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Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4 + T lymphocytes in HIV-infected immune non-responders. EBioMedicine 2022; 86:104382. [PMID: 36462403 PMCID: PMC9718960 DOI: 10.1016/j.ebiom.2022.104382] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/29/2022] [Accepted: 11/09/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood. METHODS Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed. FINDINGS We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells. INTERPRETATION Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs. FUNDING This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).
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Yoshikawa M, Kudo K, Harada T, Harashima K, Suzuki J, Ogawa K, Fujiwara T, Nishida M, Sato R, Shirai T, Bito Y. Quantitative Susceptibility Mapping versus R2*-based Histogram Analysis for Evaluating Liver Fibrosis: Preliminary Results. Magn Reson Med Sci 2021; 21:609-622. [PMID: 34483224 DOI: 10.2463/mrms.mp.2020-0175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
PURPOSE The staging of liver fibrosis is clinically important, and a less invasive method is preferred. Quantitative susceptibility mapping (QSM) has shown a great potential in estimating liver fibrosis in addition to R2* relaxometry. However, few studies have compared QSM analysis and liver fibrosis. We aimed to evaluate the feasibility of estimating liver fibrosis by using QSM and R2*-based histogram analyses by comparing it with ultrasound-based transient elastography and the stage of histologic fibrosis. METHODS Fourteen patients with liver disease were enrolled. Data sets of multi-echo gradient echo sequence with breath-holding were acquired on a 3-Tesla scanner. QSM and R2* were reconstructed by water-fat separation method, and ROIs were analyzed for these images. Quantitative parameters with histogram features (mean, variance, skewness, kurtosis, and 1st, 10th, 50th, 90th, and 99th percentiles) were extracted. These data were compared with the elasticity measured by ultrasound transient elastography and histological stage of liver fibrosis (F0 to F4, based on the new Inuyama classification) determined by biopsy or hepatectomy. The correlation of histogram parameters with intrahepatic elasticity and histologically confirmed fibrosis stage was examined. Texture parameters were compared between subgroups divided according to fibrosis stage. Receiver operating characteristic (ROC) analysis was also performed. P < 0.05 indicated statistical significance. RESULTS The six histogram parameters of both QSM and R2*were significantly correlated with intrahepatic elasticity. In particular, three parameters (variance, percentiles [90th and 99th]) of QSM showed high correlation (r = 0.818-0.844), whereas R2* parameters showed a moderate correlation with elasticity. Four parameters of QSM were significantly correlated with fibrosis stage (ρ = 0.637-0.723) and differentiated F2-4 from F0-1 fibrosis and F3-4 from F0-2 fibrosis with areas under the ROC curve of > 0.8, but those of R2* did not. CONCLUSION QSM may serve as a promising surrogate indicator in detecting liver fibrosis.
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Affiliation(s)
- Masato Yoshikawa
- Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine
| | - Kohsuke Kudo
- Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine.,Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of Medicine
| | - Taisuke Harada
- Center for Cause of Death Investigation, Hokkaido University Faculty of Medicine.,Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital
| | - Kazutaka Harashima
- Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital
| | - Jun Suzuki
- Department of Radiation Oncology, Hakodate Municipal Hospital
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine
| | - Taro Fujiwara
- Department of Radiology, Division of Medical Imaging and Technology, Hokkaido University Hospital
| | - Mutsumi Nishida
- Diagnostic Center for Sonography, Hokkaido University Hospital
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Mariani R, Pelucchi S, Paolini V, Belingheri M, di Gennaro F, Faverio P, Riva M, Pesci A, Piperno A. Prolonged exposure to welding fumes as a novel cause of systemic iron overload. Liver Int 2021; 41:1600-1607. [PMID: 33713383 PMCID: PMC8252060 DOI: 10.1111/liv.14874] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Inhalation of welding fume may cause pulmonary disease known as welder's lung. At our centre we came across a number of welders with systemic iron overload and prolonged occupational history and we aimed at characterizing this novel clinical form of iron overload. METHODS After exclusion of other known causes of iron overload, 20 welders were fully evaluated for working history, hepatic, metabolic and iron status. MRI iron assessment was performed in 19 patients and liver biopsy in 12. We included 40 HFE-HH patients and 24 healthy controls for comparison. RESULTS 75% of patients showed lung HRCT alterations; 90% had s-FERR > 1000 ng/mL and 60% had TSAT > 45%. Liver iron overload was mild in 8 and moderate-severe in 12. The median iron removed was 7.8 g. Welders showed significantly lower TSAT and higher SIS and SIS/TIS ratio than HFE-HH patients. Serum hepcidin was significantly higher in welders than in HFE-HH patients and healthy controls. At liver biopsy, 50% showed liver fibrosis that was mild in four, and moderate-severe in two. Liver staging correlated with liver iron overload. CONCLUSIONS Welders with prolonged fume exposure can develop severe liver iron overload. The mechanism of liver iron accumulation is quite different to that of HFE-HH suggesting that reticuloendothelial cells may be the initial site of deposition. We recommend routine measurement of serum iron indices in welders to provide adequate diagnosis and therapy, and the inclusion of prolonged welding fume exposure in the list of acquired causes of hyperferritinemia and iron overload.
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Affiliation(s)
- Raffaella Mariani
- Centre for Rare Diseases ‐ Disorders of Iron Metabolism ‐ ASST‐MonzaCentre of European Reference Network (EuroBloodNet)San Gerardo Hospital MonzaMonzaItaly
| | - Sara Pelucchi
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly
| | | | - Michael Belingheri
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Unit of Occupational Medicine Unit‐ ASST‐MonzaSan Gerardo HospitalMonzaItaly
| | | | - Paola Faverio
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Respiratory Unit ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
| | - Michele Riva
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Unit of Occupational Medicine Unit‐ ASST‐MonzaSan Gerardo HospitalMonzaItaly
| | - Alberto Pesci
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Respiratory Unit ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
| | - Alberto Piperno
- Centre for Rare Diseases ‐ Disorders of Iron Metabolism ‐ ASST‐MonzaCentre of European Reference Network (EuroBloodNet)San Gerardo Hospital MonzaMonzaItaly,Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Medical Genetics ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
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Czaja AJ. Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications. Aliment Pharmacol Ther 2019; 49:681-701. [PMID: 30761559 DOI: 10.1111/apt.15173] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. AIMS To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. CONCLUSIONS Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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5
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Wood MJ, Crawford DHG, Wockner LF, Powell LW, Ramm GA. Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis. Liver Int 2017; 37:1382-1388. [PMID: 28231420 DOI: 10.1111/liv.13395] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 02/16/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis. METHODS We identified 291 C282Y HFE-homozygous patients who had undergone liver biopsy for histological fibrosis staging and measurement of HIC. Ordinal logistic regression determined the best model for fibrosis stage not including serum ferritin. Then, serum ferritin was introduced into this model to assess whether the predictive power of the model was significantly increased and to evaluate the effect on other predictors of fibrosis. RESULTS Ordinal logistic regression analyses without serum ferritin demonstrated that log HIC (OR 2.89; P < .001), male gender (OR 2.93; P = .005), alcohol consumption (g/day) (OR 1.01; P = .004), steatosis (OR 2.86; P = .01), arthritis (OR 2.46; P = .01) predicted increasing fibrosis stage (n=217). Addition of serum ferritin in multivariate analysis substantially improved the predictive power of the model (χ2 = 37.15; P < .01) and was highly predictive of fibrosis stage (OR 5.44; P < .001). Inclusion of serum ferritin in this model rendered the effects of HIC, gender, alcohol and steatosis to non-significance. CONCLUSIONS In haemochromatosis, serum ferritin is a better predictor of fibrosis stage than HIC, gender, steatosis and alcohol. These data support a hypothesis that ferritin may play a role in fibrosis rather than simply acting as a passive indicator of iron storage.
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Affiliation(s)
- Marnie J Wood
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Darrell H G Crawford
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Greenslopes Hospital, The Gallipoli Medical Research Foundation, Brisbane, Queensland, Australia
| | - Leesa F Wockner
- Biostatistics Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Lawrie W Powell
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Centre for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital and the University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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Lyberopoulou A, Chachami G, Gatselis NK, Kyratzopoulou E, Saitis A, Gabeta S, Eliades P, Paraskeva E, Zachou K, Koukoulis GK, Mamalaki A, Dalekos GN, Simos G. Low Serum Hepcidin in Patients with Autoimmune Liver Diseases. PLoS One 2015; 10:e0135486. [PMID: 26270641 PMCID: PMC4535884 DOI: 10.1371/journal.pone.0135486] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Accepted: 07/22/2015] [Indexed: 12/15/2022] Open
Abstract
Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients’ sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.
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MESH Headings
- Adult
- Aged
- Cholangitis, Sclerosing/blood
- Cholangitis, Sclerosing/genetics
- Cholangitis, Sclerosing/pathology
- Diagnosis, Differential
- Down-Regulation
- Female
- Ferritins/blood
- Hepatitis B/blood
- Hepatitis B/genetics
- Hepatitis B/pathology
- Hepatitis C/blood
- Hepatitis C/genetics
- Hepatitis C/pathology
- Hepatitis, Autoimmune/blood
- Hepatitis, Autoimmune/genetics
- Hepatitis, Autoimmune/pathology
- Hepcidins/blood
- Hepcidins/genetics
- Humans
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Biliary/blood
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/pathology
- Male
- Middle Aged
- Non-alcoholic Fatty Liver Disease/blood
- Non-alcoholic Fatty Liver Disease/genetics
- Non-alcoholic Fatty Liver Disease/pathology
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Affiliation(s)
- Aggeliki Lyberopoulou
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece
- Institute for Research & Technology—Thessaly (IRETETH), Larissa, Greece
| | - Georgia Chachami
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece
- Institute for Research & Technology—Thessaly (IRETETH), Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Eleni Kyratzopoulou
- Laboratory of Molecular Biology and Immunobiotechnology, Hellenic Pasteur Institute, Athens, Greece
| | - Asterios Saitis
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Petros Eliades
- Laboratory of Molecular Biology and Immunobiotechnology, Hellenic Pasteur Institute, Athens, Greece
| | - Efrosini Paraskeva
- Laboratory of Physiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - George K. Koukoulis
- Department of Pathology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Avgi Mamalaki
- Laboratory of Molecular Biology and Immunobiotechnology, Hellenic Pasteur Institute, Athens, Greece
| | - George N. Dalekos
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece
- * E-mail: (GS); (GND)
| | - George Simos
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece
- Institute for Research & Technology—Thessaly (IRETETH), Larissa, Greece
- * E-mail: (GS); (GND)
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Montaldo C, Mattei S, Baiocchini A, Rotiroti N, Del Nonno F, Pucillo LP, Cozzolino AM, Battistelli C, Amicone L, Ippolito G, van Noort V, Conigliaro A, Alonzi T, Tripodi M, Mancone C. Spike-in SILAC proteomic approach reveals the vitronectin as an early molecular signature of liver fibrosis in hepatitis C infections with hepatic iron overload. Proteomics 2014; 14:1107-15. [PMID: 24616218 DOI: 10.1002/pmic.201300422] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/08/2014] [Accepted: 01/09/2014] [Indexed: 01/06/2023]
Abstract
Hepatitis C virus (HCV)-induced iron overload has been shown to promote liver fibrosis, steatosis, and hepatocellular carcinoma. The zonal-restricted histological distribution of pathological iron deposits has hampered the attempt to perform large-scale in vivo molecular investigations on the comorbidity between iron and HCV. Diagnostic and prognostic markers are not yet available to assess iron overload-induced liver fibrogenesis and progression in HCV infections. Here, by means of Spike-in SILAC proteomic approach, we first unveiled a specific membrane protein expression signature of HCV cell cultures in the presence of iron overload. Computational analysis of proteomic dataset highlighted the hepatocytic vitronectin expression as the most promising specific biomarker for iron-associated fibrogenesis in HCV infections. Next, the robustness of our in vitro findings was challenged in human liver biopsies by immunohistochemistry and yielded two major results: (i) hepatocytic vitronectin expression is associated to liver fibrogenesis in HCV-infected patients with iron overload; (ii) hepatic vitronectin expression was found to discriminate also the transition between mild to moderate fibrosis in HCV-infected patients without iron overload.
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Affiliation(s)
- Claudia Montaldo
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; "L. Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
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Lin D, Ding J, Liu JY, He YF, Dai Z, Chen CZ, Cheng WZ, Zhou J, Wang X. Decreased serum hepcidin concentration correlates with brain iron deposition in patients with HBV-related cirrhosis. PLoS One 2013; 8:e65551. [PMID: 23776499 PMCID: PMC3679136 DOI: 10.1371/journal.pone.0065551] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/25/2013] [Indexed: 02/06/2023] Open
Abstract
Purpose Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. Methods Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. Results Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. Conclusions Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.
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Affiliation(s)
- Dong Lin
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian-Ying Liu
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Feng He
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cai-Zhong Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei-Zhong Cheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai, China
- * E-mail:
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Moon MS, Kang BH, Krzeminski J, Amin S, Aliaga C, Zhu J, McDevitt EI, Kocher S, Richie JP, Isom HC. 3,5,5-trimethyl-hexanoyl-ferrocene diet protects mice from moderate transient acetaminophen-induced hepatotoxicity. Toxicol Sci 2011; 124:348-58. [PMID: 21908766 DOI: 10.1093/toxsci/kfr231] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Acetaminophen (APAP) overdose is the most frequent cause of adult acute liver failure. Susceptibility or resistance to APAP toxicity is most likely accounted for by the interplay of several factors. One factor important in multiple different chronic liver diseases that may play a role in APAP toxicity is elevated hepatic iron. Hereditary hemochromatosis is traditionally associated with hepatic iron overload. However, varying degrees of elevated hepatic iron stores observed in chronic hepatitis C and B, alcoholic liver disease and nonalcoholic fatty liver disease also have clinical relevance. We employed an animal model in which mice are fed a 3,5,5-trimethyl-hexanoyl-ferrocene (TMHF)-supplemented diet to evaluate the effect of elevated hepatic iron on APAP hepatotoxicity. Three hundred milligrams per kilogram APAP was chosen because this dosage induces hepatotoxicity but is not lethal. Since both excess iron and APAP induce oxidative stress and mitochondrial dysfunction, we hypothesized that the TMHF diet would enhance APAP hepatotoxicity. The results were the opposite. Centrilobular vacuolation/necrosis, APAP adducts, nitrotyrosine adducts, and a spike in serum alanine aminotransferase, which were observed in control mice treated with APAP, were not observed in TMHF-fed mice treated with APAP. Further analysis showed that the levels of CYP2E1 and CYP1A2 were not significantly different in TMHF-treated compared with control mice. However, the magnitude of depletion of glutathione following APAP treatment was considerably less in TMHF-treated mice than in mice fed a control diet. We conclude that a TMHF diet protects mice from moderate transient APAP-induced hepatotoxicity prior to the formation of APAP adducts, and one contributing mechanism is reduction in glutathione depletion.
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Affiliation(s)
- Mi Sun Moon
- Department of Microbiology and Immunology, Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania 17033, USA
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10
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Abstract
In chronic viral hepatitis, the role of liver biopsy as a diagnostic test has seen a decline, paralleled by its increasing importance for prognostic purposes. Nowadays, the main indication for liver biopsy in chronic viral hepatitis is to assess the severity of the disease, in terms of both necro-inflammation (grade) and fibrosis (stage), which is important for prognosis and therapeutic management. Several scoring systems have been proposed for grading and staging chronic viral hepatitis and there is no a general consensus on the best system to be used in the daily practice. All scoring systems have their drawbacks and all may be affected by sampling and observer variability. Whatever the system used, a histological score is a reductive approach since damage in chronic viral hepatitis is a complex biological process. Thus, scoring systems are not intended to replace the detailed, descriptive, pathology report. In fact, lesions other than those scored for grading and staging may have clinical relevance and should be assessed and reported. This paper aims to provide a systematic approach to the interpretation of liver biopsies obtained in cases of chronic viral hepatitis, with the hope of helping general pathologists in their diagnostic practice.
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Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis 2011; 43:89-95. [PMID: 20739232 DOI: 10.1016/j.dld.2010.07.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Accepted: 07/22/2010] [Indexed: 02/06/2023]
Abstract
Following the model of hereditary hemochromatosis, the possible role of iron overload as a cofactor for disease progression in acquired liver diseases has been investigated with controversial results. In recent years, progress has been made in understanding the regulation of iron metabolism, thereby allowing the evaluation of the mechanisms linking liver diseases to excessive iron accumulation. Indeed, deregulation of the transcription of hepcidin, emerging as the master regulator of systemic iron metabolism, has been implicated in the pathogenesis of hepatic iron overload in chronic liver diseases. Whatever the cause, hepatocellular iron deposition promotes liver fibrogenesis, while an emerging possible aggravating factor is represented by the strong link between iron stores and insulin resistance, a recently recognized risk factor for the progression of liver diseases. Overall, these pathogenic mechanisms, together with the known proliferative and mutagenic effect of excess iron, converge in determining an increased susceptibility to hepatocellular carcinoma. Finally, an association between serum ferritin levels and mortality in patients with end-stage liver disease has recently been reported. Prospective, randomized studies are required to evaluate whether iron depletion may reduce fibrosis progression, hepatocellular carcinoma development, and eventually mortality in patients with chronic liver diseases.
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Affiliation(s)
- Silvia Fargion
- The Department of Internal Medicine, Università degli Studi, Fondazione IRCCS Ospedale Maggiore Policlinico Ca' Granda IRCCS, Milan, Italy.
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The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol 2010; 22:1204-10. [PMID: 20555268 DOI: 10.1097/meg.0b013e32833bec1e] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients. AIM To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C. METHODS Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations. RESULTS Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. CONCLUSION THE: H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits.
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13
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Signal intensity loss on T2-weighted gradient-recalled echo magnetic resonance images in the basal ganglia in a patient with chronic hepatic encephalopathy. Neurologist 2010; 16:265-8. [PMID: 20592571 DOI: 10.1097/nrl.0b013e3181ad5d4f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Bilaterally symmetrical hyperintensity on T1-weighted magnetic resonance images (MRIs) without abnormalities on T2-weighted images in the basal ganglia is described in patients with chronic liver disease. Manganese, which escapes hepatic clearance because of a portosystemic shunt or liver dysfunction, is thought to be involved in alterations of signal intensity on MRIs, and exerts neurotoxicity, which results in neuropsychiatric disturbances including extrapyramidal symptoms. RATIONALES AND CASE Currently, reports evaluating interpretations of hyperintensity on T1- and normal intensity on T2-weighted images still provide conflicting results. T2-weighted gradient-recalled echo (GRE) MR imaging is dependent on magnetic susceptibility effect and is highly sensitive to static magnetic field inhomogeneity. Field distortions caused by material with high magnetic susceptibility induce signal intensity loss, resulting in typical signal intensity voids. This article describes asymmetric signal intensity loss on T2-weighted GRE MRIs in the globus pallidus in a patient with chronic hepatitis C infection presenting with a gradual onset of lethargy, dysarthria, and gait instability; whereas T1-weighted MRIs showed symmetrical hyperintensity in this region and the midbrain and T2-weighted images showed normal signal intensity. CONCLUSION T2-weighted GRE MR imaging should be included in brain MR imaging studies of patients with chronic liver disease presenting with extrapyramidal symptoms for better localization of the lesions.
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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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Nahon P, Ganne-Carrié N, Trinchet JC, Beaugrand M. Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis. ACTA ACUST UNITED AC 2009; 34:1-7. [PMID: 19762191 DOI: 10.1016/j.gcb.2009.07.032] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Accepted: 07/02/2009] [Indexed: 12/18/2022]
Abstract
Iron accumulation in the liver is considered to be a co-factor for progression of liver disease. Iron overload can enhance the effects of oxidative stress and influence the natural history of patients with cirrhosis, exposing them to a higher risk of hepatocellular carcinoma. The results of clinical studies designed to assess the impact of liver iron content on the risk of tumor development have remained controversial for some time. It is known that common factors can affect both liver iron overload and the risk of cancer, necessitating multivariate analyses of these features in large cohorts of cirrhotic patients. Furthermore, the causes and consequences of hepatic iron overload appear to depend on the cause of the underlying liver disease. Thus, the only solid evidence of a relationship between liver iron overload and event occurrence has come from longitudinal studies conducted in homogeneous cohorts of patients with cirrhosis. So far, the available data suggest that iron accumulation in the liver is an independent risk factor for hepatocellular carcinoma in patients with alcoholic cirrhosis and/or nonalcoholic hepatosteatosis, but not in those with viral hepatitis C cirrhosis.
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Affiliation(s)
- P Nahon
- Service d'hépatogastroentérologie, hôpital Jean-Verdier, AP-HP, avenue du 14juillet, 93140 Bondy, France.
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Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: a confounding factor in chronic hepatitis C. BIOCHIMICA ET BIOPHYSICA ACTA 2009; 1790:650-62. [PMID: 19393721 DOI: 10.1016/j.bbagen.2009.04.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Revised: 04/06/2009] [Accepted: 04/15/2009] [Indexed: 12/13/2022]
Abstract
Historically, iron overload in the liver has been associated with the genetic disorders hereditary hemochromatosis and thalassemia and with unusual dietary habits. More recently, elevated hepatic iron levels also have been observed in chronic hepatitis C virus (HCV) infection. Iron overload in the liver causes many changes including induction of oxidative stress, damage to lysosomes and mitochondria, altered oxidant defense systems and stimulation of hepatocyte proliferation. Chronic HCV infection causes numerous pathogenic changes in the liver including induction of endoplasmic reticulum stress, the unfolded protein response, oxidative stress, mitochondrial dysfunction and altered growth control. Understanding the molecular and cellular changes that could occur in a liver which has elevated hepatic iron levels and in which HCV replication and gene expression are ongoing has clinical relevance and represents an area of research in need of further investigation.
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Affiliation(s)
- Harriet C Isom
- Department of Microbiology and Immunology, The Pennsylvania State College of Medicine, Hershey, PA 17033, USA.
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17
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Minisini R, Fabris C, Toniutto P, Pirisi M. Combinatorial use of single nucleotide polymorphisms to help predict liver fibrosis in patients with hepatitis C infections. ACTA ACUST UNITED AC 2009; 3:355-70. [DOI: 10.1517/17530050902893311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Gitto S, Micco L, Conti F, Andreone P, Bernardi M. Alcohol and viral hepatitis: a mini-review. Dig Liver Dis 2009; 41:67-70. [PMID: 18602355 DOI: 10.1016/j.dld.2008.05.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Revised: 04/29/2008] [Accepted: 05/05/2008] [Indexed: 02/07/2023]
Abstract
Due to their high prevalence in the general population, alcohol use and abuse can be associated with hepatitis B and C virus infections and it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver disease. There is evidence that alcohol abuse accelerates the progression of liver fibrosis and affects the survival of patients with chronic hepatitis C. The mechanism by which alcohol worsens hepatitis C virus-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response could play a relevant role. Alcohol abuse also seems to reduce both sensitivity to interferon and adherence to treatment. It sounds reasonable to presume that the mechanisms enhancing liver damage in patients affected by hepatitis B are similar to those involved in hepatitis C virus infection. However, more studies are warranted to improve our knowledge about the interaction between alcohol intake and hepatitis B virus infection. In conclusion alcohol abuse is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of hepatocellular carcinoma, and higher mortality. Abstinence could reverse some of these deleterious effects.
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Affiliation(s)
- S Gitto
- Department of Medicine, University of Bologna, Bologna, Italy
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Wallace DF, Subramaniam VN. Co-factors in liver disease: the role of HFE-related hereditary hemochromatosis and iron. Biochim Biophys Acta Gen Subj 2008; 1790:663-70. [PMID: 18848602 DOI: 10.1016/j.bbagen.2008.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 07/25/2008] [Accepted: 09/09/2008] [Indexed: 12/15/2022]
Abstract
The severity of liver disease and its presentation is thought to be influenced by many host factors. Prominent among these factors is the level of iron in the body. The liver plays an important role in coordinating the regulation of iron homeostasis and is involved in regulating the level of iron absorption in the duodenum and iron recycling by the macrophages. Iron homeostasis is disturbed by several metabolic and genetic disorders, including various forms of hereditary hemochromatosis. This review will focus on liver disease and how it is affected by disordered iron homeostasis, as observed in hereditary hemochromatosis and due to HFE mutations. The types of liver disease covered herein are chronic hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), end-stage liver disease, hepatocellular carcinoma (HCC) and porphyria cutanea tarda (PCT).
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Affiliation(s)
- Daniel F Wallace
- Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
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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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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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Guyader D, Thirouard AS, Erdtmann L, Rakba N, Jacquelinet S, Danielou H, Perrin M, Jouanolle AM, Brissot P, Deugnier Y. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007; 46:587-95. [PMID: 17156889 DOI: 10.1016/j.jhep.2006.09.021] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Revised: 08/30/2006] [Accepted: 09/22/2006] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Patients with chronic hepatitis C have frequently mild to moderate liver iron overload which increases with fibrosis stage. Thus, it has been postulated that iron could enhance the progression of fibrosis. However, the real impact of iron is still controversial. The study was undertaken to determine the effect of confounding variables. All factors known to influence both iron overload and fibrosis were taken into account. METHODS Five hundred and eighty-six patients, who had liver biopsy performed prior to antiviral treatment, were included. Serum ferritin and liver iron were correlated with clinical, biological and histological variables in univariate and multivariate analysis. The impact of iron on fibrosis was evaluated in multivariate analysis in the whole group and in the subgroup of 380 patients with available date of infection. RESULTS Hyperferritinemia, encountered in 27%, was associated with liver iron deposits in only 46% of cases. Liver iron was elevated in 17%, and correlated with age, male sex, and alcohol intake. The univariate strong link which existed between liver iron and fibrosis disappeared after adjustment for confounding variables. CONCLUSIONS According to the results of this study, liver iron should be considered more as a surrogate marker for disease severity than as a fibrogenic factor per se.
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Abstract
Magnetic susceptibility measurements on the liver can quantify iron overload accurately and noninvasively. However, established susceptometer designs, using superconducting quantum interference devices (SQUIDs) that work in liquid helium, have been too expensive for widespread use. This paper presents a less expensive liver susceptometer that works at room temperature. This system uses oscillating magnetic fields, which are produced and detected by copper coils. The coil design cancels the signal from the applied field, eliminating noise from fluctuations of the source-coil current and sensor gain. The coil unit moves toward and away from the patient at 1 Hz, cancelling drifts due to thermal expansion of the coils. Measurements on a water phantom indicated instrumental errors less than 30 microg of iron per gram of wet liver tissue, which is small compared with other errors due to the response of the patient's body. Liver-iron measurements on eight thalassemia patients yielded a correlation coefficient r = 0.98 between the room-temperature susceptometer and an existing SQUID. These results indicate that the fundamental accuracy limits of the room-temperature susceptometer are similar to those of the SQUID.
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Affiliation(s)
- William F Avrin
- Insight Magnetics, 9598 Carroll Canyon Road #165, San Diego, CA 92126, USA.
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Tanaka N, Horiuchi A, Yamaura T, Komatsu M, Tanaka E, Kiyosawa K. Efficacy and safety of 6-month iron reduction therapy in patients with hepatitis C virus-related cirrhosis: a pilot study. J Gastroenterol 2007; 42:49-55. [PMID: 17322993 DOI: 10.1007/s00535-006-1967-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2006] [Accepted: 10/04/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Iron reduction therapy (IRT) has been recognized as beneficial for chronic hepatitis C patients. However, its efficacy for hepatitis C virus-related liver cirrhosis (LC-C) has not been elucidated. We evaluated the efficacy and safety of IRT for LC-C patients. METHODS Twenty-two LC-C patients were treated with biweekly phlebotomy and low iron diet for 6 months, in addition to regular hepatoprotective therapy. Nineteen sex- and age-matched patients who refused to receive IRT were used as controls. The efficacy of IRT was evaluated on the basis of biochemical parameters. RESULTS Of 22 patients receiving IRT, 19 completed the 6-month treatment. IRT significantly reduced serum levels of aspartate aminotransferase (from 89 to 57 U/L; P = 0.003), alanine aminotransferase (from 101 to 54 U/L; P < 0.001), and alpha-fetoprotein (from 28 to 12 ng/mL; P = 0.003). These changes were not observed in the controls. Two patients whose serum albumin concentrations were less than 3.6 g/dL at the beginning of IRT withdrew from IRT because of the new appearance of ascites. CONCLUSIONS IRT improved the serum levels of aminotransferases and alpha-fetoprotein in LC-C patients and was generally safe; however, IRT should be performed in patients who maintain serum albumin concentrations of more than 3.6 g/dL.
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Affiliation(s)
- Naoki Tanaka
- Department of Gastroenterology, Showa Inan General Hospital, Komagane, Japan
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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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