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Ali I, Muhammad S, Naqvi SSZH, Wei L, Yan W, Khan MF, Mahmood A, Liu H, Shah W. Hepatitis B Virus-Associated Liver Carcinoma: The Role of Iron Metabolism and Its Modulation. J Viral Hepat 2025; 32:e14016. [PMID: 39445513 DOI: 10.1111/jvh.14016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 08/17/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.
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Affiliation(s)
- Imran Ali
- Department of General Surgery, Subspecialty Hepatobiliary Surgery, Shanxi First Medical Hospital Affiliated With Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Shoaib Muhammad
- Department of Urology, First Hospital of Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Syed Shah Zaman Haider Naqvi
- Department of Endocrinology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences; Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Lingxi Wei
- Laboratory of Physiology, Shanxi Medical University, Jing Zhong, China
| | - Wenqi Yan
- Shandong University, Ji Nan, Shandong, China
| | - Muhammad Fiaz Khan
- Department of Zoology, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Ahmad Mahmood
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hong Liu
- Department of General Surgery, Subspecialty Hepatobiliary Surgery, Shanxi First Medical Hospital Affiliated With Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Wahid Shah
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, China
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, China
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Pan C, Kong X, Wu Z, Fei Q. The role of hepatitis B virus surface protein in inducing Sertoli cell ferroptosis. Andrology 2024; 12:643-654. [PMID: 37644905 DOI: 10.1111/andr.13520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUNDS Hepatitis B virus infection could result in male infertility with sperm defects and dysfunction. Sertoli cells are essential for testis function and play a crucial role in spermatogenesis. Sertoli cell death contributes to spermatogenesis impairment, leading to poor sperm quality. Ferroptosis has been implicated as a mechanism of Sertoli cell death. The issue in studying the relationship between hepatitis B virus and Sertoli cell ferroptosis has not yet been addressed. OBJECTIVES To explore the mechanisms underlying ferroptosis in hepatitis B virus-exposed Sertoli cells. MATERIALS AND METHODS Human Sertoli cells were treated in vitro with levels of 25, 50, and 100 μg/mL of hepatitis B virus surface protein (HBs). Cell viability and levels of glutathione, malondialdehyde, cellular ferrous ion (Fe2+ ), lipid peroxidation, and N6-methyladenosine in Sertoli cells were detected. The level of glutathione peroxidase 4, transferrin receptor 1, ferritin heavy chain, tripartite motif (TRIM) 37, methyltransferase like 3, and insulin-like growth factor 2 mRNA binding protein 2 was examined. Cell transfection was carried out to alter expression of ferroptosis-related proteins. qPCR and immunoblotting were performed to measure protein expression level. Immunoprecipitation was applied to determine the protein and protein-RNA interaction. Luminescence analysis was performed to identify the target of methyltransferase like 3. RESULTS HBs exposure triggered ferroptosis featured with increased intracellular Fe2+ ion, reduced cell viability and expression of glutathione peroxidase 4 in Sertoli cells. HBs treatment significantly increased TRIM37 expression, which suppressed glutathione peroxidase 4 expression through ubiquitination. TRIM37 silencing attenuated the effect of HBs exposure-regulated cell viability and ferroptosis. HBs upregulated N6-methyladenosine modification in TRIM37 3'-UTR by increasing methyltransferase like 3 expression. The binding of N6-methyladenosine reader insulin-like growth factor 2 mRNA binding protein 2 and TRIM37 3'-UTR enhanced the stability of TRIM37 mRNA. CONCLUSION HBs can decrease human Sertoli cell viability by promoting ferroptosis induced by the loss of glutathione peroxidase 4 activity through TRIM37-mediated ubiquitination of glutathione peroxidase 4. The findings highlight the role of TRIM37/glutathione peroxidase 4 signaling responsible for ferroptosis regulation in hepatitis B virus-infected Sertoli cells.
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Affiliation(s)
- Chengshuang Pan
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangbin Kong
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhigang Wu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qianjin Fei
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Ye Y, Xie J, Wang L, He C, Tan Y. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report. Open Med (Wars) 2023; 18:20230693. [PMID: 37016704 PMCID: PMC10066873 DOI: 10.1515/med-2023-0693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/17/2023] [Accepted: 03/17/2023] [Indexed: 04/01/2023] Open
Abstract
Abstract
Chronic hepatitis B (CHB) often causes iron overload in the liver but rarely causes severe secondary hemochromatosis (SH). A 48-year-old man was infected with CHB via vertical transmission. For 21 years, nonstandard treatment with second-line hepatitis B antiviral drugs has been administered. Repeated abnormalities in the liver transaminase function and continuous low-level replication of the hepatitis B virus (HBV) have been detected. The skin had turned black 5 years back. Biochemical tests and imaging revealed the presence of hemochromatosis. A liver biopsy suggested severe iron overload. Two genetic tests ruled out hereditary hemochromatosis. The patient was diagnosed with SH and treated with 400 ml bloodletting once per week and an iron-chelating agent. After 12 weeks, liver function was normal, and the skin turned white. First, hepatitis B surface antigen (HBsAg) was lost, and HBV DNA was copied at low levels. The patient was diagnosed with an occult hepatitis B infection. HBV DNA was undetectable after 4 weeks of antiviral treatment with tenofovir. Upon reviewing the patient’s medical history, hemochromatosis was believed to be related to CHB with chronic inflammatory damage and no complete virological response. Improvements in hemochromatosis may promote HBsAg disappearance.
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Affiliation(s)
- Yun Ye
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Jing Xie
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Lina Wang
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Cong He
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Youwen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
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Rujeerapaiboon N, Tantiworawit A, Piriyakhuntorn P, Rattanathammethee T, Hantrakool S, Chai-Adisaksopha C, Rattarittamrong E, Norasetthada L, Fanhchaksai K, Charoenkwan P. Correlation Between Serum Ferritin and Viral Hepatitis in Thalassemia Patients. Hemoglobin 2021; 45:175-179. [PMID: 34121572 DOI: 10.1080/03630269.2021.1926277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Serum ferritin is an acute phase protein; importantly, its level is noticeably increased in response to iron overload and systemic inflammation. The iron overload status in thalassemia patients has been recognized as a potential way to measure liver iron concentration (LIC) levels using magnetic resonance imaging (MRI). The aim of this study was to investigate the effect of chronic viral hepatitis on the level of serum ferritin in patients with thalassemia. A cross-sectional study was conducted involving chronic viral hepatitis infection. Mean serum ferritin and LIC levels were recorded. The LIC values were used to divide the patients into two groups; a higher LIC group (>5 mg Fe/g) and a lower LIC group (<5 mg Fe/g). Mean serum ferritin levels were then compared between the two LIC groups. We identified 32 thalassemia patients comprising of 13 chronic viral hepatitis patients, seven patients with hepatitis B virus (HBV), and six patients with hepatitis C virus (HCV). With regard to the group with higher LIC values, the mean serum ferritin levels in the hepatitis group were significantly higher than for those in the non hepatitis group (1776 ± 488 vs. 967 ± 860 ng/mL, p = 0.03). Furthermore, the linear correlation between the mean serum ferritin levels and the viral load in the non transfusion-dependent thalassemia (NTDT) group were found to be significantly correlated (r = 0.7, p = 0.04). Chronic viral hepatitis was determined to be a possible casualty of disproportionately high ferritin levels in the NTDT group.
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Affiliation(s)
- Natthapat Rujeerapaiboon
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Adisak Tantiworawit
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pokpong Piriyakhuntorn
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Thanawat Rattanathammethee
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Sasinee Hantrakool
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chatree Chai-Adisaksopha
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Ekarat Rattarittamrong
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Lalita Norasetthada
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kanda Fanhchaksai
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pimlak Charoenkwan
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Shoja Z, Chenari M, Jafarpour A, Jalilvand S. Role of iron in cancer development by viruses. Rev Med Virol 2019; 29:e2045. [PMID: 30994254 DOI: 10.1002/rmv.2045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
Increased levels of iron in body are attributed to higher cancer risk. Given the fact that 16% of all human cancers are caused by viral infections, iron is suggested to play an important role in carcinogenesis particularly those induced by viral infections. The present study provides an updated summary of the literature and the plausible mechanisms of iron involvement in cancer development by viruses. Our understanding about the interplay between viral infections and iron in different settings particularly cancer development is yet to be improved as it may shed a new light in development of new therapeutic strategies.
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Affiliation(s)
| | - Maryam Chenari
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Jafarpour
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Jalilvand
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Miyanishi K, Tanaka S, Sakamoto H, Kato J. The role of iron in hepatic inflammation and hepatocellular carcinoma. Free Radic Biol Med 2019; 133:200-205. [PMID: 30017991 DOI: 10.1016/j.freeradbiomed.2018.07.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023]
Abstract
Iron is an essential for organisms and the liver plays a major role in its storage. In pathologic conditions, where iron absorption from the intestine or iron uptake into the hepatocytes is increased, excess iron accumulates in the hepatocytes, leading to hepatocyte injury through the production of free radicals. Iron exerts its toxicity by catalyzing the generation of reactive oxygen species (ROS). ROS causes cell injury by inducing damage to the lysosomal, cytoplasmic, nuclear and mitochondrial membranes, apoptosis through activation of the caspase cascade, and hyperoxidation of fatty chains. In this manuscript, we reviewed the articles regarding role of iron in hepatic inflammation and hepatocellular carcinoma.
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Affiliation(s)
- Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; Department of Infection Control, and Laboratory Medicine, Sapporo Medical University, School of Medicine, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
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Gao YH, Wang JY, Liu PY, Sun J, Wang XM, Wu RH, He XT, Tu ZK, Wang CG, Xu HQ, Niu JQ. Iron metabolism disorders in patients with hepatitis B-related liver diseases. World J Clin Cases 2018; 6:600-610. [PMID: 30430115 PMCID: PMC6232559 DOI: 10.12998/wjcc.v6.i13.600] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/12/2018] [Accepted: 10/16/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the relationship between levels of iron metabolism markers and hepatitis B virus (HBV)-related chronic liver diseases.
METHODS This case-control study with 318 participants included 78 cases of chronic hepatitis B, 85 cases of HBV-related liver cirrhosis, 77 cases of HBV-related hepatocellular carcinoma, and 78 healthy controls. Markers of iron metabolism were detected in participants. Hematological and biochemical parameters and HBV-DNA were assessed. Child-Pugh grade and Barcelona Clinic Liver Cancer stage were determined for each hepatocellular carcinoma patient. Perls’ staining was performed on liver sections. The SPSS program was used for all statistical analyses, and statistical significance was considered if a P-value < 0.05.
RESULTS Significantly higher serum ferritin and lower serum hepcidin levels were detected in all groups of HBV-infected patients compared with healthy controls. Serum iron, total iron binding capacity, and serum transferrin levels were significantly lower in patients with cirrhosis and hepatocellular carcinoma, whereas the hepcidin level was higher than that in chronic hepatitis B patients. Correlation analysis indicated that serum hepcidin was negatively correlated with HBV-DNA load (P < 0.01). Serum ferritin and transferrin saturation levels increased proportionally to the extent of liver cirrhosis and poorer Child-Pugh scores (P < 0.05). The decreased serum iron and transferrin saturation levels were significantly correlated with a smaller hepatocellular carcinoma tumor burden according to Barcelona Clinic Liver Cancer staging. Liver histology showed a clearly increasing trend in iron deposition in the liver tissues with increased fibrosis, which became prominent at stages 3 (severe liver fibrosis) and 4 (cirrhosis).
CONCLUSION Iron metabolism disorders occur in patients with HBV-related liver diseases. The serum markers of iron metabolism disorders vary in different stages of HBV-related liver diseases.
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Affiliation(s)
- Yan-Hang Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Jing-Yun Wang
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
- Department of Gastroenterology, Weihaiwei People’s Hospital, Weihai 264200, Shandong Province, China
| | - Pei-Yan Liu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Jing Sun
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
- Department of Gastroenterology, Heping Hospital, Changzhi Medical College, Changzhi 046011, Shanxi Province, China
| | - Xiao-Mei Wang
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Hong Wu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Xiu-Ting He
- Department of Geriatrics, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng-Kun Tu
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Chun-Guang Wang
- Department of Surgery, The Second Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Jun-Qi Niu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun 130021, Jilin Province, China
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Zou DM, Rong DD, Zhao H, Su L, Sun WL. Improvement of chronic hepatitis B by iron chelation therapy in a patient with iron overload: A case report. Medicine (Baltimore) 2017; 96:e9566. [PMID: 29384977 PMCID: PMC6392519 DOI: 10.1097/md.0000000000009566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
RATIONALE This report describes seroconversion of hepatitis B surface antigen (HBsAg) in a patient with marked iron overload caused by chronic hepatitis B (CHB) after receiving iron chelation therapy and discusses the role of iron chelation therapy in CHB. PATIENT CONCERNS Increased serum ferritin level for 2 months. DIAGNOSIS Secondary iron overload and CHB. INTERVENTION To relieve iron load of the body, the patient underwent regular phlebotomy therapy and deferoxamine (DFO) therapy. During the therapy, serum ferritin and hepatitis B virus (HBV) were monitored and the iron concentration of the liver and heart were followed by T2* of magnetic resonance imaging (MRI) scan. OUTCOMES Serum ferritin gradually decreased. Approximately 1 year after the therapy, HBsAg turned persistently negative. LESSONS Iron chelation therapy may attenuate HBV infection.
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Affiliation(s)
| | - Dong-Dong Rong
- Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, P. R. China
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Natural history of chronic hepatitis C development and progression as a consequence of iron and HFE or TfR1 mutations. EGYPTIAN LIVER JOURNAL 2017. [DOI: 10.1097/01.elx.0000524701.59978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Gerayli S, Pasdar A, Shakeri MT, Sepahi S, Hoseini SM, Ahadi M, Rostami S, Meshkat Z. Haplotype Analysis of Hemochromatosis Gene Polymorphisms in Chronic Hepatitis C Virus Infection: A Case Control Study. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e24675. [PMID: 27621921 PMCID: PMC5002998 DOI: 10.5812/ircmj.24675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 04/05/2015] [Accepted: 04/27/2015] [Indexed: 11/16/2022]
Abstract
Background Chronic hepatitis C virus (HCV) infection is frequently associated with elevated serum iron markers. Polymorphisms in the hemochromatosis (HFE) genes are responsible for iron accumulation in most cases of hemochromatosis, and may play a role in HCV infection. Objectives We aimed to assess the prevalence of HFE gene polymorphisms in a group of Iranian HCV-infected patients, and to explore the association of these polymorphisms with HCV infection. Patients and Methods HFE gene polymorphisms were examined in a total of 69 HCV patients and 69 healthy controls using polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and diplotype analyses were performed using PHASE software. Results In a recessive analysis model of the His63Asp (H63D) locus (HH vs. HD + DD), the HH genotype was more common in patients compared to controls (adjusted P = 0.012; OR = 6.42 [95% CI: 1.51 - 27.33]). Also, in a recessive analysis model of the Cys282Tyr (C282Y) locus (CC vs. CY + YY), the CC genotype was more frequent in patients compared to controls (adjusted P = 0.03; OR = 5.06 [95% CI: 1.13 - 22.06]). In addition, there was a significant association between the HC haplotype and the HCDC diplotype and HCV infection. Conclusions Polymorphism in the hemochromatosis gene may confer some degree of risk for HCV infection, and individuals carrying the H and C alleles may be susceptible to this disease; however, a larger sample of HCV patients and healthy individuals may be necessary to further illustrate the role of these polymorphisms in HCV.
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Affiliation(s)
- Sina Gerayli
- Department of Biology, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, IR Iran
- Department of Biology, Western University, London, Ontario, N6A 5B7, Canada
| | - Alireza Pasdar
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Mohammad Taghi Shakeri
- Department of Biostatistics, Public Health School, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Samaneh Sepahi
- Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Seyed Mousalreza Hoseini
- Department of Gastroenterology and Hepatology, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Mitra Ahadi
- Department of Gastroenterology and Hepatology, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Sina Rostami
- Department of Biology, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, IR Iran
- The Influenza Centre, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway
| | - Zahra Meshkat
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Corresponding Author: Zahra Meshkat, Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, IR Iran. Tel: +98-5138012453, Fax: +98-5138002960, E-mail:
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Abstract
OBJECTIVE In patients with chronic hepatitis B virus (HBV) infection, it is not known whether altered serum iron markers are directly because of the infection or the associated liver injury. We determined the serum iron status of patients with chronic HBV infection, and investigated whether it is HBV infection or HBV-related liver injury that likely causes abnormal serum iron markers in chronic HBV infection. MATERIALS AND METHODS For a retrospective study, chronic HBV-infected patients (80 patients with cirrhosis and 76 patients without cirrhosis) and 58 healthy controls were enrolled. Serum alanine transaminase levels were measured to ascertain liver damage. Indicators of iron status included serum iron, ferritin, and transferrin. RESULTS Compared with noncirrhotic patients and healthy controls, the serum transferrin of cirrhotic patients was lower and the serum iron and ferritin values were higher (P < 0.001, all). In cirrhotic patients, the serum iron and ferritin levels correlated positively with serum alanine transaminase levels and the transferrin levels were inversely related to both end-stage liver disease scores and iron levels (all P < 0.01). CONCLUSION Serum iron markers tended to be aberrant in chronic HBV-infected patients with cirrhosis. The liver injury associated with HBV infection, but not chronic HBV infection directly, is likely the main cause for iron metabolism disorder.
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Fang C, Zhao C, Liu X, Yang P, Lu H. Protein alteration of HepG2.2.15 cells induced by iron overload. Proteomics 2012; 12:1378-1390. [PMID: 22589187 DOI: 10.1002/pmic.201100335] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 02/09/2012] [Indexed: 01/17/2023]
Abstract
Hepatitis B can progress into hepatocellular carcinoma. Body irons may interfere with the clearance of hepatitis B virus (HBV) and contribute to genesis of tumor. To investigate the role of iron played in HBV-related pathogenesis, here we studied the effect of iron with different concentrations and valence states on growth of HepG2.2.15 cells and secretion of virus proteins. A strong tolerance of HepG2.2.15 cells to iron challenge was found. The concentration of hepatitis B surface antigen in cell culture medium was decreased after iron stimulation. Lower concentrations of iron facilitated hepatitis B e-antigen (HBeAg) secretion. Fe(2+) appeared more effective on HBeAg secretion than Fe(3+) did. In parallel, the differential protein profiles in HepG2.2.15 cells were studied by iTRAQ and LC-MS/MS. The differentially expressed proteins were mainly involved in stress response, signal transduction, apoptosis, etc. Four proteins (14-3-3 β/α, VCP, migration inhibitory factor, and Nup153) were verified by Western-blotting and found to be consistent with the iTRAQ data. Interestingly, nuclear import of Nuclear factor kappa B (NFκB) and its activity were found to be affected by the decreased Nup153 in iron stimulated HepG2.2.15 cells. The results may indicate possible molecular mechanism how the synergism of HBV and iron stimulation damages host liver cells.
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Affiliation(s)
- Caiyun Fang
- Department of Chemistry, Fudan University, Shanghai, P. R. China
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Sebastiani G, Tempesta D, Alberti A. Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. J Viral Hepat 2012; 19:e170-6. [PMID: 22239515 DOI: 10.1111/j.1365-2893.2011.01508.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatic iron overload has been described in chronic hepatitis C as a cofactor affecting fibrosis progression. Data in patients with chronic hepatitis B infection are scarce. We investigated hepatic iron deposits and serum iron indices in 205 consecutive patients with hepatitis B and compensated liver disease. Mean age of the patients was 42.4 ± 12.4 years and 72.5% were males. Coinfection with hepatitis delta virus (HDV) was present in 8.8%. At least one of the serum iron indices was elevated in 41.5% of cases. Hepatic iron deposits were detected in 35.1% of patients, most of them being minimal (grade I) (59.7%) or mild (grade II) (27.8%). Variables significantly associated with hepatic iron deposits were male gender (P = 0.001), serum ferritin (P = 0.008), γGT (P = 0.05) and alkaline phosphatase (P = 0.05) levels. By multivariate analysis hepatic iron deposits correlated with serum ferritin [odds ratio (OR) 1.2, 95% confidence interval (CI) 1.05-1.4, P = 0.002]. Presence of mild-moderate (grades II and III) hepatic iron deposits could be excluded with high negative predictive value (90%) when serum ferritin was within normal values. A significant correlation between coinfection with HDV and hepatic iron deposits was also found (OR 4.23, 95% CI 1.52-11.82, P = 0.003). When compared to monoinfected cases, HDV positive patients had more elevated γGT (P = 0.03), more advanced fibrosis and more severe iron deposits (P < 0.0001). In conclusion, in well-compensated chronic hepatitis B infection, hepatic iron deposits and elevation of serum iron indices are common, especially in male gender and in patients coinfected with HDV. As HBV/HDV liver disease is generally more rapidly progressive than that caused by HBV monoinfection, we speculate that iron overload may be one of the factors contributing to the severity of liver disease.
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Affiliation(s)
- G Sebastiani
- Digestive Diseases, Hepatology and Clinical Nutrition Department, Dell'Angelo Hospital, Venice, Italy.
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14
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Ezzikouri S, Rebbani K, Mostafa A, El feydi AE, Afifi R, Brahim I, Kitab B, Benazzouz M, Kandil M, Nadifi S, Pineau P, Benjelloun S. Influence of mutation of the HFE gene on the progression of chronic viral hepatitis B and C in Moroccan patients. J Med Virol 2011; 83:2096-2102. [DOI: 10.1002/jmv.22245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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15
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Nair S, Arathy DS, Issac A, Sreekumar E. Differential gene expression analysis of in vitro duck hepatitis B virus infected primary duck hepatocyte cultures. Virol J 2011; 8:363. [PMID: 21781334 PMCID: PMC3152538 DOI: 10.1186/1743-422x-8-363] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 07/23/2011] [Indexed: 12/11/2022] Open
Abstract
Background The human hepatitis B virus (HBV), a member of the hepadna viridae, causes acute or chronic hepatitis B, and hepatocellular carcinoma (HCC). The duck hepatitis B virus (DHBV) infection, a dependable and reproducible model for hepadna viral studies, does not result in HCC unlike chronic HBV infection. Information on differential gene expression in DHBV infection might help to compare corresponding changes during HBV infection, and to delineate the reasons for this difference. Findings A subtractive hybridization cDNA library screening of in vitro DHBV infected, cultured primary duck hepatocytes (PDH) identified cDNAs of 42 up-regulated and 36 down-regulated genes coding for proteins associated with signal transduction, cellular respiration, transcription, translation, ubiquitin/proteasome pathway, apoptosis, and membrane and cytoskeletal organization. Those coding for both novel as well as previously reported proteins in HBV/DHBV infection were present in the library. An inverse modulation of the cDNAs of ten proteins, reported to play role in human HCC, such as that of Y-box binding protein1, Platelet-activating factor acetylhydrolase isoform 1B, ribosomal protein L35a, Ferritin, α-enolase, Acid α-glucosidase and Caspase 3, copper-zinc superoxide dismutase (CuZnSOD), Filamin and Pyruvate dehydrogenase, was also observed in this in vitro study. Conclusions The present study identified cDNAs of a number of genes that are differentially modulated in in vitro DHBV infection of primary duck hepatocytes. Further correlation of this differential gene expression in in vivo infection models would be valuable to understand the little known aspects of the hepadnavirus biology.
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Affiliation(s)
- Sajith Nair
- Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Kerala, India
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16
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Rashed MN. The role of trace elements on hepatitis virus infections: a review. J Trace Elem Med Biol 2011; 25:181-187. [PMID: 21880473 DOI: 10.1016/j.jtemb.2011.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 05/23/2011] [Accepted: 07/07/2011] [Indexed: 02/07/2023]
Abstract
The significance of the nutritional roles of trace metals (includes some heavy metals) is widely recognized, since these elements are as constituent components of many metal proteins and metalloenzymes serum trace metals levels, and their ratios are frequently reported to be good marker for diagnosing various diseases. Trace metals play an important role in liver disease particularly liver degeneration. Influence of trace elements has been studied in a large number of viruses belonging to different groups. This review reported the role of some trace elements iron (Fe), copper (Cu), cobalt (Co), manganese (Mn) and zinc (Zn) as well as toxic elements Pb on hepatitis virus infections.
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17
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Sebastiani G, Pantopoulos K. Disorders associated with systemic or local iron overload: from pathophysiology to clinical practice. Metallomics 2011; 3:971-86. [DOI: 10.1039/c1mt00082a] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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18
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Abstract
Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular injury and cell death. Within the liver, iron related oxidative stress can lead to fibrosis and ultimately to cirrhosis. Here we review the role of excessive iron in the pathologies associated with various chronic diseases of the liver. We also describe the molecular mechanism by which iron contributes to the development of hepatic fibrosis.
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Affiliation(s)
- Marie-A Philippe
- Hepatic Fibrosis Group, The Queensland Institute of Medical Research, PO Royal Brisbane and Women's Hospital, Brisbane 4029, Australia
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19
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Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol 2007; 13:4673-89. [PMID: 17729389 PMCID: PMC4611189 DOI: 10.3748/wjg.v13.i35.4673] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 05/01/2007] [Accepted: 05/09/2007] [Indexed: 02/06/2023] Open
Abstract
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
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Affiliation(s)
- Giada Sebastiani
- Venetian Institute of Molecular Medicine (VIMM), Padova and Digestive Diseases, Hepatology and Clinical Nutrition Department, Umberto I Hospital, Venice, Italy.
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20
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Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis 2007; 11:482-7. [PMID: 17600748 DOI: 10.1016/j.ijid.2007.04.007] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Revised: 02/26/2007] [Accepted: 04/05/2007] [Indexed: 02/06/2023] Open
Abstract
Withholding iron from potential pathogens is a host defense strategy. There is evidence that iron overload per se compromises the ability of phagocytes to kill microorganisms. Several hypotheses exist to explain the association of hemochromatosis with infection. A combination of mechanisms likely contributes to the increase in susceptibility to infection in these patients. A review of the current literature delineating various pathogens to which patients with hemochromatosis are potentially susceptible, and recent advances in the understanding of the association of hemochromatosis with infection, are discussed.
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Affiliation(s)
- Fida A Khan
- Department of Medicine, Section of Infectious Diseases, Ohio Valley Medical Center, 2000 Eoff Street, Wheeling, WV 26003, USA.
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21
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Ghaziani T, Alavian SM, Zali MR, Shahraz S, Agah M, Jensen KP, Ansari S, Sendi H, Lambrecht RW, Covault J, Bonkovsky HL. Serum measures of iron status and HFE gene mutations in patients with hepatitis B virus infection. Hepatol Res 2007; 37:172-8. [PMID: 17362299 DOI: 10.1111/j.1872-034x.2007.00026.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
AIM We tested associations between HFE mutations and hepatitis B virus (HBV) infection. We also explored measures of total body iron status and their association with chronic HBV infection. METHODS Serum measures of iron status and HFE mutations (C282Y, H63D, and S65C) were assessed in 344 Iranian patients with chronic HBV infection (214 asymptomatic carriers, 130 patients with chronic progressive liver disease [CPLD]) and 302 controls. RESULTS Frequencies of HFE mutations did not differ between patients with chronic HBV infection and controls (C282Y: P=0.9, H63D: P= 0.8, S65C: P=0.9). By logistic regression, advanced hepatic fibrosis was associated with HFE H63D mutation (OR=13.1, P=0.006; 95% CI=2.0-84.1). Higher levels of serum ferritin and transferrin saturation were observed in patients with CPLD than in healthy controls (P=0.0001 and 0.01, respectively, adjusted for age and sex). None of the serum iron measures was related to liver fibrosis stage or necroinflammatory grade. CONCLUSION Serum iron measures are associated with chronic progressive hepatitis B. Carriage of HFE mutations is not associated with the presence of chronic HBV infection or values of serum iron measures in this population, although HFE H63D is associated with more advanced hepatic fibrosis.
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Affiliation(s)
- Tahereh Ghaziani
- Department of Medicine, University of Connecticut Health Center, Farmington, USA
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22
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Bonkovsky HL, Naishadham D, Lambrecht RW, Chung RT, Hoefs JC, Nash SR, Rogers TE, Banner BF, Sterling RK, Donovan JA, Fontana RJ, Di Bisceglie AM, Ghany MG, Morishima C. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006; 131:1440-51. [PMID: 17101320 DOI: 10.1053/j.gastro.2006.08.036] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2006] [Accepted: 07/03/2006] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Iron overload may cause or contribute to hepatic injury and fibrosis. Mutations in the HFE gene may influence development or progression of chronic liver disease by increasing iron stores or modulating immune responses. The aim of this work was to assess the influence of HFE mutations and serum and hepatic measures of iron status on baseline features and response to lead-in therapy in subjects with advanced chronic hepatitis C enrolled in the Hepatitis C Anti-viral Long-term Treatment to prevent Cirrhosis (HALT-C) Trial. METHODS Entry criteria included an Ishak fibrosis score >2 and lack of iron overload (Scheuer iron grade <3+) according to local study pathologists. All baseline biopsy specimens were rescored by consensus of study pathologists, and detailed assessment of stainable iron was performed. Hepatic iron concentrations were measured on portions of 144 liver biopsy specimens. A total of 1051 out of 1145 subjects agreed to HFE mutational testing (C282Y, H63D, S65C). RESULTS Thirty-five percent carried at least one HFE gene mutation. There were no significant differences in the prevalence of HFE gene mutations among subjects with fibrosis (35.5%) versus cirrhosis (32.9%). Thirty-three percent of subjects had end-of-treatment and 16% sustained virologic responses. Presence of HFE mutations, in particular the H63D variation, was associated with increased end-of-treatment (40% vs 29%, P = .0078) and sustained virologic responses (20% with HFE mutation vs 14% sustained virologic response without HFE mutation; P = .009). CONCLUSIONS Although HFE mutations (especially the most frequent H63D mutation) are associated with increased iron loading, they are also associated with increased sustained virologic responses in US patients with advanced chronic hepatitis C.
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Affiliation(s)
- Herbert L Bonkovsky
- Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
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23
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Sendi H, Ghaziani T, Zali MR, Adibi P, Agah M, Jazayeri M, Shahraz S, Magnius L, Bonkovsky HL. Hemochromatosis Mutations in Iranians with Hepatitis B Virus Infection. Clin Infect Dis 2005; 40:e19-21. [PMID: 15668853 DOI: 10.1086/426143] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2004] [Accepted: 08/19/2004] [Indexed: 01/23/2023] Open
Abstract
In this study, the frequencies of the common hemochromatosis gene mutations were assessed in 75 Iranian subjects with chronic hepatitis B infection. We found that the major C282Y mutation was significantly more frequent in subjects infected with hepatitis B virus (4%) than in 194 control subjects (0%, P=.02; Fisher's exact test).
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Affiliation(s)
- Hossein Sendi
- Research Center for Gastroenterology and Liver Diseases, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
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24
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Nozić D, Balint B, Stanković N, Dimitrijević J, Nesković G. Significance of iron reduction for the therapy of chronic hepatitis C. VOJNOSANIT PREGL 2005; 62:161-4. [PMID: 15787170 DOI: 10.2298/vsp0502161n] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background. It has been established that many patients with chronic hepatitis C have elevated serum iron, feritin levels and iron deposits in the liver. Therefore, the liver damage due to hepatitis C virus may be aggravated with iron overload. In many studies higher levels of iron in the blood and the liver were connected with the decreased response to interferon-alfa therapy for chronic viral hepatitis C. Recent introduction of pegylated interferons plus ribavirin has improved the therapeutic response, so it is now possible to cure more than 50% of the patients. Case report. Three patients with chronic hepatitis C and iron overload were presented. Iron reduction therapy using phlebotomy or eritrocytapheresis with plasmapheresis was done at different times in regard to specific antiviral therapy or as a sole therapy. Conclusion. It has been shown that iron reduction, sole or combined with antiviral therapy, led to the deacreased aminotransferase serum activity and might have slow down the evolution of chronic hepatitis C viral infection.
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Affiliation(s)
- Darko Nozić
- Vojnomedicinska akademija, Klinika za infektivne i tropske bolesti, Beograd
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25
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Abstract
Heavy iron overload, in both primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, especially the liver. The toxicity of iron is believed to involve increased oxidative stress, with iron-catalyzed production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Results of recent studies have demonstrated high prevalences (about 60%-80%) of HFE gene mutations in patients with porphyria cutanea tarda. Chronic hepatitis C is another risk factor for porphyria cutanea tarda. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. A role for modest iron overload in increasing severity of alcohol-induced liver disease has been well established from results of experimental studies. However, it is currently unresolved whether mild-to-moderate hepatic iron deposition or heterozygosity for the C282Y mutation plays a role in human alcoholic liver disease or in nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. There is persuasive evidence that iron reduction decreases insulin resistance, and it likely also decreases oxidative stress, two key pathogenic features of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Iron loading has also been described after portosystemic shunts and in end-stage liver disease.
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Affiliation(s)
- Herbert L Bonkovsky
- University of Connecticut Health Center, MC: 1111, 263 Farmington Avenue, Farmington, CT 06030-1111, USA.
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26
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27
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Lal P, Fernandes H, Koneru B, Albanese E, Hameed M. C282Y mutation and hepatic iron status in hepatitis C and cryptogenic cirrhosis. Arch Pathol Lab Med 2000; 124:1632-5. [PMID: 11079015 DOI: 10.5858/2000-124-1632-cmahis] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Increased iron deposition in liver is seen in both primary and secondary hemochromatosis. However, it is not uncommon to see significant iron deposition in a liver biopsy, explant, or autopsy specimen without any significant clinical risk factor. Because of the discovery of the candidate gene (HFE) for hereditary hemochromatosis, we may now be able to screen high-risk patient populations for the abnormal mutation (C282Y). MATERIALS AND METHODS In this study we analyzed the livers of 50 transplant patients with a diagnosis of either hepatitis C cirrhosis or cryptogenic cirrhosis for the prevalence of the more common C282Y mutation of the HFE gene and correlated the findings to hepatic iron concentration. RESULTS Of the 26 cases of hepatitis C cirrhosis, 3 were found to be heterozygous for the C282Y mutation. Of the 22 cases of cryptogenic cirrhosis, 1 was found to be heterozygous for the C282Y mutation. Stainable iron was increased in hepatitis C cirrhosis (76.9%) as compared to cryptogenic cirrhosis (50%) (P =. 05). Of the 3 heterozygotes with hepatitis C cirrhosis, 2 showed hepatic iron concentrations of 3+ and 4+, and 1 showed 1+. CONCLUSIONS We conclude that patients with hepatitis C have an increased tendency to accumulate iron in the liver, and mutations in the HFE gene play a minor role in hepatic accumulation of iron in these patients.
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Affiliation(s)
- P Lal
- Department of Pathology, University of Medicine and Dentistry--New Jersey Medical School, Newark 07103, USA
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28
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Abstract
Iron, either in the form of heme or non-heme compounds, is essential to life, but it can also pose serious health risks. The liver is a principal target for iron toxicity because it is chiefly responsible for taking up and storing excessive amounts of iron. The major hepatic toxicities of iron overload include damage to multiple cell types (hepatocytes, Kupffer cells, hepatic stellate cells) and to multiple subcellular organelles (mitochondria, lysosomes, and smooth endoplasmic reticulum). Heavy iron overload, as occurs in primary (hereditary) or secondary forms of hemochromatosis, may cause cirrhosis, liver failure, and hepatocellular carcinoma. In addition, iron has been shown to be a contributory factor in the development or progression of alcoholic liver disease, nonalcoholic liver steatohepatitis, chronic viral hepatitis, prophyria cutanea tarda, and, perhaps, in alpha 1-antitrypsin deficiency and end-stage liver disease, regardless of cause.
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Affiliation(s)
- H L Bonkovsky
- Department of Medicine, University of Massachusetts Medical School, USA
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29
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Herrera JL. Iron depletion is not effective in inducing a virologic response in patients with chronic hepatitis C who failed to respond to interferon therapy. Am J Gastroenterol 1999; 94:3571-5. [PMID: 10606321 DOI: 10.1111/j.1572-0241.1999.01648.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Some studies have suggested that increased iron stores may impact negatively on the response to interferon in patients with chronic hepatitis C infection. We performed this prospective trial to determine the effects of iron depletion on ALT and HCV-RNA levels in patients with chronic hepatitis C infection and to assess whether the response to interferon in patients who had previously failed to respond to interferon was enhanced by iron depletion. METHODS Patients with chronic hepatitis C resistant to interferon therapy and no evidence of iron overload underwent weekly phlebotomies until the serum ferritin level was below lower limits of normal for the subject's age and sex. Patients were then started on interferon-alpha2b, 3 million units subcutaneously three times per week for a period of 24 weeks. Iron studies, ALT, and HCV-RNA levels were monitored at baseline, after phlebotomy and at 12 and 24 weeks of interferon therapy. RESULTS Thirty-three patients were enrolled, 28 completed the study. A mean of 7.2 units of blood were removed to achieve iron depletion. ALT levels decreased significantly with phlebotomy (142 IU/L before phlebotomy vs 82 IU/L after phlebotomy; p < 0.001), but log HCV-RNA levels remained unchanged (6.49 before phlebotomy vs 6.51 after phlebotomy). Interferon therapy did not improve ALT levels further. HCV-RNA levels were minimally reduced during interferon therapy (log HCV-RNA 6.49 before interferon vs 6.00 after 24 weeks of interferon therapy). Two patients achieved a virologic end of treatment response, both relapsed within 3 months after discontinuation of interferon. No patient achieved a sustained virologic response. CONCLUSIONS In patients who previously failed treatment with interferon, iron depletion induced by phlebotomy improves ALT levels but is ineffective in achieving viral eradication in patients retreated with interferon 3 million units three times per week.
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Affiliation(s)
- J L Herrera
- University of South Alabama College of Medicine, Mobile, USA
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30
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Smith BC, Gorve J, Guzail MA, Day CP, Daly AK, Burt AD, Bassendine MF. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 1998; 27:1695-9. [PMID: 9620344 DOI: 10.1002/hep.510270631] [Citation(s) in RCA: 142] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.
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Affiliation(s)
- B C Smith
- Centre for Liver Research, University of Newcastle upon Tyne, England, UK
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31
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Beinker NK, Voigt MD, Arendse M, Smit J, Stander IA, Kirsch RE. Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C. J Hepatol 1996; 25:633-8. [PMID: 8938538 DOI: 10.1016/s0168-8278(96)80231-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND/AIMS In hepatitis C, iron depletion may improve serum aminotransferases and the response to interferon, but it is not known whether inflammation and fibrosis correlate with hepatic iron content. Our aim was to establish whether hepatic iron content correlates with histological and serum indices of hepatic inflammation and fibrosis in hepatitis B and C. METHODS Total hepatic iron was measured using computerized histomorphometry, and hepatic inflammation and fibrosis using a modified Knodell score, on histological slides from 31 patients with chronic hepatitis B and 38 with hepatitis C. RESULTS Total hepatic iron was similar in the hepatitis B and C groups (0.82 +/- 1.72% and 0.56 +/- 1.12%; mean +/- SD). No iron was detectable in 11 patients with hepatitis B and 13 with hepatitis C. Alanine aminotransferase (85.96 +/- 67.1 vs 44.2 +/- 39.7 p < 0.05), aspartate aminotransferase (93.8 +/- 75.6 vs 47 +/- 33.5 IU/ml p < 0.05) and histological inflammatory score (9.33 +/- 3.51 vs 7.79 +/- 3.3 p = 0.07) were increased in those with stainable hepatic iron compared to those without. However, where iron was present, no association was found between the amount of hepatic iron and inflammatory or fibrosis scores. In hepatitis C, fibrosis was minimal in 77% of patients if iron was absent vs 24% with iron present, while marked fibrosis was present in 56% with iron vs 15% without iron (p < 0.01, Fisher's exact test). CONCLUSION Hepatic iron is associated with increased hepatic inflammation in chronic hepatitis B and hepatitis C and with high fibrosis scores in hepatitis C. There is a threshold effect, and once present, increasing iron does not correlate with increasing inflammation or fibrosis.
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Affiliation(s)
- N K Beinker
- MRC/UCT Liver Research Centre, Groote Schuur Hospital, Cape Town, South Africa
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32
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Abstract
A variety of laboratory and clinical investigations during the past 15 years have observed that one of the dangers of excessive iron is its ability to favor animal viral infections. The metal is essential for host cell synthesis of virions and can also impair defense cell function and increase oxidative stress. In both animal models and humans, viral infections cause upregulation of the iron withholding defense system. Factors that suppress the system enhance viral progression; factors that strengthen the system augment host defense. Procedures designed to reinforce the system are being developed and tested; some of these may become useful adjuncts in prevention and management of viral diseases.
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Affiliation(s)
- E D Weinberg
- Department of Biology, Indiana University, Bloomington 47405, USA
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Fargion S, Fracanzani AL, Piperno A, Braga M, D'Alba R, Ronchi G, Fiorelli G. Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. Hepatology 1994; 20:1426-31. [PMID: 7982640 DOI: 10.1002/hep.1840200608] [Citation(s) in RCA: 84] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
To identify factors that might be useful as prognostic indexes for the risk of hepatocellular carcinoma in Italian patients with genetic hemochromatosis, 152 homozygotes were studied prospectively for 1 to 229 mo. Factors that were considered in estimating the risk of developing hepatocellular carcinoma were age, sex, cirrhosis (Child class), HBsAg, antibodies to HBsAg, antibodies to HBcAg, hepatitis C antibodies, alcohol abuse and the amount of iron removed during therapeutic phlebotomy to produce iron depletion. At diagnosis, cirrhosis was present in 97 patients and absent in 55. During follow-up, hepatocellular carcinoma developed in 28 of the 97 patients with cirrhosis but in none of those without. Among patients with cirrhosis, the cumulative probability of being free of hepatocellular carcinoma at 10 yr was 70%. For patients with and without HBsAg the probabilities of being free of liver cancer at 10 yr were, respectively, 54% and 75%; for those with and without history of alcoholism, 58% and 78%; and for those younger and older than 55 yr, 90% and 54%. In patients with cirrhosis, multivariate analysis using proportional-hazards (Cox) regression found that the only factors contributing significantly to the estimation of a prognostic index were age, presence of HBsAg and alcohol abuse. Age over 55 yr increased the relative risk of hepatocellular carcinoma 13.3-fold (p < 0.001), the presence of HBsAg increased it 4.9-fold (p < 0.02) and alcohol abuse increased it 2.3-fold (p < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S Fargion
- Institute of Internal Medicine and Medical Physiopathology, University of Milan, Italy
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Tabor E, Kim CM. Inhibition of human hepatocellular carcinoma and hepatoblastoma cell lines by deferoxamine. J Med Virol 1991; 34:45-50. [PMID: 1715897 DOI: 10.1002/jmv.1890340108] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Inhibition of human hepatocellular carcinoma (PLC/PRF/5 and Hep3B) or hepatoblastoma (Hep G2) cell lines by inclusion of deferoxamine mesylate (desferrioxamine) (DFX) in the culture medium was evaluated. When PLC/PRF/5 cells were maintained for 7 days in 30 or 60 microM DFX, the cell number was decreased by 30-60%, little or no alpha-fetoprotein (AFP) was produced, and supernatant endpoint dilution titers of hepatitis B surface antigen (HBsAg) were reduced 1-2 logs. PLC/PRF/5 cells maintained for 7 days without DFX (simultaneous controls) grew to confluence, produced AFP that reached 10-60 ng/ml in the supernate, and the HBsAg titer remained constant or increased 1 log. Similar effects were observed in Hep3B and Hep G2 cells maintained in DFX (except that Hep G2 cells do not produce HBsAg), compared to simultaneous control cells grown in the absence of DFX. The growth of a human embryonic lung fibroblast cell line (Wl 38) was not significantly inhibited by DFX, although it grew at a slower rate than simultaneous control cells grown without DFX. Subsequent growth in FeSO4 of PLC/PRF/5, Hep3B, and Hep G2 cells that previously had been maintained in DFX did not reverse the effects of DFX. PLC/PRF/5 cells were also inhibited when maintained in medium containing equimolar concentrations of DFX and FeCl3 and in medium containing equimolar concentrations of DFX and FeSO4. PLC/PRF/5 cells were not inhibited by maintenance in up to 60 microM of another chelating agent that has a similar affinity for iron, calcium disodium versenate (EDTA). These studies show that DFX inhibits the growth of human hepatocellular carcinoma and hepatoblastoma cell lines regardless of the presence (PLC/PRF/5, Hep3B) or absence (Hep G2) of integrated hepatitis B virus DNA. The findings also suggest that the inhibition may have been due to mechanisms other than iron chelation.
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Affiliation(s)
- E Tabor
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Abstract
Four epidemiological studies have been performed that are generally consistent with the hypothesis that increased available body iron stores increase the risk of cancer or of general mortality. In a study based on the First National Health and Nutrition Examination Survey in the United States (NHANES), 232 men who developed cancer over a ten year period had a mean transferrin saturation of 33.1% at least 4 years before diagnosis, whereas 3,113 men who did not develop cancer had a transferrin saturation of 30.7% (p = 0.002). The hypothesis is based on two possible biological mechanisms. First, iron can catalyse the production of oxygen radicals and these may be proximate carcinogens. Second, iron may be a limiting nutrient to the growth and replication of a cancer cell. There are at least five areas of potential research related to iron and cancer based on these biological mechanisms: (1) etiology of cancer, (2) etiology of radiation-induced cancer, (3) prognosis after cancer diagnosis, (4) cancer risk resulting from therapy, and (5) interactions with other biochemical factors. An unexpected finding of the human studies done to date has been a highly significant negative association of serum albumin and long term cancer risk. Serum albumin is lower in smokers and older people, however, the negative association persists after controlling for these factors.
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Affiliation(s)
- R G Stevens
- Pacific Northwest Laboratory, Richland, WA 99352
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Loeb LA, James EA, Waltersdorph AM, Klebanoff SJ. Mutagenesis by the autoxidation of iron with isolated DNA. Proc Natl Acad Sci U S A 1988; 85:3918-22. [PMID: 2453880 PMCID: PMC280331 DOI: 10.1073/pnas.85.11.3918] [Citation(s) in RCA: 107] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Oxygen free radicals are highly reactive species generated by many cellular oxidation-reduction processes. These radicals damage cellular constituents and have been causally implicated in the pathogenesis of many human diseases. We report here that oxygen free radicals generated by Fe2+ in aqueous solution are mutagenic. Aerobic incubation of luminal diameter X174 am3 (amber 3 mutation) DNA with Fe2+ results in decreased phage survival when the treated DNA is transfected into Escherichia coli spheroplasts. Transfection of the treated DNA into SOS-induced spheroplasts results in an increase in mutagenesis as great as 50-fold. Both killing and mutagenesis can be prevented by binding of Fe2+ with deferoxamine or by the addition of catalase or mannitol. These results suggest that DNA damage and mutagenesis brought about by Fe2+ are likely to occur by a Fenton-type mechanism that involves the generation of (i) hydrogen peroxide by the autoxidation of iron and (ii) hydroxyl radicals by the interaction of the hydrogen peroxide with Fe2+. DNA sequence analysis of the Fe2+-induced mutants indicates that reversion of the phage phenotype to wild type occurs largely by a transversion type of mutation involving substitution of deoxyadenosine for thymidine opposite a template deoxyadenosine. Mutagenesis is not abolished by incubation of Fe2+-treated luminal diameter X174 am3 DNA with an apurinic endonuclease and only partially abolished by incubation with alkali, suggesting that a large fraction of the mutagenesis by oxygen free radicals is not caused by formation of apurinic sites but instead involves an as-yet-to-be-defined alteration in deoxyadenosine. These findings raise the possibility that free iron localized in cellular DNA may cause mutations by the generation of oxygen free radicals.
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Affiliation(s)
- L A Loeb
- The Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology SM-30, University of Washington School of Medicine, Seattle 98195
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Zhou XD, DeTolla L, Custer RP, London WT. Iron, ferritin, hepatitis B surface and core antigens in the livers of Chinese patients with hepatocellular carcinoma. Cancer 1987; 59:1430-7. [PMID: 3028601 DOI: 10.1002/1097-0142(19870415)59:8<1430::aid-cncr2820590808>3.0.co;2-a] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Surgically resected specimens, consisting of tumor and adjacent non-neoplastic liver tissue, were obtained from 40 patients with primary liver cancer at Zhong Shan Hospital, Shanghai Medical University, the People's Republic of China, between March 1983 and July 1984. All were hepatocellular carcinomas (HCC), one being admixed with cholangiocarcinoma. The relationship of hepatitis B virus (HBV) markers with iron and ferritin was evaluated in liver tissues from patients with primary liver cancers. The serum HBsAg (Hepatitis B surface antigen) positive rate was 80.0% (32/40). Cirrhosis was observed in 97.5% (39/40). HBsAg was identified in 82.5% (33/40) of uninvolved liver, and 35.0% (14/40) of HCC tissues (P less than 0.001). HBcAg (hepatitis B core antigen) was detected in 25.0% (10/40) of liver, and 7.5% (3/40) of HCC tissues (P less than 0.05). Stainable iron was found in 65.0% (26/40) of unaffected livers, and 10.0% (4/40) of HCC tissues (P less than 0.001). Ferritin was demonstrated in 75% (30/40) of non-neoplastic liver, and 40% (16/40) of HCC tissues (P less than 0.001). Twenty-two of 33 HCC patients (66.7%) with HBsAg positive cells in their livers also showed stainable iron. Of 16 patients positive for ferritin in HCC cells, iron was found in only two. Iron was found in nine of ten patients with HBcAg in non-neoplastic hepatocytes (P = 0.056); a finding compatible with the hypothesis that iron accumulates in cells replicating HBV. The other results indicate that: immunohistologic ferritin in HCC is not due to increased stainable iron; tumor cells may produce ferritin; polyclonal antibodies to human liver ferritin react better with non-neoplastic hepatocytes than with HCC cells; the high prevalence of HBsAg and cirrhosis in HCC suggests that HBV plays a major etiologic role in hepatocarcinogenesis in China; and one case of HCC is attributed to Schistosoma japonicum infestation via cirrhosis.
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Abstract
Higher serum iron and ferritin levels noted in hepatitis B antigen (HBAg) carriers than in noncarriers suggests that virus might actively replicate in hepatocytes, stimulate ferritin synthesis, and result in increased liver iron stores. A comparative semiquantitative study of immunohistochemical ferritin (0-12) and hemosiderin (0-9) was performed on 54 normal, 13 cirrhotic, and 70 nonneoplastic livers from patients with hepatocellular carcinoma, in each group, comparing amounts in HBAg-positive and HBAg-negative patients. Mean scores for ferritin and hemosiderin were high in all three groups, normal livers averaging 8.3 and 6, respectively, cirrhotic livers, 8.5 and 7.4, respectively, and carcinoma livers, 5.6 and 6.1, respectively. In each group, there was no significant difference in ferritin and hemosiderin mean scores in HBAg-positive and HBAg-negative patients. The large liver iron stores do not appear to be a consequence of hepatitis B virus infection alone. Their role in the development of hepatocellular carcinoma is still to be elucidated.
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Abstract
Normal and neoplastic cells have similar needs for iron, but the latter may exhibit altered mechanisms of iron acquisition that permit continued multiplication in host iron-restricted tissues. For example, neoplastic cells may form low molecular weight siderophores as well as increase the number of transferrin binding glycoproteins on their cell surfaces. The hosts attempt to withhold iron from neoplastic cells by preventing the return of the metal to plasma and diverting it to storage, by increasing the synthesis of ferritin to accommodate the added stores, and by surrounding tumor cells with macrophages that can ingest lactoferrin-bound iron, but these mechanisms are often not effective against the iron-accumulating mechanisms of the tumor. Persons or animals with iron overload (via ingestion, inhalation, injection, or pathophysiologic process) tend to be at greater risk than normal hosts in the development of neoplasms. The tumors are often associated with the site(s) of deposition of the metal. In addition to its neoplastic cell nutrient function, excess iron might suppress tumorcidal action of macrophages and interfere with lymphocyte traffic. Severe iron deficiency can interfere with the ability of the host to detoxify potential carcinogens as well as with its ability to activate antitumor lymphocytes.
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