Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12226
Anticardiolipin Antibodies in Children with Helicobacter pylori Infection Serdar Umit Sarıcı,* Orhan Gursel,* Emin Kurekci,* Vural Kesik,* Avni Atay,* Vedat Okutan,* Ali Inal,† Aysel Pekel,† Mehmet Ali Ozguven‡ and Okan Ozcan* *Department of Pediatrics, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey, †Department of Immunology, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey, ‡Department of Nuclear Medicine, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey
Keywords H. pylori, anticardiolipin antibodies, children. Reprint requests to: Orhan Gursel, Department of Pediatrics Gulhane Military Medical Academy and Medical Faculty, 06018 Etlik, Ankara, Turkey. E-mail: [email protected]
Abstract Background: Anticardiolipin (aCL) antibodies are associated with thrombosis and have an important role in the etiology of diseases such as stroke and myocardial infarction whose etiologies were based on thrombosis. H. pylori has been proposed to be responsible for the pathophysiology of some diseases including stroke, myocardial infarction, thrombosis, and autoimmune diseases. From this point of view, we hypothesized a possible relationship between H. pylori infection and aCL antibodies and initially aimed to determine the prevalence of aCL antibody positivity in children with H. pylori infection. Materials and Methods: Anticardiolipin antibodies were studied in 84 patients before and after eradication therapy and in a control group including 40 children. Results: The pretreatment aCL IgA (median 12.78 APL/mL), aCL IgM (median 21.60 MPL/mL), and aCL IgG antibody levels (median 14.22 GPL/mL) were significantly higher than those of post-treatment results (median 5.38 APL/mL, 7.02 MPL/mL, and 6.64 GPL/mL, respectively) and controls (median 5.90 APL/mL, 4.80 MPL/mL, and 4.81 GPL/mL, respectively). Anticardiolipin antibodies revealed no significant differences between the study group after therapy and the control group. Conclusions: In our particular experience, H. pylori can cause aCL antibody positivity in children and eradication of H. pylori provides the disappearance of these antibodies.
Anticardiolipin (aCL) antibodies are antibodies directed against cardiolipin, which is a negative charged phospholipid in the organism. These antibodies are classically present in autoimmune diseases, such as systemic lupus erythematosus, and are associated with thrombosis. Some infectious agents, especially viral ones may also cause production of aCL antibodies [1]. Helicobacter pylori (H. pylori) infection is the most commonly encountered infection of the gastrointestinal system, and it contributes to the development of several diseases, including peptic ulcer, iron deficiency anemia, thrombosis, autoimmune diseases, and carcinogenesis [2,3]. H. pylori has been also proposed to be responsible for the pathophysiology of some other diseases including chronic idiopathic thrombocytopenic purpura,
418
stroke, and myocardial infarction. Furthermore, complete remission has been achieved in a patient with antiphospholipid syndrome after eradication of H. pylori [4]. From this point of view, we hypothesized a possible relationship between H. pylori infection and aCL antibodies and initially aimed to determine the prevalence of aCL antibody positivity in children with H. pylori infection.
Methods This study was performed on children admitted with the complaint of abdominal pain and diagnosed to have H. pylori gastritis on the basis of positive H. pylori stool antigen (HpSA) test and C14 urea breath test. The mean age
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Sarıcı et al.
of the patients was 9.74 2.69 years (range 6 to 16 years), and a total of 84 children (46 female [54.8%], 38 male [45.2%]) included (study group). Serum levels of aCL IgM, aCL IgA, and aCL IgG were measured before and after treatment of clarithromycin (20 mg/kg in two doses) and amoxicillin (40 mg/kg in three doses) for 15 days, and lansoprazole (1 mg/kg in single dose) treatment for one month (PAC therapy: P: proton-pump inhibitor, A: amoxicillin, C: clarithromycin) [5]. Nine patients who failed to respond PAC therapy received the second-line PAC therapy, resulting in an eradication rate of 100%. A control group was constituted from cases presented with the complaint of abdominal pain but found to have negative soluble H. Pylori antigen and C14 urea breath tests. A total of 40 cases (23 female [57.5%], 17 male [42.5%]) with a mean age of 8.88 1.92 years (range 6–16 years) served as the control. Children, who ingested of any antibiotics, H2 receptor blockers, protonpump inhibitors, or bismuth-containing drugs in the last 30 days, were excluded from the study. Written informed consent was obtained from the parents of the cases in both groups, and the study was approved by the local ethics committee. Complete blood count (CBC) analyses were determined by automated equipment (Technicon H-1 System, Technicon Co. Tournai, Belgium). Rapid HpSA test (Linear Chemicals, Barcelona, Spain) was performed in fresh stool according to the manufacturer’s recommendations. C14–Urea breath test was performed by the method previously described [6]. The anticardiolipin IgG, IgM, and IgA were studied by ELISA with the original kit by Orgentec Diagnostika GmbH. (Carl-Zeiss— Strasse 49 55129 Mainz) for “Anticardiolipin IgG, IgM, and IgA’’. The results were read by ELx800 ELISA plaque reader. It is recommended for each laboratory to establish in-house cut-off values obtained on a population of healthy volunteers with local reagent/instruments combination [7]. Anticardiolipin antibody levels were considered normal (0–10 U/mL) and mildly elevated (10–20 U/mL), moderately elevated (20–80 U/ mL), highly elevated (>80 U/mL). Statistical analyses were carried out using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) Program Version 14 for windows. All data were expressed as median and range. The normal distribution was detected by Kolmogorov–Smirnov test. The differences between groups were measured by Mann–Whitney U-test. p < .05 was considered to be significant.
Results There were no statistically significant differences between the study and control groups with respect to
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Anticardiolipin Antibodies in Children with H. pylori
age and gender (p > .05). The study group pretreatment and post-treatment CBC parameters and control group CBC parameters did not differ significantly. The pretreatment aCL antibody test (IgM, IgA, and IgG) results were significantly higher than those of post-treatment results (Table 1). Rates of the “high” anticardiolipin IgM, IgA, and IgG test results before and after treatment were 35.7% vs 9.5%, 21.4% vs 7.2%, and 19% vs 7.2%, respectively. No complications were observed in patients with high aCL antibodies. When the pretreatment aCL antibody levels of the study group were compared with those of the control group, there were also significant differences regarding antiIgM, anti-IgA, and anti-IgG antibodies. In the study group, the positivity ratio of pretreatment aCL IgG level was decreased from 16% to 7.2% after treatment. The decrease in aCL IgA level was from 21.4% to 7.2% and aCL IgM from 35.7% to 9.5% (Table 2). There was not any subject with high aCL IgG level in control group. However, the positivity was in two patients (5%) for aCL IgA, and five subjects (12.5%) for aCL IgM in the control group.
Discussion Anticardiolipin antibodies are detected with an incidence of 1–14% in the healthy population, and its prevalence increases with increasing age. Bacterial, viral, and parasitic infections during childhood trigger anticardiolipin antibody synthesis and most of the transient aCL antibody increases in children are explained by this mechanism [8]. ACL are typically present in autoimmune diseases, such as in antiphospholipid syndrome or in systemic lupus erythematosus, but they are also reported in several clinical disorders including infectious and malignant diseases [9]. Anticardiolipin antibodies are formed against cardiolipin and responsible for thrombosis, pregnancy loss, stroke, and myocardial infarction [10]. The pathologic mechanisms accused in the etiology are not clear. Human monoclonal aCLs have been shown to increase the affinity of protein S/C4b-binding protein system (C4BP) for protein S but only in combination with beta2 glycoprotein and cardiolipin resulting with free protein S deficiency and increased risk of thrombosis [11]. Studies have suggested that chronic infections with H. pylori may be associated with the risk of coronary heart disease and stroke [12,13]. Various animal model studies showed that H. pylori infection induced local platelet aggregate formation in gastric and mesentery circulation [14,15]. H. pylori, which has been recently implied in the pathogenesis of idiopathic thrombocytopenic purpura, could also function as a triggering factor
419
Anticardiolipin Antibodies in Children with H. pylori
Sarıcı et al.
Table 1 Comparison of the anticardiolipin antibody test results between the study group and the control group Study group (n = 84) Parameters aCL antibody
Pretreatment
Post-treatment
Control (n = 40)
p value
IgA (APL/mL)
12.78 (0.06–106.2)
5.38 (0–26.34)
5.90 (2.1–19.2)
IgM (MPL/mL)
21.60 (0.18–111.50)
7.02 (0–32.21)
4.80 (1.2–10.2)
IgG (GPL/mL)
14.22 (0.4–74.3)
6.64 (0–40.6)
4.81 (1.2–6.5)
SGPreT and SGPostT: 0.002 SGPreT and CG: 0.018 SGPostT and CG: > 0.05 SGPreT and SGPostT: 0.05 SGPreT and SGPostT: 0.006 SGPreT and CG: 0.029 SGPostT and CG: > 0.05
Values are given as median (minimum–maximum). All of the bold p values are less than 0.05, and these are statistically significant. SGPreT, study group pretreatment; SGPostT, study group post-treatment; CG, control group; APL, IgA phospholipid units; MPL, IgM phospholipid units; GPL, IgG phospholipid units.
Table 2 The number of the cases and ratio of aCL positivity in the study group and the control group Study group (n = 84) Parameters aCL antibody titer
Pretreatment
Post-treatment
aCL IgG (GPL/mL) 10–20 20–80 >80 aCL IgA (APL/mL) 10–20 20–80 >80 aCL IgM (MPL/mL) 10–20 20–80 >80
16 (19%) 13 3 – 18 (21.4%) 10 7 1 30 (35.7%) 20 9 1
6 (7.2%) 5 1 – 6 (7.2%) 5 1 – 8 (9.5%) 6 2 –
Control group (n = 40) Control – – – 2 (5%) 2 – – 5 (12.5%) 5 – –
APL, IgA phospholipid units; MPL, IgM phospholipid units; GPL, IgG phospholipid units.
in thrombotic thrombocytopenic purpura by inducing platelet aggregation through an interaction with von Willebrand factor [16]. All these studies have raised a question whether H. pylori infection affects platelet functions. On the other hand, Gursel et al. [3] demonstrated that H. pylori infection in children may significantly decrease platelet response to ADP (ADP-like defect), which can be reversed by eradication therapy. Bacteria and viruses can trigger the autoimmune response in the organism [17]. H. pylori is also a trigger of autoimmunity being a common agent in the general population and having the potential to develop immune tolerance in the genetically susceptible individuals [18]. The relationship between H. pylori infections
420
and autoimmunity is based on indirect evidence that antibodies of immunoglobulin nature are produced against this specific microorganism in the serum. Antibody production against gastric parietal cells during H. pylori infections is explained by the molecular similarity mechanism. H. pylori is one of the microorganisms that induce organ-specific immunity [19]. Organ-specific autoimmune diseases are characterized by a long and asymptomatic preclinical period with autoantibodies synthesized against the target organ. It is thought that these antibodies produced during childhood and cause several diseases in adulthood by surviving in the circulation for years. However, the recovery from chronic ITP or antiphospholipid antibody syndrome in patients with H. pylori infection shows that H. pylori does not always induce organ-specific immunity. Cicconi et al. reported the disappearance of antiphospholipid antibody syndrome in a 70-year-old patient after H. pylori eradication. They suggested that although it is indefinite, H. pylori may have triggered the antiphospholipid (aPL) activity [4]. In our study, we measured the levels of aCl antibodies that are indicators of autoimmune process in the body. Although they are nonspecific, they are sensitive enough to indicate the presence of an autoimmune reaction. Thus, we detected higher pretreatment aCL IgM, IgA, and IgG antibodies in children with H. pylori in comparison with controls. Although aCLs have been shown to form predisposition to thrombosis—not even in all diseases—there was no clinical implication on children with H. pylori having high titers of aCLs. In our opinion, these children should be followed closely if a family history of thrombosis or thrombosis-related diseases are present. The deleterious effects of H. pylori
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Anticardiolipin Antibodies in Children with H. pylori
Sarıcı et al.
are not limited to gastrointestinal system, and the onset of its systemic effects may extend to early childhood. Thus, the eradication of H. pylori in children is exclusively important. In our particular experience, H. pylori can cause aCL antibody positivity in children and eradication of H. pylori provides the disappearance of these antibodies. Early and late clinical importance of these findings should be investigated in further large-scale studies.
10
Acknowledgements and Disclosures
11
The authors alone are responsible for the content and writing of this article. Competing interests: the authors report no conflict of interests.
12
7 8
9
References 1 H€ orkk€ o S, Olee T, Mo L, Branch DW, Woods VL Jr, Palinski W, Chen PP, Witztum JL. Anticardiolipin antibodies from patients with the antiphospholipid antibody syndrome recognize epitopes in both beta(2)-glycoprotein 1 and oxidized low-density lipoprotein. Circulation 2001;103:941–6. 2 Sherman PM, Lin FY. Extradigestive manifestation of Helicobacter pylori infection in children and adolescents. Can J Gastroenterol 2005;19:421–4. 3 Gursel O, Atay A, Kurekci E, Avcu F, Nevruz O, Senses Z, Ozturk E, Hasimi A, Ozcan O. Platelet aggregation in children with Helicobacter pylori infection. Clin Appl Thromb Hemost 2010;16:637–42. 4 Cicconi V, Carloni E, Franceschi F, Nocente R, Silveri NG, Manna R, Servidei S, Bentivoglio AR, Gasbarrini A, Gasbarrini G. Disappearance of antiphospholipid antibodies syndrome after Helicobacter pylori eradication. Am J Med 2001;111:163–4. 5 Kato S, Konno M, Maisawa S, Tajiri H, Yoshimura N, Shimizu T, Toyoda S, Nakayama Y, Iinuma K. Results of triple eradication therapy in Japanese Children: a retrospective multicenter study. J Gastroenterol 2004;39:838–43. 6 Ozt€ urk E, Yesßilova Z, Ilgan S, Arslan N, Erdil A, Celasun B, Ozg€ uven M, Da galp K, Ovali O, Bayhan H. A new, practical, low-dose 14C-Urea breath test for the diagnosis of Helicobacter
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
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pylori infection: clinical validation and comparison with the standard method. Eur J Nucl Med Mol Imaging 2003;30:1457–62. Wong RC. Consensus guidelines for anticardiolipin antibody testing. Thromb Res 2004;114:559–71. Avcin T, Cimaz R, Meroni PL. Recent advances in antiphospholipid antibodies and antiphospholipid syndromes in pediatric populations. Lupus 2002;11:4–10. Ricci G, Maldini MC, Patrizi A, Pagliara L, Bellini F, Masi M. Anticardiolipin antibodies in children with atopic dermatitis. J Autoimmun 2005;24:221–5. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013;368: 1033–44. Atsumi T, Khamashta MA, Ames PR, Ichikawa K, Koike T, Hughes GR. Effect of beta-2 glycoprotein I and human monoclonal anticardiolipin antibody on the protein S/C4b-binding protein system. Lupus 1997;6:358–64. Rupprecht HJ, Blankenberg S, Bickel C, Rippin G, Hafner G, Prellwitz W, Schlumberger W, Meyer J; AutoGene Investigators. Impact of viral and bacterial infectious burden on longterm prognosis in patients with coronary artery disease. Circulation 2001;104:25–31. Gunn M, Stephens J, Thompson JR, Rathbone BJ, Samani NJ. Significant association of Cag A Positive Helicobacter Pylori strains with risk of premature myocardial infarction. Heart 2000;84:267–71. Aguejouf O, Mayo K, Monteiro L, Doutremepuich F, Doutremepuich C, Megraud F. Increase of arterial thrombosis parameters in chronic Helicobacter pylori infection in mice. Thromb Res 2003;108:245–8. Elizalde IJ, Gomez J, Panes J, Lozano M, Casadevall M, Ramırez J, Pizcueta P, Marco F, Rojas FD, Granger DN, Pique JM. Platelet activation in mice and human Helicobacter Pylori infection. J Clin Invest 1997;100:996–1005. Franchini M. Thrombotic thrombocytopenic purpura: proposal of a new pathogenic mechanism involving Helicobacter pylori infection. Med Hypotheses 2005;65:1128–31. Sorice M, Pittoni V, Griggi T, Losardo A, Leri O, Magno MS, Misasi R, Valesini G. Specificity of anti-phospholipid antibodies in infectious mononucleosis: a role for anti-cofactor protein antibodies. Clin Exp Immunol 2000;120:301–6. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340–5. Guariso G, Brotto F, Basso D, Alaggio R, Betterle C. Organ-specific autoantibodies in children with Helicobacter pylori infection. Helicobacter 2004;9:622–8.
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Anticardiolipin Antibodies in Children with Helicobacter pylori Infection Serdar Umit Sarıcı,* Orhan Gursel,* Emin Kurekci,* Vural Kesik,* Avni Atay,* Vedat Okutan,* Ali Inal,† Aysel Pekel,† Mehmet Ali Ozguven‡ and Okan Ozcan* *Department of Pediatrics, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey, †Department of Immunology, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey, ‡Department of Nuclear Medicine, Gulhane Military Medical Academy and Medical Faculty, Ankara, Turkey
Keywords H. pylori, anticardiolipin antibodies, children. Reprint requests to: Orhan Gursel, Department of Pediatrics Gulhane Military Medical Academy and Medical Faculty, 06018 Etlik, Ankara, Turkey. E-mail: [email protected]
Abstract Background: Anticardiolipin (aCL) antibodies are associated with thrombosis and have an important role in the etiology of diseases such as stroke and myocardial infarction whose etiologies were based on thrombosis. H. pylori has been proposed to be responsible for the pathophysiology of some diseases including stroke, myocardial infarction, thrombosis, and autoimmune diseases. From this point of view, we hypothesized a possible relationship between H. pylori infection and aCL antibodies and initially aimed to determine the prevalence of aCL antibody positivity in children with H. pylori infection. Materials and Methods: Anticardiolipin antibodies were studied in 84 patients before and after eradication therapy and in a control group including 40 children. Results: The pretreatment aCL IgA (median 12.78 APL/mL), aCL IgM (median 21.60 MPL/mL), and aCL IgG antibody levels (median 14.22 GPL/mL) were significantly higher than those of post-treatment results (median 5.38 APL/mL, 7.02 MPL/mL, and 6.64 GPL/mL, respectively) and controls (median 5.90 APL/mL, 4.80 MPL/mL, and 4.81 GPL/mL, respectively). Anticardiolipin antibodies revealed no significant differences between the study group after therapy and the control group. Conclusions: In our particular experience, H. pylori can cause aCL antibody positivity in children and eradication of H. pylori provides the disappearance of these antibodies.
Anticardiolipin (aCL) antibodies are antibodies directed against cardiolipin, which is a negative charged phospholipid in the organism. These antibodies are classically present in autoimmune diseases, such as systemic lupus erythematosus, and are associated with thrombosis. Some infectious agents, especially viral ones may also cause production of aCL antibodies [1]. Helicobacter pylori (H. pylori) infection is the most commonly encountered infection of the gastrointestinal system, and it contributes to the development of several diseases, including peptic ulcer, iron deficiency anemia, thrombosis, autoimmune diseases, and carcinogenesis [2,3]. H. pylori has been also proposed to be responsible for the pathophysiology of some other diseases including chronic idiopathic thrombocytopenic purpura,
418
stroke, and myocardial infarction. Furthermore, complete remission has been achieved in a patient with antiphospholipid syndrome after eradication of H. pylori [4]. From this point of view, we hypothesized a possible relationship between H. pylori infection and aCL antibodies and initially aimed to determine the prevalence of aCL antibody positivity in children with H. pylori infection.
Methods This study was performed on children admitted with the complaint of abdominal pain and diagnosed to have H. pylori gastritis on the basis of positive H. pylori stool antigen (HpSA) test and C14 urea breath test. The mean age
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Sarıcı et al.
of the patients was 9.74 2.69 years (range 6 to 16 years), and a total of 84 children (46 female [54.8%], 38 male [45.2%]) included (study group). Serum levels of aCL IgM, aCL IgA, and aCL IgG were measured before and after treatment of clarithromycin (20 mg/kg in two doses) and amoxicillin (40 mg/kg in three doses) for 15 days, and lansoprazole (1 mg/kg in single dose) treatment for one month (PAC therapy: P: proton-pump inhibitor, A: amoxicillin, C: clarithromycin) [5]. Nine patients who failed to respond PAC therapy received the second-line PAC therapy, resulting in an eradication rate of 100%. A control group was constituted from cases presented with the complaint of abdominal pain but found to have negative soluble H. Pylori antigen and C14 urea breath tests. A total of 40 cases (23 female [57.5%], 17 male [42.5%]) with a mean age of 8.88 1.92 years (range 6–16 years) served as the control. Children, who ingested of any antibiotics, H2 receptor blockers, protonpump inhibitors, or bismuth-containing drugs in the last 30 days, were excluded from the study. Written informed consent was obtained from the parents of the cases in both groups, and the study was approved by the local ethics committee. Complete blood count (CBC) analyses were determined by automated equipment (Technicon H-1 System, Technicon Co. Tournai, Belgium). Rapid HpSA test (Linear Chemicals, Barcelona, Spain) was performed in fresh stool according to the manufacturer’s recommendations. C14–Urea breath test was performed by the method previously described [6]. The anticardiolipin IgG, IgM, and IgA were studied by ELISA with the original kit by Orgentec Diagnostika GmbH. (Carl-Zeiss— Strasse 49 55129 Mainz) for “Anticardiolipin IgG, IgM, and IgA’’. The results were read by ELx800 ELISA plaque reader. It is recommended for each laboratory to establish in-house cut-off values obtained on a population of healthy volunteers with local reagent/instruments combination [7]. Anticardiolipin antibody levels were considered normal (0–10 U/mL) and mildly elevated (10–20 U/mL), moderately elevated (20–80 U/ mL), highly elevated (>80 U/mL). Statistical analyses were carried out using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) Program Version 14 for windows. All data were expressed as median and range. The normal distribution was detected by Kolmogorov–Smirnov test. The differences between groups were measured by Mann–Whitney U-test. p < .05 was considered to be significant.
Results There were no statistically significant differences between the study and control groups with respect to
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Anticardiolipin Antibodies in Children with H. pylori
age and gender (p > .05). The study group pretreatment and post-treatment CBC parameters and control group CBC parameters did not differ significantly. The pretreatment aCL antibody test (IgM, IgA, and IgG) results were significantly higher than those of post-treatment results (Table 1). Rates of the “high” anticardiolipin IgM, IgA, and IgG test results before and after treatment were 35.7% vs 9.5%, 21.4% vs 7.2%, and 19% vs 7.2%, respectively. No complications were observed in patients with high aCL antibodies. When the pretreatment aCL antibody levels of the study group were compared with those of the control group, there were also significant differences regarding antiIgM, anti-IgA, and anti-IgG antibodies. In the study group, the positivity ratio of pretreatment aCL IgG level was decreased from 16% to 7.2% after treatment. The decrease in aCL IgA level was from 21.4% to 7.2% and aCL IgM from 35.7% to 9.5% (Table 2). There was not any subject with high aCL IgG level in control group. However, the positivity was in two patients (5%) for aCL IgA, and five subjects (12.5%) for aCL IgM in the control group.
Discussion Anticardiolipin antibodies are detected with an incidence of 1–14% in the healthy population, and its prevalence increases with increasing age. Bacterial, viral, and parasitic infections during childhood trigger anticardiolipin antibody synthesis and most of the transient aCL antibody increases in children are explained by this mechanism [8]. ACL are typically present in autoimmune diseases, such as in antiphospholipid syndrome or in systemic lupus erythematosus, but they are also reported in several clinical disorders including infectious and malignant diseases [9]. Anticardiolipin antibodies are formed against cardiolipin and responsible for thrombosis, pregnancy loss, stroke, and myocardial infarction [10]. The pathologic mechanisms accused in the etiology are not clear. Human monoclonal aCLs have been shown to increase the affinity of protein S/C4b-binding protein system (C4BP) for protein S but only in combination with beta2 glycoprotein and cardiolipin resulting with free protein S deficiency and increased risk of thrombosis [11]. Studies have suggested that chronic infections with H. pylori may be associated with the risk of coronary heart disease and stroke [12,13]. Various animal model studies showed that H. pylori infection induced local platelet aggregate formation in gastric and mesentery circulation [14,15]. H. pylori, which has been recently implied in the pathogenesis of idiopathic thrombocytopenic purpura, could also function as a triggering factor
419
Anticardiolipin Antibodies in Children with H. pylori
Sarıcı et al.
Table 1 Comparison of the anticardiolipin antibody test results between the study group and the control group Study group (n = 84) Parameters aCL antibody
Pretreatment
Post-treatment
Control (n = 40)
p value
IgA (APL/mL)
12.78 (0.06–106.2)
5.38 (0–26.34)
5.90 (2.1–19.2)
IgM (MPL/mL)
21.60 (0.18–111.50)
7.02 (0–32.21)
4.80 (1.2–10.2)
IgG (GPL/mL)
14.22 (0.4–74.3)
6.64 (0–40.6)
4.81 (1.2–6.5)
SGPreT and SGPostT: 0.002 SGPreT and CG: 0.018 SGPostT and CG: > 0.05 SGPreT and SGPostT: 0.05 SGPreT and SGPostT: 0.006 SGPreT and CG: 0.029 SGPostT and CG: > 0.05
Values are given as median (minimum–maximum). All of the bold p values are less than 0.05, and these are statistically significant. SGPreT, study group pretreatment; SGPostT, study group post-treatment; CG, control group; APL, IgA phospholipid units; MPL, IgM phospholipid units; GPL, IgG phospholipid units.
Table 2 The number of the cases and ratio of aCL positivity in the study group and the control group Study group (n = 84) Parameters aCL antibody titer
Pretreatment
Post-treatment
aCL IgG (GPL/mL) 10–20 20–80 >80 aCL IgA (APL/mL) 10–20 20–80 >80 aCL IgM (MPL/mL) 10–20 20–80 >80
16 (19%) 13 3 – 18 (21.4%) 10 7 1 30 (35.7%) 20 9 1
6 (7.2%) 5 1 – 6 (7.2%) 5 1 – 8 (9.5%) 6 2 –
Control group (n = 40) Control – – – 2 (5%) 2 – – 5 (12.5%) 5 – –
APL, IgA phospholipid units; MPL, IgM phospholipid units; GPL, IgG phospholipid units.
in thrombotic thrombocytopenic purpura by inducing platelet aggregation through an interaction with von Willebrand factor [16]. All these studies have raised a question whether H. pylori infection affects platelet functions. On the other hand, Gursel et al. [3] demonstrated that H. pylori infection in children may significantly decrease platelet response to ADP (ADP-like defect), which can be reversed by eradication therapy. Bacteria and viruses can trigger the autoimmune response in the organism [17]. H. pylori is also a trigger of autoimmunity being a common agent in the general population and having the potential to develop immune tolerance in the genetically susceptible individuals [18]. The relationship between H. pylori infections
420
and autoimmunity is based on indirect evidence that antibodies of immunoglobulin nature are produced against this specific microorganism in the serum. Antibody production against gastric parietal cells during H. pylori infections is explained by the molecular similarity mechanism. H. pylori is one of the microorganisms that induce organ-specific immunity [19]. Organ-specific autoimmune diseases are characterized by a long and asymptomatic preclinical period with autoantibodies synthesized against the target organ. It is thought that these antibodies produced during childhood and cause several diseases in adulthood by surviving in the circulation for years. However, the recovery from chronic ITP or antiphospholipid antibody syndrome in patients with H. pylori infection shows that H. pylori does not always induce organ-specific immunity. Cicconi et al. reported the disappearance of antiphospholipid antibody syndrome in a 70-year-old patient after H. pylori eradication. They suggested that although it is indefinite, H. pylori may have triggered the antiphospholipid (aPL) activity [4]. In our study, we measured the levels of aCl antibodies that are indicators of autoimmune process in the body. Although they are nonspecific, they are sensitive enough to indicate the presence of an autoimmune reaction. Thus, we detected higher pretreatment aCL IgM, IgA, and IgG antibodies in children with H. pylori in comparison with controls. Although aCLs have been shown to form predisposition to thrombosis—not even in all diseases—there was no clinical implication on children with H. pylori having high titers of aCLs. In our opinion, these children should be followed closely if a family history of thrombosis or thrombosis-related diseases are present. The deleterious effects of H. pylori
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 418–421
Anticardiolipin Antibodies in Children with H. pylori
Sarıcı et al.
are not limited to gastrointestinal system, and the onset of its systemic effects may extend to early childhood. Thus, the eradication of H. pylori in children is exclusively important. In our particular experience, H. pylori can cause aCL antibody positivity in children and eradication of H. pylori provides the disappearance of these antibodies. Early and late clinical importance of these findings should be investigated in further large-scale studies.
10
Acknowledgements and Disclosures
11
The authors alone are responsible for the content and writing of this article. Competing interests: the authors report no conflict of interests.
12
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