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Luo J, Liu Z, Wang Q, Tan S. Liver iron overload and fat content analyzed by magnetic resonance contribute to evaluatingthe progression of chronic hepatitis B. Biomed Rep 2024; 20:23. [PMID: 38169881 PMCID: PMC10758915 DOI: 10.3892/br.2023.1711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/22/2023] [Indexed: 01/05/2024] Open
Abstract
Chronic hepatitis B (CHB) and its complications still have a major role in liver-related mortality. It has been indicated that hepatic iron and steatosis may influence liver fibrosis and carcinogenesis. The present study aimed to assess the liver iron and fat in patients with CHB by MRI in order to estimate the associations among liver iron, fat and the severity and progression of liver fibrosis. In the present retrospective study, consecutive patients with CHB examined from August 2018 to August 2020 were analyzed. Liver iron and fat content were assessed by MRI, which was measured as liver iron content (LIC) and proton density fat fraction (PDFF). A total of 340 patients were included in the current study. For LIC, the median value was 1.68 mg/g and elevated LIC was seen in 122 patients (35.9%). For liver fat content, the median value of PDFF was 3.1%, while only 15.0% of patients had liver steatosis (PDFF ≥5%). Age, total bilirubin and sex were independent predictive factors of liver iron overload [odds ratio (OR)=1.036, 1.005 and 8.834, respectively]. A higher platelet count (OR=1.005) and no portal hypertension (OR=0.381) independently predicted liver steatosis. The areas under the receiver operating characteristic curves of PDFF for the identification of liver cirrhosis estimated by different non-invasive tools ranged from 0.629 to 0.704. It was concluded that iron overload was common in patients with CHB, particularly in those with older age, male sex and high total bilirubin level, and liver steatosis was less common in CHB. Liver iron and fat content analyzed by MRI may contribute to the evaluation of the severity and progression of CHB.
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Affiliation(s)
- Jinni Luo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhenzhen Liu
- Department of Radiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Qian Wang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Elbedewy TA, Abd-Elsalam S, Mostafa SM, Abdellatif RS, Fouad A, Youssef M, Abo-Amer YEE, Elsebaey MA. Sofosbuvir/Ledipasvir for Treatment of Chronic Hepatitis C Infection in Adult Patients with β- Thalassemia Major: A Real-Life Study. Endocr Metab Immune Disord Drug Targets 2022; 22:290-296. [PMID: 33530921 DOI: 10.2174/1871530321666210202150538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/06/2020] [Accepted: 12/14/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND & AIMS Patients with thalassemia have a lifelong need for blood transfusion, which makes them more risky to hepatitis C virus (HCV). Iron overload and chronic HCV are considered risk factors for patients with thalassemia to develop liver insults. The aim of the present study is to investigate the safety and efficacy of sofosbuvir/ledipasvir in the treatment of chronic HCV infection in Egyptian adult patients with β- thalassemia major. METHODS A retrospective study included 53 patients with β-thalassemia major with chronic HCV treated with sofosbuvir (400 mg) and ledipasvir (90 mg) as a single pill fixed-dose combination once daily for 12 weeks. The effectiveness of the treatment was assessed by the sustained virologic response (SVR) at 12 weeks after the end of the treatment. RESULTS SVR was achieved in 96.23% of patients. 47.17% of patients had minor side effects. There was a significant reduction in ALT, AST, and serum ferritin 12 weeks post-therapy. There was an insignificant change in hemoglobin level or blood transfusion requirement 12 weeks posttherapy. There was no change in iron chelators doses throughout the study period. CONCLUSION Sofosbuvir/ledipasvir regimen seems to be safe and highly effective in the treatment of chronic HCV in patients with β-thalassemia major.
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Affiliation(s)
- Tamer A Elbedewy
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sherief Abd-Elsalam
- Tropical Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sahar Mohamed Mostafa
- Hepato-gastroentrology and Infectious Diseases Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Raghda Samir Abdellatif
- Clinical pathology department, National hepatolgy and tropical medicine research institute, Cairo, Egypt
| | - Amina Fouad
- Clinical pathology department, National hepatolgy and tropical medicine research institute, Cairo,Egypt
| | - Mona Youssef
- Department of Hepatology, Gastroenterology and Infectious Diseases, Benha Teaching Hospital, Benha, Egypt
| | - Yousry Esam-Eldin Abo-Amer
- Hepatology, Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Gharbia, Egypt
| | - Mohamed A Elsebaey
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Bou Daher H, Sharara AI. Treatment of Chronic HCV Infection in Patients With Thalassemia. Clin Liver Dis (Hoboken) 2019; 14:199-202. [PMID: 32015868 PMCID: PMC6988433 DOI: 10.1002/cld.853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 06/07/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Halim Bou Daher
- Division of Gastroenterology, Department of Internal MedicineAmerican University of Beirut Medical CenterBeirutLebanon
| | - Ala I. Sharara
- Division of Gastroenterology, Department of Internal MedicineAmerican University of Beirut Medical CenterBeirutLebanon
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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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Arain SA, Kazi TG, Afridi HI, Talpur FN, Mughal MA, Shah F, Arain SS, Panhwar AH. Estimation of copper and iron burden in biological samples of various stages of hepatitis C and liver cirrhosis patients. Biol Trace Elem Res 2014; 160:197-205. [PMID: 24973874 DOI: 10.1007/s12011-014-0058-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/22/2014] [Indexed: 01/19/2023]
Abstract
There is accumulative evidence that the metabolism of iron (Fe) and copper (Cu) is altered in human due to infections, indicating that both elements have roles in pathogenesis and progress of viral diseases. In the present study, the correlation of Cu and Fe was evaluate in biological samples (serum and scalp hair) of hepatitis C (hepatitis C virus (HCV)) patients of both genders at different stages. For comparative study, the scalp hair and serum samples of healthy individuals of same age group (30-50 years) and socioeconomic status were collected. The biological samples were analyzed for Fe and Cu by atomic absorption spectroscopy after microwave-assisted acid digestion. The validity and accuracy of methodology were checked by certified reference materials of same matrixes. The levels of Cu and Fe in biological samples were enhanced in hepatic disorder patients, including acute (after diagnosis test, anti-HCV sero-positive) hepatic fibrosis and liver cirrhosis as compared to healthy referents. The difference was significant (p < 0.01) in the case of liver cirrhotic patients. It was observed that the data of Cu and Fe in referents and patients of both genders had normal distributions. The inter-elemental correlation (r) among Cu vs Fe in serum and scalp hair samples of referents and patients were not significant in both genders (p > 0.1) except in the first stage of HCV (p < 0.1). It was concluded that the increase of Cu and Fe content in human body seems to contribute to the development of cirrhosis in patients with viral hepatitis C.
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Affiliation(s)
- Salma Aslam Arain
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, Pakistan,
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Yuan Z, Shen Z, Guo L, Wang X, Wang S, Zhao B. Improving detection of siderotic nodules in patients with liver disease using 2D ESWAN technique. Acad Radiol 2014; 21:971-6. [PMID: 25018068 DOI: 10.1016/j.acra.2014.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 03/10/2014] [Accepted: 03/11/2014] [Indexed: 01/17/2023]
Abstract
RATIONALE AND OBJECTIVES To conduct a preliminary evaluation of the use of two-dimensional (2D) enhanced multiecho T2*-weighted angiography (ESWAN) sequence for detection and quantification of siderotic nodules (SNs) in patients with liver disease. MATERIALS AND METHODS Seventy-four patients with liver cirrhosis SNs confirmed by pathology were imaged using conventional T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2*-weighted imaging (T2*WI), and 2D ESWAN. The signal intensity ratio (SIR) and the lesion-to-liver contrast-to-noise ratio (CNR) were calculated. The quality of SNs identification of the ESWAN images was evaluated. RESULTS The SIR of SNs on ESWAN was lower than those in any other sequence, whereas the CNR of SNs on ESWAN was significantly greater than those in the other sequences (P < .05). The conspicuity of SNs was shown to be significantly different between every pair of techniques (P < .05). The nodules had the better conspicuity in ESWAN images than in the T1WI, T2WI, and T2*WI. Almost all (97.3%, 72 of 74) patients were considered to have excellent grade 3 conspicuity on ESWAN imaging, compared to 40.5% (30 of 74) for T2*WI. The signal intensity of small hepatic cancer on ESWAN was greater than those of SNs. CONCLUSIONS The detection and conspicuity of SNs is substantially improved using breath-hold 2D ESWAN. Therefore, 2D ESWAN imaging may be an alternative for the accurate detection of hepatic SNs in the future.
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Affiliation(s)
- Zhenguo Yuan
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, Shandong, China
| | - Zhen Shen
- Medical Imaging Center of the Affiliated Hospital, Weifang Medical University, 7166#, Baotong West St, Weifang, Shandong 261053, China
| | - Lingfei Guo
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, Shandong, China
| | - Xizhen Wang
- Medical Imaging Center of the Affiliated Hospital, Weifang Medical University, 7166#, Baotong West St, Weifang, Shandong 261053, China.
| | - Shiyan Wang
- Taishan Medical University, Taian, Shandong, China
| | - Bin Zhao
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, Shandong, China
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Imran M, Manzoor S, Khattak NM, Tariq M, Khalid M, Javed F, Bhatti S. Correlation of OAS1 gene polymorphism at exon 7 splice accepter site with interferon-based therapy of HCV infection in Pakistan. Viral Immunol 2014; 27:105-11. [PMID: 24673406 DOI: 10.1089/vim.2013.0107] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The most useful treatment for HCV infection worldwide is peg-interferon plus ribavirin, although the response varies from person to person. Hence, host genetics are significantly involved in the treatment response to HCV infection. The 2'-5' oligoadenylate synthetase (OAS) is one of the most important components of the immune system having significant antiviral functions. The aim of this study was to investigate the role of single nucleotide polymorphism (SNP) at the exon 7 splice acceptor site (SAS) of OAS1 to interferon-based therapy of HCV infection. OAS1 genotyping was performed in 140 HCV patients by restriction fragment length polymorphism polymerase chain reaction method (RFLP-PCR). These patients were enrolled for the study in 2010-2013. OAS1 SNP was also established in 120 healthy controls. Correlation of HCV genotypes, OAS1 SNP, and other factors with response to interferon therapy were statistically analyzed by SPSS 13 software. There were no significant differences in the distribution of OAS1 genotypes between healthy and patients subjects. The distribution of AG and AA genotypes of OAS1 genotypes between sustained virological responders (SVRs) and the non-responders (NRs) group were also comparable. However, Pearson chi square analysis indicated that the patients possessing a GG genotype of the OAS1 gene at exon 7 SAS demonstrated significantly positive association with treatment response to HCV infection (p=0.039). This study determined that SNP at exon 7 SAS of OAS1 was significantly associated with response to interferon-based therapy of HCV infection in our population.
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Affiliation(s)
- Muhammad Imran
- Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology , Islamabad 44000, Pakistan
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Arain SA, Afridi HI, Kazi TG, Talpur FN, Shah F, Arain SS, Panhwar AH, Brahman KD. Investigation of Alteration in the Levels of Iron and Copper in Scalp Hair Samples of Patients Having Different Types of Viral Hepatitis. Biol Trace Elem Res 2013; 156:5-11. [PMID: 24122058 DOI: 10.1007/s12011-013-9832-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 09/18/2013] [Indexed: 12/20/2022]
Abstract
The aim of this study was to measure the alterations of copper and iron contents in scalp hair samples of hepatitis A-E patients of both genders, same age group, and socioeconomic status. For comparative study, the scalp hair samples of healthy individuals of the same age and socioeconomic status were collected. The concentrations of copper and iron were measured using an atomic absorption spectrophotometer, after microwave-assisted acid digestion. The validity and accuracy of methodology was checked using a certified reference material. The results of this study showed that the mean values of copper and iron were higher in scalp hair samples of hepatitis patients than those of age-matched control subjects, while the difference was significant in the cases of patients having viral hepatitis B, C, and D as compared to those who have viral hepatitis A and E (p < 0.001). It was concluded that the overload of copper and iron in the human body may cause lipid peroxidation and eventually damage the hepatic system.
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Affiliation(s)
- Salma Aslam Arain
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan,
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Alavian SM, Lankarani KB, Sharara AI. Treatment of Chronic HCV in Special Populations: Thalassemia, Hemophilia, and Hemodialysis Patients. CURRENT HEPATITIS REPORTS 2012; 11:256-262. [DOI: 10.1007/s11901-012-0147-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Sini M, Sorbello O, Civolani A, Demelia L. Hemochromatosis gene mutations: prevalence and effects on pegylated-interferon and ribavirin therapy response in chronic hepatitis C in sardinia. J Clin Exp Hepatol 2012; 2:211-7. [PMID: 25755436 PMCID: PMC3940629 DOI: 10.1016/j.jceh.2012.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 06/09/2012] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Considerable evidence suggests that iron could be a comorbid factor for liver injury in chronic hepatitis C (CHC). Elevated iron indices are frequently described in CHC and may impact negatively on the course of liver disease and on the response to interferon alfa therapy. The aim of this study was to evaluate the frequency of hemochromatosis gene mutations in Sardinian CHC patients, the association with iron overload and the impact on response to therapy. METHODS Sixty-nine CHC patients were enrolled. Iron indices, hepatic and viral parameters were detected. C282Y, H63D and S65C mutations were identified through a PCR. Liver biopsy was performed for hepatic fibrosis evaluation. All patients were treated for 6 months (viral genotype 2/3) or 12 months (viral genotype 1/4) with pegylated-interferon 180 mcg once weekly and ribavirin 1000-1200 mg/daily. Sustained virological response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment. RESULTS HFE gene mutation was detected in 29 patients (42%). The presence of HFE mutations was significantly associated with elevated transferrin saturation (P < 0.01). Hepatic fibrosis was more advanced in HFE mutation carriers (χ (2), P = 0.04). Among mutation carriers 27.5% achieved responses at the end of treatment compared with 60% of non-carriers (P = 0.005). Patients with HFE wildtype produced significant SVR compared with patients with HFE mutations (P = 0.03). CONCLUSIONS The literature shows discordant results about the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C. Our findings shows that HFE gene mutations could favor, synergically with CHC and other genetic or acquired factors, the development of liver damage and could influence the outcome of interferon treatment with higher rate of non-response.
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Key Words
- ALT, alanine aminotransferase
- AP, alkaline phosphatase
- AST, aspartate aminotransferase
- CHC, Chronic hepatitis C
- ETR, End of treatment response
- GGT, g-glutamyl transpeptidase
- HCV, Hepatitis virus C infection determination
- HFE gene
- HFE, Human hemochromatosis protein
- HH, Hereditary Hemochromatosis
- SVR, Sustained virologic response
- TSI, Transferin saturation index
- ULN, Upper normal limit
- WT, wildtype
- iron overload
- viral hepatitis
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Affiliation(s)
| | - Orazio Sorbello
- Address for correspondence: Orazio Sorbello, Department of Gastroenterology, Azienda Ospedaliero-Universitaria di Cagliari, SS 554 bivio per Sestu, 09130 Cagliari, Italy. Tel./fax: +39 070 51096100.
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Ishizu Y, Katano Y, Honda T, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Goto H. Clinical impact of HFE mutations in Japanese patients with chronic hepatitis C. J Gastroenterol Hepatol 2012; 27:1112-6. [PMID: 22098610 DOI: 10.1111/j.1440-1746.2011.06976.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM HFE mutations, a common cause of hereditary hemochromatosis (HH), are reportedly associated with hepatic iron overload, severe liver fibrosis, and good response to interferon treatment in European patients with chronic hepatitis C (CHC). HH shows ethnicity-based differences and little is known about the effects of HH mutations on CHC in the Japanese. Thus, the aim of this study was to clarify the clinical influence of HFE mutations in Japanese CHC patients. METHODS In a total of 251 patients with CHC, we analyzed the frequencies of H63D and S65C mutations in the HFE gene, and the influence of these mutations on clinical parameters and response to pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin therapy. RESULTS Fourteen patients (5.6%) carried the H63D mutation; all were heterozygotes. No S65C mutations were found. Only hemoglobin levels in the H63D heterozygotes were higher than in wild-type patients. Eleven of 14 H63D heterozygotes achieved sustained virological response (SVR). On univariate analysis, factors associated with SVR were interleukin 28B (IL28B) polymorphism, age, hepatitis C virus (HCV) genotype, HCV viral load, white blood cell count, stage of fibrosis and H63D mutation. All patients with both TT genotype in IL28B (rs8099917) and H63D mutation in HFE (n = 10) achieved SVR. CONCLUSIONS The H63D mutation has little impact on the clinical characteristics of CHC, but is related to favorable response to PEG-IFN plus ribavirin therapy, particularly in patients with the TT allele in IL28B.
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Affiliation(s)
- Yoji Ishizu
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Wang Q, Liu Y, An D, Diao H, Xu W, He X, Sun R, Wei L, Li L. Regulation of hepatitis C virus translation initiation by iron: role of eIF3 and La protein. Virus Res 2012; 167:302-9. [PMID: 22634302 DOI: 10.1016/j.virusres.2012.05.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 05/16/2012] [Accepted: 05/17/2012] [Indexed: 12/18/2022]
Abstract
Eukaryotic initiation factors (eIFs) are required for encoding polyprotein of hepatitis C virus (HCV) which is mediated by an internal ribosome-entry site (IRES). Iron overload, a common finding among HCV patients, may be correlated with HCV pathology, but the underlying molecular mechanisms are poorly understood. In this study, we investigated the possible relationship among iron status, eIFs and HCV IRES-mediated translation in vitro. Using bicistronic reporter gene constructs carrying HCV IRES sequence, we found that the levels of intracellular iron were positively associated with the HCV IRES-dependent translation initiation in Huh-7 cells. RT-PCR method showed that iron treatment specifically increased the levels of eIF3A mRNA and La mRNA, whereas iron chelation reduced them. Western blots also confirmed that iron-dependent changes in eIF3A mRNA and La mRNA affected the expression of their proteins. Moreover, antisense phosphorothioate oligodeoxynucleotides to eIF3A and La successfully suppressed the levels of eIF3A and La protein and significantly reduced iron-dependent HCV translation. Taken together, our results suggest that iron promotes the translation initiation of HCV by stimulating the expression of eIF3A and La proteins. Inhibition of eIF3A and La proteins substantially repressed iron-dependent HCV translation, a beneficial effect that may have significant clinical implications.
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Affiliation(s)
- Qiang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou 310003, China
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Dai Y, Zeng M, Li R, Rao S, Chen C, DelProposto Z, Haacke EM, Hu J, Renate J. Improving detection of siderotic nodules in cirrhotic liver with a multi-breath-hold susceptibility-weighted imaging technique. J Magn Reson Imaging 2012; 34:318-25. [PMID: 21780226 DOI: 10.1002/jmri.22607] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
PURPOSE To evaluate the role of abdominal susceptibility-weighted imaging (SWI) in the detection of siderotic nodules in cirrhotic liver. MATERIALS AND METHODS Forty patients with pathologically identified liver cirrhosis and 40 age/sex-matched normal controls underwent T1-, T2-, T2*-weighted imaging and SWI at 3T. Two radiologists prospectively analyzed all magnetic resonance imaging (MRI) studies. Siderotic nodules detected by each imaging technique were counted for comparison. The conspicuity of siderotic nodules was assessed using a scale from 1 to 3 (1, weak; 2, moderate; 3, prominent). RESULTS The number of siderotic nodules detected by SWI (3863) was significantly greater than that of T1-weighted imaging (262, P < 0.001), T2-weighted imaging (842, P < 0.001), and T2*-weighted imaging (2475, P < 0.001). No suspected siderotic nodules were detected in normal controls by any imaging technique. CONCLUSION SWI appears to provide the most sensitive method to detect siderotic nodules in cirrhotic liver.
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Affiliation(s)
- Yongming Dai
- Siemens Healthcare China, MR Collaborations NE Asia, Shanghai, China
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Liu Y, An D, Sun R, Jin L, Wang Q. Inhibition of translation initiation factors might be the potential therapeutic targets for HCV patients with hepatic iron overload. Med Hypotheses 2011; 78:142-3. [PMID: 22047986 DOI: 10.1016/j.mehy.2011.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Accepted: 10/11/2011] [Indexed: 12/21/2022]
Abstract
Standard therapy, interferon-alpha (IFN-α) and ribavirin, remains the only available option for treatment of patients with hepatitis C virus (HCV) infection. However, iron overload, a common finding among HCV patients, have a poor response to treatment with current therapy. These data suggest that both host and viral factors are involved in the determination of the outcome of the therapy. Currently, novel antiviral compounds focus on the development of indirect antiviral drugs. The process of the viral translation is considered as the potential therapeutic targets. Coincidentally, study has found that hepatic iron load enhances the levels of eukaryotic initiation factor 3 (eIF3), which is essential for HCV translation. Reversely, iron chelation could reduce eIF3 p170 translation. Our hypothesis is that iron overload may specifically enhance cellular eIFs. As a result, the cellular mechanisms, in patients with iron overload, are utilized for translating viral mRNA into protein. Thus, treatment strategies that target eIFs should be an exceptionally good candidate therapeutic method for HCV patients with hepatic iron overload.
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Affiliation(s)
- Yiping Liu
- Center of Hygiene Assessment, Institute of Disease Prevention and Control, Academy of Military Medical Sciences, Beijing 100071, China.
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Kolachi NF, Kazi TG, Afridi HI, Kazi N, Kandhro GA, Shah AQ, Baig JA, Wadhwa SK, Khan S, Shah F, Jamali MK, Arain MB. Distribution of copper, iron, and zinc in biological samples (scalp hair, serum, blood, and urine) of Pakistani viral hepatitis (A-E) patients and controls. Biol Trace Elem Res 2011; 143:116-30. [PMID: 20872092 DOI: 10.1007/s12011-010-8852-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 09/09/2010] [Indexed: 12/17/2022]
Abstract
The aim of the present study was to compare the level of copper (Cu), iron (Fe) and zinc (Zn) in biological samples (serum, blood, urine, and scalp hair) of patients suffering from different viral hepatitis (A, B, C, D, and E; n = 521) of both gender age ranged 31-45 years. For comparative study, 255 age-matched control subjects, of both genders residing in the same city were selected as referents. The elements in the biological samples were analyzed by flame atomic absorption spectrophotometry, prior to microwave-assisted acid digestion. The validity and accuracy of the methodology was checked by using certified reference materials (CRMs) and with those values obtained by conventional wet acid digestion method on same CRMs. The results of this study showed that the mean values of Cu and Fe were higher in blood, sera, and scalp hair samples of hepatitis patients, while Zn level was found to be lower than age-matched control subjects. The urinary levels of these elements were found to be higher in the hepatitis patients than in the age-matched healthy controls (p < 0.05). These results are consistent with literature-reported data, confirming that the deficiency of zinc and hepatic iron and copper overload can directly cause lipid peroxidation and eventually hepatic damage.
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Affiliation(s)
- Nida Fatima Kolachi
- National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080 Sindh, Pakistan
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Jafroodi M, Asadi R, Heydarzadeh A, Besharati S. Effect of hepatic iron concentration and viral factors in chronic hepatitis C-infected patients with thalassemia major, treated with interferon and ribavirin. Int J Gen Med 2011; 4:529-33. [PMID: 21845061 PMCID: PMC3150176 DOI: 10.2147/ijgm.s19643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Indexed: 01/22/2023] Open
Abstract
Background: Beta thalassemia major patients are vulnerable to transfusion-transmitted infection, especially hepatitis C virus (HCV), and iron overload. These comorbidities lead to cirrhosis and hepatocellular carcinoma in these patients. In order to prevent these complications, treatment of HCV infection and regular iron chelating seems to be necessary. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) and viral factors on the sustained virological response (SVR) in chronic HCV-infected patients, with beta thalassemia major being treated with interferon and ribavirin. Materials and methods: We enrolled 30 patients with thalassemia major and chronic HCV who were referred to the Hematology Clinic of Guilan University of Medical Sciences, between December 2002 and April 2006. HIC was measured by atomic absorption spectroscopy before treatment. The viral factors (viral load, genotype) and HIC were compared between those who achieved a SVR and nonresponders. Results: Mean age of the 30 thalassemic patients, was 22.56 ± 4.28 years (14–30 years). Most patients were male (56.7%). Genotype 1a was seen in 24 (80%) cases. SVR was achieved in 15 patients (50%). There were no significant correlations between HIC (P = 1.00), viral load (P = 0.414), HCV genotype (P = 0.068), and SVR. No difference was observed in viral load (P = 0.669) and HIC (P = 0.654) between responders and nonresponders. Conclusion: HIC, HCV viral load, and HCV genotype were not correlated with virological response, and it seems that there is no need to postpone antiviral treatment for more vigorous iron chelating therapy.
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Affiliation(s)
- Maryam Jafroodi
- Department of Hematology, Gulian University of Medical Sciences, Rasht, Guilan, Iran
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20
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Bartolomei G, Cevik RE, Marcello A. Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. J Gen Virol 2011; 92:2072-2081. [PMID: 21593278 DOI: 10.1099/vir.0.032706-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Several clinical observations point to an intricate crosstalk between iron (Fe) metabolism and chronic hepatitis C virus (HCV) infection. In this study, we wanted to investigate the molecular control that Fe levels exert on HCV replication at the hepatocyte level. In keeping with previous observations we confirmed that supra-physiological intracellular Fe induced by haemin treatment down-modulated HCV replication from subgenomic replicons. We also found that RNAi-mediated knockdown of the key Fe modulator hepcidin increased intracellular ferritin and inhibited HCV replication. Conversely, HCV replication did not modulate ferritin content in hepatocytes. Finally, we demonstrated that hepcidin is modulated at the mRNA level by alpha interferon through STAT3. We propose that in Huh7 cells hepcidin modulation leads to an unfavourable intracellular environment for HCV replication. These data may therefore contribute to a better understanding of the complex interplay between HCV and cellular physiology during infection.
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Affiliation(s)
- Giody Bartolomei
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Recep Emrah Cevik
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Alessandro Marcello
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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21
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Fiorino S, Conti F, Gramenzi A, Loggi E, Cursaro C, Di Donato R, Micco L, Gitto S, Cuppini A, Bernardi M, Andreone P. Vitamins in the treatment of chronic viral hepatitis. Br J Nutr 2011; 105:982-989. [PMID: 21255469 DOI: 10.1017/s0007114510004629] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid- and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C.
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Affiliation(s)
- Sirio Fiorino
- Operative Unit of Internal Medicine, Budrio Hospital, Budrio, BO, Italy
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22
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Fujita N, Nakanishi M, Mukai J, Naito Y, Ichida T, Kaito M, Yoshikawa T, Takei Y. Identification of treatment efficacy-related host factors in chronic hepatitis C by ProteinChip serum analysis. Mol Med 2010; 17:70-8. [PMID: 20927485 DOI: 10.2119/molmed.2010.00124] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Accepted: 10/04/2010] [Indexed: 01/28/2023] Open
Abstract
Recent development of proteomic array technology, including protein profiling coupling ProteinChip array with surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS), provides a potentially powerful tool for discovery of new biomarkers by comparison of its profiles according to patient phenotypes. We used this approach to identify the host factors associated with treatment response in patients with chronic hepatitis C (CHC) receiving a 48-wk course of pegylated interferon (PEG-IFN) alpha 2b plus ribavirin (RBV). Protein profiles of pretreatment serum samples from 32 patients with genotype 1b and high viral load were conducted by SELDI-TOF/MS by using the three different ProteinChip arrays (CM10, Q10, IMAC30). Proteins showed significantly different peak intensities between sustained virological responders (SVRs), and non-SVRs were identified by chromatography, SDS-PAGE, TOF/MS and tandem mass spectrometry (MS/MS) assay. Eleven peak intensities were significantly different between SVRs and non-SVRs. The three SVR-increased peaks could be identified as two apolipoprotein (Apo) fragments and albumin and, among the eight non-SVR-increased proteins, four peaks identified as two iron-related and two fibrogenesis-related protein fragments, respectively. Multivariate analysis showed that the serum ferritin and three peak intensity values (Apo A1, hemopexin and transferrin) were independent variables associated with SVRs, and the area under the receiver operating characteristic (ROC) curves for SVR prediction by using the Apo A1/hemopexin and hemopexin/transferrin were 0.964 and 0.936. In conclusion, pretreatment serum protein profiling by SELDI-TOF/MS is variable for identification of response-related host factors, which are useful for treatment efficacy prediction in CHC receiving PEG-IFN plus RBV. Our data also may help us understand the mechanism for treatment resistance and development of more effective antiviral therapy targeted toward the modulation of lipogenesis or iron homeostasis in CHC patients.
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Affiliation(s)
- Naoki Fujita
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan.
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23
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Pereira PDSF, Silva ISDSE, Uehara SNDO, Emori CT, Lanzoni VP, Silva AEB, Ferraz MLG. Chronic hepatitis C: hepatic iron content does not correlate with response to antiviral therapy. Rev Inst Med Trop Sao Paulo 2010; 51:331-6. [PMID: 20209268 DOI: 10.1590/s0036-46652009000600004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Accepted: 10/28/2009] [Indexed: 12/16/2022] Open
Abstract
The complex interaction between hepatitis C virus infection, iron homeostasis and the response to antiviral treatment remains controversial. The aim of this study was to evaluate the influence of hepatic iron concentration (HIC) on the sustained virological response (SVR) to antiviral therapy in patients with chronic hepatitis C. A total of 50 patients who underwent pretreatment liver biopsy with assessment of HIC by graphite furnace atomic absorption spectroscopy and were subsequently submitted to antiviral treatment with interferon/peginterferon and ribavirin were included in the study. Patients with alcoholism, history of multiple blood transfusion, chronic kidney disease, hemolytic anemia and parenteral iron therapy were excluded. The iron related markers and HIC were compared between those who achieved an SVR and non-responders (NR) patients. The mean age was 45.7 years and the proportion of patients' gender was not different between SVR and NR patients. The median serum iron was 138 and 134 microg/dL (p = 0.9), the median serum ferritin was 152.5 and 179.5 ng/mL (p = 0.87) and the median HIC was 9.9 and 8.2 micromol/g dry tissue (p = 0.51), for SVR and NR patients, respectively. Thus, hepatic iron concentration, determined by a reliable quantitative method, was not a negative predictive factor of SVR in patients with chronic hepatitis C presenting mild to moderate hepatic iron accumulation.
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The role of iron in the pathophysiology and treatment of chronic hepatitis C. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2010; 23:822-8. [PMID: 20011735 DOI: 10.1155/2009/290383] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Increased hepatic iron content may be observed in patients with chronic hepatitis C infection, and may contribute to disease severity. The presence of hemochromatosis gene mutations is associated with increased hepatic iron accumulation and may lead to accelerated disease progression. Hepatic iron depletion has been postulated to decrease the risk of hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. It is possible that iron depletion stabilizes or improves liver histology and slows disease progression in these individuals. The present article reviews the prevalence and risk factors for hepatic iron overload in chronic hepatitis C, with emphasis on the available data regarding the efficacy of iron depletion in the treatment of this common liver disease.
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25
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Price L, Kowdley KV. The role of iron in the pathophysiology and treatment of chronic hepatitis C. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2010; 29:1141-4. [PMID: 20011735 DOI: 10.1093/ndt/gft467] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Increased hepatic iron content may be observed in patients with chronic hepatitis C infection, and may contribute to disease severity. The presence of hemochromatosis gene mutations is associated with increased hepatic iron accumulation and may lead to accelerated disease progression. Hepatic iron depletion has been postulated to decrease the risk of hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. It is possible that iron depletion stabilizes or improves liver histology and slows disease progression in these individuals. The present article reviews the prevalence and risk factors for hepatic iron overload in chronic hepatitis C, with emphasis on the available data regarding the efficacy of iron depletion in the treatment of this common liver disease.
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Affiliation(s)
- Leslie Price
- Center for Liver Disease, Virginia Mason Medical Center, Seattle, Washington 98101, USA
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26
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Gentile I, Viola C, Paesano L, D'Onofrio M, D'Agostino E, Cerini R, Borrelli F, Piazza M, Borgia G. Iron depletion before HCV antiviral therapy: a pilot, randomized, controlled trial. J Clin Apher 2010; 24:190-6. [PMID: 19760753 DOI: 10.1002/jca.20210] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It is not known whether iron depletion before pegylated IFN or combination treatment improves sustained virological response (SVR) rate in patients with chronic hepatitis C, despite its use in clinical practice in this setting. We aimed to investigate whether blood letting improves the efficacy (SVR) and tolerability of PEG-IFNalpha2b + Ribavirin in chronic hepatitis C patients. Patients with chronic hepatitis C and ferritin >100 ng/mL were randomized to: (1) repeated phlebotomies to obtain a ferritin level <50 ng/mL followed by pegylated-Interferon alpha2b + ribavirin (active arm); or (2) pegylated-Interferon alpha2b + ribavirin (control arm). Primary endpoint was SVR rate, secondary endpoint was frequency of clinical and laboratory grade 3-4 adverse events. Thirty-three patients were enrolled in the study (19 in active arm, 14 in control arm). The 19 patients in the active arm underwent a median of 5 phlebotomies (range: 1-9) to achieve the targeted ferritin (<50 ng/mL). Phlebotomies significantly reduced ferritin, iron, transferrin saturation, aspartate aminotransferase, alanine aminotransferase, and hemoglobin levels. Platelet count significantly increased, whereas HCV-RNA levels remained unchanged. After antiviral therapy overall SVR was 31.6% in active arm and 21.4% in control arm (P = 0.698). Considering only the 18 patients who were naive to antiviral therapy, SVR was 60% in active arm versus 25% in control arm (P = 0.188). Tolerability, drug dose reduction or withdrawal were similar in the two arms. In conclusion phlebotomies do not increase the overall efficacy of antiviral therapy. However, the strong trend to higher SVR in naive patients undergoing phlebotomies warrants further investigation.
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Affiliation(s)
- Ivan Gentile
- Department of Public Medicine and Social Security, Section of Infectious Diseases, University Federico II, Naples, Italy.
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27
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Hou WH, Rossi L, Shan Y, Zheng JY, Lambrecht RW, Bonkovsky HL. Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells. World J Gastroenterol 2009; 15:4499-510. [PMID: 19777608 PMCID: PMC2751994 DOI: 10.3748/wjg.15.4499] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [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
AIM: To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.
METHODS: Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.
RESULTS: Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up-regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them.
CONCLUSION: Excess iron up-regulates HMOX1 and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.
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28
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Licata A, Nebbia ME, Cabibbo G, Iacono GL, Barbaria F, Brucato V, Alessi N, Porrovecchio S, Di Marco V, Craxì A, Cammà C. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009. [PMID: 19418586 DOI: 10.3748/wjg.15.2132.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
AIM To investigate the relationship between ferritin and steatosis in patients with chronically abnormal liver function tests (LFTs) and high ferritin level. METHODS One hundred and twenty-four consecutive patients with hyperferritinemia (male > 300 ng/mL, female > 200 ng/mL) were evaluated; clinical, biochemical and serological data, iron status parameters, HFE gene mutations and homeostasis model assessment score were obtained. Steatosis was graded by ultrasound as absent or present. Histology was available in 53 patients only. RESULTS Mean level of ferritin was 881 +/- 77 ng/mL in men and 549 +/- 82 ng/mL in women. The diagnosis was chronic hepatitis C in 53 (42.7%), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in 57 (45.9%), and cryptogenic liver damage in 14 (11.3%). None was diagnosed as hereditary hemochromatosis (HH). Hepatic siderosis on liver biopsy was present in 17 of 54 (32%) patients; grade 1 in eight and grade 2 in nine. Overall, 92 patients (74.2%) had steatosis. By logistic regression, ferritin and gamma-glutamyltransferase were independent predictors of steatosis. Ferritin levels were significantly related to low platelet count, steatosis and hepatitis C virus infection. CONCLUSION In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs without HH, high serum ferritin level is a risk factor for steatosis.
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Affiliation(s)
- Anna Licata
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, University of Palermo, 90127 Palermo, Italy.
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29
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Licata A, Nebbia ME, Cabibbo G, Iacono GL, Barbaria F, Brucato V, Alessi N, Porrovecchio S, Di Marco V, Craxì A, Cammà C. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009; 15:2132-8. [PMID: 19418586 PMCID: PMC2678584 DOI: 10.3748/wjg.15.2132] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [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
AIM: To investigate the relationship between ferritin and steatosis in patients with chronically abnormal liver function tests (LFTs) and high ferritin level.
METHODS: One hundred and twenty-four consecutive patients with hyperferritinemia (male > 300 ng/mL, female > 200 ng/mL) were evaluated; clinical, biochemical and serological data, iron status parameters, HFE gene mutations and homeostasis model assessment score were obtained. Steatosis was graded by ultrasound as absent or present. Histology was available in 53 patients only.
RESULTS: Mean level of ferritin was 881 ± 77 ng/mL in men and 549 ± 82 ng/mL in women. The diagnosis was chronic hepatitis C in 53 (42.7%), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in 57 (45.9%), and cryptogenic liver damage in 14 (11.3%). None was diagnosed as hereditary hemochromatosis (HH). Hepatic siderosis on liver biopsy was present in 17 of 54 (32%) patients; grade 1 in eight and grade 2 in nine. Overall, 92 patients (74.2%) had steatosis. By logistic regression, ferritin and γ-glutamyltransferase were independent predictors of steatosis. Ferritin levels were significantly related to low platelet count, steatosis and hepatitis C virus infection.
CONCLUSION: In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs without HH, high serum ferritin level is a risk factor for steatosis.
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30
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Afridi HI, Kazi TG, Kazi NG, Jamali MK, Sarfaraz RA, Arain MB, Kandhro GA, Shah AQ, Baig JA, Jalbani N, Ansari R. Determination of copper and iron in biological samples of viral hepatitis (A-E) female patients. Biol Trace Elem Res 2009; 129:78-87. [PMID: 19104758 DOI: 10.1007/s12011-008-8297-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2008] [Accepted: 12/09/2008] [Indexed: 01/09/2023]
Abstract
There is accumulative evidence that the metabolism of iron and copper is altered in viral hepatic diseases, and these nutrients might have specific roles in their pathogenesis and progress. The aim of present study was to compare the level of copper (Cu) and iron (Fe) in biological samples (serum, urine, and scalp hair) of female patients suffering from different viral hepatitis (A, B, C, D, and E; n = 253) of age range 31-45 years. For comparative study, 95 healthy females of the same age group residing in the same city were selected. The elements in the biological samples were analyzed by flame atomic absorption spectrophotometry, prior to microwave-assisted acid digestion. The validity and accuracy of the methodology was checked by using certified reference materials (CRMs) and with those values obtained by conventional wet acid digestion method on same CRMs. The results of this study showed that the mean values of Cu and Fe were higher in sera and scalp hair samples of hepatitis patients than age-matched control subjects, while the difference was significant (p < 0.001), in the cases of viral hepatitis B and viral hepatitis C as compared to viral hepatitis A, D, and E. The urinary levels of these elements were found higher in the hepatitis patients than in the age-matched healthy controls (p < 0.05). These results are consistent with literature-reported data, confirming that hepatic iron and copper overload can directly cause lipid peroxidation and eventually hepatic damage.
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Affiliation(s)
- Hassan Imran Afridi
- National Center of Excellence in Analytical Chemistry, Sindh University, Jamshoro, Pakistan.
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31
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Abstract
Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.
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Affiliation(s)
- Annika Kau
- Zentrum der Inneren Medizin, Medizinische Klinik 1, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany
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Franchini M, Targher G, Capra F, Montagnana M, Lippi G. The effect of iron depletion on chronic hepatitis C virus infection. Hepatol Int 2008; 2:335-40. [PMID: 19669262 PMCID: PMC2716881 DOI: 10.1007/s12072-008-9076-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2007] [Accepted: 03/21/2008] [Indexed: 02/07/2023]
Abstract
Increasing evidence exists that iron overload, a common finding in chronic hepatitis C virus (HCV) infection, plays an important role in the pathophysiology of this disease. The mechanisms by which iron excess induces liver damage along with the benefit of iron depletion via phlebotomy on biochemical and histological outcomes in patients with chronic HCV infection have been discussed in this review. Finally, we focus on the effect of iron reduction on the rate of response to interferon antiviral therapy.
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Affiliation(s)
- Massimo Franchini
- Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Azienda Ospedaliera di Verona, Ospedale Policlinico, Piazzale Ludovico Scuro, Verona, 37134, Italy,
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Abstract
A 51-year-old Caucasian female presented with asymmetric arthritis and a positive rheumatoid factor. She was initially treated for rheumatoid arthritis. However, she had features such as abnormal liver function tests and osteoarthritis in an unusual location, the metacarpophalangeal joint. Further workup revealed that the patient had active hepatitis C and hereditary hemochromatosis. Phlebotomy treatment initiation seemed to be associated with improvement in joint symptoms but, more importantly, may have prevented future risk of cirrhosis and hepatocellular cancer. Treatment for the hepatitis C may also be needed. Clinicians should look for underlying systemic illnesses leading to atypical inflammatory arthritis.
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Blair CS, Haydon GH, Hayes PC. Section Review Anti-infectives: Current perspectives on the treatment and prevention of hepatitis C infection. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.12.1657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Desai TK, Jamil LH, Balasubramaniam M, Koff R, Bonkovsky HL. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci 2008; 53:815-22. [PMID: 17846887 DOI: 10.1007/s10620-007-9945-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2007] [Accepted: 07/17/2007] [Indexed: 02/06/2023]
Abstract
Prospective randomized controlled trials (RCTs) comparing phlebotomy and interferon (IFN) treatment to IFN alone in patients with chronic hepatitis C (CHC) have suggested a benefit for the phlebotomy group. However, statistical significance was achieved in only one of these trials. We performed a meta-analysis of RCTs comparing phlebotomy and IFN to IFN alone for the treatment of CHC. The MEDLINE database and Cochrane registry of controlled trials were searched using the key words "phlebotomy" and "treatment of hepatitis C." Reference lists of review articles discussing the interaction between iron and CHC, and prospective RCTs comparing phlebotomy plus IFN therapy to IFN alone were searched to identify additional RCTs that compared phlebotomy plus IFN to IFN alone. Peto odds ratios with their 95% confidence intervals and Forrest plots were generated for each variable to assess the relationships among the studies that had provided that information. Statistical analysis was performed using Comprehensive META-Analysis version 2.0. Six prospective RCTs were identified: all used sustained viral response (SVR) as an endpoint. The three largest RCTs excluded patients with cirrhosis. Two RCTs specifically included only patients with either high ferritin or high hepatic iron content. IFN treatment regimes varied. Length of treatment varied between 6 and 12 months. The phlebotomy plus IFN group and the IFN group did not differ with respect to the percentage of patients with cirrhosis or genotype 1. SVR was attained in 50/182 (27%) patients in the phlebotomy plus IFN group, compared to 22/185 (12%) patients in the IFN group. Peto odds ratio for SVR in phlebotomy plus IFN group was 2.7; 95% CI 1.6-4.5, P < 0.0001. All five RCTs published in manuscript form showed a trend towards a benefit from the phlebotomy plus IFN in attaining SVR, and the results of the meta-analysis were not dependent on any single RCT, since excluding any single RCT did not change the results. Phlebotomy improves the SVR in response to IFN treatment in patients with CHC. Confirmation of this will require RCT with detailed pre-treatment iron studies and appropriately powered to demonstrate a statistically significant benefit.
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Luna-Morales ME, Collazo-Reyes F. Historic and bibliometric analysis of the Latin American and Caribbean journals in the international Science Indexes: 1961-2005. REVISTA ESPANOLA DE DOCUMENTACION CIENTIFICA 2007. [DOI: 10.3989/redc.2007.v30.i4.403] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Fujita N, Sugimoto R, Urawa N, Araki J, Mifuji R, Yamamoto M, Horiike S, Tanaka H, Iwasa M, Kobayashi Y, Adachi Y, Kaito M. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 2007; 22:1886-93. [PMID: 17914965 DOI: 10.1111/j.1440-1746.2006.04759.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy. METHODS We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks. RESULTS CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 +/- 5.34 vs 4.41 +/- 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake (P = 0.0213, r = 0.290), transaminase level (P = 0.0126, r = 0.247), platelet count (P = 0.0002, r = -0.369), histological grading (P = 0.0121, r = 0.248) and staging (P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 +/- 5.76 vs 4.39 +/- 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin (P = 0.0277). CONCLUSIONS Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment.
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MESH Headings
- Adult
- Aged
- Alcohol Drinking/adverse effects
- Antiviral Agents/therapeutic use
- Disease Progression
- Drug Resistance, Multiple, Viral
- Drug Therapy, Combination
- Female
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/metabolism
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/metabolism
- Hepatitis C, Chronic/pathology
- Humans
- Interferon alpha-2
- Interferon-alpha/therapeutic use
- Iron/metabolism
- Iron Overload/metabolism
- Iron Overload/pathology
- Iron Overload/virology
- Liver/metabolism
- Liver/pathology
- Liver/virology
- Male
- Middle Aged
- Platelet Count
- Recombinant Proteins
- Ribavirin/therapeutic use
- Risk Factors
- Severity of Illness Index
- Sex Factors
- Transaminases/blood
- Treatment Outcome
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Affiliation(s)
- Naoki Fujita
- Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical Science, Mie University Graduate School of Medicine, Mie, Japan.
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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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Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance. World J Gastroenterol 2007; 13:4699-706. [PMID: 17729391 PMCID: PMC4611191 DOI: 10.3748/wjg.v13.i35.4699] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There are several cofactors which affect body iron metabolism and accelerate iron overload. Alcohol and hepatic viral infections are the most typical examples for clarifying the role of cofactors in iron overload. In these conditions, iron is deposited in hepatocytes and Kupffer cells and reactive oxygen species (ROS) produced through Fenton reaction have key role to facilitate cellular uptake of transferrin-bound iron. Furthermore, hepcidin, antimicrobial peptide produced mainly in the liver is also responsible for intestinal iron absorption and reticuloendothelial iron release. In patients with ceruloplasmin deficiency, anemia and secondary iron overload in liver and neurodegeneration are reported. Furthermore, there is accumulating evidence that fatty acid accumulation without alcohol and obesity itself modifies iron overload states. Ineffective erythropoiesis is also an important factor to accelerate iron overload, which is associated with diseases such as thalassemia and myelodysplastic syndrome. When this condition persists, the dietary iron absorption is increased due to the increment of bone marrow erythropoiesis and tissue iron overload will thereafter occurs. In porphyria cutanea tarda, iron is secondarily accumulated in the liver.
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Affiliation(s)
- Yutaka Kohgo
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Midorigaoka-higashi 2-1, Asahikawa 078-8510, Japan.
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Abstract
BACKGROUND Since the discovery of the hepatitis C virus (HCV), extensive literature has emerged on alcohol and HCV interaction. GOAL To understand the impact of alcohol and HCV infection on the severity of liver disease and the mechanisms of interaction between the two. STUDY Of 1269 articles (1991 to 2006) searched through MEDLINE and cited cross references, 133 were thoroughly reviewed to assess: (a) prevalence of combined alcohol use and HCV, (b) severity of liver disease (c) treatment response, and (d) mechanisms of interaction between HCV and alcohol. Data on study design, patient demographics, diagnostic tests used, and study outcomes were extracted for critical analysis. RESULTS Prevalence of HCV is 3-fold to 30-fold higher in alcoholics compared with the general population. Patients with HCV infection and alcohol abuse develop more severe fibrosis with higher rate of cirrhosis and hepatocellular cancer compared with nondrinkers. Increased oxidative stress seems to be the dominant mechanism for this synergism between alcohol and the HCV. Abstinence is the key to the management of liver disease due to HCV and alcohol. Data have shown that lower response rates to interferon in alcoholics with HCV infection are likely due to noncompliance. CONCLUSIONS Alcoholics with HCV infection have more severe liver disease compared with nondrinkers. Patients should be encouraged to enroll in rehabilitation programs so as to improve treatment adherence and response.
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Affiliation(s)
- Ashwani K Singal
- James J Peters Bronx Veterans Affairs Medical Center, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10468, USA.
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Alexander J, Tung BY, Croghan A, Kowdley KV. Effect of iron depletion on serum markers of fibrogenesis, oxidative stress and serum liver enzymes in chronic hepatitis C: results of a pilot study. Liver Int 2007; 27:268-73. [PMID: 17311623 DOI: 10.1111/j.1478-3231.2007.01449.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Hepatic iron deposition has been associated with decreased response to interferon-alpha monotherapy, and has been speculated to contribute to disease progression in chronic hepatitis C (CHC). We performed this study to evaluate the effect of iron depletion on biochemical and virologic markers, and markers of lipid peroxidation and fibrogenesis. MATERIALS AND METHODS Eighteen patients with CHC who did not have a virologic response to interferon monotherapy underwent weekly phlebotomies until iron depletion (serum ferritin <50 ng/ml). Serum levels of alanine transaminase (ALT), hepatitis C virus-RNA, transferrin saturation, ferritin, 8-isoprostane, hyaluronic acid, amino-terminal procollagen III peptide and YKL-40 were measured before and after iron depletion. RESULTS There was a statistically significant reduction of serum ALT, transferrin saturation and serum ferritin after iron depletion (range 4-11 phlebotomies). Serum ALT returned to normal after iron depletion in four (22%) patients. There was a significant reduction in serum procollagen III peptide level among patients who achieved biochemical response. No significant reduction was noted in serum levels of other markers. CONCLUSIONS Iron depletion was associated with a biochemical response in 22% of patients who did not respond to interferon monotherapy. There was a significant reduction in a key marker of fibrogenesis among patients with biochemical response. These data support longer-term studies of iron depletion in CHC.
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Affiliation(s)
- Jacob Alexander
- Department of Medicine, Division of Gastroenterology, University of Washington Medical Center, Seattle, WA, USA
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Alexander J, Kowdley KV. Effects of iron and HFE mutations on response to therapy in chronic hepatitis C: an ironic interaction? Gastroenterology 2006; 131:1635-8. [PMID: 17067603 DOI: 10.1053/j.gastro.2006.09.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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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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Sumida Y, Kanemasa K, Yamaoka Y, Imamura S, Katoh N, Nakashima T, Tachibana S, Mitsuyoshi H, Itoh Y, Okanoue T. Influence of Helicobacter pylori infection on iron accumulation in hepatitis C. Liver Int 2006; 26:827-33. [PMID: 16911465 DOI: 10.1111/j.1478-3231.2006.01305.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
GOAL Iron may play a role in the pathogenesis of chronic hepatitis C. Helicobacter pylori (Hp) infection was recently associated with iron-deficiency anemia. We examined the influence of Hp infection on hepatic iron accumulation in hepatitis C. METHODS Ninety-five hepatitis C virus (HCV)-RNA-positive patients, including 60 chronic hepatitis, 17 cirrhosis and 18 hepatocellular carcinoma as well as 95 age- and sex-matched normal subjects without HCV infection as control, were studied. Liver biopsies were also obtained from 44 HCV-infected patients. Serum Hp antibodies were measured by an enzyme-linked immunosorbent assay and clinical data, including iron parameters and histological findings, were compared between Hp-positive and -negative HCV-infected patients. RESULTS The percentage of serum Hp antibodies was lower in HCV-infected patients than in controls (52/95 (54.7%) vs. 68/95 (71.6%); P<0.05). HCV-infected patients had higher serum ferritin levels than controls (120 [2.8-1700] vs. 58 [2.2-420] ng/ml; P<0.0001). In HCV-infected patients, the serum ferritin levels (medians and [ranges]) in Hp-positive patients were significantly lower than those of Hp-negative patients (99 [8.5-770] vs. 150 [2.8-1700] ng/ml; P<0.05). The grades of hepatic iron deposit in Hp-positive patients were significantly lower than those in Hp-negative patients (P<0.01). CONCLUSIONS Hp infection may at least partly affect hepatic iron accumulation in HCV-related liver diseases.
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Affiliation(s)
- Yoshio Sumida
- Department of Gastroenterology and Hepatology, Nara City Hospital, Nara, Japan.
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Paeshuyse J, Coelmont L, Vliegen I, Van hemel J, Vandenkerckhove J, Peys E, Sas B, De Clercq E, Neyts J. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin. Biochem Biophys Res Commun 2006; 348:139-44. [PMID: 16875675 DOI: 10.1016/j.bbrc.2006.07.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Accepted: 07/04/2006] [Indexed: 12/16/2022]
Abstract
We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC(50)) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78+/-21 microM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 microM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.
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Affiliation(s)
- Jan Paeshuyse
- Rega Institute for Medical Research, Minderbroedersstraat 10, KU Leuven, B-3000 Leuven, Belgium
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Sebastiani G, Vario A, Ferrari A, Pistis R, Noventa F, Alberti A. Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C. J Viral Hepat 2006; 13:199-205. [PMID: 16475996 DOI: 10.1111/j.1365-2893.2005.00662.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 microg/L in females and 450 microg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy.
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Affiliation(s)
- G Sebastiani
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
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Loftis JM, Matthews AM, Hauser P. Psychiatric and substance use disorders in individuals with hepatitis C: epidemiology and management. Drugs 2006; 66:155-74. [PMID: 16451091 DOI: 10.2165/00003495-200666020-00003] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) infection is a major health concern in the US as well as in other countries worldwide. Treatment issues and disease management strategies are complicated by the extremely high rate of psychiatric and substance use disorders in those who have HCV. The majority of new and existing cases of HCV are related to injection drug use and, in this population, the prevalence of psychiatric comorbidity is high. Optimally, all patients with HCV should be screened for psychiatric and substance use disorders before initiation of antiviral therapy. If a patient screens positive, he or she should be referred to a mental healthcare provider or addiction specialist, assessed for the presence of a psychiatric or substance use disorder, and appropriately treated prior to initiation of antiviral (i.e. interferon) therapy. Although interferon-based therapies can lead to severe neuropsychiatric adverse effects, including in rare instances suicide, evidence suggests that many patients with comorbid psychiatric and substance use diagnoses can be treated safely and effectively using comanagement strategies. However, most patients with HCV are not treated with antiviral therapy. Therefore, we must expand our definition of HCV 'treatment' to include treatment of the comorbid psychiatric and substance use disorders that accompany HCV infection and precede antiviral therapy. This paper reviews the epidemiology and management of psychiatric and substance use disorders in patients with HCV, the issue of psychiatric and substance use disorders as contraindications for antiviral therapy, and current treatment strategies for HCV patients with these comorbid conditions.
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Affiliation(s)
- Jennifer M Loftis
- Department of Psychiatry, Oregon Health & Science University, Portland, Oregon, USA
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48
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Pearlman BL. Hepatitis C virus infection in African Americans. Clin Infect Dis 2005; 42:82-91. [PMID: 16323096 DOI: 10.1086/498512] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2005] [Accepted: 08/07/2005] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C is more prevalent among African Americans than among persons of any other racial group in the United States. However, comparatively little data are available on the natural history and treatment of hepatitis C in this population. Compared with white persons, African American persons have a lower rate of viral clearance and, consequently, a higher rate of chronic hepatitis C. Nonetheless, African American persons may have a lower rate of fibrosis progression than do white persons. African American persons with hepatitis C-related cirrhosis have higher rates of both hepatocellular carcinoma and liver cancer-related mortality than do white persons with hepatitis C-related cirrhosis. In nearly all treatment trials that enrolled a significant proportion of African American subjects, such patients had inferior treatment responses, compared with those of white subjects. The prevalence of infection with hepatitis C virus genotype 1 is higher among African American patients than white patients, although this difference does not account for a greatly dissimilar response to therapy. Some of the postulated mechanisms for these disparate treatment responses and natural histories of infection are also reviewed.
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Affiliation(s)
- Brian L Pearlman
- Center for Hepatitis C, Atlanta Medical Center, Medical College of Georgia, Atlanta, GA, USA.
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Ko WS, Guo CH, Yeh MS, Lin LY, Hsu GSW, Chen PC, Luo MC, Lin CY. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol 2005; 11:4697-702. [PMID: 16094713 PMCID: PMC4615414 DOI: 10.3748/wjg.v11.i30.4697] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the extent of micronutrient and oxidative stress in blood and to examine their linkages with viral loads in chronic hepatitis C patients.
METHODS: Hepatitis C virus (HCV)-RNA levels were quantified in the serum from 37 previously untreated patients with chronic hepatitis C. The plasma and erythrocyte micronutrients (zinc, selenium, copper, and iron) were estimated, and malondialdehyde (MDA) contents were determined as a marker to detect oxidative stress. Antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase (GR) activities in blood were also measured. The control group contained 31 healthy volunteers.
RESULTS: The contents of zinc (Zn), and selenium (Se) in plasma and erythrocytes were significantly lower in hepatitis C patients than in the controls. On the contrary, copper (Cu) levels were significantly higher. Furthermore, plasma and erythrocyte MDA levels, and the SOD and GR activities in erythrocytes significantly increased in hepatitis C patients compared to the controls. However, the plasma GPX activity in patients was markedly lower. Plasma Se (r = -0.730, P < 0.05), Cu (r = 0.635), and GPX (r = -0.675) demonstrated correlations with HCV-RNA loads. Significant correlation coefficients were also observed between HCV-RNA levels and erythrocyte Zn (r = -0.403), Se (r = -0.544), Cu (r = 0.701) and MDA (r = 0.629) and GR (r = 0.441).
CONCLUSION: The levels of Zn, Se, Cu, and oxidative stress (MDA), as well as related anti-oxidative enzymes (GR and GPX) in blood have important impact on the viral factors in chronic hepatitis C. The distribution of these parameters might be significant biomarkers for HCV.
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Affiliation(s)
- Wang-Sheng Ko
- Department of Food and Nutrition, Hung Kuang University, Taichung, Taiwan, China
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Shan Y, Lambrecht RW, Bonkovsky HL. Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey. Clin Infect Dis 2005; 40:834-41. [PMID: 15736017 DOI: 10.1086/428062] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2004] [Accepted: 11/10/2004] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND There is growing evidence that mildly increased amounts of iron in the liver can increase hepatic injury, particularly if combined with other hepatotoxic factors, such as alcohol use, use of porphyrogenic drugs, or chronic viral hepatitis. In the present study, the association of hepatitis C virus (HCV) infection with serum measurements of iron status was assessed in the US population. METHODS We analyzed data from a total of 14,462 participants in the Third National Health and Nutrition Examination Survey. We excluded subjects who were aged <12 years, subjects for whom measurements of serum levels of iron or ferritin or the results of liver function tests were missing, and subjects who had a serum transferrin saturation of > or =50% (to help exclude subjects with hemochromatosis). RESULTS Mean serum levels of ferritin and iron (+/- standard error) were significantly higher among subjects with HCV infection (100+/-3 ng/mL and 229+/-17 microg/dL, respectively) than among subjects without liver disease (83+/-0.3 ng/mL and 101+/-2.1 microg/dL, respectively) (P<.0001). Serum levels of ferritin were directly and significantly correlated with serum levels of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase (r=0.25, r=0.24, and r=0.28, respectively; P<.0001), whereas platelet counts were inversely correlated with serum levels of ferritin (r=-0.12; P<.0001). CONCLUSION HCV infection is significantly associated with higher serum levels of ferritin and iron in the US population.
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Affiliation(s)
- Ying Shan
- Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
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