezanost težine kliničke slike oboljelog od moždanog udara s infekcijom H. pylori. U ovu prospektivnu studiju provedenu u jednom centru uključena su 82 bolesnika s akutnim moždanim udarom i 93 zdrava ispitanika u kontrolnoj skupini. Rezulati studije nisu pokazali značajnu razliku u distribuciji infekcije H. pylori u ispi-tanika i kontrolnoj skupini (34,8 vs. 25,8%) i nije nađena značajna razlika u težini bolesti prema seropozitivnosti na H. pylori. Značajna razlika uočena je između HBPI i oboljelih od stenoze karotide. Potrebne su veće multicentrične studije za određivanje precizne uloge H. pylori infekcije u nastanku akutnog moždanog udara.

Helicobacter Pylori Infection and Acute Stroke

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Helicobacter Pylori Infection and Acute Stroke

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