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Navidifar T, Meftah E, Baghsheikhi H, Kazemzadeh K, Karimi H, Rezaei N. Dual role of hepcidin in response to pathogens. Microb Pathog 2025; 203:107496. [PMID: 40118299 DOI: 10.1016/j.micpath.2025.107496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.
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Affiliation(s)
- Tahereh Navidifar
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Meftah
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Baghsheikhi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Kazemzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
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Zhang M, Zhong J, Song Z, Xu Q, Chen Y, Zhang Z. Regulatory mechanisms and potential therapeutic targets in precancerous lesions of gastric cancer: A comprehensive review. Biomed Pharmacother 2024; 177:117068. [PMID: 39018877 DOI: 10.1016/j.biopha.2024.117068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/27/2024] [Accepted: 06/27/2024] [Indexed: 07/19/2024] Open
Abstract
Precancerous lesions of gastric cancer (PLGC) represent a critical pathological stage in the transformation from normal gastric mucosa to gastric cancer (GC). The global incidence of PLGC has been rising over the past few decades, with a trend towards younger onset ages. Increasing evidence suggests that early prevention and treatment of PLGC can effectively reverse the malignant development of gastric mucosal epithelial cells. However, there is currently a lack of effective therapeutic drugs and methods. Recent years have witnessed substantial advancements in PLGC research, with the elucidation of novel regulatory mechanisms offering promising avenues for clinical intervention and drug development. This review aims to delineate potential targets for early prevention and diagnosis of GC while exploring innovative approaches to PLGC management. This article focuses on elucidating the regulatory mechanisms of the inflammatory microenvironment, bile acids (BA), glycolysis, autophagy, apoptosis, ferroptosis, and cellular senescence. We pay particular attention to potential therapeutic targets for PLGC, with the goal of providing insights and theoretical basis for clinical research on PLGC.
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Affiliation(s)
- Maofu Zhang
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Jialin Zhong
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Zhongyang Song
- Department of Oncology, Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu 730020, China
| | - Qian Xu
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Yuchan Chen
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Zhiming Zhang
- Department of Oncology, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, Gansu 730050, China.
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Zhao Y, Zhao J, Ma H, Han Y, Xu W, Wang J, Cai Y, Jia X, Jia Q, Yang Q. High Hepcidin Levels Promote Abnormal Iron Metabolism and Ferroptosis in Chronic Atrophic Gastritis. Biomedicines 2023; 11:2338. [PMID: 37760781 PMCID: PMC10525531 DOI: 10.3390/biomedicines11092338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/15/2023] [Accepted: 08/20/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and premalignant lesion of gastric cancer. As an antimicrobial peptide, hepcidin can maintain iron metabolic balance and is susceptible to inflammation. OBJECTIVES The objective of this study was to clarify whether hepcidin is involved in abnormal iron metabolism and ferroptosis during CAG pathogenesis. METHODS Non-atrophic gastritis (NAG) and chronic atrophic gastritis (CAG) patient pathology slides were collected, and related protein expression was detected by immunohistochemical staining. The CAG rat model was established using MNNG combined with an irregular diet. RESULTS CAG patients and rats exhibited iron deposition in gastric tissue. CAG-induced ferroptosis in the stomach was characterized by decreased GPX4 and FTH levels and increased 4-HNE levels. Hepcidin, which is mainly located in parietal cells, was elevated in CAG gastric tissue. The high gastric level of hepcidin inhibited iron absorption in the duodenum by decreasing the protein expression of DMT1 and FPN1. In addition, the IL-6/STAT3 signaling pathway induced hepcidin production in gastric tissue. CONCLUSION Our results showed that the high level of gastric hepcidin induced ferroptosis in the stomach but also inhibited iron absorption in the intestines. Inhibiting hepcidin might be a new strategy for the prevention of CAG in the future.
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Affiliation(s)
- Yashuo Zhao
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Jianing Zhao
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Hongyu Ma
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Yan Han
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Weichao Xu
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Jie Wang
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Yanru Cai
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Xuemei Jia
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
| | - Qingzhong Jia
- School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
| | - Qian Yang
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang 050013, China
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang 050013, China
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Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. CHILDREN 2022; 9:children9071083. [PMID: 35884067 PMCID: PMC9322908 DOI: 10.3390/children9071083] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022]
Abstract
H. pylori is involved in the development of 80% of gastric cancers and 5.5% of all malignant conditions worldwide. Its persistence within the host’s stomach causes chronic inflammation, which is a well-known hallmark of carcinogenesis. A wide range of cytokines was reported to be involved in the initiation and long-term persistence of this local and systemic inflammation. IL-8 was among the first cytokines described to be increased in patients with H. pylori infection. Although, this cytokine was initially identified to exert a chemoattracting effect that represents a trigger for the activation of inflammatory cells within H.-pylori-infected mucosa, more recent studies failed in encountering any association between IL-8 and H. pylori infection. IL-6 is a multifunctional, pleiotropic and multipotent cytokine involved in mediating the interaction between innate and adaptive immunity with a dichotomous role acting as both a proinflammatory and an anti-inflammatory cytokine depending on the signaling pathway. IL-1α functions as a promoter of angiogenesis and vascular endothelial cell proliferation in gastric carcinoma since it is closely related to H.-pylori-induced inflammation in children. IL-1β is an essential trigger and enhancer of inflammation. The association between a low IL-1β level and an increased TNF-α level might be considered a risk factor for peptic ulcer disease in the setting of H. pylori infection. IL-10 downregulates both cytotoxic inflammatory responses and cell-mediated immune responses. H. pylori uses the immunosuppressive role of IL-10 to favor its escape from the host’s immune system. TGFβ is a continuous inflammatory mediator that promotes the adherence of H. pylori to the host’s cells and their subsequent colonization. The role of H.-pylori-induced inflammatory responses in the onset of gastric carcinogenesis seems to represent the missing puzzle piece for designing effective preventive and therapeutic strategies in patients with H.-pylori-associated gastric cancer.
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Sharndama HC, Mba IE. Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz J Microbiol 2022; 53:33-50. [PMID: 34988937 PMCID: PMC8731681 DOI: 10.1007/s42770-021-00675-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is an organism associated with ulcer disease and gastric cancer. The latter is one of the most prevalent malignancies and currently the fourth major cause of cancer-related deaths globally. The pathogen infects about 50% of the world population, and currently, no treatment ensures its total elimination. There has been an increase in our understanding of the pathophysiology and pathogenesis mechanisms of H. pylori over the years. H. pylori can induce several genetic alterations, express numerous virulence factors, and trigger diverse adaptive mechanisms during its adherence and colonization. For successful colonization and infection establishment, several effector proteins/toxins are released by the organism. Evidence is also available reporting spiral to coccoid transition as a unique tactic H. pylori uses to survive in the host's gastrointestinal tract (GIT). Thus, the virulence and pathogenicity of H. pylori are under the control of complex interplay between the virulence factors, host, and environmental factors. Expounding the role of the various virulence factors in H. pylori pathogenesis and clinical outcomes is crucial for vaccine development and in providing and developing a more effective therapeutic intervention. Here we critically reflect on H. pylori infection and delineate what is currently known about the virulence and pathogenesis mechanisms of H. pylori.
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Affiliation(s)
| | - Ifeanyi Elibe Mba
- Department of Microbiology, University of Nigeria, Nsukka, Enugu, Nigeria.
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Alexander SM, Retnakumar RJ, Chouhan D, Devi TNB, Dharmaseelan S, Devadas K, Thapa N, Tamang JP, Lamtha SC, Chattopadhyay S. Helicobacter pylori in Human Stomach: The Inconsistencies in Clinical Outcomes and the Probable Causes. Front Microbiol 2021; 12:713955. [PMID: 34484153 PMCID: PMC8416104 DOI: 10.3389/fmicb.2021.713955] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
Pathogenic potentials of the gastric pathogen, Helicobacter pylori, have been proposed, evaluated, and confirmed by many laboratories for nearly 4 decades since its serendipitous discovery in 1983 by Barry James Marshall and John Robin Warren. Helicobacter pylori is the first bacterium to be categorized as a definite carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO). Half of the world’s population carries H. pylori, which may be responsible for severe gastric diseases like peptic ulcer and gastric cancer. These two gastric diseases take more than a million lives every year. However, the role of H. pylori as sole pathogen in gastric diseases is heavily debated and remained controversial. It is still not convincingly understood, why most (80–90%) H. pylori infected individuals remain asymptomatic, while some (10–20%) develop such severe gastric diseases. Moreover, several reports indicated that colonization of H. pylori has positive and negative associations with several other gastrointestinal (GI) and non-GI diseases. In this review, we have discussed the state of the art knowledge on “H. pylori factors” and several “other factors,” which have been claimed to have links with severe gastric and duodenal diseases. We conclude that H. pylori infection alone does not satisfy the “necessary and sufficient” condition for developing aggressive clinical outcomes. Rather, the cumulative effect of a number of factors like the virulence proteins of H. pylori, local geography and climate, genetic background and immunity of the host, gastric and intestinal microbiota, and dietary habit and history of medicine usage together determine whether the H. pylori infected person will remain asymptomatic or will develop one of the severe gastric diseases.
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Affiliation(s)
| | | | - Deepak Chouhan
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.,Centre for Doctoral Studies, Manipal Academy of Higher Education, Manipal, India
| | | | | | - Krishnadas Devadas
- Department of Gastroenterology, Government Medical College, Trivandrum, India
| | - Namrata Thapa
- Biotech Hub, Department of Zoology, Nar Bahadur Bhandari Degree College, Gangtok, India
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Haile K, Timerga A. Evaluation of Hematological Parameters of Helicobacter pylori-Infected Adult Patients at Southern Ethiopia: A Comparative Cross-Sectional Study. J Blood Med 2021; 12:77-84. [PMID: 33654446 PMCID: PMC7910148 DOI: 10.2147/jbm.s294958] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/11/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is a global public health problem, a higher burden of the infection was reported in developing countries including Ethiopia. It has been associated with several gastrointestinal diseases, and recently implicated in some hematological abnormalities. Despite the high prevalence of H. pylori infection in Ethiopia, there was limited data regarding the relationship between hematological parameters with H. pylori infection. Therefore, this study aimed to evaluate selected hematological parameters of H. pylori-infected patients attending Wachemo University Nigist Eleni Mohammed Memorial Referral Hospital (WUNEMMRH), Hosanna, Southern, Ethiopia. METHODS AND MATERIALS A comparative cross-sectional study was conducted from January to May 2019 among 374 (187 H. pylori-infected patients and 187controls) study participants. Data on socio-demographic characteristics were collected using a structured questionnaire. A five-milliliter venous blood sample was collected for hematological parameter analysis. Approximately two gram of stool specimen was collected to assess the presence of H. pylori antigen. Data were entered and analyzed by using SPSS version 21. Pearson correlation analysis and independent sample T-test was performed, and P-value < 0.05 was considered statistically significant. RESULTS Mean value of Hgb (p<0.001), RBC count (p<0.001), HCT (p<0.001), MCV (p=0.003), MCH (p=0.008), and MCHC (p=0.006) of H. pylori-infected patients were significantly lower than control group. However, the mean value of RDW (p=0.003) in H. pylori-infected patients was significantly higher than in the control group. About 13.3%, 7%, 6.4%, and 18.2% of H. pylori-infected patients showed reduced Hgb concentration, RBC count, HCT, and MCV values, respectively. CONCLUSION The study showed a statistically significant difference in the mean value of Hgb, RBC count, HCT, MCV, MCH, MCHC, and RDW of H. pylori-infected patients and controls. Thus, hematological parameters should be considered for proper diagnosis and management of H. pylori-infected patients and eradication of this microorganism from infected patients, determination of hematological parameters for H. pylori-infected patients were recommended.
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Affiliation(s)
- Kassahun Haile
- Department of Medical Laboratory Science, College of Medicine and Health Sciences, Wolkite University, Wolkite, Ethiopia
| | - Abebe Timerga
- Department of Biomedical Science, Wolkite University, Wolkite, Ethiopia
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Stefanelli G, Viscido A, Longo S, Magistroni M, Latella G. Persistent Iron Deficiency Anemia in Patients with Celiac Disease Despite a Gluten-Free Diet. Nutrients 2020; 12:E2176. [PMID: 32708019 PMCID: PMC7468819 DOI: 10.3390/nu12082176] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 12/12/2022] Open
Abstract
Celiac disease (CD) is an autoimmune disorder characterized by intolerance to dietary gluten in genetically predisposed subjects. Iron deficiency anemia (IDA) is a common sign in CD, being the only abnormality in approximately 40% of celiac patients. A multifactorial etiology leads to IDA in CD. The two main causes are the villous atrophy of the mucosa at the site of iron absorption (the duodenum) and the resulting inflammation, which triggers the mechanism that leads to the anemia of chronic disease. Until now, it has been unclear why some patients with CD continue to have IDA despite a careful gluten-free diet (GFD) and the normalization of villous atrophy. Furthermore, some celiac patients are refractory to oral iron supplementation despite the healing of the mucosa, and they thus require periodic intravenous iron administration. The Marsh classification evaluates the degree of inflammation and villous atrophy, but it does not assess the possible persistence of ultrastructural and molecular alterations in enterocytes. The latter was found in CD in remission after adopting a GFD and could be responsible for the persistently reduced absorption of iron and IDA. Even in non-celiac gluten sensitivity, anemia is present in 18.5-22% of patients and appears to be related to ultrastructural and molecular alterations in intestinal microvilli. It is possible that a genetic component may also play a role in IDA. In this review, we evaluate and discuss the main mechanisms of IDA in CD and the possible causes of its persistence after adopting a GFD, as well as their therapeutic implications.
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Affiliation(s)
| | | | | | | | - Giovanni Latella
- Gastroenterology, Hepatology and Nutrition Division, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.S.); (A.V.); (S.L.); (M.M.)
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Enko D, Wagner H, Kriegshäuser G, Wögerer J, Halwachs-Baumann G, Schnedl WJ, Zelzer S, Fauler G, Mangge H, Markus H, Meinitzer A. Iron status determination in individuals with Helicobacter pylori infection: conventional vs. new laboratory biomarkers. Clin Chem Lab Med 2019; 57:982-989. [PMID: 31154451 DOI: 10.1515/cclm-2018-1182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 12/05/2018] [Indexed: 12/28/2022]
Abstract
Background Helicobacter pylori has been associated with iron deficiency (ID). This study is aimed at investigating ID with conventional (ferritin, transferrin saturation [TSAT]) and new biomarkers (soluble transferrin receptor [sTfR], sTfR/log ferritin, reticulocyte hemoglobin content [CHr], hepcidin-25) in patients sub-grouped by the presence or absence of H. pylori infection. Methods In total, 200 consecutive outpatients, who were referred for the H. pylori 13C-urea breath test (13C-UBT), underwent blood testing for ID. Additionally, Thomas-plot (TP)-analyses (sTfR/log ferritin, CHr) were calculated. Results Fifty-three and 147 individuals were found with and without H. pylori infection, respectively. Patients with H. pylori infection showed a higher sTfR concentration (p<0.02) and a higher sTfR/log ferritin ratio (p<0.05). Based on a ferritin <30 μg/L and/or a TSAT <20%, 25/53 (47.2%) patients with H. pylori infection and 63/147 (42.9%) without H. pylori infection showed ID. Based on TP-analyses, 10/53 (18.9%) patients with and 17/147 (11.6%) without H. pylori infection were identified with ID. Completed eradication therapy tended to be associated with functional ID. Conclusions Helicobacter pylori infection was associated with significantly higher plasma sTfR concentrations and sTfR/log ferritin ratios. Patients with H. pylori eradication therapy were more often detected with functional ID compared to patients without eradication therapy, when using the new biomarkers.
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Affiliation(s)
- Dietmar Enko
- Institute of Clinical Chemistry and Laboratory Medicine, General Hospital Steyr, Steyr, Austria.,Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Helga Wagner
- Department of Applied Statistics, Johannes Kepler University Linz, Linz, Austria
| | - Gernot Kriegshäuser
- Institute of Clinical Chemistry and Laboratory Medicine, General Hospital Steyr, Steyr, Austria.,Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Julia Wögerer
- Institute of Clinical Chemistry and Laboratory Medicine, General Hospital Steyr, Steyr, Austria
| | | | | | - Sieglinde Zelzer
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Harald Mangge
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Herrmann Markus
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Andreas Meinitzer
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
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Chen ST, Ni YH, Li CC, Liu SH. Hepcidin correlates with interleukin-1β and interleukin-6 but not iron deficiency in children with Helicobacter pylori infection. Pediatr Neonatol 2018; 59:611-617. [PMID: 29548703 DOI: 10.1016/j.pedneo.2018.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 12/26/2017] [Accepted: 02/07/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Helicobacter pylori infection is associated with iron deficiency (ID) in children. Inflammatory cytokine reactions could influence the consequences of H. pylori infection. Hepcidin is an important regulator in iron homeostasis and could be induced by chronic inflammation. The relationship between hepcidin and cytokine levels in children infected with H. pylori remains controversial. METHODS Based on serology testing for anti-H. pylori IgG, participants (43 seropositive and 43 seronegative) aged 10-18 years were enrolled. Serum hepcidin levels and iron profiles, including iron, ferritin, and total iron-binding capacity, were measured. ID is defined as iron saturation less than 15%. Seropositive children were divided into low hepcidin (n = 22) and high hepcidin (n = 21) groups. IL-1β, IL-6, and IL-8 serum levels were compared. RESULTS Serum IL-1β and IL-6 levels were comparable between H. pylori seropositive and seronegative children, as were the median serum hepcidin levels (6.5 ng/mL versus 8.6 ng/mL; P = 0.1318). Median levels of serum iron, ferritin, and iron saturation were significantly lower in seropositive children with low hepcidin than in those with high hepcidin (P = 0.0123, P = 0.0001, and P = 0.0004, respectively). The prevalence of ID was significantly higher in those with low serum hepcidin levels (33.3% versus 4.5%; P = 0.015). Compared to the high hepcidin seropositive group, the low hepcidin group had significantly lower median serum levels of cytokines IL-1β and IL-6, but not IL-8 (P = 0.0151 and P = 0.0015, respectively). CONCLUSIONS Inflammatory cytokines IL-1β and IL-6, but not IL-8, might be associated with increased hepcidin levels among H. pylori-seropositive children. Further studies are needed to clarify the role of hepcidin.
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Affiliation(s)
- Szu-Ta Chen
- Department of Pediatrics, National Taiwan University Hospital Yun-Lin Branch, National Taiwan University, Taiwan; Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan
| | - Chuan-Chun Li
- Department of Laboratory Medicine, National Taiwan University Hospital Yun-Lin Branch, National Taiwan University, Taiwan
| | - Shing-Hwa Liu
- Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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11
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Doguer C, Ha JH, Collins JF. Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Compr Physiol 2018; 8:1433-1461. [PMID: 30215866 DOI: 10.1002/cphy.c170045] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.
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Affiliation(s)
- Caglar Doguer
- Food Science and Human Nutrition Department, University of Florida, Florida, Gainesville, USA.,Nutrition and Dietetics Department, Namık Kemal University, Tekirdag, Turkey
| | - Jung-Heun Ha
- Food Science and Human Nutrition Department, University of Florida, Florida, Gainesville, USA.,Department of Food and Nutrition, Chosun University Note: Caglar Doguer and Jung-Heun Ha have contributed equally to this work., Gwangju, Korea
| | - James F Collins
- Food Science and Human Nutrition Department, University of Florida, Florida, Gainesville, USA
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Abstract
Helicobacter pylori infection is the principal cause of peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. Recent studies have shown that it may interfere with many biological processes and determine or influence the occurrence of many diseases outside the stomach. Currently, the role of H. pylori in idiopathic thrombocytopenic purpura and iron deficiency anemia is well documented. Emerging evidence suggests that it may also contribute to vitamin B12 deficiency, insulin resistance, metabolic syndrome, diabetes mellitus and non-alcoholic liver disease. Additionally, it may increase the risk of acute coronary syndrome, cerebrovascular disease, neurodegenerative disease and other miscellaneous disorders. Different pathogenic mechanisms have been hypothesized, including the occurrence of molecular mimicry and the induction of a low-grade inflammation. This review summarizes the results of the most relevant studies on the extra-gastroduodenal manifestations of H. pylori infection.
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Affiliation(s)
- Feng-Woei Tsay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, 386 Ta Chung 1st Road, Kaohsiung, 813 Taiwan, Republic of China
- Cheng Shiu University, Kaohsiung, Taiwan, Republic of China
| | - Ping-I Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, 386 Ta Chung 1st Road, Kaohsiung, 813 Taiwan, Republic of China
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Collins JF, Flores SR, Wang X, Anderson GJ. Mechanisms and Regulation of Intestinal Iron Transport. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2018:1451-1483. [DOI: 10.1016/b978-0-12-809954-4.00060-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Maruyama M, Kamimura K, Hoshiyama A, Hoshiyama K, Hoshiyama M, Hoshiyama Y, Terai S. Effect of Helicobacter pylori eradication on elder cases: Observational study in community-based medicine. World J Clin Cases 2017; 5:412-418. [PMID: 29291198 PMCID: PMC5740184 DOI: 10.12998/wjcc.v5.i12.412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/27/2017] [Accepted: 10/29/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To examine the effect of Helicobacter pylori (H. pylori) eradication therapy on the extra-gastrointestinal factors in elderly patients by a before-after observational study in community medicine. METHODS Medical records (1 May 2013-31 January 2014) of 130 patients who underwent H. pylori eradication therapy with 2-year after-eradication observation in our institute were reviewed. Data on sex; age; body weight; body mass index (BMI); mean corpuscular volume (MCV); total protein; low-density lipoprotein cholesterol, triglyceride, haemoglobin A1c and haemoglobin levels and gastric hyperplastic polyps (GHPs) at eradication was extracted. Two-year after-eradication change in data was analysed by paired-sample t-test; relationship between GHPs and subclinical iron deficiency anaemia (IDA) improvement was evaluated. RESULTS The mean patient age (median, interquartile range) at eradication was 69.6 (71.5, 64-77) years. Paired-sample t-tests showed that body weight, BMI and MCV increased by 0.52 kg (P = 0.018), 0.25 kg/m2 (P = 0.006) and 0.83 fL (P < 0.001), respectively. The nonparametric Mann-Whitney test showed no significant difference in the change rate of MCV after eradication between the groups with and without GHPs (P = 0.892). CONCLUSION H. pylori eradication therapy prevented weight loss and subclinical IDA in elderly individuals. GHPs were not associated with subclinical IDA.
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Affiliation(s)
- Masaki Maruyama
- Department of Gastroenterology, Kashiwazaki General Hospital and Medical Center, Kashiwazaki, Niigata 945-8535, Japan
- Department of Internal Medicine, Kashiwazaki Chuo Hospital, Kashiwazaki, Niigata 945-0055, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Ayako Hoshiyama
- Department of Internal Medicine, Kashiwazaki Chuo Hospital, Kashiwazaki, Niigata 945-0055, Japan
| | - Koki Hoshiyama
- Department of Internal Medicine, Kashiwazaki Chuo Hospital, Kashiwazaki, Niigata 945-0055, Japan
| | - Mari Hoshiyama
- Department of Internal Medicine, Kashiwazaki Chuo Hospital, Kashiwazaki, Niigata 945-0055, Japan
| | - Yoshihiro Hoshiyama
- Department of Surgery, Kashiwazaki Chuo Hospital, Kashiwazaki, Niigata 945-0055, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
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Stein J, Connor S, Virgin G, Ong DEH, Pereyra L. Anemia and iron deficiency in gastrointestinal and liver conditions. World J Gastroenterol 2016; 22:7908-7925. [PMID: 27672287 PMCID: PMC5028806 DOI: 10.3748/wjg.v22.i35.7908] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 07/18/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
Iron deficiency anemia (IDA) is associated with a number of pathological gastrointestinal conditions other than inflammatory bowel disease, and also with liver disorders. Different factors such as chronic bleeding, malabsorption and inflammation may contribute to IDA. Although patients with symptoms of anemia are frequently referred to gastroenterologists, the approach to diagnosis and selection of treatment as well as follow-up measures is not standardized and suboptimal. Iron deficiency, even without anemia, can substantially impact physical and cognitive function and reduce quality of life. Therefore, regular iron status assessment and awareness of the clinical consequences of impaired iron status are critical. While the range of options for treatment of IDA is increasing due to the availability of effective and well-tolerated parenteral iron preparations, a comprehensive overview of IDA and its therapy in patients with gastrointestinal conditions is currently lacking. Furthermore, definitions and assessment of iron status lack harmonization and there is a paucity of expert guidelines on this topic. This review summarizes current thinking concerning IDA as a common co-morbidity in specific gastrointestinal and liver disorders, and thus encourages a more unified treatment approach to anemia and iron deficiency, while offering gastroenterologists guidance on treatment options for IDA in everyday clinical practice.
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Gao P, Liu M, Zhou YN. Correlation of nodular gastritis with Helicobacter pylori infection. Shijie Huaren Xiaohua Zazhi 2015; 23:5177-5183. [DOI: 10.11569/wcjd.v23.i32.5177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nodular gastritis (NG) is a form of chronic Helicobacter pylori (H. pylori) associated gastritis affecting the gastric antrum, which is characterized endoscopically by the presence of small nodular lesions resembling gooseflesh. It is generally accepted that NG is characterized histologically by hyperplasia of lymphoid follicles. At present, there is a wide range of H. pylori infections in the world, and NG is an endoscopic sign of H. pylori infection. After H. pylori eradication therapy, the clinical manifestations, pathology and endoscopic performance of NG patients can be improved significantly. Therefore, H. pylori eradication should be performed as early as possible in NG patients. The research data about NG is still very limited. The relationship between NG as potentially precancerous lesions and gastroduodenal diseases is still a debate and needs to be further explored. Here we review the research progress in understanding the correlation between NG and H. pylori.
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Burns M, Muthupalani S, Ge Z, Wang TC, Bakthavatchalu V, Cunningham C, Ennis K, Georgieff M, Fox JG. Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice. PLoS One 2015; 10:e0142630. [PMID: 26575645 PMCID: PMC4648568 DOI: 10.1371/journal.pone.0142630] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 10/23/2015] [Indexed: 01/25/2023] Open
Abstract
Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world’s population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6–9 weeks of age, and were necropsied at 27–29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1-infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression.
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Affiliation(s)
- Monika Burns
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Timothy C. Wang
- Department of Medicine, Columbia University, New York, New York, United States of America
| | - Vasudevan Bakthavatchalu
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Catriona Cunningham
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, United Kingdom
| | - Kathleen Ennis
- Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Michael Georgieff
- Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- * E-mail:
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Franceschi F, Gasbarrini A, Polyzos SA, Kountouras J. Extragastric Diseases and Helicobacter pylori. Helicobacter 2015; 20 Suppl 1:40-6. [PMID: 26372824 DOI: 10.1111/hel.12256] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The extragastric manifestations of Helicobacter pylori infection still remain a very strong topic throughout the H. pylori world. Indeed, H. pylori may interfere with many biological processes, both inside and outside of the stomach, possibly influencing or determining the occurrence of many diseases outside of the stomach. While its role in idiopathic thrombocytopenic purpura and sideropenic anemia has already been recognized, emerging evidence suggests that H. pylori may increase the risk of acute coronary syndrome, contribute to insulin resistance and be associated with neurodegenerative, respiratory, and other miscellaneous disorders previously associated with other conditions. Different pathogenic mechanisms have been hypothesized, including the induction of a low-grade inflammatory state and the occurrence of molecular mimicry mechanisms. This review summarizes the results of the most relevant studies published on this topic in the last year.
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Affiliation(s)
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Catholic University of Rome, Rome, Italy
| | - Stergios A Polyzos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Macedonia, Greece
| | - Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Macedonia, Greece
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Emiralioglu N, Yenicesu I, Sari S, Egritas O, Poyraz A, Pasaoglu OT, Celik B, Dalgic B. An insight into the relationships between prohepcidin, iron deficiency anemia, and interleukin-6 values in pediatric Helicobacter pylori gastritis. Eur J Pediatr 2015; 174:903-910. [PMID: 25567795 DOI: 10.1007/s00431-014-2482-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 10/21/2014] [Accepted: 11/21/2014] [Indexed: 02/08/2023]
Abstract
UNLABELLED 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 inflammation-driven 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. pylori-positive 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.
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Affiliation(s)
- Nagehan Emiralioglu
- Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Ankara, Turkey,
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