Eur J Pediatr DOI 10.1007/s00431-014-2482-4
ORIGINAL ARTICLE
An insight into the relationships between prohepcidin, iron deficiency anemia, and interleukin-6 values in pediatric Helicobacter pylori gastritis Nagehan Emiralioglu & Idil Yenicesu & Sinan Sari & Odul Egritas & Aylar Poyraz & Ozge Tugce Pasaoglu & Bulent Celik & Buket Dalgic
Received: 19 July 2014 / Revised: 21 October 2014 / Accepted: 21 November 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract The link between Helicobacter pylori and iron deficiency (ID) or iron deficiency anemia (IDA) has been investigated recently. We suggested that IDA/ID associated with H. pylori infection might be mediated by inflammationdriven hepcidin production. Patients with complaints of recurrent abdominal pain and dyspepsia aged between 7–16 years were included in this study. Patients were divided into two groups according to H. pylori status in upper gastrointestinal endoscopy. Group I who had H. pylori gastritis (n=50) received triple antibiotic therapy. Group II (n=50) who had H. pylori-negative gastritis only received proton pump inhibitor. Thirty healthy children with the similar age and gender were included in the study as a control group. Complete blood count, serum iron levels, iron-binding capacity, ferritin levels, prohepcidin and interleukin-6 (IL-6) values were evaluated in all children at the first visit. Initial tests were repeated after H. pylori eradication. Initial levels of ferritin (p=0.002),
prohepcidin (p=0.003), and IL-6 (p=0.004) were found significantly lower in group I compared to group II and the control group. The mean prohepcidin level was lower in the anemic H. pylori-positive group than in non-anemic H. pyloripositive group; however, the difference was not statistically significant. While significant increases in hematocrit and mean corpuscular volume were observed, no significant difference was found in serum ferritin, prohepcidin, or IL-6 level after eradication treatment in H. pylori-positive group. Conclusion: H. pylori-induced gastritis appears to cause an increase in prohepcidin levels and a decrease in ferritin levels, supporting our hypothesis; but this relationship has not been proven.
Keywords Prohepcidin . Iron deficiency anemia . Helicobacter pylori . Gastritis
Communicated by David Nadal N. Emiralioglu Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
A. Poyraz Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
I. Yenicesu Pediatric Hematology, Faculty of Medicine, Gazi University, Ankara, Turkey e-mail: [email protected]
O. T. Pasaoglu Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey e-mail: [email protected]
S. Sari : O. Egritas : B. Dalgic Pediatric Gastroenterology, Faculty of Medicine, Gazi University, Ankara, Turkey S. Sari e-mail: [email protected] O. Egritas e-mail: [email protected] B. Dalgic e-mail: [email protected]
B. Celik Department of Biostatistics, Faculty of Health Sciences, Gazi University, Ankara, Turkey e-mail: [email protected]
N. Emiralioglu (*) Department of Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey e-mail: [email protected]
Eur J Pediatr
Abbreviations H. pylori Helicobacter pylori IDA Iron deficiency anemia IL-6 Interleukin-6 LPS Lipopolysaccharides MCV Mean corpuscular volume SD Standard deviation
Introduction Iron deficiency remains a major health problem in the 21st century, more than half a millennium since medieval physicians first diagnosed and treated the condition. Recognition of the functional impacts of iron deficiency has been extended from reduced red blood cell formation to many other physiologic aspects, including cognition [32, 34]. However, the continuous development of new pharmacologic resources to correct iron deficiency and the identification of related gene mutations have failed to resolve the problem in the general population or in those with confounding medical conditions, such as Helicobacter pylori-induced gastritis [32]. The link between H. pylori and iron deficiency anemia (IDA) has been investigated recently, contributing to the clarification of its pathophysiologic role [5, 14, 18]. Major population surveys involving thousands of subjects in diverse geographic areas have demonstrated that H. pylori positivity is associated with an increased prevalence of iron deficiency [33]. The United States National Health and Nutrition Examination Survey showed that H. pylori infection was associated with a 40 % increase in the prevalence of iron deficiency [8, 36]. The most convincing evidence of a cause– effect relationship between IDA and H. pylori infection is the beneficial effect of H. pylori eradication on pre-existing IDA [19]. Several mechanisms have been proposed to explain the relationship between H. pylori-induced gastritis and IDA, including occult gastrointestinal bleeding and bacterial competition for dietary iron. Beutler [4] suggested that H. pylori might subvert the human iron regulatory mechanism in a manner that is beneficial to the microorganism but deleterious to the host. This effect might occur through hepcidin. Hepcidin is a peptide hormone expressed predominantly in the liver, but extrahepatic hepcidin expression has been documented in the kidney, heart, pancreas, biliary system, and very recently, in gastric parietal cells. An antimicrobial peptide, hepcidin, is the central regulator of iron metabolism; by inducing the internalization and degradation of ferroportin and divalent metal transporter-1, hepcidin limits intestinal iron absorption and iron release from macrophages [29].
Hepcidin expression is induced by iron stores and inflammation, particularly that caused by interleukin-6 (IL-6). It is down-regulated by hypoxia, anemia, and erythropoiesis. Mediators such as hemojuvelin and bone morphogenetic proteins are central to hepcidin-signaling pathways. In humans, functional mutations of the transmembrane protease, serine 6 gene, an inhibitor of hepcidin expression, result in inappropriately high levels of hepcidin production and severe iron-refractory IDA [15]. Refractory IDA associated with H. pylori infection might be mediated by inflammation-driven hepcidin production [26, 30]. Few data substantiating these putative roles of hepcidin in IDA or H. pylori infection have been reported, and pediatric data are particularly lacking. We explored associations between IDA and serum prohepcidin and IL-6 levels in a pediatric population with H. pylori-positive and H. pylori-negative gastritis.
Methods Study population Patients aged 7–16 years who visited the Gazi University Pediatric Gastroenterology Clinic with complaints of recurrent abdominal pain and dyspepsia were included in this study [27]. Exclusion criteria were: (1) chronic inflammatory disease, chronic or acute infection, or gastrointestinal bleeding or malignancy; (2) previous H. pylori eradication treatment; and (3) identification of peptic ulcer, hemorrhagic gastritis, or esophagitis by endoscopic investigation. The ethics committee of Gazi University granted permission for this prospective study (No. 247), and patients and their parents were provided with written informed consent. Diagnosis and treatment of H. pylori infection Upper gastrointestinal endoscopy was performed in patients with complaints of recurrent abdominal pain and dyspepsia [27]. Positivity for H. pylori-induced gastritis was identified histologically by hematoxylin and eosin staining of antrum and/ or corpus biopsies. The patients were divided into two groups according to H. pylori status. In patients with H. pylori-induced gastritis (group I, n=50), complete blood count, iron-binding capacity, and serum iron, ferritin, prohepcidin, and IL-6 levels were measured before the initiation of therapy. Eradication therapy [amoxicillin (50 mg/kg/day) and clarithromycin (15 mg/kg/day) for 2 weeks + proton pump inhibitor treatment (1 mg/kg/day) for 8 weeks] was administered to H. pyloripositive children. Eradication was monitored by performing a 13 C urea breath test 4 weeks after the end of therapy, and initial tests were repeated after eradication. Patients with H. pylorinegative gastritis (group II, n=50) received only proton pump
Eur J Pediatr
inhibitor treatment for 8 weeks, and initial tests were not repeated after the completion of treatment. Thirty age- and sex-matched healthy individuals were also included in the study as a control group (Fig. 1). Definitions of iron deficiency and anemia Anemia was defined according to the cut-off values proposed by Wilson [35]: hemoglobin
ORIGINAL ARTICLE
An insight into the relationships between prohepcidin, iron deficiency anemia, and interleukin-6 values in pediatric Helicobacter pylori gastritis Nagehan Emiralioglu & Idil Yenicesu & Sinan Sari & Odul Egritas & Aylar Poyraz & Ozge Tugce Pasaoglu & Bulent Celik & Buket Dalgic
Received: 19 July 2014 / Revised: 21 October 2014 / Accepted: 21 November 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract The link between Helicobacter pylori and iron deficiency (ID) or iron deficiency anemia (IDA) has been investigated recently. We suggested that IDA/ID associated with H. pylori infection might be mediated by inflammationdriven hepcidin production. Patients with complaints of recurrent abdominal pain and dyspepsia aged between 7–16 years were included in this study. Patients were divided into two groups according to H. pylori status in upper gastrointestinal endoscopy. Group I who had H. pylori gastritis (n=50) received triple antibiotic therapy. Group II (n=50) who had H. pylori-negative gastritis only received proton pump inhibitor. Thirty healthy children with the similar age and gender were included in the study as a control group. Complete blood count, serum iron levels, iron-binding capacity, ferritin levels, prohepcidin and interleukin-6 (IL-6) values were evaluated in all children at the first visit. Initial tests were repeated after H. pylori eradication. Initial levels of ferritin (p=0.002),
prohepcidin (p=0.003), and IL-6 (p=0.004) were found significantly lower in group I compared to group II and the control group. The mean prohepcidin level was lower in the anemic H. pylori-positive group than in non-anemic H. pyloripositive group; however, the difference was not statistically significant. While significant increases in hematocrit and mean corpuscular volume were observed, no significant difference was found in serum ferritin, prohepcidin, or IL-6 level after eradication treatment in H. pylori-positive group. Conclusion: H. pylori-induced gastritis appears to cause an increase in prohepcidin levels and a decrease in ferritin levels, supporting our hypothesis; but this relationship has not been proven.
Keywords Prohepcidin . Iron deficiency anemia . Helicobacter pylori . Gastritis
Communicated by David Nadal N. Emiralioglu Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
A. Poyraz Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
I. Yenicesu Pediatric Hematology, Faculty of Medicine, Gazi University, Ankara, Turkey e-mail: [email protected]
O. T. Pasaoglu Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey e-mail: [email protected]
S. Sari : O. Egritas : B. Dalgic Pediatric Gastroenterology, Faculty of Medicine, Gazi University, Ankara, Turkey S. Sari e-mail: [email protected] O. Egritas e-mail: [email protected] B. Dalgic e-mail: [email protected]
B. Celik Department of Biostatistics, Faculty of Health Sciences, Gazi University, Ankara, Turkey e-mail: [email protected]
N. Emiralioglu (*) Department of Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey e-mail: [email protected]
Eur J Pediatr
Abbreviations H. pylori Helicobacter pylori IDA Iron deficiency anemia IL-6 Interleukin-6 LPS Lipopolysaccharides MCV Mean corpuscular volume SD Standard deviation
Introduction Iron deficiency remains a major health problem in the 21st century, more than half a millennium since medieval physicians first diagnosed and treated the condition. Recognition of the functional impacts of iron deficiency has been extended from reduced red blood cell formation to many other physiologic aspects, including cognition [32, 34]. However, the continuous development of new pharmacologic resources to correct iron deficiency and the identification of related gene mutations have failed to resolve the problem in the general population or in those with confounding medical conditions, such as Helicobacter pylori-induced gastritis [32]. The link between H. pylori and iron deficiency anemia (IDA) has been investigated recently, contributing to the clarification of its pathophysiologic role [5, 14, 18]. Major population surveys involving thousands of subjects in diverse geographic areas have demonstrated that H. pylori positivity is associated with an increased prevalence of iron deficiency [33]. The United States National Health and Nutrition Examination Survey showed that H. pylori infection was associated with a 40 % increase in the prevalence of iron deficiency [8, 36]. The most convincing evidence of a cause– effect relationship between IDA and H. pylori infection is the beneficial effect of H. pylori eradication on pre-existing IDA [19]. Several mechanisms have been proposed to explain the relationship between H. pylori-induced gastritis and IDA, including occult gastrointestinal bleeding and bacterial competition for dietary iron. Beutler [4] suggested that H. pylori might subvert the human iron regulatory mechanism in a manner that is beneficial to the microorganism but deleterious to the host. This effect might occur through hepcidin. Hepcidin is a peptide hormone expressed predominantly in the liver, but extrahepatic hepcidin expression has been documented in the kidney, heart, pancreas, biliary system, and very recently, in gastric parietal cells. An antimicrobial peptide, hepcidin, is the central regulator of iron metabolism; by inducing the internalization and degradation of ferroportin and divalent metal transporter-1, hepcidin limits intestinal iron absorption and iron release from macrophages [29].
Hepcidin expression is induced by iron stores and inflammation, particularly that caused by interleukin-6 (IL-6). It is down-regulated by hypoxia, anemia, and erythropoiesis. Mediators such as hemojuvelin and bone morphogenetic proteins are central to hepcidin-signaling pathways. In humans, functional mutations of the transmembrane protease, serine 6 gene, an inhibitor of hepcidin expression, result in inappropriately high levels of hepcidin production and severe iron-refractory IDA [15]. Refractory IDA associated with H. pylori infection might be mediated by inflammation-driven hepcidin production [26, 30]. Few data substantiating these putative roles of hepcidin in IDA or H. pylori infection have been reported, and pediatric data are particularly lacking. We explored associations between IDA and serum prohepcidin and IL-6 levels in a pediatric population with H. pylori-positive and H. pylori-negative gastritis.
Methods Study population Patients aged 7–16 years who visited the Gazi University Pediatric Gastroenterology Clinic with complaints of recurrent abdominal pain and dyspepsia were included in this study [27]. Exclusion criteria were: (1) chronic inflammatory disease, chronic or acute infection, or gastrointestinal bleeding or malignancy; (2) previous H. pylori eradication treatment; and (3) identification of peptic ulcer, hemorrhagic gastritis, or esophagitis by endoscopic investigation. The ethics committee of Gazi University granted permission for this prospective study (No. 247), and patients and their parents were provided with written informed consent. Diagnosis and treatment of H. pylori infection Upper gastrointestinal endoscopy was performed in patients with complaints of recurrent abdominal pain and dyspepsia [27]. Positivity for H. pylori-induced gastritis was identified histologically by hematoxylin and eosin staining of antrum and/ or corpus biopsies. The patients were divided into two groups according to H. pylori status. In patients with H. pylori-induced gastritis (group I, n=50), complete blood count, iron-binding capacity, and serum iron, ferritin, prohepcidin, and IL-6 levels were measured before the initiation of therapy. Eradication therapy [amoxicillin (50 mg/kg/day) and clarithromycin (15 mg/kg/day) for 2 weeks + proton pump inhibitor treatment (1 mg/kg/day) for 8 weeks] was administered to H. pyloripositive children. Eradication was monitored by performing a 13 C urea breath test 4 weeks after the end of therapy, and initial tests were repeated after eradication. Patients with H. pylorinegative gastritis (group II, n=50) received only proton pump
Eur J Pediatr
inhibitor treatment for 8 weeks, and initial tests were not repeated after the completion of treatment. Thirty age- and sex-matched healthy individuals were also included in the study as a control group (Fig. 1). Definitions of iron deficiency and anemia Anemia was defined according to the cut-off values proposed by Wilson [35]: hemoglobin
